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Volume 10, Issue 4 (8-2012)
IJRM 2012, 10(4): 373-376 |
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Mosaddegh M H, Ghasemi N, Jahaninejad T, Mohsenifar F, Aflatoonian A. Treatment of recurrent pregnancy loss by Levothyroxine in women with high Anti-TPO antibody. IJRM 2012; 10 (4) :373-376
URL: http://ijrm.ir/article-1-292-en.html
URL: http://ijrm.ir/article-1-292-en.html
Mohammad Hosein Mosaddegh1 
, Nasrin Ghasemi * 2, Tahere Jahaninejad3 , Fatemeh Mohsenifar4 , Abbas Aflatoonian5
, Nasrin Ghasemi * 2, Tahere Jahaninejad3 , Fatemeh Mohsenifar4 , Abbas Aflatoonian5
1- Department of Pharmacology, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2- Department of Medical Genetics, Research and Clinical Centre for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran , n479g@yahoo.co.uk
3- Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4- Yazd Azad University, Yazd, Iran
5- Department of Obstetrics and Gynecology, Research and Clinical Centre for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2- Department of Medical Genetics, Research and Clinical Centre for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran , n479g@yahoo.co.uk
3- Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4- Yazd Azad University, Yazd, Iran
5- Department of Obstetrics and Gynecology, Research and Clinical Centre for Infertility, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Introduction
Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses before twenty week of gestation, which affects 1-3% of couples. It is caused by variety of genetics and non-genetics factors. Genetic disorders, reproductive tract anatomical pathologies, infectious diseases, endocrine dysfunctions, thrombophilia and autoimmune diseases are known to be the most important risk factors for RPL (1-6).
There is evidence that thyroid autoimmunity is associated with pregnancy loss, because maternal thyroid hormones (TH) play a critical role in the development of both fetus and placenta (7). Pregnancy loss in women with positive thyroid autoantibodies occurs within the first trimester of gestation, when the fetus is dependent on maternal thyroid hormones (8, 9). Following implantation, the preservation of the pregnancy is reliant on a mass of immunological events that will assistance in the successful growth and development of the fetus (7).
So, Thyroid autoantibodies generally enhanced autoimmune reactivity against the feto-placental unit as a consequence of hypothyroidism (10). The presence of thyroid autoantibodies can cause infertility and delay pregnancy. Women with high concentration thyroid autoantibodies in their blood circulation usually become pregnant in older age and encounter with a higher risk of pregnancy loss (11-13).
In the other hand, the presence of thyroid autoantibodies in women during pregnancy could be associated with a lack in thyroid hormone concentrations or a poorer ability of the thyroid gland to sufficiently conform to the requests of pregnancy. Treatment of thyroid insufficiency, caused by auto antibodies, during pregnancy is important in avoiding hostile maternal and fetal outcome (14).
Table I. Mean of anti-TPO in women with recurrent abortion.
90-128-3/Table_1.jpg)
Table II. Success rate of pregnancy in women with abnormal anti-TPO with and without treatment.
90-128-3/Table_2.jpg)
Discussion
Recurrent pregnancy loss is an important clinical problem and classically defined as two or more pregnancy losses before the fetus has reached viability. The leading etiologies associated with it include a variety of causes such as autoimmune diseases (15).
Nilsson et al in 1975 found for first time that levels of circulating anticoagulant were higher in women with recurrent pregnancy loss than in control subjects (16). This anticoagulant was later found to be the lupus anticoagulant antibody. Since that time several studies have established the relationship between autoimmune diseases such as anti-phospholipid syndrome, rheumatoid arthritis and systemic lupus erythematous with abortion (17, 18).
A number of studies have revealed relation between thyroid autoantibodies and recurrent abortions. It is suggested that the presence of thyroid autoantibodies could cause a generalized activation of the immune system, which unregulated activity of the immune system at the fetal-maternal interface (19). Lejune et al found that frequency of circulating anti-thyroid antibodies were higher in women with recurrent abortion than in control subjects (20).
