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Habitual abortion: causes, diagnosis, and treatment
Reviews in Gynaecological Practice 3 (2003) 75–80
Habitual abortion: causes, diagnosis, and treatment Hussein S. Qublan∗ Department of Obstetrics and Gynecology, King Hussein Medical Centre, Irbid-Aidun, P.O. Box 97, Jordan Received 27 January 2003; accepted 13 March 2003
Abstract Habitual abortion is defined as three or more consecutive pregnancy losses before 20 weeks of gestation and affects 1% of couples trying to conceive. It is a heterogeneous condition with a number of possible underlying causes: uterine, infectious, genetic, thrombophilic, endocrine, metabolic, immunologic, and environmental. Some of these causes are overdiagnosed because of the different methodologies employed. Over the past few years, attention has been paid to the role of infection (bacterial vaginosis and chlamydial infection) in the etiology of habitual abortion, but studies determining the role of intervention in improving pregnancy outcome are needed. Controversy surrounds the treatment of the different causes of habitual abortion. This is related to problems such as the size of the studies and the different methodologies that have been used in treatment and patient selection. To overcome this, large randomized controlled studies are necessary. Despite the various investigations, the etiology of recurrent abortions remains unknown in about half of all cases. For these individuals, psychologic support and reassurance, rather empirical treatment, are recommended. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Habitual abortion; Auto-immunity; Infection; Endocrine disorders; Uterine anomalies; Thrombophilia
1. Introduction Habitual abortion is defined as three or more consecutive pregnancy losses before 20 weeks of gestation. This condition, frustrating for both the couple involved and the physician, affects 1% of women of reproductive age [1]. The etiology remains unexplained in about 50% of cases. The known causes cover uterine, infectious, genetic, thromobophilic, endocrine, metabolic, immunologic, environmental, and unexplained factors [2–9]. In this article, the different possible causes of recurrent pregnancy loss, along with their diagnostic tools and treatment, are reviewed.
2. Uterine abnormalities Structural anomalies of the uterus have long been recognized as a cause of obstetric complications, including habitual abortion. Approximately 15–25% of miscarriages are thought to result from mullerian fusion defects, and almost all are associated with uterine septa [2]. The proposed mechanism of habitual abortion is poor implantation dynamics, resulting from poor blood supply to the septum and the sex ∗ Tel.:
+962-77410465; fax: +962-27247142. E-mail address: [email protected] (H.S. Qublan).
steroid receptor deficiency in the malformed uterus, which causes abnormal uterine contraction with subsequent fetal wastage and abortion [10]. In women with habitual abortion, hysteroscopic resection rather uterine surgery is advocated because of the risk for post-operative adhesions and infertility in the latter [2]. Uterine fibroids may be observed in 1–4% of pregnancies [11]. Pregnancy loss may occur in 40 and 17% of cases in the first and second trimester, respectively, with the intramural and submucosal types of this benign tumour [12]. It has been suggested that uterine fibroids increase the risk for pregnancy loss by affecting implantation or calcium metabolism in the myometrial myocytes, resulting in abnormal uterine contraction [13]. The rate of pregnancy loss was found to be reduced significantly following myomectomy [12]. Sudden rupture of the membranes in the second trimester followed by painless explosion of the fetus is defined as cervical incompetence. Cervical incompetence is overdiagnosed as an etiological factor involved in habitual abortion, and only one-third of cases may actually have such a diagnosis [14]. The application of cervical cerclage has been found to reduce the rate of pre-term delivery, but without a significant improvement in the fetal outcome [14]. A rare acquired condition implicated in the etiology of habitual abortion is Asherman’s syndrome. Post-traumatic intrauterine adhesions may reduce the size of the uterine
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00022-4
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cavity and the responsiveness to steroid hormones, leading to impaired implantation and pregnancy wastage; hysteroscopic resection of the adhesions will correct these abnormalities [15].
tions in the coagulation proteins can lead to habitual abortion by the development of microthrombi at the feto-maternal interface, with subsequent pregnancy wastage.
5. Thrombophilia 3. Infectious causes The role of maternal and fetal infection in habitual abortion remains controversial. It appears that TORCH (toxoplasmsa, rubella, cytomegalovirus, and herpes) infection has no role in habitual abortion [3]. Recently, concern has been raised by certain infections such as bacterial vaginosis and infection caused by Chlamydia trachomatis [16,17]. A significant association has been found between bacterial vaginosis detected early in pregnancy, and pre-term delivery and also late miscarriage [16]. Furthermore, significantly high titers of chlamydial antibodies were found in the sera of women with habitual abortion [17]. They postulated that an immune response to an epitope shared by a chlamydial and a fetal antigen is responsible for recurrent miscarriage. There are, however, no data available to confirm the role of intervention in improving the outcome of pregnancy.
