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Assisted Reproduction and Thyroid Autoimmunity: An Unfortunate Combination?

Departments of Endocrinology (K.P., B.V.), Reproductive Medicine (H.T., P.D., A.V.S.), and Biostatistics (L.K.), Vrije Universiteit Brussel, Brussels 1090, Belgium; and Department of Endocrinology (D.G.), Université Libre de Bruxelles, Brussels 1000, Belgium

Address correspondence and reprint requests to: K. Poppe, Department of Endocrinology, Free University Brussels (AZ-VUB), Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail: hemopek{at}az.vub.ac.be.

	Abstract

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The association between positive thyroid antibodies and an increased miscarriage rate in pregnancies after assisted reproduction technology (ART) remains controversial.

We wanted to clarify this issue by performing a prospective cohort study in 234 women by systematically screening for thyroid peroxidase antibodies (TPO-Ab), serum TSH, and free T₄(FT₄) before the first ART cycle. Women with overt thyroid dysfunction were excluded.

Fourteen percent of the cohort had positive TPO-Ab. Baseline characteristics [age, 33 ± 5 yr; TSH, 1.6 (0.02–4.1) mU/liter; and FT₄, 12.2 (9.1–18) ng/liter] were comparable to those of the 86% of women without antibodies [age, 32 ± 5 yr; TSH, 1.3 (0.05–3.6) mU/liter; and FT₄, 11.7 (9.5–16.5) ng/liter]. In the antibody-positive group, the pregnancy rate was 53% vs. 43% in the antibody-negative group, with an odds ratio of 0.67 [95% confidence interval (CI) (0.32–1.41); P = not significant]; however within the group that was pregnant, the miscarriage rate was 53% and 23%, respectively, with an odds ratio of 3.77 [95% CI (1.29–11.05); P = 0.016]. The age of the women was an independent risk factor for miscarriage, odds ratio 1.08 [95% CI (1.03–1.15); P = 0.005].

We conclude that women with positive TPO-Ab before the first ART cycle have a significantly increased risk for miscarriage.

	Introduction

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WOMEN OF INFERTILE couples, with a female cause of infertility (i.e endometriosis, tubal disease, and ovulatory dysfunction), have a significantly increased risk of associated thyroid autoimmunity (TAI) compared with age-matched parous fertile women (1). The association between organ- and nonorgan-specific autoantibodies and infertility has been reported previously (2).

Today, most infertile couples undergo assisted reproduction technologies (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection. Spontaneous pregnancies and pregnancies achieved after ART are complicated by miscarriage in 20–30% of the women. Different risk factors of miscarriage such as genetic, infectious, hormonal, anatomic, and environmental factors have been identified (3, 4, 5). Euthyroid women with TAI features and women with (subclinical) thyroid dysfunction are known to have an increased risk for miscarriage (6). The association was further examined in pregnancies after ART, yielding conflicting data (7, 8, 9, 10, 11).

We designed the present prospective study in women of infertile couples to assess whether the presence of positive thyroid antibodies measured before a first ART may influence the outcome, particularly the rate of pregnancy and miscarriage.

	Patients and Methods

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A prospective analysis was undertaken in 234 women consulting at the Center for Reproductive Medicine between October 1999 and November 2000. Women with different causes of infertility (19% ovarian dysfunction, 15% tubal factors, 5% endometriosis, 11% idiopathic, and 50% male factor) were included.

Patients’ ages ranged from 20–50 yr (32 ± 5 yr; mean ± SD). All women were systematically screened for the presence of thyroid peroxidase antibodies (TPO-Ab), serum TSH, and free T₄ (FT₄) before undergoing ART. Women with overt thyroid dysfunction were excluded. In the analysis of the outcome, only women undergoing a first ART procedure were taken into account. All patients received controlled ovarian superovulation. Using conventional IVF, each oocyte was inseminated within 3–4 h after retrieval by adding 5,000–20,000 motile spermatozoa per oocyte. The intracytoplasmic sperm injection procedure was carried out as described earlier (12). After fertilization, one to three embryos were transferred depending on their morphological quality. Pregnancy was diagnosed on two occasions at least 10 d after transfer by rising human chorionic gonadotropin levels of at least 20 IU/ml in serum. Clinical pregnancies were diagnosed by ultrasonography performed 5 wk after embryo transfer. The endpoints of ART were the pregnancy rates (PR), miscarriage rates (MR), and delivery rates (DR). MR also included early pregnancy loss (biochemical pregnancies). The institutional review board at our institution approved the study protocol.

