http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, 2014; 30(2): 100–102 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2013.864271
HASHIMOTO THYROIDITIS
Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy Ivana Bozic Antic1, Djuro Macut1,2, Bojana Popovic1, Tatjana Isailovic1, Milan Petakov1,2, Sanja Ognjanovic1, and Svetozar Damjanovic1,2 1
Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and 2Faculty of Medicine, University of Belgrade, Belgrade, Serbia Abstract
Keywords
Introduction: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. Case report: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. Conclusion: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.
Alopecia areata, Hashimoto thyroiditis, hypothyroidism, pregnancy, recurrent spontaneous abortions
Recurrent spontaneous abortion (RSA) represents frequent obstetric problem, particularly among women over 30 years of age [1]. Approximately one-third of all recognised pregnancies terminate as spontaneous abortions of which 1 to 2% are recurrent [2]. RSAs are defined as three or more consecutive abortions occurring before 20 weeks post-menstruation [3]. The risk of miscarriage recurrence increases with the maternal age and number of successive pregnancy losses [4]. Evaluation classically begins after three consecutive miscarriages of less than 10 weeks of gestation, but may be warranted earlier if a prior miscarriage was found to be euploid, or if there is a concomitant infertility and/or advanced maternal age [5]. Causes of RSA are various with approximately 40% that remains of unknown origin [6]. The most common causes are chromosomal abnormalities, uterine anatomic abnormalities, endocrine disturbances, thrombophilia, autoimmune diseases and infections [3,5]. It is known that hypothyroidism is associated with infertility and higher miscarriage rate [2,7]. However, a number of studies confirmed that not only overt hypothyroidism is associated with fetal loss, but also the presence of anti-TPO antibodies (anti-TPO-Ab) in both euthyroid women and those with subclinical hypothyroidism [2,8]. The treatment recommendations for patients with RSA of known cause are based on the therapy for the underlying Address for correspondence: Dr Ivana Bozic Antic, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Dr Subotica 13, 11000 Belgrade, Serbia. Tel: +381 63 453 624 (Mobile). Fax: +381 11 2685 357. E-mail: [email protected]
Received 6 August 2013 Revised 26 October 2013 Accepted 6 November 2013 Published online 6 December 2013
pathology, but there are still no universal treatment modalities for patients with RSA of unknown cause.
Case report A 35-year-old pregnant woman came for the first time to the endocrine outpatient clinic in fourth gestation week of third pregnancy. Hashimoto thyroiditis causing hypothyroidism was diagnosed at the age of 31, after a spontaneous abortion in the sixth week of first pregnancy (Table 1). At that time L-thyroxin was introduced and euthyroid state achieved with 100 mg qd. At the age of 32, a spontaneous abortion occurred in the seventh week of second pregnancy. She was euthyroid at that time with high levels of antithyroid-peroxidase antibodies (anti-TPO-Ab) (Table 1). The pathohistological findings of both embryos were non-specific and with normal karyotypes (46XX and 46XY, respectively). Our patient was RhD-negative and although RhDantibodies were not measured, she received the Rho(D)-ImmuneGlobulin after both miscarriages. The patient and her husband had normal karyotypes (46XX and 46XY). Our patient was diagnosed with alopecia areata (AA) at the age of 10, which progressed into alopecia totalis (AT) at the age of 14. She did not have other chronic diseases, and the existence of anatomic anomalies of reproductive organs, systemic lupus erythematodes, antiphospholipid syndrome, hereditary thrombophilia (presence of factor V Leiden, deficit of C and S proteins, methylenetetrahydrofolate-reductase mutation, disturbance in antithrombin III) were excluded. There were no hereditary or chronic diseases (including alopecia areata) in patient’s family. The third pregnancy was confirmed at the age of 34. In the fourth week of gestation, the morphologic parameters of the
20 14
Introduction
History
Recurrent abortions and thyroiditis
DOI: 10.3109/09513590.2013.864271
101
Table 1. Thyroid hormones and antithyroid antibodies at the time of previous recurrent spontaneous abortions and current pregnancy, in a patient with Hashimoto thyroiditis and alopecia areata. Third pregnancy Analysis (normal value)
First pregnancy
Second pregnancy
4.gestational weeks
38.gestational weeks
TSH (0.27–4.2 mIU/mL) fT4 (10–22 pmol/L) fT3 (2.3–6.29 pmol/L) Anti-Tg Ab (1:100) Anti-TPO Ab (1:100)
13.7 12 2.6 41:1600 41:1 638 400
4.1 20 4.12 41:1600 41:1 638 400
4.65 12.1 n.m n.m n.m
2.8 16.3 n.m n.m n.m
n.m – not measured.