4. Genetic causes Both parental and embryonic chromosomal abnormalities have been implicated in the etiology of habitual abortion. The frequency of abnormal embryonic karyotypes was found to be significantly lower, and that of normal karyotypes significantly higher, with an increasing number of previous miscarriages, reaching >50% when this number reached more than six abortions [18]. The effect of maternal age in couples with habitual abortion is important as the frequency of trisomies due to non-disjunction or translocation increases with advancing age [1]. Women younger than 36 years of age with habitual abortion have been found to have a higher frequency of euploid miscarriage [6]. A parental chromosomal abnormality—most frequently a balanced reciprocal or Robertsonian translocation—is present in 6% of couples presenting with habitual abortion [19]. Parental trisomy 21 mosaicism and pereferential X-chromosome inactivation have recently been reported as etiological factors in habitual abortion, raising the question of whether all couples presenting with habitual abortion should undergo a detailed cytogenetic analysis [20,21]. Furthermore, karyotyping of the abortus should be obtained, and counselling for the future pregnancy and prenatal diagnosis should be offered if findings are abnormal [14]. In habitual abortion with a normal karyotype, a substantial role may exist for molecular mutations. Recurrent abortions have been found significantly to be associated with mutations in G1691A factor V (Leiden), G20210A prothrombin, and C677T methylenetetrahydrofolate reductase, and coagulation factor XII genetic polymorphism [22,23]. These muta-
Acquired and hereditary thrombophilic conditions have been described in association with adverse pregnancy outcome, including habitual abortion. The proposed mechanism responsible for pregnancy loss is attributed to thrombosis in the utero-placental vasculature [7,24]. The most common acquired thrombophilia is the anti-phospholipid syndrome, in which anti-phospholipid antibodies are directed against phospholipids, resulting in the various manifestations of this syndrome. The most commonly detected sub-groups of these antibodies are lupus anticoagulant, anti-cardiolipin, and anti-b2 glycoprotein I antibodies [24]. Anti-phospholipid antibodies have been found in 10–20% of women with habitual abortion compared to 2–5% in women without a previous history of abortion [25]. Habitual abortion may occur as a result of poor placental perfusion caused by localized thrombosis. Furthermore, anti-phospholipid antibodies may also impair trophoblastic invasion and hormonal production, leading to an early and late pregnancy loss [25]. Various modalities of treatment have been described to treat women with anti-phospholipid syndrome suffering from habitual abortion, including aspirin, prednisolone, heparin, and immunoglobulin infusion. In a recent meta-analysis of 10 randomized controlled trials, the combination therapy of heparin and aspirin was association with a significantly better outcome than aspirin alone or in combination with prednisolone [26]. Numerous hereditary thrombophilic conditions have been described as contributing significantly to habitual abortion; these include anti-thrombin III deficiency, protein S and C deficiencies, and the molecular mutations mentioned above. In a recent study, activated protein C resistance was found to be the most common thrombophilic defect documented in 39% of women with habitual abortion [7].
6. Endocrine causes Habitual abortion has also been linked to underlying abnormal endocrine disorders. An endocrine factor, for example a luteal phase defect, insulin-dependent diabetes mellitus, thyroid disorder, or a hypersecretion of luteinizing hormone (LH), is responsible for 20% of cases of habitual abortion [4]. Luteal phase insufficiency, defined as the inadequate secretion of progesterone by the corpus luteum in the secretory phase of the menstrual cycle and early pregnancy, is reported as a cause of habitual abortion in 20–60% of women with the condition [27]. This wide range of incidence is related to the different methodologies used to diagnose the luteal phase deficiency. Sub-normal levels of progesterone
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lead to an underdeveloped endometrium unable to maintain implantation and embryo growth [15]. Endometrial dysfunction caused by progesterone deficiency may be manifested by a disturbance in endometrial protein secretion. The concentrations of placental protein 14 and mucin-1 in uterine flushings were both significantly reduced in women with habitual abortion compared to normal controls [15]. Luteal phase insufficiency has traditionally been treated with exogenous progesterone or human chronic gonadotropin supplementation after conception. Results from controlled randomized trials have, however, failed to support the efficacy of these treatments in improving outcome [27,28]. The hypersecretion of LH in women with polycystic ovary syndrome is considered to be a marker of habitual abortion. High levels of LH were found in 27–81% of women with habitual abortion who had polycystic ovaries on ultrasound imaging [29]. It has been postulated that elevated levels of LH are responsible for habitual abortion by adversely affecting oocyte quality or the endometrium, either directly or indirectly, by producing elevated levels of androgens and estrogens [29]. More recent studies have failed to confirm the relationship between elevated LH level and habitual abortion [30,31]. In these studies, women with an elevated serum LH concentration showed no significant difference in future pregnancy outcome when compared to those with normal concentrations. In a prospective, randomized, placebo-controlled study, Clifford et al. [32] reported no improvement in the live birth rate after suppressing high endogenous LH secretion with gonadotropin-releasing hormone agonists. It has recently has been suggested that hyperinsulinemia and insulin resistance in women with polycistic ovary syndrome augment the LH-driven production of androgens from the ovarian theca cells [33]. The amelioration of insulin resistance has been achieved after treatment with metformin (an insulin sensitizer). In a prospective. randomized. placebo-controlled study, we found a significant reduction in the concentrations of LH and androgens after treatment with metformin, as well as a low miscarriage rate compared to the placebo group [34]. Hyperprolactinemia without evidence of corpus luteum dysfunction has recently been described as a causative factor in habitual abortion [35]. The authors suggested that a high level of prolactin might cause recurrent miscarriage by endometrial alteration of the extracellular matrix or by some immunologic mechanism. In a randomized controlled trial, they found a significant improvement in pregnancy outcome after treatment with bromocriptine. The association between thyroid disorders and habitual abortion is controversial. In recent years, concern has arisen over thyroid auto-immunity. A significant association between the presence of thyroid antibodies in euthyroid women and the risk for habitual abortion has been reported [36]. The mechanism involved in thyroid auto-immunity and habitual abortion is unclear, but activation of the immune system, particularly T cells, has been suggested.