In 1990, Stagnaro-Green et al tested 552 women for thyroid auto-antibodies in the first trimester of pregnancy. Pregnancy loss rate in women with high antibody was twice than women with normal antibody (10). Regarding prevention of abortion, there are a few studies showing that thyroxin treatment may be efficient in decreasing the number of abortion when given during the early stages of pregnancy. Negro et al treated euthyroid women with high thyroid autoantibodies who underwent IVF.
Half of them received levothyroxine and other half received placebo. The pregnancy loss rate in the placebo group was 52% compared to 33% in the group in which levothyroxine was given. However, because of the small number of investigated patients in their study the difference was not statistically significant (21). In Roussev study, 187 patients were randomized for evaluating the effect of levothyroxine treatment on pregnancy outcomes (22).
Also in Poppe study levothyroxine was prescribed for 187 women with unexplained recurrent pregnancy loss, and compare live birth rates among two groups (23). In both studies women with normal thyroid function with thyroid autoantibodies were selected. Both studies showed a decrease in pregnancy loss rates (36% and 75% relative reductions). Wang et al screened a total of 756 women in the first trimester of pregnancy for thyroid functions after Levothyroxine treatment and then follow up them until delivery. They found that therapy decreased the incidence of spontaneous abortions (24).
Conclusion
In conclusion, high anti-TPO antibody in women with RPL could increase risk of pregnancy loss, and treatment with levothyroxine helps them to have normal pregnancy.
Acknowledgments
Authors like to thank Yazd Reproductive Sciences Institute for financial support of this project, and thank Prof. Bashardoost for statistical analysis.
Conflict of interest
None of the authors have any conflict of interest in this project.
Recurrent pregnancy loss (RPL) is defined as two or more consecutive pregnancy losses before twenty week of gestation, which affects 1-3% of couples. It is caused by variety of genetics and non-genetics factors. Genetic disorders, reproductive tract anatomical pathologies, infectious diseases, endocrine dysfunctions, thrombophilia and autoimmune diseases are known to be the most important risk factors for RPL (1-6).
There is evidence that thyroid autoimmunity is associated with pregnancy loss, because maternal thyroid hormones (TH) play a critical role in the development of both fetus and placenta (7). Pregnancy loss in women with positive thyroid autoantibodies occurs within the first trimester of gestation, when the fetus is dependent on maternal thyroid hormones (8, 9). Following implantation, the preservation of the pregnancy is reliant on a mass of immunological events that will assistance in the successful growth and development of the fetus (7).
So, Thyroid autoantibodies generally enhanced autoimmune reactivity against the feto-placental unit as a consequence of hypothyroidism (10). The presence of thyroid autoantibodies can cause infertility and delay pregnancy. Women with high concentration thyroid autoantibodies in their blood circulation usually become pregnant in older age and encounter with a higher risk of pregnancy loss (11-13).
In the other hand, the presence of thyroid autoantibodies in women during pregnancy could be associated with a lack in thyroid hormone concentrations or a poorer ability of the thyroid gland to sufficiently conform to the requests of pregnancy. Treatment of thyroid insufficiency, caused by auto antibodies, during pregnancy is important in avoiding hostile maternal and fetal outcome (14).
This study assessed the effect of Levothyroxine therapy on the live-birth rate in women with a history of at least two recurrent unexplained pregnancy loss, which were anti-TPO antibody positive. It also compared anti-thyroid peroxidase antibodies levels before and after treatment.
Materials and methods
This project evaluated 900 women with recurrent pregnancy loss. They had referred to the Recurrent Abortion Clinic of Yazd Reproductive Sciences Institute. They were evaluated for uterine and cervical anatomical disorders (using pelvic ultrasonography or hysteroscopy), ovarian dysfunction, chromosome abnormality (using conventional karyotype), and then evaluated for thyroid disorders, and autoimmune antibodies. This study approved by ethic committee of yazd Reproductive Science Institute.