embryo and level of bHCG (13465 mIU/ml) were adequate to the gestational age. Except slightly enlarged thyroid gland (grade I), her other clinical findings on examination were normal. The blood count, biochemical analyses and level of immunoglobulin fractions were within the normal range. TSH was high, with a lownormal fT4 (Table 1). From 4th to 25th week of gestation she was treated with intravenous non-specific human immunoglobulin (IVIg) (0.2 g per kg body weight every 4th week), low-molecularweight heparin (5000 IU sc qd) and acetylsalicylic acid (100 mg qd). During pregnancy L-thyroxin dose was gradually increased up to 150 mg qd and euthyroid state maintained (Table 1) while blood count, coagulation parameters, liver function tests and other biochemical analyses were within the normal range. The patient delivered healthy female child. After delivery, L-thyroxin dose was reduced to 75 mg qd. Soon after the initiation of immunoglobulin therapy her scalp hair started re-growing, gaining full normalisation at the time of delivery, but total alopecia re-occurred three months later.
Discussion We presented an unusual case of a woman with RSA, total alopecia and concomitant Hashimoto thyroiditis that successfully delivered a child and re-growth her hair after the introduction of IVIg therapy. Numerous studies indicate the association between positive antithyroid antibodies and RSA, independently from the antibodies titre and the presence of thyroid dysfunction [8,9]. In addition, it was frequently stated that anti-TPO-Ab may be an independent marker for reproductive failure during in vitro fertilisation (IVF), considering that spontaneous abortions occur more frequently within positive than with negative anti-TPO-Ab women [10]. Besides these facts, a debate on the rationality of detecting antithyroid antibodies in euthyroid women with RSA and generally in pregnant women still exists [7]. Spontaneous abortions in euthyroid women with positive antithyroid antibodies generally occur during the first trimester of pregnancy [10]. The pathogenesis is still unknown and some of the possible explanations are as follows: (1) although these women are formally euthyroid, subtle hypothyroidism may be present, (2) presence of antithyroid antibodies may reflect a general autoimmune imbalance that results in more frequent fetal rejection, (3) direct cytostatic effect of antithyroid antibodies, (4) women with an autoimmune thyroid disease and subfertility more often conceive at a later age (after 30), which is a risk factor per se for spontaneous abortions and is related to the increasing levels of TSH [11,12]. Intravenous immunoglobulin therapy has been frequently used in treating idiopathic RSA. The effects of IVIg on the pregnancy outcome were controversial [13,14]. The exact mechanism of this therapy is unknown. Possible explanations are: speeding the lysosome catabolism of own IgG, blockage of Fc receptors on macrophages and effector cells, modulation of production and release of various cytokines, lymphocyte proliferation and
their function, or attenuation of complement-mediated damage and natural killer (NK) cells suppression [15]. A combined therapy with low-molecular-weight heparin and acetylsalicylic acid was proved to be successful in maintaining pregnancy and preventing spontaneous abortions in pregnant women with antiphospholipid syndrome [16]. Some studies showed that the adjuvant application of heparin and aspirin along with the IVIg therapy is more successful than the application of immunoglobulin alone, especially in cases with high antithyroid antibodies titres [17,18]. It was proved that beside inhibition of aberrant coagulation, the combination of heparin and aspirin modulate trophoblast apoptosis while additionally, heparin directly or indirectly participates in facilitation of blastocyst adhesion to the endometrium [19]. According to the literature, this is a first case report describing an association of recurrent spontaneous abortions in a patient with Hashimoto thyroiditis and alopecia areata. Several studies