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Previous reports failed to identify an association between diabetes and habitual abortion [37]. A significant correlation has, however, been reported between an increased spontaneous abortion rate and increasing concentrations of first-trimester hemoglobin A1c [38]. Maternal hyperglycemia has been linked to an increased rate of malformation that may be incompatible with embryonic or fetal life, leading to miscarriage. Furthermore, an increased risk for habitual abortion seems to be related to abnormal placentation resulting from increased atherosclerosis or fibrin deposition in women with diabetes [39]. There is a recent evidence that well-controlled insulin-dependent diabetes mellitus is not associated with habitual abortion [40].
7. Metabolic causes Hyperhomocysteinemia, as a consequence of folate and Vitamin B12 deficiency, is a risk factor that predisposes to thrombophilic events and is linked to habitual abortion [5]. A 1-month treatment with high-dose folic acid (15 mg per day) and Vitamin B6 (750 mg per day) in women with hyperhomocysteinemia and habitual abortion proved effective in normalizing their homocysteine level, with a significant improvement in fetal outcome [41]. Celiac disease is a relatively frequent disease, with an incidence of 0.5%. It is a digestive disease resulting from gluten intolerance that damages the small intestine and interferes with the absorption of nutrients from food. Celiac disease may be atypical or silent. The association of the disease with recurrent abortion has recently been reported [42]. The efficacy of a gluten-free diet during pregnancy on decreasing the miscarriage rate remains to be investigated.
8. Immunologic causes During pregnancy, the maternal immune system confronts the conceptus with a host-defense reaction based on the recognition of paternally derived fetal and placental antigens. To avoid rejection of the semi-allogenic concepts, the maternal immune response is suppressed during normal pregnancy [43]. The mechanism by which habitual abortion is linked to allo-immunity is not clear. Lim et al. [43] have postulated three mechanisms by which allo-immunity could be responsible for habitual abortion: human leukocyte antigen (HLA) sharing, a deficiency of blocking antibodies, and a mechanism involving immune mediators and suppresser cells. If the problem arises from HLA-sharing, maternal recognition of the fetus is impaired because they share some polymorphic genes. Such a fetus is therefore unable to induce maternal blocking antibodies and will subsequently be aborted [44]. Some studies, although not the majority, have confirmed the hypothesis of increased HLA-sharing among women with habitual abortion [8]. It has been suggested that
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the production of blocking antibodies by the mother is necessary to prevent pregnancy wastage [45]. More recent studies indicate that these antibodies have no predictive value with respect to pregnancy outcome [8]. In recent years, attention has focused on an immune mediator and suppressor cell mechanism. Increased cytotoxic activity arising from activation of natural killer cells, leukocytes, lymphocytes, and macrophages has been found in women with habitual abortion [46]. Macrophages are capable of producing cytokines of the T-helper 1 (Th1) type: interleukin-2 (IL-2), tumour necrosis factor-␣, and interferon-␥. These cytokines are produced in increased amounts at the materno–fetal interface. They are considered deleterious to the pregnancy by direct embryotoxic activity or by damaging the placental trophoblast. Conversely, high concentrations of the anti-inflammatory cytokines IL-4, -6, -10, and -13 (Th2 type) are beneficial to the developing embryo by enhancing placental growth and function [47]. On the basis of these hypotheses, various immunomodulatory therapies could be employed to inhibit natural killer cell cytotoxicity, enhance the formation of blocking antibodies, or promote a Th1–2 cytokine shifting. Such therapies include allogenic lymphocyte immunotherapy and intravenous immunoglobulin (IVIG). The efficacy of both treatments in
the prevention of habitual abortion of the euploid embryo is, however, controversial. This may be related to a number of scientific problems, for example different treatment methodologies, patient selection, and small-size studies that result in an underestimation of the actual results in the general population, with high false-positive and false-negative rates. Two multi-centre meta-analyses [48,49] have investigated women receiving lymphocyte immunotherapy; the first showed a 10% absolute improvement in take-home baby rate, while the second showed no statistically significant improvement. This type of treatment should be balanced against the potential risks of transfusion, mainly those of allergy and viral infection [4]. IVIG seems to be more advantageous because it is well tolerated and the potential risks associated with lymphocyte immunotherapy are rare. In a meta-analysis of three placebo-controlled trials of IVIG in the treatment of habitual abortion, a significant improvement in pregnancy outcome was reported for the treated group compared to controls receiving placebo [8]. The natural immunosuppressive effect of progesterone has recently been studied. In vitro studies have shown that progesterone specifically blocks Th1 immunity to the trophoblast, which has a deleterious effect on the developing embryo [50].