Women with positive thyroid peroxidase antibodies (anti-TPO) and normal TSH were entered to this study. Thyroid peroxidase (TPO) was tested with a chemiluminescence immunoassay, and women with anti-TPO more than 40 UI/ml were treated with levothyroxine after signing inform consent.
After two months anti-TPO was tested again. Levothyroxine doses were depended on the levels of anti-TPO, which were decided by endocrinologist. It was 25-100 μg every day. Treatment continued with levothyroxine and aspirin till pregnancy happened and these continued during pregnancy until delivery. All women were followed during pregnancy to the end.
Statistical analysis
Mean of anti-TPO antibodies in each group were tested before and after 2 months with paired t-test using SPSS (version 16) and p-value<0.05 is significant.
Results
Forty five unexplained RPL women had anti-TPO more than 40 UI/ml with normal TSH. Mean of anti-TPO in women without treatment and with treatment before pregnancy were 462.45 and 488.35 respectively, which was not significantly different (p>0.05). Mean of anti-TPO in women after treatment was 123.35. The difference between mean before and after treatment was significant (p<0.05) (Table I).
Thirty nine women received Levothyroxine and six women never used Levothyroxine by their own decision. Four of 39 cases never get pregnant (in follow up time). From the remaining 35 cases treated with Levothyroxine, 14 had normal delivery, 9 passed 20 weeks of gestation, 6 had preterm labors with normal child, and 6 had miscarriages. Three of 6 women never used levothyroxine, get pregnant, but all had abortion again. Three of six cases never get pregnant again (Table II).
Materials and methods
This project evaluated 900 women with recurrent pregnancy loss. They had referred to the Recurrent Abortion Clinic of Yazd Reproductive Sciences Institute. They were evaluated for uterine and cervical anatomical disorders (using pelvic ultrasonography or hysteroscopy), ovarian dysfunction, chromosome abnormality (using conventional karyotype), and then evaluated for thyroid disorders, and autoimmune antibodies. This study approved by ethic committee of yazd Reproductive Science Institute.
Women with positive thyroid peroxidase antibodies (anti-TPO) and normal TSH were entered to this study. Thyroid peroxidase (TPO) was tested with a chemiluminescence immunoassay, and women with anti-TPO more than 40 UI/ml were treated with levothyroxine after signing inform consent.
After two months anti-TPO was tested again. Levothyroxine doses were depended on the levels of anti-TPO, which were decided by endocrinologist. It was 25-100 μg every day. Treatment continued with levothyroxine and aspirin till pregnancy happened and these continued during pregnancy until delivery. All women were followed during pregnancy to the end.
Statistical analysis
Mean of anti-TPO antibodies in each group were tested before and after 2 months with paired t-test using SPSS (version 16) and p-value<0.05 is significant.
Results
Forty five unexplained RPL women had anti-TPO more than 40 UI/ml with normal TSH. Mean of anti-TPO in women without treatment and with treatment before pregnancy were 462.45 and 488.35 respectively, which was not significantly different (p>0.05). Mean of anti-TPO in women after treatment was 123.35. The difference between mean before and after treatment was significant (p<0.05) (Table I).
Thirty nine women received Levothyroxine and six women never used Levothyroxine by their own decision. Four of 39 cases never get pregnant (in follow up time). From the remaining 35 cases treated with Levothyroxine, 14 had normal delivery, 9 passed 20 weeks of gestation, 6 had preterm labors with normal child, and 6 had miscarriages. Three of 6 women never used levothyroxine, get pregnant, but all had abortion again. Three of six cases never get pregnant again (Table II).
Table I. Mean of anti-TPO in women with recurrent abortion.
Table II. Success rate of pregnancy in women with abnormal anti-TPO with and without treatment.
Discussion
Recurrent pregnancy loss is an important clinical problem and classically defined as two or more pregnancy losses before the fetus has reached viability. The leading etiologies associated with it include a variety of causes such as autoimmune diseases (15).
