Fig. 7.1
Implantation spectrum
Pregnancy itself is a prothrombotic state – characterized by an increase in the levels of pro-coagulant factors, a simultaneous decrease in the levels of anticoagulant proteins, and activation of fibrinolysis [4–6]. The evolutionary advantage of this is thought to counteract the inherent instability of hemochorial placentation. Over the last 20 years, the hypothesis has been developed that many cases of recurrent miscarriage are due to an abnormal or exaggerated hemostatic response in pregnancy [7]. This hypothesis is supported by data reporting increased markers of thrombin generation among women with recurrent miscarriage outside of pregnancy [7, 8], an increased prevalence of coagulation defects among women with recurrent miscarriage [9–11], and histological evidence of placental thrombosis in some cases of recurrent miscarriage [12, 13].
Remarkably few studies have reported the placental histological findings among the pregnancies of women with recurrent miscarriage. Nayar and Lage [14] were the first to reported massive infarction in the first-trimester placenta from a pregnancy of a woman with antiphospholipid antibodies (aPL) and recurrent miscarriage. Our own unit reported a significantly increased prevalence of placental infarction among the pregnancies of women with recurrent miscarriage (10 %), irrespective of the presence of aPL, versus 1 % using the same criteria to assess infarction, among those with a previously uncomplicated reproductive history [12].
This chapter examines the role of thrombophilic defects – both heritable and acquired – in the pathogenesis of recurrent miscarriage.
7.2 Antiphospholipid Syndrome
7.2.1 Introduction
Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent miscarriage. Antiphospholipid antibodies are also associated with adverse pregnancy outcome at later gestational ages including preeclampsia and preterm delivery (Box 7.1). In relation to adverse pregnancy outcome, lupus anticoagulant and anticardiolipin antibodies (aCL; both IgG and IgM) together with anti-beta 2 glycoprotein I (aβ2GPI) antibodies appear to be the most important members of the family of aPL. In accordance with the revised Sapporo (Sydney) International consensus criteria [15], a diagnosis of obstetric antiphospholipid syndrome demands the presence of one of the defining criteria listed in Box 7.1 together with persistently positive tests for one or more of lupus anticoagulant, aCL and aβ2GPI.
Box 7.1: Pregnancy Morbidity Associated with Antiphospholipid Syndrome
One or more unexplained deaths of a morphologically healthy fetus at or beyond the 10th week of gestation, with healthy fetal morphology documented by ultrasound or by direct examination of the fetus
One or more premature births of a morphologically healthy newborn baby before the 34th week of gestation because of eclampsia or severe preeclampsia defined according to standard definitions or recognized features of placental failure
Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomical or hormonal abnormalities and paternal and maternal chromosomal causes excluded
7.2.2 Prevalence
Approximately 15 % of women with recurrent miscarriage have obstetric APS [10, 16]. In contrast, the prevalence of aPL in women with a “low-risk” obstetric history is less than 2 % [17, 18]. The largest prevalence study (500 consecutive women with recurrent miscarriage attending a specialist recurrent miscarriage clinic) reported the prevalence of persistently positive tests for lupus anticoagulant to be 9.6 %, IgG aCL 3.3 %, and IgM aCL 2.2 %. Importantly, among the miscarriage population there appears to be little crossover between lupus anticoagulant and aCL positivity and a large number of women have only transiently positive tests (66 % lupus anticoagulant and 37 % for either IgG or IgM aCL).
7.2.3 Outcome of Untreated Pregnancies
The outcome of pregnancy in untreated women with aPL and a history of recurrent miscarriage is poor. The earliest studies reported that the fetal loss rate in women with APS was in the range of 50–70 % [17, 19]. It was subsequently realized that these figures underestimated the scale of the problem because recruitment only took place after these women had presented for antenatal care (at approximately 12 weeks) by which time the majority of miscarriages have already occurred. A prospective observational study in which women with APS were identified prior to pregnancy and followed from the time of a positive pregnancy test reported the miscarriage rate to be 90 % with no pharmacological treatment [10, 16]. In contrast, the miscarriage rate among a control group of aPL-negative women with recurrent miscarriage was significantly lower – in the region of 40 %. In untreated pregnancies, women with APS are also at significant increased risk for later pregnancy complications. In a population-based analysis of 141,286 deliveries in Florida, USA, positivity for aPL increased the risk for both preeclampsia and placental insufficiency (adjusted odds ratio 2.93 [95 % CI 1.51–5.61] and 4.58 [2.0–10.5]), respectively [20].
7.2.4 Mechanisms of aPL Pregnancy Loss
Pregnancy loss associated with aPL has traditionally been attributed to thrombosis of the placental vasculature [21–23]. However, thrombosis is neither a universal nor a specific feature in antiphospholipid-associated miscarriages [23]. Advances in our understanding of early pregnancy development and phospholipid biology have highlighted alternative mechanisms of action of these antibodies in the pathogenesis of pregnancy loss.