Table 1 Clinical causes and diagnosis of habitual abortion Cause
Diagnosis
Method
Uterine anomalies
Hysterosalpingography Hysteroscopy Laparoscopy Ultrasonography
Infection
Endocervical and posteriro vaginal formix swabs Anti-chlamydial antibody titer
Gram or papanicolaou staining Microimmunofluorescence
Genetic
Parental karyotype Fetal karyotype Quantitative X-chromosome inactivation
Cytogentic analysis Cytogenetic analysis Polymerase chain reaction
Thrombophilia
Protein C measurement Protein S measurement Anti-thrombin III measurement Genetic analysis for molecular mutations
Clotting assay Clotting assay Amidolytic assay Polymerase chain reaction amplification
Endocrine
Endometrial biopsy Luteal phase progesterone level Luteining hormone, follicle-stimulating hormone, prolactin, and androgen levels Thyroid-stimulating hormone Hemoblobin A1c level, fasting glucose concentration, glucose tolerance test
Timed by urinary luteinizaing hormone peak Radio-immunoassay Radio-immunoassay Automated flurimetric enzyme immunoassay Immunofluorometric assay
Metabolic
Serum homocystine Small bowel biopsy Antibodies to gluten
Fluorescence polarization immuno-assay
Immunologic
Anti-cardiolipin antibodies (IgG, IgM, IgA) Lupus anticoagulant Cytokine levels Humant leukocyte antigen typing
ELISA APTT, KCT, dRVVT ELISA DNA techniques
Environmental Unexplained
History All investigations
Exclusion of other causes
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9. Environmental causes The lifestyle of pregnant women appears to affect the rate of habitual abortion as smoking, alcohol, and heavy coffee consumption can adversely affect fetal development. The risk for recurrent abortion increases linearly with the number of cigarettes smoked and number of drinks, of either alcohol or coffee, taken; education and an avoidance of these substances will decrease this risk [9].
10. Unexplained factors Despite through investigations according to various clinical protocols, the underlying cause of habitual abortion remains unexplained in about half of all cases. In this category, psychotherapy rather empiric treatment is needed. A ‘tender loving care’ type of psychotherapy in a present or a subsequent pregnancy appears improve pregnancy outcome significantly [1]. Causes of and various investigations for recurrent miscarriage are summarized in Table 1.
11. Practice points • The etiology of habitual abortion remains unexplained in about 50% of cases. • Cervical incompetence and hormonal abnormalities are overdiagnosed as causes of habitual abortion because of the different methodologies employed. • Large randomized controlled studies and international investigations are needed to determine the role of chlamydial infection and bacterial vaginosis in habitual abortion. • In diabetes and thyroid disease, auto-immunity related to the underlying disease, rather than organ dysfunction, may be responsible for recurrent abortion. • In recurrent first- and second-trimester abortions of euploid fetuses, searching for acquired or hereditary thrombophilia is recommended. • The importance of auto-immunity in the etiology of habitual abortion is increasing, and the role of progesterone as natural immunossuppressant needed to be investigated in a randomized controlled trials.
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[5] Nelen WLD, Blom HJ, Steegers EA, et al. Hyperhomocysyteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000;74:1196–9. [6] Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod 2002;17:446–51. [7] Sarig G, Younis JS, Hoffman R, et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002;77:342–7. [8] Christiansen OB. A fresh look at the causes and treatment of recurrent miscarriage, especially its immunological aspects. Hum Reprod Update 1996;2:271–93. [9] Armstrong BG, McDonald AD, Sloan M. Cigarette, alcohol and coffee consumption and spontaneous abortion. Am J Publ Health 1992;82:85–7. [10] Rock JA, Murph AA. Anatomic abnormalities. Clin Obstet Gynecol 1986;29:886–911. [11] Rosati P, Bellati U, Exacoustos C, et al. Uterine myoma in pregnancy: ultrasound study. Int J Gynecol Obstet 1989;28:109–17. [12] Li TC, Mortimer R, Cooke ID. Myomectomy: a retrospective study to examine reproductive performance before and after surgery. Hum Reprod 1999;14:1735–40. [13] Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update 2000;6:614–20. [14] Rai R, Clifford K, Regan L. The modern preventative treatment of recurrent miscarriage. Br J Obstet Gynecol 1996;103:106–10. [15] Li TC, Tuckerman EM, Laird SM. Endometrial factors in recurrent miscarriage. Hum Reprod Update 2002;8:43–52. [16] Hay PE, Lamont RF, Taylor-Robinson D, et al. Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage. BMJ 1994;308:295–8. [17] Witkin SS, Ledger WJ. Antibodies to Chlamydia trachomatis in sera of women with recurrent spontaneous abortion. Am J Obstet Gynecol 1992;167:135–9. [18] Ogasawara M, Aoki K, Okada S, Suzumori K. Embryo karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000;73:300–4. [19] Hatasaka HH. Recurrent miscarriage: epidemiological factors, definitions, and incidence. Clin Obstet Gynecol 1994;37:625–34. [20] Kuo PL. Maternal trisomy 21 mosaicism and recurrent spontaneous abortion. Fertil Steril 2002;78:432–3. [21] Uehara S, Hashiyada M, Sato K, et al. Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. Fertil Steril 2001;76:908–14. [22] Reznikoff-Etievant MF, Cayol V, Cabonne B, et al. Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. Br J Obstet Gynecol 2001;108:1251–4. [23] Linuma Y, Sugiura-Ogasawara M, Makino A, et al. Coagulation factor XII activity, but not an asssociated common genetic polymorphism (46C/T) is linked to recurrent miscarriage. Fertil Steril 2002;77:353–6. [24] Levine JS, Branch W, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752–64. [25] Haywood L, Brown MD. Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol 1991;34:1–17. [26] Empson M, Lassere M, Craig JC, Scott JR. Recurrent pregnancy loss with antiphospholipid antibody: a systemic review of therapeutic trials. Obstet Gynecol 2002;99:135–44. [27] Karamardian LM, Grimes DA. Luteal phase deficiency: effect of treatment on pregnancy rates. Am J Obstet Gynecol 1992;167:1391– 8. [28] Harrison RF. Human chorionic gonadotrophin in the management of recurrent abortion: results of multi-centre placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992;72:175–9. [29] Waston H, Kiddy DS, Hamilton-Fairley D, et al. Hypersecretion of luteinizing hormone and ovarian steroids in women with recurrent early miscarriage. Hum Reprod 1993;8:829–33.