provided evidence for correlation between AA and autoimmune diseases [20,21]. It is observed that approximately 12% of individuals with AA go on to develop an autoimmune disease [21]. The prevalence of autoimmune thyroid disease in patients with AA varies from 8 to 28% [22]. Alopecia areata is a disease of very broad spectrum and only 10% of patients with its severe forms (alopecia totalis-AT and alopecia universalis-AU) could expect full recovery [23]. It is believed that AA onset before puberty implies its worse prognosis [23,24]. Accordingly, several studies reported that in comparison to patients with patch AA, patients with AT or AU were younger at the age of onset, had positive family history for AA and more likely had concomitant, autoimmune disorders [24,25]. Our patient had early-onset of AA with early progression to AT and concomitant autoimmune disease, but her family history was unremarkable. This is in accordance to the data published in the recent study of Cho et al. who showed that significant number of patients with early-onset AA (85.7%) have negative family history of AA [24]. IVIg therapy is not widely used for treatment of AA, AT or AU, and there are only a few published observations of their successful responding to IVIg therapy [26,27]. Bearing in mind that AA is a T-cell, and probable NK cell, mediated autoimmune disease, it could be possible that IVIg therapy had a beneficial effect on our patient’s scalp hair growth [28]. Actually, the response to IVIg therapy in our case could be a consequence of the favourable effect of IVIg on tumor necrosis factor alpha (TNFa) levels, as elevated TNF-a levels were associated with both AA and RSA [29,30]. The etiopathogenesis of RSA in primiparas with concomitant autoimmune disease is still unclear. Furthermore, it usually concerns pregnant women of an older age, which implies subfertility from the beginning by default. Our patient with RSA and Hashimoto thyroiditis had two additional risk factors for maintaining current pregnancy: advanced age and hypothyroidism, which, bearing in mind the history of preterm endings of previous
102
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pregnancies, prompted for quick treatment decision. We can only speculate to what extent each of these drugs (L-thyroxin, immunoglobulin, heparin and aspirin) contributed to the maintaining of pregnancy. However, it is a fact that during the gestation and IVIg therapy her scalp hair re-grew. We suggest that in older primiparas with recurrent spontaneous abortions and Hashimoto thyroiditis, treatment with intravenous gamma globulin combined with anticoagulation and antiaggregation therapy should be considered.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Cramer DW, Wise LA. The epidemiology of recurrent pregnancy loss. Semin Reprod Med 2000;18:331–9. 2. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004;150:751–5. 3. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21:2216–22. 4. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999;14:2868–71. 5. Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 2010;93:1234–43. 6. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 1996;66:24–9. 7. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92: S1–47. 8. Stagnaro-Green A, Glinoer D. Thyroid autoimmunity and the risk of miscarriage. Best Pract Res Clin Endocrinol Metab 2004;18:167–81. 9. Sieiro Netto L, Medina Coeli C, Micmacher E, et al. Influence of thyroid autoimmunity and maternal age on the risk of miscarriage. Am J Reprod Immunol 2004;52:312–16. 10. Poppe K, Glinoer D, Tournaye H, et al. Assisted reproduction and thyroid autoimmunity: an unfortunate combination? J Clin Endocrinol Metab 2003;88:4149–52. 11. Nybo AA, Wohlfahrt J, Christens P, et al. Is maternal age an independent risk factor for fetal loss? West J Med 2000;173:331. 12. Benhadi N, Wiersinga WM, Reitsma JB, et al. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009;160: 985–91. 13. Stephenson MD, Kutteh WH, Purkiss S, et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 2010;25:2203–9.