In vitro studies demonstrate that aPL have a direct deleterious effect on implantation by affecting both the function of the uterine decidua and of the trophoblast. Antiphospholipid antibodies (a) impair signal transduction mechanisms controlling endometrial cell decidualization and impair endometrial angio-genesis [24, 25], (b) increase trophoblast apoptosis [26], and (c) decrease trophoblast fusion and impair trophoblast invasion [26, 27]. Interestingly, the effects of aPL on trophoblast function are reversed, at least in vitro, by low molecular weight heparin (LMWH) [26–28].
More recently, attention has focused on the role of complement activation in aPL related pregnancy loss. Injection of aPL into pregnant mice results in antibody and C3 deposition in the decidua, along with focal necrosis and apoptosis and neutrophil infiltration [29]. These effects are accompanied by a fourfold increase in the frequency of fetal resorption; fetal loss can be reversed by simultaneous treatment with soluble recombinant complement receptor 1-related gene/protein y (Crry), which also prevents C3 deposition and neutrophil infiltration. Finally, a causative role for complement activation was shown conclusively by injecting aPL antibodies into C3-deficient mice, which became resistant to aPL antibody-mediated fetal loss. To reevaluate the link between aPL and thrombosis, the authors showed that aPL induce thrombus formation following local vascular injury and that soluble Crry significantly decreases the size of the thrombi. Thus, complement activation is likely to be an important upstream mediator in both aPL IgG-induced vascular thrombosis and fetal loss.
7.2.5 Management of Recurrent Miscarriage Associated with aPL
The management of women with APS depends on comprehensive investigation prior to pregnancy, definition of the management plan and counseling regarding (a) the live birth rate with treatment; (b) treatment not preventing the loss of a genetically abnormal pregnancy; (c) the increased risk of later pregnancy complications such as preeclampsia and placental insufficiency necessitating preterm delivery; (d) risks of an APS-related complications in the neonate; and (e) increased risk to the mother herself during pregnancy and postpartum and the need for thromboprophylaxis.
7.2.5.1 Treatment of Obstetric Antiphospholipid Syndrome
Over the last 25 years, a variety of pharmaceutical agents have been used, either individually or in combination, in attempts to improve the pregnancy outcome of women with obstetric APS. Low-dose aspirin (LDA) in combination with heparin remains the mainstay of treatment, as confirmed in two meta-analyses [25, 30]. This treatment combination leads to a live birth rate of over 70 % [31, 32].
Two prospective randomized controlled trials [31, 32] and one where women were alternately assigned to treatment have reported that LDA and unfractionated heparin (UFH) improve the live birth rate in women with APS when compared to aspirin alone [33]. In the trial reported by Rai et al. [34], 90 women were randomized at the time of a positive urinary pregnancy test to receive either LDA or LDA and heparin daily until the time of miscarriage or 34 weeks gestation. The live birth rate with LDA and heparin was 71 % compared to 42 % with LDA alone (OR 3.37, 95 % CI 1.40–8.10). Importantly, there was no difference in live birth rates between the two treatment groups in those pregnancies that advanced beyond 13 weeks. This implies that the beneficial effect of adjuvant heparin therapy is conferred in the first trimester of pregnancy, at a time when the intervillous circulation has not been fully established and hence cannot be due to the anticoagulant actions of heparin. It appears that the combination of LDA and heparin promotes successful embryonic implantation in the early stages of pregnancy by protecting the trophoblast from attack by aPL. Later in pregnancy, the combination therapy helps protect against subsequent thrombosis of the uteroplacental vasculature.
Treatment with LDA and heparin significantly reduces the severity of the defective endovascular trophoblastic invasion in women with APS, allowing them to achieve a live birth. However, it is important to remember that a proportion of pregnant women with aPL will remain at risk for late pregnancy complications due to the underlying uteroplacental vasculopathy. In a prospective series of 150 treated women with APS, a high risk for preterm delivery, placental abruption, fetal growth restriction, and the development of pregnancy-induced hypertension was found [35]. Once the pregnancy advances beyond the first trimester, specialist antenatal surveillance is required. Uterine artery Doppler ultrasonography at 22–24 weeks, followed by serial fetal growth and Doppler scans during the third trimester are useful tools with which to predict preeclampsia and intrauterine growth restriction in APS pregnancies [36]. Women with a circulating lupus anticoagulant or high positive IgG aCL or aβ2GPI antibodies are at particularly high risk of these complications.
Two studies have challenged the view that LDA and heparin is the treatment of choice for pregnant women with APS. Farquharson et al. [37] reported that LDA alone is as effective as LMWH, but they included women with low positive aCL, who were randomly assigned to treatment at a late stage in the first trimester, when pregnancy outcome was more likely to be successful. In addition, nearly 25 % of the study participants switched treatment groups. The more recent study by Laskin et al. [38] aimed to investigate whether treatment with LMWH plus LDA results in an increased rate of live births compared to treatment with LDA alone, but the study group was highly heterogeneous. The authors included women with two or more unexplained pregnancy losses prior to 32 weeks of gestation, accompanied by one or more of the following: positive aPL, positive antinuclear antibodies (ANA), or an inherited thrombophilic defect. A total of 88 women were recruited to the study over a 4-year period, but the RCT was then stopped prematurely when an interim analysis showed no difference in live birth rates in the two groups and a lower rate of pregnancy loss in the aspirin group than expected.