Nilsson et al in 1975 found for first time that levels of circulating anticoagulant were higher in women with recurrent pregnancy loss than in control subjects (16). This anticoagulant was later found to be the lupus anticoagulant antibody. Since that time several studies have established the relationship between autoimmune diseases such as anti-phospholipid syndrome, rheumatoid arthritis and systemic lupus erythematous with abortion (17, 18).
A number of studies have revealed relation between thyroid autoantibodies and recurrent abortions. It is suggested that the presence of thyroid autoantibodies could cause a generalized activation of the immune system, which unregulated activity of the immune system at the fetal-maternal interface (19). Lejune et al found that frequency of circulating anti-thyroid antibodies were higher in women with recurrent abortion than in control subjects (20).
In 1990, Stagnaro-Green et al tested 552 women for thyroid auto-antibodies in the first trimester of pregnancy. Pregnancy loss rate in women with high antibody was twice than women with normal antibody (10). Regarding prevention of abortion, there are a few studies showing that thyroxin treatment may be efficient in decreasing the number of abortion when given during the early stages of pregnancy. Negro et al treated euthyroid women with high thyroid autoantibodies who underwent IVF.
Half of them received levothyroxine and other half received placebo. The pregnancy loss rate in the placebo group was 52% compared to 33% in the group in which levothyroxine was given. However, because of the small number of investigated patients in their study the difference was not statistically significant (21). In Roussev study, 187 patients were randomized for evaluating the effect of levothyroxine treatment on pregnancy outcomes (22).
Also in Poppe study levothyroxine was prescribed for 187 women with unexplained recurrent pregnancy loss, and compare live birth rates among two groups (23). In both studies women with normal thyroid function with thyroid autoantibodies were selected. Both studies showed a decrease in pregnancy loss rates (36% and 75% relative reductions). Wang et al screened a total of 756 women in the first trimester of pregnancy for thyroid functions after Levothyroxine treatment and then follow up them until delivery. They found that therapy decreased the incidence of spontaneous abortions (24).
Conclusion
In conclusion, high anti-TPO antibody in women with RPL could increase risk of pregnancy loss, and treatment with levothyroxine helps them to have normal pregnancy.
Acknowledgments
Authors like to thank Yazd Reproductive Sciences Institute for financial support of this project, and thank Prof. Bashardoost for statistical analysis.
Conflict of interest
None of the authors have any conflict of interest in this project.
Type of Study: Original Article |
References
1. Toth B, Jeschke U, Rogenhofer N, Scholz C, Würfel W, Thaler CJ, et al. Recurrent miscarriage: current concepts in diagnosis and treatment. J Reprod Immunol 2010; 85: 25-32. [DOI:10.1016/j.jri.2009.12.006]
2. Carrington B, Sacks G, Regan L. Recurrent miscarriage: pathophysiology and outcome. Curr Opin Obstet Gynecol 2005; 17: 591-597. [DOI:10.1097/01.gco.0000194112.86051.26]
3. Monien S, Kadecki O, Baumgarten S, Salama A, Dörner T, Kiesewetter H. Use of heparin in women with early and late miscarriages with and without thrombophilia. Clin Appl Thromb Hemost 2009; 15: 636-644. [DOI:10.1177/1076029609335501]
4. Rai R, Regan L. Recurrent miscarriage. Lancet 2006; 368: 601-611. [DOI:10.1016/S0140-6736(06)69204-0]