Gynecol Endocrinol, 2014; 30(2): 100–102
14. Hutton B, Sharma R, Fergusson D, et al. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. BJOG 2007;114:134–42. 15. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747–55. 16. Shetty S, Ghosh K. Anti-phospholipid antibodies and other immunological causes of recurrent foetal loss – a review of literature of various therapeutic protocols. Am J Reprod Immunol 2009;62:9–24. 17. Fiedler K, Wurfel W. Effectivity of heparin in assisted reproduction. Eur J Med Res 2004;9:207–14. 18. Sher G, Matzner W, Feinman M, et al. The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am J Reprod Immunol 1998;40:74–82. 19. Bose P, Black S, Kadyrov M, et al. Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure. Am J Obstet Gynecol 2005;192:23–30. 20. Barahmani N, Schabath MB, Duvic M. History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 2009;61:581–91. 21. Safavi KH, Muller SA, Suman VJ, et al. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin Proc 1995;70:628–33. 22. Puavilai S, Puavilai G, Charuwichitratana S, et al. Prevalence of thyroid diseases in patients with alopecia areata. Int J Dermatol 1994;33:632–3. 23. Alkhalifah A, Alsantali A, Wang E, et al. Alopecia areata update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 2010;62:177–88. 24. Cho HH, Jo SJ, Paik SH, et al. Clinical characteristics and prognostic factors in early-onset alopecia totalis and alopecia universalis. J Korean Med Sci 2012;27:799–802. 25. Goh C, Finkel M, Christos PJ, Sinha AA. Profile of 513 patients with alopecia areata: associations of disease subtypes with atopy, autoimmune disease and positive family history. J Eur Acad Dermatol Venereol 2006;20:1055–60. 26. Ostlere LS, Harris DW, Wood M, Rustin MH. Alopecia areata responding to immunoglobulin, with varying response to different preparations. Br J Dermatol 1994;131:735–6. 27. Boonyaleepun S, Boonyaleepun C, Schlactus JL. Effect of IVIG on the hair regrowth in a common variable immune deficiency patient with alopecia universalis. Asian Pac J Allergy Immunol 1999;17: 59–62. 28. Kaufman G, d’Ovidio R, Kaldawy A, et al. An unexpected twist in alopecia areata pathogenesis: are NK cells protective and CD49bþ T cells pathogenic? Exp Dermatol 2010;19:e347–9. 29. Winger EE, Reed JL, Ashoush S, et al. Degree of TNF-alpha/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adalimumab (Humira) and IVIG. Am J Reprod Immunol 2011;65:610–18. 30. Redler S, Albert F, Brockschmidt FF, et al. Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata. Br J Dermatol 2012; 167:1360–5.
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HASHIMOTO THYROIDITIS
Recurrent spontaneous abortions, Hashimoto thyroiditis and alopecia totalis: response to anticoagulation and intravenous immunoglobulin therapy Ivana Bozic Antic1, Djuro Macut1,2, Bojana Popovic1, Tatjana Isailovic1, Milan Petakov1,2, Sanja Ognjanovic1, and Svetozar Damjanovic1,2 1
Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia and 2Faculty of Medicine, University of Belgrade, Belgrade, Serbia Abstract
Keywords
Introduction: Although numerous studies indicated a link between antithyroid antibodies and recurrent spontaneous abortions (RSA), consensus on the treatment of this condition is still lacking. Case report: We present a case of a 35-year-old pregnant woman (gestation week 4) with primary hypothyroidism, total alopecia, high level of positive antithyroid antibodies, and history of two recurrent spontaneous abortions in early pregnancy. Along with L-thyroxin substitution, intravenous human immunoglobulin (IVIg) combined with anticoagulation and antiaggregation therapy was introduced. During pregnancy her scalp hair completely re-grew, and following gestation week 39 she delivered healthy female child. Conclusion: Thyroid antibodies could contribute to previous recurrent abortions in our patient. It is suggested that in older primiparas with Hashimoto thyroiditis and history of RSA, a combined treatment with IVIg, anticoagulation and antiaggregation therapy should be considered.
