INTRODUCTION:

Recurrent miscarriage defined as two or more consequative failed clinical pregnancies and verified by ultrasonography or histopathological examination and consider the most common clinical problems in reproduction, and it affects 2%–5% of childbearing couple [1]. Most pregnancy losses result from chromosomal, or genetic, abnormalities, and are random events. The abnormality may be either parental, maternal, or the early embryonic. Thyroid peroxidase is an enzyme expressed mainly in the thyroid where it is secreted into colloid.

Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3) [2]. The presence of thyroid auto antibodies is relatively common in women of reproductive age. In an unselected population of women, the prevalence ranges from 6% to 20% being even higher in women with a history of recurrent pregnancy loss, at around 17-33%, and in women with a history of subfertility, at around 10-31%. Disorders of the thyroid gland are frequently caused by autoimmune mechanisms with the production of autoantibodies. The antibodies most commonly detectable are anti-thyroid peroxidase antibody (TPO-Ab) and reflect the general activation of the immune system. The TPO-Abs is primarily found at the beginning of pregnancy, then decline as gestation progresses and becoming virtually undetectable by the third trimester [3]. This study aim to assess the prevalence of positive thyroid peroxidase Antibody in women with a history of at least two unexplained recurrent miscarriages in addition to determine the effect of thyroxine administration on positive TPO-Ab of women with recurrent miscarriage.

MATERIAL AND METHOD:

This prospective case control study was carried out in the Obstetrics and Gynecology Al-Muthanna teaching hospital in Samawa city-Iraq during the period October 2018 to April 2019. This Study included 140 women who were already diagnosed with recurrent miscarriage in age range (19-45) years old. Following complete clinical workup, including history, examination and investigations, enrolled women were classified into two main groups explained recurrent miscarriage group (n= 85) and unexplained recurrent miscarriage group(n=55) , then recurrent miscarriage women were classified in two sup-group : first group are women with positive thyroid peroxidase antibody (n = 28), whereas the other group are negative thyroid peroxidase antibody group (n = 112) that including recurrent miscarriage women. First group were treated with throxine (T4) and follow up for 14 weeks than comparison was measured according to response to thyroxine treatment.

Statistical analysis:

Statistical analysis, tables and figures were carried out by using SPSS (version 22) by ANOVA test.

RESULTS:

Group classification of women with recurrent miscarriage into explained and unexplained categories. Women with only Anti-APS antibody positive results accounted for 72 (51.4%). Women with bicornuate uterus in addition to Anti-phospholipid positivity accounted for 2 (1.4%); women with cervical incompetence in addition to Anti-APS positivity accounted for 2 (1.4%); women with cytomegalovirus (CMV) and toxoplasma virus in addition to Anti-APS positivity accounted for 2 (1.4%) and women with thyroid disease in addition to Anti-APS positivity accounted for 2 (1.4%). Women with anti-phospholipid negatively who had only bicornuate uterus accounted for 4 (2.9%) and there was a single woman with only thyroid abnormality (0.7%), as shown in Table (1). Those women were regarded as explained group and they included 85 members, whereas, women with no identifiable cause, even after through clinical workup, were considered unexplained group and they had been represented by 55 members, as shown in Table (1).

Table (1): Frequency distribution of women with recurrent miscarriage according to cause of miscarriage.

Group	Cause	n	%
Explained n = 85	APS +ve	72	51.4
	APS +ve + bicornuate uterus	2	1.4
	APS +ve + Cervical incompetence	2	1.4
	APS +ve + CMV+toxoplasma	2	1.4
	APS +ve + Thyroid disease	2	1.4
	APS -ve + bicornuate uterus	4	2.9
	APS -ve + Thyroid disease	1	0.7
Unexplained n = 55	No identifiable cause	55	39.3
Total n = 140	Total n = 140	140	100.0

