Recurrent miscarriage

[Dr.Vad]

Уважаемые коллеги,

В виду определенного профессионального интереса к обследованиям при планировании беременности а так же собственного по вопросам тромбофилии и невынашивания хочется запостить недавний Ланцетовский семинар о проблемах диагностики и лечения привычного невынашивания (ПДФ файл могу переслать любому на мыло, так как здесь только текстовый фрагмент без ссылок и рисунков):

Seminar

Recurrent miscarriage

Raj Rai MD and Prof Lesley Regan MD,

Department of Obstetrics and Gynaecology, St Mary's Campus, Imperial College London, Mint Wing, South Wharf Road, London W2 1PG, UK


Available online 10 August 2006


Causes of recurrent miscarriage
Historically, recurrent miscarriage has been attributed to either genetic, structural, infective, endocrine, immune, or unexplained causes. Thrombophilic disorders are now thought to play a part in the cause of recurrent pregnancy loss, which widens the scope of investigations and management options for recurrent miscarriage.

Genetic abnormalities
Fetal aneuploidy is the most important cause of miscarriage before ten weeks' gestation.31 At least 50–60% of all miscarriages are associated with cytogenetic abnormalities, the most frequent being trisomy, followed by polyploidy and monosomy X.4, 5, 32 and 33 Most human aneuploidies arise from errors in the first meiotic division of the oocyte, which is initiated prenatally and is not complete until ovulation. An increased rate of sperm chromosome abnormalities has also been reported in couples with recurrent miscarriage,34 but only 7% of fetal trisomies have been shown to arise from paternal meiotic errors.35 Despite the recognised association between advancing maternal age and fetal aneuploidy, little is known about the underlying mechanisms. One hypothesis is that women have a limited oocyte pool, and that increasing age results in a relative scarcity of oocytes at optimum stages of maturation.36 Thus women who have lost at least one trisomic fetus have been reported to have a diminished ovarian reserve and to enter the menopause at an earlier age than those with no such history.37 and 38 Some women with recurrent miscarriage might be more prone to heterotrisomy—ie, recurrence of a different trisomy after a trisomic pregnancy.39 One screening study of couples with recurrent miscarriage undergoing in-vitro fertilisation showed that they had more abnormal embryos than an age-matched control group with no history of recurrent miscarriage.40

In about 4% of couples with recurrent miscarriage one partner carries either a balanced reciprocal translocation, in which there is an exchange of two terminal segments from different chromosomes, or a Robertsonian translocation, in which there is centric fusion of two acrocentric chromosomes.16 Carriers of a balanced reciprocal translocation are phenotypically normal, but 50–70% of their gametes and hence embryos are unbalanced, because of abnormal segregation at meiosis. The reproductive risk conferred by chromosome rearrangements is dependent on the type of rearrangement and whether it is carried by the woman or her male partner.41 The livebirth rate in couples with a structural chromosome abnormality who conceive spontaneously is higher (50–65%)42 than that currently achieved after in-vitro fertilisation and preimplantation genetic screening, which is 29% per oocyte retrieval and 38% per embryo transfer.43

Structural abnormalities
Transcervical embryoscopy has shown that aneuploid embryos have disordered growth and development (such as anencephaly and facial and limb dysplasia), and that similar abnormalities are found in up to 18% of euploid pregnancies ending in miscarriage.44

The frequency of congenital uterine abnormalities (uterine septae and bicornuate uterus) in the general population is unknown, but in women with recurrent miscarriage it has been reported to be between 1·8% and 37·6%.45, 46 and 47 This wide range reflects differences in diagnostic criteria and the imaging techniques used. A retrospective review of patients with uncorrected abnormalities suggests that they undergo high rates of miscarriage and preterm delivery.45 However, the benefits of surgical correction (open or hysteroscopic) on pregnancy outcome have not yet been assessed by a randomised trial.