5. Redline RW. Thrombophilia and placental pathology. Clin Obstet Gynecol 2006; 49: 885-894. [DOI:10.1097/01.grf.0000211957.68745.6b]
6. Firouzabadi RD, Ghasemi N, Rozbahani MA, Tabibnejad N. Association of p53 polymorphism with ICSI/IVF failure and recurrent pregnancy loss. Aust N Z J Obstet Gynaecol 2009; 49: 216-219. [DOI:10.1111/j.1479-828X.2009.00972.x]
7. Galofre JC, Davies TF. Autoimmune thyroid disease in pregnancy: a review. J Women's Health (Larchmt) 2009; 18: 1847-1856. [DOI:10.1089/jwh.2008.1234]
8. Poppe K, Glinoer D, Tournaye H, Devroey P, van Steirteghem A, Kaufman L, et al. Assisted reproduction and thyroid autoimmunity: an unfortunate combination? J Clin Endocrinol Metab 2003; 88: 4149-4152. [DOI:10.1210/jc.2003-030268]
9. Calvo RM, Jauniaux E, Gulbis B, Asunción M, Gervy C, Contempré B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab 2002; 87: 1768-1777. [DOI:10.1210/jcem.87.4.8434]
10. Stagnaro-Green A, Roman SH, Cobin RH, el-Hazary E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990; 264: 1422-1425. [DOI:10.1001/jama.1990.03450110068029]
11. Lejeune B, Grun JP, de Nayer P, Servais G, Glinoer D. Antithyroid antibodies underlying thyroid abnormalities and pregnancy lossor pregnancy induced hypertension. Br J Obstet Gynaecol 1993; 100: 669-672. [DOI:10.1111/j.1471-0528.1993.tb14236.x]
12. Menken J, Trussell J, Larsen U. Age and infertility. Science 1986; 233: 1389-1394. [DOI:10.1126/science.3755843]
13. Osmanagaoglu K, Tournaye H, Kolibianakis E, Camus M, van Steirteghem A, Devroey P. Cumulative delivery rates after ICSI in women aged >37 years. Hum Reprod 2002; 17: 940-944. [DOI:10.1093/humrep/17.4.940]
14. Rashid M, Rashid MH. Obstetric management of thyroid disease. Obstet Gynecol Surv 2007; 62: 680-688. [DOI:10.1097/01.ogx.0000281558.59184.b5]
15. Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Hum Reprod Update 2003; 9: 149-161. [DOI:10.1093/humupd/dmg012]
16. Nilsson IM, Astedt B, Hender U, Bezerin D. Intrauterine death and circulating anticoagulant "antithromboplastin". Acta Med Scand 1975; 197: 153-159. [DOI:10.1111/j.0954-6820.1975.tb04897.x]
17. Cowchock S, Smith JB, Gocial B. Antibodies to phospholipids and nuclear antigens in patients with repeated abortions. Am J Obstet Gynecol 1986; 155: 1002-1010. [DOI:10.1016/0002-9378(86)90335-2]
18. Kaplan D. Fetal wastage in patients with rheumatoid arthritis. J Rheumatol 1986; 13: 875-877.
19. Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF 3rd, Petraglia F. Inflammation and pregnancy. Reprod Sci 2009; 16: 206-215. [DOI:10.1177/1933719108329095]
20. Lejeune B, Grun JP, de Nayer P, Servais G, Glinoer D. Anti-thyroid antibodies underlying thyroid abnormalities and miscarriage and pregnancy induced hypertension. Br J Obstet Gynecol 1993; 100: 669-672. [DOI:10.1111/j.1471-0528.1993.tb14236.x]
21. Negro R, Mangieri T, Coppola L, Presicce G, Casavola EC, Gismondi R, et al. Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod 2005; 20: 1529-1533. [DOI:10.1093/humrep/deh843]
22. Roussev RG, Kaider BD, Pride DE, Coulam CB. Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol 1996; 35: 415-420. [DOI:10.1111/j.1600-0897.1996.tb00503.x]
23. Poppe K, Glinoer D, Tournaye H, Devroey P, Schiettecatte J, Haentjens P, et al. Thyroid autoimmunity and female infertility. Verh K Acad Geneeskd Belg 2006; 68: 357-377.
24. Wang S, Teng WP, Li JX, Wang WW, Shan ZY. Effects of maternal subclinicalhypothyroidism on obstetrical outcomes during early pregnancy. J Endocrinol Invest 2012; 35: 322-325.
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