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[30] Liddle HS, Sowden K, Farquhar CM. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome. Aust NZ J Obstet Gynecol 1997;37:402–6. [31] Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage: a reappraisal. Hum Reprod 2000;15:612–5. [32] Clifford K, Rai R, Waston H, et al. Does suppression luteinizing hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial. BMJ 1996;312:1508–11. [33] Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanisms and implications for pathogenesis. Endocr Rev 1997;18:774–800. [34] Malkawi HY, Qublan HS, Hamaideh AH. Medical versus surgical treatment for clomiphene-citrate resistant women with polycystic ovary syndrome. J Obstet Gynecol 2003;23:289–93. [35] Hirahara F, Andoh N, Sawai K, et al. Hyperprolactinemic recurrent miscarriage and results of randomized bromocriptine treatment trial. Fertil Steril 1998;70:246–52. [36] Pratt D, Novotny M, Kaberlein G, et al. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss. Am J Obstet Gynecol 1993;168:837–41. [37] Kalter H. Diabetes and spontaneous abortion: a historical review. Am J Obstet Gynecol 1987;147:86–94. [38] Greene MF, Hare JW, Cloherty JP, et al. First trimester hemoglobin A1c and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 1989;39:225–31. [39] Miller E, Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 1981;304:1331–4. [40] Mills JL, Simpson JL, Driscoll SG, et al. Incidence of spontaneous abortion among normal women and insulin dependent diabetic women whose pregnancies were identified with 21 days of conception. N Engl J Med 1988;319:1617–23.
[41] Quere I, Mercier E, Bellet H, et al. Vitamin supplementation and pregnancy outcome in women with early pregnancy loss and hyperhomocysteinemia. Fertil Steril 2001;75:823–5. [42] Foschi F, Diani F, Zaridini E, et al. Celiac disease and spontaneous abortion. Minerva Ginecol 2002;54:151–9. [43] Lim KJH, Odukoya OA, Li TC, Cooke ID. Cytokines and immuno-endocrine factors in recurrent miscarriage. Hum Reprod Update 1996;2:469–81. [44] Scott JR, Rote NS, Branch DW. Immunological aspects of recurrent abortion and fetal death. Obstet Gynecol 1987;70:645– 56. [45] Takakuwa K, Kanazawa K, Takeuchi S. Production of blocking antibodies by vaccination with husband’s lymphocytes in unexplained recurrent aborters: the role in successful pregnancy. Am J Reprod Microbiol 1986;10:1–9. [46] Johnson PM, Chrismas SE, Vince GS. Immunological aspects of implantation and implantation failure. Hum Reprod 1999;14(Suppl):26– 36. [47] Makhseed M, Raghupathy R, Azizieh F, et al. Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions. Hum Reprod 2000;15:2011–7. [48] Daya S, Gunby J. The effectiveness of allogenic leukocyte immunisation in unexplained primary recurrent spontaneous abortion. Recurrent Miscarriage Immunotherpy Trialists Group. Am J Reprod Immunol 1994;32:294–302. [49] Ober C, Karrison T, Odem RR, et al. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Lancet 1999;354:365–9. [50] Choi BC, Polgar K, Xiao L, Hill JA. Progesterone inhibits in-vitro embryotoxic Th1 cytokine production to trophoblast in women with recurrent pregnancy loss. Hum Reprod 2000;15(Suppl):46– 59.
Habitual abortion: causes, diagnosis, and treatment Hussein S. Qublan∗ Department of Obstetrics and Gynecology, King Hussein Medical Centre, Irbid-Aidun, P.O. Box 97, Jordan Received 27 January 2003; accepted 13 March 2003
Abstract Habitual abortion is defined as three or more consecutive pregnancy losses before 20 weeks of gestation and affects 1% of couples trying to conceive. It is a heterogeneous condition with a number of possible underlying causes: uterine, infectious, genetic, thrombophilic, endocrine, metabolic, immunologic, and environmental. Some of these causes are overdiagnosed because of the different methodologies employed. Over the past few years, attention has been paid to the role of infection (bacterial vaginosis and chlamydial infection) in the etiology of habitual abortion, but studies determining the role of intervention in improving pregnancy outcome are needed. Controversy surrounds the treatment of the different causes of habitual abortion. This is related to problems such as the size of the studies and the different methodologies that have been used in treatment and patient selection. To overcome this, large randomized controlled studies are necessary. Despite the various investigations, the etiology of recurrent abortions remains unknown in about half of all cases. For these individuals, psychologic support and reassurance, rather empirical treatment, are recommended. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Habitual abortion; Auto-immunity; Infection; Endocrine disorders; Uterine anomalies; Thrombophilia
1. Introduction Habitual abortion is defined as three or more consecutive pregnancy losses before 20 weeks of gestation. This condition, frustrating for both the couple involved and the physician, affects 1% of women of reproductive age [1]. The etiology remains unexplained in about 50% of cases. The known causes cover uterine, infectious, genetic, thromobophilic, endocrine, metabolic, immunologic, environmental, and unexplained factors [2–9]. In this article, the different possible causes of recurrent pregnancy loss, along with their diagnostic tools and treatment, are reviewed.