Uterine fibroids are present in up to 30% of women, but their effect on reproductive outcome is controversial.48 Most studies report that implantation failure after in-vitro fertilisation is linked to either intramural or submucosal fibroids, but this finding could indicate publication bias. The mechanism or mechanisms by which fibroids could cause early pregnancy loss are unclear. Traditionally, researchers have postulated that uterine fibroids have a mechanical or space-occupying effect that impedes embryonic implantation. The expression of HOX10, a gene that controls differentiation and is involved in implantation, has now been shown to be lower in uteri with fibroids than in those without.49

A diagnosis of cervical incompetence, based on a history of late miscarriage preceded by spontaneous rupture of membranes or painless cervical dilatation, is frequently cited as a cause of midtrimester recurrent miscarriage.16 and 50 However, no objective tests can reliably identify women with cervical weakness in the non-pregnant state. A Cochrane review identified no conclusive evidence that prophylactic cervical cerclage reduces the risk of recurrent midtrimester miscarriage.51 Therefore, the value of serial ultrasound assessments of cervical shortening and the insertion of a rescue cerclage for prevention of late miscarriage and preterm delivery are questionable.52 and 53 In our experience, the success of cerclage is determined by detailed clinical history, treatment of coexistent thrombophilic disorders and prophylactic antibiotics. More important is the skill and experience of the surgeon, and their ability to bury the suture material under the vaginal mucosa to keep vaginal discharge to a minimum.54 Abdominal cerclage has been advocated for selected women with previous failed vaginal cerclage. However, a systematic review comparing the two techniques concluded that although abdominal cerclage might reduce perinatal death, it is associated with a higher risk of serious operative complications.55

Infection
Infective causes of recurrent miscarriage remain speculative. For any infective agent to be implicated, it must be capable of persisting in the genital tract undetected and must cause few maternal symptoms. Because toxoplasmosis, rubella, cytomegalovirus, herpes, and listeria infections do not meet these criteria, routine screening for these diseases has now been abandoned.56 The evidence for bacterial vaginosis as a cause of early miscarriage secondary to endometritis is inconsistent,57 and 58 but the presence of bacterial vaginosis during the first trimester of pregnancy has been repeatedly reported as a risk factor for late miscarriage and early preterm birth.59 One randomised controlled trial in a low-risk obstetric population showed that the risk of late miscarriage and preterm birth is reduced by screening women for bacterial vaginosis in early pregnancy and treating with oral clindamycin.60 However, investigators in no less than eight randomised trials concluded that there is no benefit in screening and treating all pregnant women for bacterial vaginosis to prevent preterm birth. By contrast, the Cochrane review suggested that detection and treatment of bacterial vaginosis early in pregnancy might prevent preterm delivery in women with a history of preterm birth.61

[Dr.Vad]

Endocrine abnormalities
Endocrine disturbances have been postulated to cause recurrent miscarriage, but few reports withstand scrutiny. Well controlled diabetes is not a risk factor for recurrent miscarriage.62 and 63 A meta-analysis reported an association between the presence of thyroid autoantibodies, a history of one or two miscarriages, and the outcome of the next pregnancy.64 However, no association is found if analysis is restricted to those with recurrent miscarriage.64 and 65

Prolactin has a role in both ovulation and endometrial maturation. Hyperprolactinaemia is reported to cause recurrent miscarriage, and treatment with bromocriptene, which suppresses prolactin secretion by the anterior pituitary, significantly reduces the rate of miscarriage.66 Lack of expression of endometrial prolactin during the luteal phase of the menstrual cycle has also been associated with recurrent miscarriage.67

Possible links between polycystic ovaries, the various endocrinopathies associated with polycystic ovarian syndrome, and recurrent miscarriage have been investigated for the past three decades. The prevalence of polycystic ovaries is significantly higher in women with recurrent miscarriage (40%) than in women with an uncomplicated reproductive history (22%).68 However, ovarian morphology per se is not predictive of the outcome of future pregnancies without treatment.68 A placebo-controlled randomised controlled trial reported that suppression of high endogenous luteinising hormone does not improve the rate of livebirths.69

Attention is now focused on the connection between polycystic ovarian syndrome, insulin resistance, and pregnancy loss. Insulin resistance is common in women with recurrent miscarriage, and has been associated with an increased rate of miscarriage.70 and 71 The mechanism might include impairment of the fibrinolytic response, which is important in the tissue remodelling that accompanies embryonic implantation.72 Plasma concentrations of fibrin are affected by the 4G/5G polymorphism in the plasminogen activator inhibitor (PAI1) gene promoter. Homozygosity for the 4G/4G polymorphism, which is associated with hypofibrinolysis, is recorded significantly more often in women with polycystic ovaries and a history of recurrent miscarriage than in women with normal ovarian morphology.73 The fact that there is an insulin response element in the promoter region of the PAI-1 gene lends support to the hypothesis that hyperinsulinaemia is associated with impairment of fibrinoylyis, which in turn is associated with miscarriage.