Serum TSH and FT₄ were measured using a third-generation electrochemiluminescence immunoassay (Roche, Mannheim; Germany). The reference values were 0.27–4.2 mU/liter for TSH and 9.3–18.0 ng/liter (12–33.5 pmol/liter) for FT₄. TPO-Ab was determined using an RIA kit (B.R.A.H.M.S. Diagnostica, Berlin, Germany). The reference range was 0–100 kU/liter. TPO-Ab titers were considered positive when titers exceeded 100 kU/liter.

A statistical analysis was performed using an SPSS (SPSS, Inc., Chicago, IL) program, by means of Fisher’s exact test. Correlations between variables were assessed using Spearman’s test, and differences between mean values were determined by the Mann-Whitney U test. A multivariate approach was used, starting with a univariate model for each individual variable. All statistical tests were considered statistically significant whenever P < 0.05.

	Results

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Table 1 shows the characteristics of women with and without TAI features. Results are listed as the mean ± SD for age, as the median (range) for serum TSH and FT₄ concentrations, and as the number (percentage) of PR, MR, and DR in each group.

View larger version (18K): [in this window] [in a new window]   FIG. 1. Outcome of ART in women with and without TAI, with OR and 95% CI for the different outcomes when TAI features are present.

TAI was present in 32 (14%) of the 234 investigated women. Their mean age was 33.2 ± 4.6 yr; serum TSH level was 1.6 (0.02–4.1) mU/liter; and FT₄ was 12.2 (9.1–18) ng/liter. Among these 32 TAI-positive women, three had a suppressed TSH level with normal FT₄ values. TSH was significantly higher in the delivery group of TAI-positive women compared with TAI-negative women who delivered [2.5 (1.0–3.0) mU/liter vs. 1.2 (0.5–3.3) mU/liter; P = 0.006].

In the 202 women without TAI features, representing 86% of the cohort, the mean age was 31.6 ± 5.4 yr; serum TSH level was 1.3 (0.05–3.6) mU/liter; and FT₄ 11.7 (9.1–18.0) ng/liter. Among these women, two had a suppressed TSH level with normal FT₄ values (Table 1).

Outcome

In women with TAI, the pregnancy rate was 53% (17 of 32 patients). Of these 17 women, nine (53%) had a miscarriage and eight (47%) delivered.

In the 202 women without TAI features, the pregnancy rate was 43% (87 of 202). Of the pregnant women, 20 (23%) had a miscarriage and 67 (77%) delivered (Fig. 1).

The PR was not influenced by TAI features, OR 0.67 [95% CI (0.32–1.41); P = 0.29]. However, in pregnant women, the OR for miscarriage was significantly increased, 3.77 [95% CI (1.29–11.05); P = 0.016], and the delivery rate decreased when thyroid antibodies were positive, OR 0.27 [95% CI (0.09–0.78); P = 0.016].

Of the 20 women with a miscarriage in the TAI-negative group, 10 of 20 (50%) had an early miscarriage (biochemical pregnancy) compared with only one of nine (11%) in the TAI-positive group.

Age was an independent risk factor for miscarriage, OR 1.08 [95% CI (1.03–1.15); P = 0.005]. No significant correlation was found between the age and TPO-Ab (r = 0.103; P = 0.143). The number of transferred embryos was similar in TAI-positive (2.08 ± 0.44) women and in TAI-negative (2.0 ± 0.54) women.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The present prospective study showed a miscarriage rate of more than 50% in women with positive thyroid antibodies who underwent a first ART cycle. In comparison, the miscarriage rate was only 23% in the women without TAI features, i.e. a rate comparable to that observed in spontaneous pregnancies and also to the overall expected miscarriage rate in IVF patients (5).

Geva et al. (7) were the first to describe the association between organ-specific antibodies (thyroid and ovarian) and reproductive failure after IVF. The presence of increased TPO-Ab titers carries an increased risk for miscarriage after IVF, independent of other organ-specific antibodies (8). Patients with recurrent IVF failure also have a higher incidence of TAI even in the presence of euthyroidism (13, 14). The association has recently been challenged (9, 11); however the study by Kutteh et al. (9) was retrospective, and thyroid antibodies were measured during pregnancy when titers decrease due to immunological adaptations (15). The patients, thus, could have been wrongly classified. In the study by Muller et al. (11) it was not clearly stated whether patients underwent one or more IVF procedures. Because the rank of trial is an important variable in the success rate of an ART cycle, we considered only the outcome of the first ART cycle (16). Women over 35 yr have reduced delivery rates (16, 17). The present study confirmed by multivariate analysis that age was an independent risk factor for miscarriage. The mean age of the women in the TAI-positive was not significantly different from that in TAI-negative women and within the range of 30–35 yr. Pregnancy rates were comparable between TAI-positive and TAI-negative women, and the low percentage of biochemical pregnancies in women with TAI indicate that it does not interact with implantation, in accordance with previous data of Singh et al. (18). The exact mechanism underlying the association between TAI and miscarriage remains a matter of debate. The present study generates a hypothesis, and two possibilities for the observed association can be considered: immune dysfunction and/or thyroid failure in the presence of TAI during ART and subsequent pregnancy.