2. Uterine abnormalities Structural anomalies of the uterus have long been recognized as a cause of obstetric complications, including habitual abortion. Approximately 15–25% of miscarriages are thought to result from mullerian fusion defects, and almost all are associated with uterine septa [2]. The proposed mechanism of habitual abortion is poor implantation dynamics, resulting from poor blood supply to the septum and the sex ∗ Tel.:
+962-77410465; fax: +962-27247142. E-mail address: [email protected] (H.S. Qublan).
steroid receptor deficiency in the malformed uterus, which causes abnormal uterine contraction with subsequent fetal wastage and abortion [10]. In women with habitual abortion, hysteroscopic resection rather uterine surgery is advocated because of the risk for post-operative adhesions and infertility in the latter [2]. Uterine fibroids may be observed in 1–4% of pregnancies [11]. Pregnancy loss may occur in 40 and 17% of cases in the first and second trimester, respectively, with the intramural and submucosal types of this benign tumour [12]. It has been suggested that uterine fibroids increase the risk for pregnancy loss by affecting implantation or calcium metabolism in the myometrial myocytes, resulting in abnormal uterine contraction [13]. The rate of pregnancy loss was found to be reduced significantly following myomectomy [12]. Sudden rupture of the membranes in the second trimester followed by painless explosion of the fetus is defined as cervical incompetence. Cervical incompetence is overdiagnosed as an etiological factor involved in habitual abortion, and only one-third of cases may actually have such a diagnosis [14]. The application of cervical cerclage has been found to reduce the rate of pre-term delivery, but without a significant improvement in the fetal outcome [14]. A rare acquired condition implicated in the etiology of habitual abortion is Asherman’s syndrome. Post-traumatic intrauterine adhesions may reduce the size of the uterine
1471-7697/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S1471-7697(03)00022-4
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cavity and the responsiveness to steroid hormones, leading to impaired implantation and pregnancy wastage; hysteroscopic resection of the adhesions will correct these abnormalities [15].
tions in the coagulation proteins can lead to habitual abortion by the development of microthrombi at the feto-maternal interface, with subsequent pregnancy wastage.
5. Thrombophilia 3. Infectious causes The role of maternal and fetal infection in habitual abortion remains controversial. It appears that TORCH (toxoplasmsa, rubella, cytomegalovirus, and herpes) infection has no role in habitual abortion [3]. Recently, concern has been raised by certain infections such as bacterial vaginosis and infection caused by Chlamydia trachomatis [16,17]. A significant association has been found between bacterial vaginosis detected early in pregnancy, and pre-term delivery and also late miscarriage [16]. Furthermore, significantly high titers of chlamydial antibodies were found in the sera of women with habitual abortion [17]. They postulated that an immune response to an epitope shared by a chlamydial and a fetal antigen is responsible for recurrent miscarriage. There are, however, no data available to confirm the role of intervention in improving the outcome of pregnancy.
4. Genetic causes Both parental and embryonic chromosomal abnormalities have been implicated in the etiology of habitual abortion. The frequency of abnormal embryonic karyotypes was found to be significantly lower, and that of normal karyotypes significantly higher, with an increasing number of previous miscarriages, reaching >50% when this number reached more than six abortions [18]. The effect of maternal age in couples with habitual abortion is important as the frequency of trisomies due to non-disjunction or translocation increases with advancing age [1]. Women younger than 36 years of age with habitual abortion have been found to have a higher frequency of euploid miscarriage [6]. A parental chromosomal abnormality—most frequently a balanced reciprocal or Robertsonian translocation—is present in 6% of couples presenting with habitual abortion [19]. Parental trisomy 21 mosaicism and pereferential X-chromosome inactivation have recently been reported as etiological factors in habitual abortion, raising the question of whether all couples presenting with habitual abortion should undergo a detailed cytogenetic analysis [20,21]. Furthermore, karyotyping of the abortus should be obtained, and counselling for the future pregnancy and prenatal diagnosis should be offered if findings are abnormal [14]. In habitual abortion with a normal karyotype, a substantial role may exist for molecular mutations. Recurrent abortions have been found significantly to be associated with mutations in G1691A factor V (Leiden), G20210A prothrombin, and C677T methylenetetrahydrofolate reductase, and coagulation factor XII genetic polymorphism [22,23]. These muta-
Acquired and hereditary thrombophilic conditions have been described in association with adverse pregnancy outcome, including habitual abortion. The proposed mechanism responsible for pregnancy loss is attributed to thrombosis in the utero-placental vasculature [7,24]. The most common acquired thrombophilia is the anti-phospholipid syndrome, in which anti-phospholipid antibodies are directed against phospholipids, resulting in the various manifestations of this syndrome. The most commonly detected sub-groups of these antibodies are lupus anticoagulant, anti-cardiolipin, and anti-b2 glycoprotein I antibodies [24]. Anti-phospholipid antibodies have been found in 10–20% of women with habitual abortion compared to 2–5% in women without a previous history of abortion [25]. Habitual abortion may occur as a result of poor placental perfusion caused by localized thrombosis. Furthermore, anti-phospholipid antibodies may also impair trophoblastic invasion and hormonal production, leading to an early and late pregnancy loss [25]. Various modalities of treatment have been described to treat women with anti-phospholipid syndrome suffering from habitual abortion, including aspirin, prednisolone, heparin, and immunoglobulin infusion. In a recent meta-analysis of 10 randomized controlled trials, the combination therapy of heparin and aspirin was association with a significantly better outcome than aspirin alone or in combination with prednisolone [26]. Numerous hereditary thrombophilic conditions have been described as contributing significantly to habitual abortion; these include anti-thrombin III deficiency, protein S and C deficiencies, and the molecular mutations mentioned above. In a recent study, activated protein C resistance was found to be the most common thrombophilic defect documented in 39% of women with habitual abortion [7].