Immune dysfunction
From a traditional immunological perspective, survival of the semiallogenic fetus is dependent on suppression of the maternal immune response. However, although lymphocyte function changes during pregnancy, no generalised suppression of the maternal immune response has been recorded. Indeed, randomised therapeutic studies have refuted the usefulness of the concept of immunising a mother (eg, with paternal white blood cells) to prevent rejection of her genetically dissimilar fetus.74 and 75 The contemporary understanding of reproductive immunology posits a cooperative interaction between the maternal immune system and fetal antigens.76 Interest centres on the link between natural killer cells and reproductive failure. Natural killer cells are lymphocytes, and are part of the innate immune system. Peripheral blood and the uterine mucosa each contain natural killer cells, but the cells have important phenotypic and functional differences in each location.77

The temporal and spatial distribution of natural killer cells in the uterine mucosa suggests they contribute to control of trophoblast invasion. Women with recurrent miscarriage have more natural killer cells in their uterine mucosa than controls and those with the highest levels have a correspondingly high rate of miscarriage in subsequent pregnancies without treatment.78, 79 and 80 No association between the levels of natural killer cells in peripheral blood and in the uterine mucosa has been recorded, and levels of natural killer cells in peripheral blood are not predictive of pregnancy outcome in women with unexplained recurrent miscarriage. Therefore, the value of testing women with recurrent miscarriage for levels of natural killer cells in peripheral blood is therefore questionable.81

Natural killer cells in uterine mucosa contribute to the cytokine response at the maternal-fetal interface. This cytokine response is generally characterised either as a T-helper-1 (Th-1) type (with production of interleukin 2, interferon, and tumour necrosis factor α [TNFα]) or a T-helper-2 (Th-2) type (with interleukins 4, 6, and 10). Normal pregnancy might be the result of a Th-2 type cytokine response, in which blocking antibodies mask fetal trophoblast antigens from immunological recognition by a maternal Th-1 cell-mediated cytotoxic response.82 By contrast, women with recurrent miscarriage tend to produce a predominantly Th-1 type response both in the period of embryonic implantation and during pregnancy.83, 84, 85 and 86 These findings support the view that disturbances of the immune tolerance of the fetus could contribute to recurrent miscarriage. We need to investigate (1) the subgroup of women with recurrent miscarriage who produce a dominant Th-1 cytokine profile at the maternal-fetal interface during pregnancy and (2) immunomodulatory interventions designed to promote Th-2 dominance.

Some studies show high levels of various autoantibodies in women with recurrent miscarriage,87 and 88 but this association has not been conclusively proved. Prospective data on pregnancy outcomes for women with or without autoantibodies are also conflicting—but most studies suggest there is no association.65, 89, 90, 91 and 92 One placebo-controlled randomised study showed that the use of steroids to suppress autoantibody titres does not improve the livebirth rate, and moreover can increase the risk of preterm delivery.93