Anti-thyroid peroxidase (TPO) antibody was identified in 28 (20.0%) cases out of all enrolled women with recurrent miscarriage. The risk of recurrent miscarriage in association with anti-TPO positivity was estimated in terms of odds ratio (OR) which was estimated to be 3.01 (95% confidence interval of 1.28 - 7.07), as shown in Table (2). This implies that women with recurrent miscarriage and having positive anti-TPO are 4.5 times more likely to have unexplained cause (most likely thyroid abnormality) than women with recurrent miscarriage having negative anti-TPO. On the other hand, the etiologic fraction (EF) of thyroid disease, represented by anti-TPO positive results, has been estimated to be 0.41, as shown in Table (2)

Figure (1): The frequency distribution of women according to results of anti-TPO in explained and unexplained groups

Outcome of treating women having recurrent miscarriage with thyroxin:

The effect of thyroxin administration for women with recurrent miscarriage having anti-TPO positive results was evaluated in the next pregnancy and the results are demonstrated in Table (3). successful pregnancy was encountered in 26 out of 28 women treated with low doses thyroxin accounting for 92.9 % successful rate; however, there was no significant difference in successful pregnancy rate between explained and unexplained groups, 9 (81.8 %) versus 17 (100.0 %), respectively (P = 0.283), despite the presence of 2 cases of failure (7.1 %) in explained group, as shown in Table (3).

DISCUSSION:

Miscarriage is considered the most common adverse outcome in early pregnancy. It is defined as the spontaneous demise of a pregnancy from the time of conception until 24 weeks gestation (4). It can be clinically classified as first-trimester miscarriage (within 13 weeks gestation) or second-trimester miscarriage (after 12 and before 24 completed weeks gestation) (5). Recurrent miscarriage represents a significant health problem. Approximately 5% of couples trying to conceive suffer recurrent miscarriage. Different definitions for recurrent miscarriage have been described. In this study recurrent miscarriage has been defined as two or more not necessarily consecutive miscarriages (6).

As shown in Table (1) recurrent miscarriage women were classified to explained causes of recurrent miscarriage with the mean cause antiphospholipids antibodies which gave 60.7% of women with recurrent miscarriage. Whereas, unexplained recurrent miscarriage still represents a major scientific and clinical challenge in reproductive medicine, as approximately 39.3% of recurrent miscarriage (RM) are defined as unexplained at the end of the standard diagnostic workup. This is due to the lack of a full understanding of the complex mechanisms involved in proper implantation and early pregnancy development, which prevents a thorough definition of the causes and mechanisms underlying recurrent miscarriage; and the fact that there are still many methodological problems that hamper the reliability of many clinical studies on recurrent miscarriage (7) (8).

Antiphospholipid antibodies (aPL) are a family of approximately twenty autoantibodies directed against phospholipid binding plasma proteins. However, the two most clinically important aPL are the lupus anticoagulant (LA) and the anticardiolipin antibodies (aCL). Approximately 15% of women with recurrent miscarriage have persistently positive tests for either LA or aCL, compared to 2% of those with an uncomplicated obstetric history (9).

Thyroid auto antibodies are involved in both these areas and are associated with major alterations in the course of pregnancy affecting the mother, the fetus, and the neonate. Thyroid antibodies can serve as useful clinical predictors of thyroid dysfunction, for example, TPO Ab and post-partum thyroiditis and TSH receptor antibodies (TSHR-Abs) and neonatal hyperthyroidism (10). Thyroid disorders are common during pregnancy and can affect its outcome. This study revealed the overall prevalence of anti-TPO positivity to be 20% in the samples population of this study as show in table (2). The etiology of pregnancy loss in thyroid antibody-positive women remains to be elucidated. Two meta-analyses have reported a difference in the mean age and mean TSH level between thyroid antibody-positive and thyroid antibody-negative women who miscarry (11). In this results there were 17 cases of unexplained miscarriage women with positively anti-thyroid peroxidase, whereas 38 cases as negatively anti-thyroid peroxidase.