6. Endocrine causes Habitual abortion has also been linked to underlying abnormal endocrine disorders. An endocrine factor, for example a luteal phase defect, insulin-dependent diabetes mellitus, thyroid disorder, or a hypersecretion of luteinizing hormone (LH), is responsible for 20% of cases of habitual abortion [4]. Luteal phase insufficiency, defined as the inadequate secretion of progesterone by the corpus luteum in the secretory phase of the menstrual cycle and early pregnancy, is reported as a cause of habitual abortion in 20–60% of women with the condition [27]. This wide range of incidence is related to the different methodologies used to diagnose the luteal phase deficiency. Sub-normal levels of progesterone
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lead to an underdeveloped endometrium unable to maintain implantation and embryo growth [15]. Endometrial dysfunction caused by progesterone deficiency may be manifested by a disturbance in endometrial protein secretion. The concentrations of placental protein 14 and mucin-1 in uterine flushings were both significantly reduced in women with habitual abortion compared to normal controls [15]. Luteal phase insufficiency has traditionally been treated with exogenous progesterone or human chronic gonadotropin supplementation after conception. Results from controlled randomized trials have, however, failed to support the efficacy of these treatments in improving outcome [27,28]. The hypersecretion of LH in women with polycystic ovary syndrome is considered to be a marker of habitual abortion. High levels of LH were found in 27–81% of women with habitual abortion who had polycystic ovaries on ultrasound imaging [29]. It has been postulated that elevated levels of LH are responsible for habitual abortion by adversely affecting oocyte quality or the endometrium, either directly or indirectly, by producing elevated levels of androgens and estrogens [29]. More recent studies have failed to confirm the relationship between elevated LH level and habitual abortion [30,31]. In these studies, women with an elevated serum LH concentration showed no significant difference in future pregnancy outcome when compared to those with normal concentrations. In a prospective, randomized, placebo-controlled study, Clifford et al. [32] reported no improvement in the live birth rate after suppressing high endogenous LH secretion with gonadotropin-releasing hormone agonists. It has recently has been suggested that hyperinsulinemia and insulin resistance in women with polycistic ovary syndrome augment the LH-driven production of androgens from the ovarian theca cells [33]. The amelioration of insulin resistance has been achieved after treatment with metformin (an insulin sensitizer). In a prospective. randomized. placebo-controlled study, we found a significant reduction in the concentrations of LH and androgens after treatment with metformin, as well as a low miscarriage rate compared to the placebo group [34]. Hyperprolactinemia without evidence of corpus luteum dysfunction has recently been described as a causative factor in habitual abortion [35]. The authors suggested that a high level of prolactin might cause recurrent miscarriage by endometrial alteration of the extracellular matrix or by some immunologic mechanism. In a randomized controlled trial, they found a significant improvement in pregnancy outcome after treatment with bromocriptine. The association between thyroid disorders and habitual abortion is controversial. In recent years, concern has arisen over thyroid auto-immunity. A significant association between the presence of thyroid antibodies in euthyroid women and the risk for habitual abortion has been reported [36]. The mechanism involved in thyroid auto-immunity and habitual abortion is unclear, but activation of the immune system, particularly T cells, has been suggested.
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Previous reports failed to identify an association between diabetes and habitual abortion [37]. A significant correlation has, however, been reported between an increased spontaneous abortion rate and increasing concentrations of first-trimester hemoglobin A1c [38]. Maternal hyperglycemia has been linked to an increased rate of malformation that may be incompatible with embryonic or fetal life, leading to miscarriage. Furthermore, an increased risk for habitual abortion seems to be related to abnormal placentation resulting from increased atherosclerosis or fibrin deposition in women with diabetes [39]. There is a recent evidence that well-controlled insulin-dependent diabetes mellitus is not associated with habitual abortion [40].
7. Metabolic causes Hyperhomocysteinemia, as a consequence of folate and Vitamin B12 deficiency, is a risk factor that predisposes to thrombophilic events and is linked to habitual abortion [5]. A 1-month treatment with high-dose folic acid (15 mg per day) and Vitamin B6 (750 mg per day) in women with hyperhomocysteinemia and habitual abortion proved effective in normalizing their homocysteine level, with a significant improvement in fetal outcome [41]. Celiac disease is a relatively frequent disease, with an incidence of 0.5%. It is a digestive disease resulting from gluten intolerance that damages the small intestine and interferes with the absorption of nutrients from food. Celiac disease may be atypical or silent. The association of the disease with recurrent abortion has recently been reported [42]. The efficacy of a gluten-free diet during pregnancy on decreasing the miscarriage rate remains to be investigated.