Antiphospholipid syndrome
Antiphospholipid syndrome is the most important treatable cause of recurrent miscarriage. Antiphospholipid antibodies are a family of about 20 antibodies that are directed against phospholipid binding plasma proteins. They include lupus anticoagulant and anticardiolipin antibodies. Antiphospholipid syndrome was originally defined as the association between antiphospholipid antibodies and either recurrent miscarriage, thrombosis, or thrombocytopenia.94 The clinical criteria now used to diagnose antiphospholipid syndrome are shown in the panel.95 The prevalence of antiphospholipid syndrome in women with recurrent miscarriage is 15%;96 and 97 women with the syndrome have a miscarriage rate of 90% in subsequent untreated pregnancies.98 Various treatments—including aspirin, steroids, intravenous immunoglobulin and heparin—have been used in attempts to improve the pregnancy outcome of women with antiphospholipid syndrome. However, a meta-analysis shows that only a combination of heparin and aspirin can significantly improve the livebirth rate in women with recurrent miscarriage and antiphospholipid syndrome (figure 4).99 This treatment enhances pregnancy outcome by 54%, to achieve a livebirth rate of over 70% in women with the syndrome.100 and 101 Although one trial did not show a benefit in adding heparin to aspirin,102 it included several women with low positive titres for anticardiolipin antibodies, who were randomly assigned to treatment at a late stage when pregnancy outcome was more likely to be successful. Furthermore, nearly 25% of participants in this study switched treatment groups. Traditionally, pregnancy loss associated with antiphospholipid antibodies has been ascribed to thrombosis and infarction of the uteroplacental vasculature.103, 104 and 105 However these findings are neither universal nor specific to antiphospholipid syndrome,106 and 107 and have been challenged by advances in our understanding of early pregnancy development and the biology of antiphospholipid antibodies. In-vitro studies show that antiphospholipid antibodies interfere with the signal transduction mechanisms controlling endometrial cell decidualisation;108 promote trophoblast apoptosis;109 decrease trophoblast fusion;109, 110, 111 and 112 and impair trophoblast invasion.107 and 113 The effects of antiphospholipid antibodies on trophoblast function are reversed in vitro by low-molecular-weight heparin.109, 113, 114, 115 and 116



Panel. Criteria for diagnosis of antiphospholipid syndrome95


• Three or more consecutive unexplained miscarriages before 10th week of gestation

• One or more unexplained deaths of a morphologically normal fetus at 10 weeks' gestation or older

• One or more premature births of a morphologically normal fetus at 34 weeks' gestation or younger associated with severe pre-eclampsia or placental insufficiency

[Dr.Vad]

Thrombophilic disorders
Pregnancy is a hypercoaguable state.117 and 118 The evolutionary advantage of such a change in haemostasis is to counteract the inherent instability associated with haemochorial placentation, which is unique to human beings. The first studies of the prevalence of coagulation abnormalities in women with a history of adverse pregnancy outcome appeared in the mid-1990s.119 and 120 Three common thrombophilic mutations were identified: Factor V (Leiden) G1691A; factor II (prothrombin) G20210A and methylene tetrahydrofolate reductase C677T. Since then, many publications have reported that individual coagulation defects are either as frequent or more frequent in women with recurrent miscarriage than they are in controls.

Data on the frequency of genetic thrombophilia are compromised by the small size of individual studies, stratification bias and poor matching of cases and controls due to racial heterogeneity. Nonetheless, two meta-analyses have confirmed an association between recurrent miscarriage and gene mutations in Factor V Leiden and prothrombin.121 and 122 There are few prospective data on the outcome of untreated pregnancies in women with genetic thrombophilic defects. The largest published study of 19 women with unexplained first trimester recurrent miscarriage, who were heterozygous for the Factor V Leiden mutation, showed that they had a significantly lower rate of livebirth (37·5%) than a control group of 100 women with recurrent miscarriage, who had the normal Factor V genotype (69·5%; odds ratio 3·75, 95% CI 1·3–10·9).123 However, women with the Factor V Leiden mutation were not precluded from having an uncomplicated full-term pregnancy. Additional comorbid disorders probably differentiate between these outcomes, and multiple risk factors increase the likelihood of adverse pregnancy outcomes in carriers of weakly prothrombotic genotypes.124 Indeed one European cohort study identified a 14-fold increased risk of stillbirth in patients with combined thrombophilic defects.119

Since individual genetic thrombophilic defects have little value in predicting pregnancy outcome, so-called global markers of haemostatic function are used to assess women with recurrent miscarriage. These tests have shown that women with recurrent miscarriage are in a prothrombotic state outside of pregnancy.125, 126, 127 and 128 Research suggests that the prothrombotic state not only results in an exaggerated haemostatic response during pregnancy, leading to thrombosis of the uteroplacental vasculature and subsequent fetal loss,119, 129 and 130 but also confers a risk of ischaemic heart disease in later life.131