Alopecia areata, Hashimoto thyroiditis, hypothyroidism, pregnancy, recurrent spontaneous abortions
Recurrent spontaneous abortion (RSA) represents frequent obstetric problem, particularly among women over 30 years of age [1]. Approximately one-third of all recognised pregnancies terminate as spontaneous abortions of which 1 to 2% are recurrent [2]. RSAs are defined as three or more consecutive abortions occurring before 20 weeks post-menstruation [3]. The risk of miscarriage recurrence increases with the maternal age and number of successive pregnancy losses [4]. Evaluation classically begins after three consecutive miscarriages of less than 10 weeks of gestation, but may be warranted earlier if a prior miscarriage was found to be euploid, or if there is a concomitant infertility and/or advanced maternal age [5]. Causes of RSA are various with approximately 40% that remains of unknown origin [6]. The most common causes are chromosomal abnormalities, uterine anatomic abnormalities, endocrine disturbances, thrombophilia, autoimmune diseases and infections [3,5]. It is known that hypothyroidism is associated with infertility and higher miscarriage rate [2,7]. However, a number of studies confirmed that not only overt hypothyroidism is associated with fetal loss, but also the presence of anti-TPO antibodies (anti-TPO-Ab) in both euthyroid women and those with subclinical hypothyroidism [2,8]. The treatment recommendations for patients with RSA of known cause are based on the therapy for the underlying Address for correspondence: Dr Ivana Bozic Antic, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Dr Subotica 13, 11000 Belgrade, Serbia. Tel: +381 63 453 624 (Mobile). Fax: +381 11 2685 357. E-mail: [email protected]
Received 6 August 2013 Revised 26 October 2013 Accepted 6 November 2013 Published online 6 December 2013
pathology, but there are still no universal treatment modalities for patients with RSA of unknown cause.
Case report A 35-year-old pregnant woman came for the first time to the endocrine outpatient clinic in fourth gestation week of third pregnancy. Hashimoto thyroiditis causing hypothyroidism was diagnosed at the age of 31, after a spontaneous abortion in the sixth week of first pregnancy (Table 1). At that time L-thyroxin was introduced and euthyroid state achieved with 100 mg qd. At the age of 32, a spontaneous abortion occurred in the seventh week of second pregnancy. She was euthyroid at that time with high levels of antithyroid-peroxidase antibodies (anti-TPO-Ab) (Table 1). The pathohistological findings of both embryos were non-specific and with normal karyotypes (46XX and 46XY, respectively). Our patient was RhD-negative and although RhDantibodies were not measured, she received the Rho(D)-ImmuneGlobulin after both miscarriages. The patient and her husband had normal karyotypes (46XX and 46XY). Our patient was diagnosed with alopecia areata (AA) at the age of 10, which progressed into alopecia totalis (AT) at the age of 14. She did not have other chronic diseases, and the existence of anatomic anomalies of reproductive organs, systemic lupus erythematodes, antiphospholipid syndrome, hereditary thrombophilia (presence of factor V Leiden, deficit of C and S proteins, methylenetetrahydrofolate-reductase mutation, disturbance in antithrombin III) were excluded. There were no hereditary or chronic diseases (including alopecia areata) in patient’s family. The third pregnancy was confirmed at the age of 34. In the fourth week of gestation, the morphologic parameters of the
20 14
Introduction
History
Recurrent abortions and thyroiditis
DOI: 10.3109/09513590.2013.864271
101
Table 1. Thyroid hormones and antithyroid antibodies at the time of previous recurrent spontaneous abortions and current pregnancy, in a patient with Hashimoto thyroiditis and alopecia areata. Third pregnancy Analysis (normal value)
First pregnancy
Second pregnancy
4.gestational weeks
38.gestational weeks
TSH (0.27–4.2 mIU/mL) fT4 (10–22 pmol/L) fT3 (2.3–6.29 pmol/L) Anti-Tg Ab (1:100) Anti-TPO Ab (1:100)
13.7 12 2.6 41:1600 41:1 638 400
4.1 20 4.12 41:1600 41:1 638 400
4.65 12.1 n.m n.m n.m
2.8 16.3 n.m n.m n.m
n.m – not measured.