The following arguments favor a subclinical hypothyroxinemia: first, in women with threatening abortion (i.e. "vaginal bleeding with or without uterine cramps earlier than 12 wk gestation; highly sensitive human chorionic gonadotropin pregnancy test positive; cervix intact, and external uterine closed at the time of admission"; patients with blighted ova suspected by ultrasound examination and those with vaginal bleeding that appeared to originate from a cervical polyp were excluded), it has been shown that the thyroid hormone levels were significantly lower in women who had a miscarriage compared with those who delivered successfully (19). In the present study, serum TSH and FT₄ were measured before ART. Although TSH levels were somewhat higher in women with TAI who delivered, the serum FT₄ levels were comparable between the women with or without TAI features. Thyroid hormonal changes during pregnancy were not monitored. The evolution of thyroid hormones during an ART-induced pregnancy could be more important than in spontaneous pregnancies, because ovarian hyperstimulation in preparation for ART may increase thyroid hormone-binding proteins, hence leading to a decrease in free thyroid hormone levels (20). Second, one study (21) investigated the impact of thyroid hormones on the outcome of spontaneous pregnancy in women with TAI. In this small, nonplacebo, controlled study only women with a history of recurrent miscarriage were included. Thyroid hormones before and during pregnancy yielded a significantly better outcome than treatment with immunoglobulins during gestation. Third, in spontaneous pregnancies, positive thyroid antibodies seem to be an independent risk factor for miscarriage, even in the absence of antinuclear or anticardiolipin antibodies (8, 22).

Finally, studies investigating pregnancy loss in relation to the presence of antiphospholipid antibodies showed that the mean period in which miscarriage occurred was 22 weeks (23). In the present study, miscarriages occurred within the first trimester of gestation, the period when the fetus is critically dependent on maternal thyroid hormones (24). If a more common immune dysfunction were present in patients with TAI, one could expect to also observe miscarriages at a later gestational age. The debate over whether a generalized immune disorder is involved in reproductive failure is ongoing. Some authors believe that positivity for one autoantibody in a patient can be the phenotypical expression of the same at-risk genotype in other patients. This genotype has yet not been identified (25, 26, 27). However, a metaanalysis investigating the impact of antiphospholipid antibodies on the IVF outcome could not identify an adverse outcome in contrast to previous data (28). Arguments in favor of a general immune dysfunction rely on the identification of an abnormal lymphocyte subset in women with TAI and recurrent miscarriages (29). Treatments attempting to modulate the immune system of patients with TAI have been performed using intravenous immunoglobulins (30, 31, 32). Although these treatments were beneficial in terms of pregnancy outcome, the findings should be considered with caution because they included small numbers of patients, with different autoantibodies, and a lack of appropriate controls.

Microchimerism involving transplacental passage of fetal cells into the maternal thyroid may be one mechanism explaining thyroid disorders and an enhanced immune response against the fetoplacental unit (33, 34).

To test both hypotheses, appropriately designed and randomized studies comparing thyroid hormone supplements and/or immune suppressive treatment vs. placebo should be performed. The studies should be able to address three key questions: 1) Do women with (recurrent) miscarriages have a defective immune regulation compared with women who deliver? 2) Is the evolution of the thyroid hormone status in pregnant women different in those women prone to miscarriage (especially after an ART cycle)? And 3) Do women with TAI benefit from thyroid hormone supplements or immune suppressive treatment?

From the present study we may conclude that thyroid hormones and thyroid antibodies could be assessed in infertile women before ART, to delineate women at risk for clinical miscarriage.

	Acknowledgments

 
We thank W. Meul and J. Schiettecatte for data support, and I. DeWannemacker for secretarial help.

	Footnotes

 
This study was supported by grants from the Willy Gepts Foundation, Vrije Universiteit Brussels, AZ-VUB.

Abbreviations: ART, Assisted reproduction technology; CI, confidence interval; DR, delivery rates; FT₄, free T₄; IVF, in vitro fertilization; MR, miscarriage rate; NP, not pregnant; OR, odds ratio(s); PR, pregnancy rate; TAI, thyroid autoimmunity; TPO-Ab, thyroid peroxidase antibodies.

Received February 19, 2003.

Accepted May 29, 2003.

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