In-vitro studies in mice suggest that thrombosis is not the only mechanism for reproductive failure in women with thrombophilic defects. Murine trophoblast cells express many glycoproteins that promote (tissue factor) and inhibit (thrombomodulin) coagulation. Isermann and colleagues132 reported that fetal loss in thrombomodulin-deficient embryos is caused by tissue-factor-initiated activation of the blood coagulation cascade at the fetomaternal interface. The blood coagulation cascade leads to excess generation of thrombin, which then (a) signals through protease-activated receptors to promote trophoblast apoptosis and (b) stimulates production of fibrinogen split products which also accelerate apoptosis of the trophoblast.132

In about two-thirds of first trimester miscarriages there is histological evidence of premature onset of maternal blood flow into the intervillous space throughout the placenta.133 and 134 This blood flow leads to a state of oxidative stress which is associated with trophoblast apoptosis. This finding is independent of the fetal karyotype.135, 136 and 137 Some cases of recurrent miscarriage are associated with deficiencies in either glucose-6-phosphate dehydrogenase or nitric oxide synthase, which are enzymes involved in the metabolism of reactive oxygen species.138, 139 and 140

Management options and therapeutic intervention
The treatment of couples with recurrent miscarriage has traditionally been based on anecdotal evidence, personal bias, and the results of small uncontrolled studies.141 As our knowledge of early pregnancy development increases, it is incumbent on us to embrace evidence-based practice. Data on which to base such practice is being generated by newly established clinics, dedicated to recurrent miscarriage, which are able to recruit patients to clinical trials of sufficient power to establish how well a treatment works in a trial setting. These clinics aim to identify an underlying cause of recurrent miscarriage, to conduct prospective randomised controlled trials of sufficient power to determine the best possible treatment regimens, and to avoid use of treatments with no proven benefit. Our investigative protocol for assessing couples with recurrent miscarriage is shown in table 3 (RM). When assessing the effectiveness of any intervention, it is important to recognise that at least 35% of couples with a history of three consecutive miscarriages have lost pregnancies purely by chance alone, secondary to sporadic fetal aneuploidy. Such couples have a 75% chance of a successful pregnancy next time with no therapeutic intervention (table 4).

Psychological factors
Miscarriage can induce pronounced emotional responses, such as anxiety, depression, denial, anger, marital disruption, and a sense of loss and inadequacy. Various psychosocial factors influence the immune system, and it has been proposed that a so-called psychoneuroendocrine network is involved in miscarriage.142 Certainly, stress induces miscarriage in mice,143 and raised levels of CD8+ T cells, TNFα and tryptase-positive mast cells have been reported in the endometriums of women with sporadic miscarriage and a high stress score.139 Moreover, a significant association between baseline depressive symptoms and subsequent miscarriage has been identified.144 and 145 Several non-randomised studies have reported that psychological support in early pregnancy decreases the miscarriage rate in women with so-called unexplained miscarriage.146, 147 and 148

Progesterone
Progesterone is secreted mainly by the corpus luteum, which is formed in the ovary after rupture of an ovarian follicle at the time of ovulation. Because progesterone induces secretory changes in the endometrium which are essential for implantation of the embryo, it has been suggested that some cases of miscarriage might be due to inadequate secretion of progesterone, either in the postovulatory phase of the menstrual cycle or in early pregnancy. Hence progestational agents have been used, beginning in the early first trimester of pregnancy, in an attempt to prevent miscarriage. Two meta-analyses of the use of progesterone showed that it did not reduce the miscarriage rate for women with sporadic miscarriage.149 and 150 However, a subgroup analysis of women with recurrent miscarriage suggests that progesterone use in the first trimester might be of benefit.150 and 151 This could be explained by progesterone's immunomodulatory actions in shifting the proinflammatory Th-1 cytokine response to a more favourable Th-2 response.152

[Dr.Vad]

Metformin
Insulin-sensitising agents, such as metformin, have been reported to reduce hyperinsulinaemia, reverse the endocrinopathy of polycystic ovarian syndrome, and normalise endocrine, metabolic, and reproductive function. Small retrospective studies show that use of metformin during pregnancy is associated with a reduction in the miscarriage rate in women with polycystic ovarian syndrome.153 and 154 However, the effect of metformin remains to be tested in a large, prospective, placebo-controlled study of a well defined cohort of women with recurrent miscarriage.