embryo and level of bHCG (13465 mIU/ml) were adequate to the gestational age. Except slightly enlarged thyroid gland (grade I), her other clinical findings on examination were normal. The blood count, biochemical analyses and level of immunoglobulin fractions were within the normal range. TSH was high, with a lownormal fT4 (Table 1). From 4th to 25th week of gestation she was treated with intravenous non-specific human immunoglobulin (IVIg) (0.2 g per kg body weight every 4th week), low-molecularweight heparin (5000 IU sc qd) and acetylsalicylic acid (100 mg qd). During pregnancy L-thyroxin dose was gradually increased up to 150 mg qd and euthyroid state maintained (Table 1) while blood count, coagulation parameters, liver function tests and other biochemical analyses were within the normal range. The patient delivered healthy female child. After delivery, L-thyroxin dose was reduced to 75 mg qd. Soon after the initiation of immunoglobulin therapy her scalp hair started re-growing, gaining full normalisation at the time of delivery, but total alopecia re-occurred three months later.
Discussion We presented an unusual case of a woman with RSA, total alopecia and concomitant Hashimoto thyroiditis that successfully delivered a child and re-growth her hair after the introduction of IVIg therapy. Numerous studies indicate the association between positive antithyroid antibodies and RSA, independently from the antibodies titre and the presence of thyroid dysfunction [8,9]. In addition, it was frequently stated that anti-TPO-Ab may be an independent marker for reproductive failure during in vitro fertilisation (IVF), considering that spontaneous abortions occur more frequently within positive than with negative anti-TPO-Ab women [10]. Besides these facts, a debate on the rationality of detecting antithyroid antibodies in euthyroid women with RSA and generally in pregnant women still exists [7]. Spontaneous abortions in euthyroid women with positive antithyroid antibodies generally occur during the first trimester of pregnancy [10]. The pathogenesis is still unknown and some of the possible explanations are as follows: (1) although these women are formally euthyroid, subtle hypothyroidism may be present, (2) presence of antithyroid antibodies may reflect a general autoimmune imbalance that results in more frequent fetal rejection, (3) direct cytostatic effect of antithyroid antibodies, (4) women with an autoimmune thyroid disease and subfertility more often conceive at a later age (after 30), which is a risk factor per se for spontaneous abortions and is related to the increasing levels of TSH [11,12]. Intravenous immunoglobulin therapy has been frequently used in treating idiopathic RSA. The effects of IVIg on the pregnancy outcome were controversial [13,14]. The exact mechanism of this therapy is unknown. Possible explanations are: speeding the lysosome catabolism of own IgG, blockage of Fc receptors on macrophages and effector cells, modulation of production and release of various cytokines, lymphocyte proliferation and
their function, or attenuation of complement-mediated damage and natural killer (NK) cells suppression [15]. A combined therapy with low-molecular-weight heparin and acetylsalicylic acid was proved to be successful in maintaining pregnancy and preventing spontaneous abortions in pregnant women with antiphospholipid syndrome [16]. Some studies showed that the adjuvant application of heparin and aspirin along with the IVIg therapy is more successful than the application of immunoglobulin alone, especially in cases with high antithyroid antibodies titres [17,18]. It was proved that beside inhibition of aberrant coagulation, the combination of heparin and aspirin modulate trophoblast apoptosis while additionally, heparin directly or indirectly participates in facilitation of blastocyst adhesion to the endometrium [19]. According to the literature, this is a first case report describing an association of recurrent spontaneous abortions in a patient with Hashimoto thyroiditis and alopecia areata. Several studies provided evidence for correlation between AA and autoimmune diseases [20,21]. It is observed that approximately 12% of