8. Immunologic causes During pregnancy, the maternal immune system confronts the conceptus with a host-defense reaction based on the recognition of paternally derived fetal and placental antigens. To avoid rejection of the semi-allogenic concepts, the maternal immune response is suppressed during normal pregnancy [43]. The mechanism by which habitual abortion is linked to allo-immunity is not clear. Lim et al. [43] have postulated three mechanisms by which allo-immunity could be responsible for habitual abortion: human leukocyte antigen (HLA) sharing, a deficiency of blocking antibodies, and a mechanism involving immune mediators and suppresser cells. If the problem arises from HLA-sharing, maternal recognition of the fetus is impaired because they share some polymorphic genes. Such a fetus is therefore unable to induce maternal blocking antibodies and will subsequently be aborted [44]. Some studies, although not the majority, have confirmed the hypothesis of increased HLA-sharing among women with habitual abortion [8]. It has been suggested that
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the production of blocking antibodies by the mother is necessary to prevent pregnancy wastage [45]. More recent studies indicate that these antibodies have no predictive value with respect to pregnancy outcome [8]. In recent years, attention has focused on an immune mediator and suppressor cell mechanism. Increased cytotoxic activity arising from activation of natural killer cells, leukocytes, lymphocytes, and macrophages has been found in women with habitual abortion [46]. Macrophages are capable of producing cytokines of the T-helper 1 (Th1) type: interleukin-2 (IL-2), tumour necrosis factor-␣, and interferon-␥. These cytokines are produced in increased amounts at the materno–fetal interface. They are considered deleterious to the pregnancy by direct embryotoxic activity or by damaging the placental trophoblast. Conversely, high concentrations of the anti-inflammatory cytokines IL-4, -6, -10, and -13 (Th2 type) are beneficial to the developing embryo by enhancing placental growth and function [47]. On the basis of these hypotheses, various immunomodulatory therapies could be employed to inhibit natural killer cell cytotoxicity, enhance the formation of blocking antibodies, or promote a Th1–2 cytokine shifting. Such therapies include allogenic lymphocyte immunotherapy and intravenous immunoglobulin (IVIG). The efficacy of both treatments in
the prevention of habitual abortion of the euploid embryo is, however, controversial. This may be related to a number of scientific problems, for example different treatment methodologies, patient selection, and small-size studies that result in an underestimation of the actual results in the general population, with high false-positive and false-negative rates. Two multi-centre meta-analyses [48,49] have investigated women receiving lymphocyte immunotherapy; the first showed a 10% absolute improvement in take-home baby rate, while the second showed no statistically significant improvement. This type of treatment should be balanced against the potential risks of transfusion, mainly those of allergy and viral infection [4]. IVIG seems to be more advantageous because it is well tolerated and the potential risks associated with lymphocyte immunotherapy are rare. In a meta-analysis of three placebo-controlled trials of IVIG in the treatment of habitual abortion, a significant improvement in pregnancy outcome was reported for the treated group compared to controls receiving placebo [8]. The natural immunosuppressive effect of progesterone has recently been studied. In vitro studies have shown that progesterone specifically blocks Th1 immunity to the trophoblast, which has a deleterious effect on the developing embryo [50].
Table 1 Clinical causes and diagnosis of habitual abortion Cause
Diagnosis
Method
Uterine anomalies
Hysterosalpingography Hysteroscopy Laparoscopy Ultrasonography
Infection
Endocervical and posteriro vaginal formix swabs Anti-chlamydial antibody titer
Gram or papanicolaou staining Microimmunofluorescence
Genetic
Parental karyotype Fetal karyotype Quantitative X-chromosome inactivation
Cytogentic analysis Cytogenetic analysis Polymerase chain reaction
Thrombophilia
Protein C measurement Protein S measurement Anti-thrombin III measurement Genetic analysis for molecular mutations
Clotting assay Clotting assay Amidolytic assay Polymerase chain reaction amplification
Endocrine
Endometrial biopsy Luteal phase progesterone level Luteining hormone, follicle-stimulating hormone, prolactin, and androgen levels Thyroid-stimulating hormone Hemoblobin A1c level, fasting glucose concentration, glucose tolerance test
Timed by urinary luteinizaing hormone peak Radio-immunoassay Radio-immunoassay Automated flurimetric enzyme immunoassay Immunofluorometric assay
Metabolic
Serum homocystine Small bowel biopsy Antibodies to gluten
Fluorescence polarization immuno-assay
Immunologic
Anti-cardiolipin antibodies (IgG, IgM, IgA) Lupus anticoagulant Cytokine levels Humant leukocyte antigen typing
ELISA APTT, KCT, dRVVT ELISA DNA techniques
Environmental Unexplained
History All investigations
Exclusion of other causes
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9. Environmental causes The lifestyle of pregnant women appears to affect the rate of habitual abortion as smoking, alcohol, and heavy coffee consumption can adversely affect fetal development. The risk for recurrent abortion increases linearly with the number of cigarettes smoked and number of drinks, of either alcohol or coffee, taken; education and an avoidance of these substances will decrease this risk [9].
10. Unexplained factors Despite through investigations according to various clinical protocols, the underlying cause of habitual abortion remains unexplained in about half of all cases. In this category, psychotherapy rather empiric treatment is needed. A ‘tender loving care’ type of psychotherapy in a present or a subsequent pregnancy appears improve pregnancy outcome significantly [1]. Causes of and various investigations for recurrent miscarriage are summarized in Table 1.
11. Practice points • The etiology of habitual abortion remains unexplained in about 50% of cases. • Cervical incompetence and hormonal abnormalities are overdiagnosed as causes of habitual abortion because of the different methodologies employed. • Large randomized controlled studies and international investigations are needed to determine the role of chlamydial infection and bacterial vaginosis in habitual abortion. • In diabetes and thyroid disease, auto-immunity related to the underlying disease, rather than organ dysfunction, may be responsible for recurrent abortion. • In recurrent first- and second-trimester abortions of euploid fetuses, searching for acquired or hereditary thrombophilia is recommended. • The importance of auto-immunity in the etiology of habitual abortion is increasing, and the role of progesterone as natural immunossuppressant needed to be investigated in a randomized controlled trials.
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