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 (12). Lejeune et al (1993) found that frequency of circulating anti-thyroid antibodies were higher in women with recurrent abortion than in control subjects (13). 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(14)and this confirmed the result that obtained from women with positive anti thyroid peroxidase and its relationship with recurrent miscarriage.

Thyroid hormones are essential for the developing fetus. Hence, a pregnant woman needs thyroxin more than non-pregnant lady to provide T4 to both herself and her developing fetus. The fetus's thyroid gland is not fully functional until after 12 weeks of pregnancy. If the mother does not have sufficient thyroid hormones, she may be at increased risk of miscarriage. Since the majority of women are not sure that they are pregnant until four to six weeks after the last menstrual period, they do not go to see doctors and test their thyroid function until the first trimester is more than half over. It is advisable to suggest thyroid investigation to the pregnant women with history of recurrent miscarriage as soon as possible after knowing they are pregnant. Management of thyroid diseases during pregnancy requires special considerations because pregnancy induces major changes in thyroid function, and maternal thyroid disease can have adverse effects on the pregnancy and the fetus. Care requires coordination among several healthcare professionals. Avoiding maternal and fetal thyroid dysfunction is of major importance because of potential damage to fetal neural development, an increased incidence of miscarriage, and preterm delivery (15) (16) (17). In 1990, Stagnaro-Green et al tested 552 (18) 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. 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.

Also, in Poppe et al (2006) study thyroxine was prescribed for 187 women with unexplained recurrent pregnancy loss, and compare live birth rates among two groups (19). 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 (2012) 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 (20). They found that therapy decreased the incidence of spontaneous abortion. This agreement with this study which show that 92.9% of recurrent miscarriage women with positive anti-thyroid peroxidase that show positive response to treatment with thyroxin after fourteen weeks of treatment. Some studies have shown that thyroid hormones may play a determinant role in the physiology of early pregnancy and that thyroxin treatment of infertile women may improve the conception rate (21) (22). This study agree with result that showed 100% of women unexplained causes with positive anti-thyroid peroxidase show successful pregnancy response after treatment with thyroxin follow up fourteen weeks, whereas 92.9% explained recurrent miscarriage women with also positive thyroid peroxidase show positive response after treatment with thyroxin and there are no significant in treatment with thyroxin (T4) in women with positive anti-thyroid peroxidase. Whether in explained recurrent miscarriage women or unexplained recurrent miscarriage and this confirm the important role of thyroxin treatment in increase conception rate of pregnancy in women with positive anti thyroid peroxidase antibody.

REFERENCES:

1. El Hachem, H., Crepaux, V., May-Panloup, P., Descamps, P., Legendre, G. and Bouet, P. E. Recurrent pregnancy loss: current perspectives. International journal of women's health, 2017, 9, 331.

2. Ruf, J., and Carayon, P. Structural and functional aspects of thyroid peroxidase. Arch. Biochem. Biophys., 2006, 445(2), 269-277

3. Gupta A., Wajdi, N., Verma, A. and Pal, M. Role of anti-thyroid peroxidase antibodies in adverse pregnancy outcomes. Int J Reprod Contracept Obstet Gynecol, 2016, 5(9):3001-3005.

4. Shand, A.W., Bell, J.C., McElduff, A., Morris, J. and Roberts, C.L. Outcomes of pregnancies in women with pre‐gestational diabetes mellitus and gestational diabetes mellitus; a population‐based study in New South Wales, Australia, 1998–2002. Diab. Med., 2008, 25(6): 708-715.

5. McNamara, K., Meaney, S., O’Connell, O., McCarthy, M., Greene, R. A. and O’Donoghue, K. Healthcare professionals’ response to intrapartum death: a cross-sectional study. Arch. Gynecol. Obst., 2017, 295(4): 845-852.

6. Morris, A., Meaney, S., Spillane, N. and O’Donoghue, K. The postnatal morbidity associated with second-trimester miscarriage. J. Maternal-Fetal Neonat. Med., 2016, 29(17), 2786-2790.