individuals with AA go on to develop an autoimmune disease [21]. The prevalence of autoimmune thyroid disease in patients with AA varies from 8 to 28% [22]. Alopecia areata is a disease of very broad spectrum and only 10% of patients with its severe forms (alopecia totalis-AT and alopecia universalis-AU) could expect full recovery [23]. It is believed that AA onset before puberty implies its worse prognosis [23,24]. Accordingly, several studies reported that in comparison to patients with patch AA, patients with AT or AU were younger at the age of onset, had positive family history for AA and more likely had concomitant, autoimmune disorders [24,25]. Our patient had early-onset of AA with early progression to AT and concomitant autoimmune disease, but her family history was unremarkable. This is in accordance to the data published in the recent study of Cho et al. who showed that significant number of patients with early-onset AA (85.7%) have negative family history of AA [24]. IVIg therapy is not widely used for treatment of AA, AT or AU, and there are only a few published observations of their successful responding to IVIg therapy [26,27]. Bearing in mind that AA is a T-cell, and probable NK cell, mediated autoimmune disease, it could be possible that IVIg therapy had a beneficial effect on our patient’s scalp hair growth [28]. Actually, the response to IVIg therapy in our case could be a consequence of the favourable effect of IVIg on tumor necrosis factor alpha (TNFa) levels, as elevated TNF-a levels were associated with both AA and RSA [29,30]. The etiopathogenesis of RSA in primiparas with concomitant autoimmune disease is still unclear. Furthermore, it usually concerns pregnant women of an older age, which implies subfertility from the beginning by default. Our patient with RSA and Hashimoto thyroiditis had two additional risk factors for maintaining current pregnancy: advanced age and hypothyroidism, which, bearing in mind the history of preterm endings of previous
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pregnancies, prompted for quick treatment decision. We can only speculate to what extent each of these drugs (L-thyroxin, immunoglobulin, heparin and aspirin) contributed to the maintaining of pregnancy. However, it is a fact that during the gestation and IVIg therapy her scalp hair re-grew. We suggest that in older primiparas with recurrent spontaneous abortions and Hashimoto thyroiditis, treatment with intravenous gamma globulin combined with anticoagulation and antiaggregation therapy should be considered.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Cramer DW, Wise LA. The epidemiology of recurrent pregnancy loss. Semin Reprod Med 2000;18:331–9. 2. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004;150:751–5. 3. Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 2006;21:2216–22. 4. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999;14:2868–71. 5. Jaslow CR, Carney JL, Kutteh WH. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil Steril 2010;93:1234–43. 6. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 1996;66:24–9. 7. Abalovich M, Amino N, Barbour LA, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92: S1–47. 8. Stagnaro-Green A, Glinoer D. Thyroid autoimmunity and the risk of miscarriage. Best Pract Res Clin Endocrinol Metab 2004;18:167–81. 9. Sieiro Netto L, Medina Coeli C, Micmacher E, et al. Influence of thyroid autoimmunity and maternal age on the risk of miscarriage. Am J Reprod Immunol 2004;52:312–16. 10. Poppe K, Glinoer D, Tournaye H, et al. Assisted reproduction and thyroid autoimmunity: an unfortunate combination? J Clin Endocrinol Metab 2003;88:4149–52. 11. Nybo AA, Wohlfahrt J, Christens P, et al. Is maternal age an independent risk factor for fetal loss? West J Med 2000;173:331. 12. Benhadi N, Wiersinga WM, Reitsma JB, et al. Higher maternal TSH levels in pregnancy are associated with increased risk for miscarriage, fetal or neonatal death. Eur J Endocrinol 2009;160: 985–91. 13. Stephenson MD, Kutteh WH, Purkiss S, et al. Intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial. Hum Reprod 2010;25:2203–9.
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