1 Department of Internal Medicine, 2 Department of Obstetrics and Gynecology, Division of Physiopathology of Human Reproduction, Casa di Cura Salus, Brindisi, 3 Department of Internal Medicine, District Hospital, Fidenza, Italy and 4 Endocrine Unit, RIPAS Hospital, Bandar Seri Begawan, Brunei
5 To whom correspondence should be addressed at: Department of Endocrinology, District Hospital Vito Fazzi, Piazza F. Muratore 73100 Lecce, Italy. Email: robnegro{at}tiscali.it
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Abstract |
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Key words: assisted reproductive technologies/autoimmunity/levothyroxine/thyroid
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Introduction |
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In infertile women, the prevalence of those positive for thyroid peroxidase antibodies [TPOAb (+)] is higher than their fertile control (Poppe et al., 2002). The pregnancy rate of those undergoing assisted reproduction technologies appears to be significantly lower in subjects who are positive for organ-specific autoantibodies such as antithyroid and antiovarian antibodies (Geva et al., 1996
). Furthermore, women who are positive for thyroid antibodies (either anti-peroxidase or anti-thyroglobulin) show an increased miscarriage rate (Kim et al., 1998
) and a poor pregnancy/delivery outcome (although conflicting data have been published on this subject) (Kutteh et al., 1999
). The issues raised are whether positive thyroid autoantibodies in patients undergoing assisted reproduction technologies are: (i) only a marker of autoimmunity; (ii) directly responsible for reduced pregnancy and/or delivery rate; or (iii) an indirect sign of a mild thyroid dysfunction.
Aim of the study was to investigate if the poor pregnancy and delivery outcome of TPOAb (+) women may be due to a mild thyroid dysfunction and also whether levothyroxine (LT4) treatment may improve this situation.
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Materials and methods |
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The Institutional Review Board approved the study protocol and all the participants gave written informed consent. All study patients completed the protocol.
All patients underwent ovulation induction. Recombinant FSH (rFSH) (Puregon; NV Organon, The Netherlands) and GnRH antagonist (Orgalutran; NV Organon) were used for ovarian stimulation. rFSH was started on day 2 of the menstrual cycle at 200 IU per day; the dosage remained the same in all patients during stimulation. Ovulation triggering was performed using 10 000 IU of hCG (Pregnyl; NV Organon) as soon as at least three 17 mm follicles were present on ultrasound scan. Using conventional IVF, each oocyte was inseminated within 34 h after retrieval by adding 500020 000 motile sperm per oocyte. If the semen sample on the day of oocyte recovery contained few motile sperm, ICSI was performed. For each patient, six or seven oocytes were retrieved by the vaginal route and after fertilization one to three embryos were transferred depending on their morphological quality. Pregnancy was diagnosed on two occasions 10 days after transfer by rising serum hCG levels of
20 IU/ml. Clinical pregnancies were diagnosed by ultrasonography performed 5 weeks after embryo transfer. The endpoints of assisted reproduction technologies were pregnancy rates, miscarriage rates and delivery rates. Miscarriage rates also included early pregnancy loss (biochemical pregnancies).
Serum TSH and FT4 were measured using a third-generation electrochemiluminescence immunoassay (Roche, Germany). The reference values were 0.274.2 mIU/l for TSH and 9.318.0 ng/l (1233.5 pmol/l) for FT4. TPOAb were determined using a radioimmunoassay kit (B.R.A.H.M.S. Diagnostica, Germany). The reference range was 0100 kIU/l. TPOAb titres >100 kIU/l were considered positive.
Statistical analysis was performed using an SPSS (SPSS, Inc., USA) 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 MannWhitney 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.
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Results |
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Outcomes for patients (pregnancy rate, delivery rate and miscarriage rate) are shown in Figure 1.
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Miscarriage rate
The miscarriage rate was significantly higher in TPOAb (+) women in comparison to TPOAb () women [relative risk: 2.01 (95% CI 1.133.56), P=0.028]. There was a significantly increased miscarriage rate in group B compared to group C. The risk of pregnancy loss was doubled in the former group (the group not subjected to LT4 treatment) compared to the latter [relative risk: 1.89 (95% CI 1.23.2), P=0.034].
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Discussion |
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Our data suggest that the presence of thyroid autoimmune disease should be taken into consideration when approaching investigation of female infertility. However, since the prevalence of TPOAb observed in our study population was not different from that of the general population (Knudsen et al., 1999; Pedersen et al., 2003
) we suggest that thyroid autoimmunity may not be a cause of infertility per se because its prevalence would have otherwise been higher. Poppe et al. (2002)
reported a non-significantly higher number of TPOAb (+) women among infertile women in whom elevated TSH values represent a strong factor against fertility.