Aspirin
Aspirin offers a thromboprophylactic effect by inhibiting platelet aggregation. But two studies have reported that aspirin does not improve the livebirth rate in women with unexplained recurrent miscarriage.155 and 156 Although the use of aspirin and other non-steroidal anti-inflammatory agents prior to conception has been associated with a high miscarriage rate,26 and 157 these studies were methodologically weak—one investigated fewer than 20 pregnancies.153 Both a case-controlled study158 and a meta-analysis159 have reported a two-fold to three-fold increased risk of fetal gastroschisis in mothers taking aspirin during the first trimester of pregnancy, further emphasising the dangers of empirical therapy for women with recurrent miscarriage. Aspirin has not yet been demonstrated to be beneficial for women in whom a thrombophilic defect has been identified as the cause of their pregnancy failures.

Heparin
Heparin, and the structurally related heparin sulphate, are typically classed as thromboprophylactic agents, but have other properties which act at the fetomaternal interface. Heparin can bind to antiphospholipid antibodies and can also antagonise the action of the Th-1 cytokine interferon gamma, thereby protecting the trophoblast and maternal vascular endothelium from damage in early pregnancy. Later in pregnancy, when the intervillous circulation has been established, heparin helps to ameliorate the risk of placental fibrin deposition, thrombosis, and infarction. A prospective placebo-controlled study would be needed to establish the efficacy of heparin in the treatment of women with recurrent miscarriage of unknown cause.160

Immunomodulation
Some women with recurrent miscarriage are being given intravenous immunoglobulin, anti-TNFα drugs, and glucocorticoids to dampen a so-called excessive immune response. These interventions are not based on evidence, and furthermore could potentially cause morbidity.161 Intravenous immunoglobulin is a pooled-blood product and is associated with anaphylactic response, fever, flushing, muscle pains, nausea, and headache.162 Anti-TNFα agents have been linked with the development of lymphoma, granulomatous diseases such as tuberculosis, demyelinating disease, congestive cardiac failure, and syndromes similar to systemic lupus erythematosus.163 Although TNFα is viewed mainly as a cytokine, and as a trigger for a maternal immune response to fetal antigens, it has other roles in antiapoptotic signalling pathways and regulation of cell proliferation. Studies in TNFα knock-out mice also suggest that TNFα might affect embryo development and help to prevent structural abnormalities (which might not become apparent until later infant life).164 Glucocorticoids during pregnancy are associated with a risk of preterm delivery secondary to rupture of membranes and the development of pre-eclampsia and gestational diabetes.93

Embryo aneuploidy screening
Aneuploidy is the most common cause of miscarriage. In-vitro fertilisation allows preimplantation embryos to be screened for aneuploidy, using fluorescent in-situ hybridisation. Although the embryo aneuploidy rate is higher in women with recurrent miscarriage than in age-matched controls,40 aneuploidy screening and the replacement of chromosomally normal embryos does not improve the rate of livebirths.165 Moreover, women with recurrent miscarriage aged less than 37 years only had a 26% livebirth rate after in-vitro fertilisation and aneuploidy screening. By contrast, after spontaneous conception the livebirth rate is 75%.17, 18 and 147

Conclusion
Maternal age at conception and previous reproductive history are strong and independent risk factors for miscarriage. The chance of a successful pregancy in a woman aged 40 years or more is poor. The demonstration that some women with recurrent miscarriage are in a prothrombotic state outside of pregnancy has emphasised the role of haemostatic pathways in early pregnancy development and the value of anticoagulant treatment in the management of recurrent miscarriage. Advances in reproductive immunology, endocrinology, and genetics have enabled a more multidisciplinary approach to studying and treating couples with recurrent miscarriage. The high chance of a successful pregnancy in couples with no identifiable cause for recurrent miscarriage coupled with the paucity of data from randomised trials mean that clinicians should resist the use of empirical treatments which might deliver no benefit or might even cause harm. Instead, patients with recurrent miscarriage should be recruited to adequately powered placebo-controlled studies, especially as the value of psychological support in improving pregnancy outcome has been shown in several studies.

[Svetlana18]

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