7. Vissenberg, R., Van Dijk, M. M., Fliers, E., van der Post, J. A. M., van Wely, M., Bloemenkamp, K. W. M. and Rombout-de Weerd, S. Effect of levothyroxine on live birth rate in euthyroid women with recurrent miscarriage and TPO antibodies (T4-LIFE study). Contemporary clinical trials, 2015, 44: 134-138.

8. Ticconi, C., Giuliani, E., Sorge, R., Patrizi, L., Piccione, E. and Pietropolli, A. Gestational age of pregnancy loss in women with unexplained recurrent miscarriage. J. Obst. Gynaecol. Res., 2016, 42(3), 239-245.

9. Checko, A., Christiansen, H.L., Yan, Y., Scolari, L., Kardaras, G., Berger, M.S. and Dittmann, L. Cloud RAN for mobile networks—A technology overview. IEEE Communications surveys and tutorials, 2014, 17(1), pp.405-426.

10. Dobson, S. J. A. and Jayaprakasan, K. M. Aetiology of recurrent miscarriage and the role of adjuvant treatment in its management: a retrospective cohort review. J. Obstet. Gynaecol., 2018, 38(7), 967-974.

11. Twig, G., Shina, A., Amital, H. and Shoenfeld, Y. Pathogenesis of infertility and recurrent pregnancy loss in thyroid autoimmunity. J. Autoimm., 2012, 38(2-3): J275-J281.

12. Stagnaro-Green, A. Thyroid antibodies and miscarriage: where are we at a generation later?. Journal of thyroid research, 2011.

13. Challis, J. R., Lockwood, C. J., Myatt, L., Norman, J. E., Strauss III, J. F. and Petraglia, F. Inflammation and pregnancy. Reprod. Sci., 2009, 16(2): 206-215.

14. Lejeune, B., Grun, J. P., De Nayer, P. H., Servais, G. and Glinoer, D. (1993). Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension. BJOG: An Int. J. Obstet. Gynaecol., 1993, 100(7): 669-672.

15. Bramson, J. and Stagnaro-Green, A. Thyroid antibodies and fetal loss: an evolving story. Thyroid, 2001, 11(1): 57-63.

16. Thompson, W., Russell, G., Baragwanath, G., Matthews, J., Vaidya, B. and Thompson‐Coon, J. Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta‐analysis. Clin. Endocrinol., 2018, 88(4): 575-584.

17. Abalovich, M., Amino, N., Barbour, L. A., Cobin, R. H., De Groot, L. J., Glinoer, D. and Stagnaro-Green, A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metabol., 2007, 92(8-supplement): s1-s7.

18. Zahran, A. B. H. Thyroid function and thyroid antibodies in recurrent miscarriage women, 2010.

19. Poppe, K., Glinoer, D., Tournaye, H., Devroey, P., Schiettecatte, J., Haentjens, P. and Velkeniers, B. Thyroid autoimmunity and female infertility. Verhandelingen-Koninklijke Academie voor Geneeskunde van Belgie, 2006, 68(5-6): 357-377.

20. Wang, S., Teng, W. P., Li, J. X., Wang, W. W. and Shan, Z. Y. Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy. J. Endocrinol. Investigat., 2012, 35(3): 322-325.

21. Negro, R., Formoso, G., Mangieri, T., Pezzarossa, A., Dazzi, D. and Hassan, H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J. Clin. Endocrinol. Metabol., 2006, 91(7): 2587-2591.

22. Mosaddegh, M. H., Ghasemi, N., Jahaninejad, T., Mohsenifar, F. and Aflatoonian, A. Treatment of recurrent pregnancy loss by Levothyroxine in women with high Anti-TPO antibody. Iranian Reprod. Med., 2012, 10(4): 373.

Received on 24.10.2019 Modified on 19.12.2019

Research J. Pharm. and Tech. 2020; 13(10):4702-4706.

DOI: 10.5958/0974-360X.2020.00827.6