In our study, the pregnancy rates were not different between TPOAb (+) and TPOAb () women, while thyroid autoimmunity appeared to significantly influence the miscarriage rate. These findings confirm those of Poppe et al. (2003), who showed that women with positive TPOAb before the first assisted reproduction treatment cycle have a significantly increased risk for miscarriage but a similar pregnancy rate when compared to those without TPOAb. The underlying mechanisms for this are unclear, but three hypotheses have been proposed: (i) the miscarriage seen in women with thyroid antibodies may be due to subtle deficiency of thyroid hormone; (ii) there may be a direct effect(s) of thyroid autoantibodies on the placenta; (iii) thyroid autoantibodies may only be markers of an abnormal immune state, responsible for unstable implant (Abramson and Stagnaro-Green, 2001
). Conflicting data exist on the association between thyroid autoimmunity and pregnancy (Van Voorhis and Stovall, 1997
). Some authors have found no correlation between TPOAb and the incidence of recurrent abortions (Muller et al., 1999
; Rushworth et al., 2000
). A study by Kutteh et al. (1999)
has shown that the number of pregnancies, miscarriages and deliveries were not different in thyroid Ab (+) and () women. Bussen and Steck (1997)
have found that the incidence of thyroid autoantibodies in women with recurrent miscarriages was significantly increased compared to controls. Some studies have confirmed the association between recurrent miscarriages and autoimmunity, in particular by showing an increased number of CD5+/20+ positive cells and an abnormal T helper (Th-1) preponderance (Roberts et al., 1996
; Gleicher, 2002
). Thus, the presence of TPOAb may only be a marker of autoimmunity, whereas the presence of a peripheral marker for abnormal T cell function may be responsible for a poor pregnancy outcome (Stagnaro-Green et al., 1992
).
In the same context, subclinical hypothyroidism can also exert a negative influence on early pregnancy (Abalovich et al., 2002; Vaquero et al., 2002
). Some studies have shown that thyroid hormones may play a determinant role in the physiology of early pregnancy and that LT4 treatment of infertile women may improve the conception rate (Maruo et al., 1992
; Raber et al., 2003
). A meta-analysis performed by Prummel and Wiersinga (2004)
, who looked at the association between thyroid autoimmunity and miscarriage rates, suggested that the increased miscarriage rate in TPOAb (+) women may be due to mild thyroid failure, as serum TSH concentrations in TPOAb (+) women are higher than in TPOAb () women (Marx and Bucher, 2003
; Prummel and Wiersinga, 2004
). Calvo et al. (2002)
have shown differences between the maternal thyroid status and the fetal concentrations of thyroid hormones. The fetal compartment shows 100-fold lower serum concentrations of T3 and T4 compared to the mother and serum FT4 concentrations reach values that are about one-third of those biologically active in the respective euthyroid mothers (Calvo et al., 2002
). As a consequence, even slight reduction in maternal serum FT4 concentrations may cause a relevant and significant decrease in fetal serum FT4 concentrations. Furthermore, it has been shown that, in euthyroid women undergoing assisted reproduction treatment, controlled ovarian stimulation during early pregnancy leads to a decrease in serum FT4 and a concomitant rise in serum TSH concentrations (Muller et al., 2000
).
Lastly, the presence of thyroid autoimmunity may be associated with an increased incidence of miscarriage rate due to the phenomenon of microchimerism (Ando and Davies, 2004). Fetal microchimerism is defined as the presence of fetal cells in maternal tissues occurring during pregnancy. It involves transplacental passage of fetal cells into the maternal thyroid and may be one mechanism explaining thyroid disorders and an enhanced immune response against the fetoplacental unit (Ando and Davies, 2003
). The study by Imaizumi et al. (2001)
has shown that in murine experimental autoimmune thyroiditis, microchimerism is responsible for increased miscarriage rate without differences in thyroid function between the control mice and the Tg-immunized pregnant mice. In addition, thyroid autoantibodies were associated with higher miscarriage rates. This study was carried out in mice but suggests that microchimerism in humans may be involved in the setting of autoimmunity and hypothyroidism.
In summary, our study shows that in women undergoing assisted reproduction technologies: (i) the pregnancy rate is not influenced by either the presence of TPOAb or treatment with LT4; (ii) the miscarriage rate is greater in TPOAb (+) compared to TPOAb () women; (iii) LT4 treatment in TPOAb (+) women does not improve the delivery rate. Thyroid autoimmunity represents a risk factor for miscarriage, which appears to be linked to an abnormal immune response rather than to subsequent mild thyroid failure.
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Acknowledgements |
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References |
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Submitted on December 17, 2004; resubmitted on February 8, 2005; accepted on February 15, 2005.
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