A meta-analysis of data from five trials involving 334 patients with recurrent miscarriage [39], showed that the overall live birth rates were 74.3 and 55.9 % in women who received a combination of UFH/LMWH plus LDA versus that in those treated with LDA alone. Patients who received combination treatment had significantly higher live birth rates (RR 1.301; 95 % CI 1.040, 1.629) than with aspirin alone. No significant differences in pre-eclampsia, preterm labor and birth weight were found between two groups.
The relative effectiveness of UFH versus LMWH as regards the prevention of recurrent pregnancy loss in women with APS is not established. The results of two pilot studies suggest that the combination of LMWH and LDA might be equivalent to UFH and LDA in preventing recurrent pregnancy loss [40, 41]. The American College of Chest Physicians (ACCP) recommends prophylactic or intermediate dose UFH or prophylactic dose LMWH in combination with LDA for the treatment of obstetric APS associated with a history of recurrent miscarriages [42]. The British Committee for Standards in Haematology (BCSH) guidance is that women who fulfill the International consensus criteria for obstetric APS should be screened for aPL, and in women with obstetric APS, antenatal administration of heparin combined with low dose aspirin (LDA) is recommended throughout pregnancy, in general starting as soon as pregnancy is confirmed and continuing until 6 weeks post-partum [43].
While treatment with LDA and heparin leads to a high live birth rate, some women do experience further miscarriages despite treatment. The single most important investigation to perform if a woman miscarries while taking treatment is to obtain fetal tissue for karyotype analysis. If the fetal karyotype is abnormal, pregnancy loss was not a failure of treatment and the woman can be offered treatment with LDA and heparin again in a future pregnancy. However, if the fetal karyotype was normal, one has to assume that pregnancy loss was a failure of treatment. This situation, although uncommon, has led to the use of other adjuvant therapies including intravenous immunoglobulin (IVIg). There is however considerable evidence that IVIg is of no benefit in the treatment of obstetric APS and its use is not to be recommended [44, 45]. Potential novel therapeutic agents that may be of benefit include complement inhibitors and hydroxychloroquine. With respect to the latter, it has recently been reported that hydroxychloroquine protects the anticoagulant annexin A5 shield that surrounds the trophoblast from damage induced by antiphospholipid antibodies [46]. Bramham et al. suggest that the addition of first trimester low-dose prednisolone to conventional treatment may be useful in the management of refractory aPL-related loss(es), although complications remain increased [47].
Non-criteria Obstetric Antiphospholipid Syndrome
The international consensus (revised Sapporo) criteria for obstetric APS [15] do not include low positive aCL and aβ2GPI (i.e. <99th centile) and/or certain clinical criteria such as two unexplained miscarriages, three non-consecutive miscarriages, late preeclampsia, placental abruption, late premature birth, or two or more unexplained in vitro fertilisation failures. Prospective [48] and retrospective [49–51] cohort studies of women with pregnancy morbidity, particularly recurrent pregnancy loss, suggest that elimination of aCL and/or IgM aβ2GPI, or low positive aCL or aβ2GPI from APS laboratory diagnostic criteria may result in missing the diagnosis in a sizeable number of women who could be regarded to have obstetric APS. Such studies also suggest that women with non-criteria, clinical and/or laboratory, obstetric APS (‘obstetric morbidity associated with APS (OMAPS)’) may benefit from standard treatment for obstetric APS with LMWH plus LDA, with good pregnancy outcomes. Thus, non-criteria manifestations of obstetric APS may be clinically relevant, and merit investigation of therapeutic approaches [52].
7.2.5.2 Neonatal Complications
Babies born to mothers with APS are at risk of the consequences of pre-term delivery. A Pan-European study reported that among 138 pregnancies, 16.3 % of babies were delivered at less than 37 weeks of gestation, 17 % were low birth weight, and, in addition, 11.3 % of neonates were small for gestational age. During the follow-up period of 6 years, 5 of the 141 babies exhibited behavioral abnormalities [53]. Almost 30 % of babies will passively acquire aPL [54]. There have been individual case reports of neonatal stroke – both hemorrhagic secondary to thrombocytopenia, and thrombotic – as well as thrombosis of the renal and axillary veins.
7.2.6 Heritable Thrombophilias
The relationship between heritable thrombophilias and recurrent first-trimester miscarriage is controversial. Indeed, many studies have been of a small size, prone to stratification and admixture bias, in which there has been poor matching of cases and controls as a result of racial heterogeneity. In addition, publication bias is evident, as judged by the discrepancy between the number of published abstracts reporting a lack of association between congenital thrombophilia and the number of peer-reviewed papers reporting an association.
A meta-analysis of pooled data from 31 retrospective studies suggested that the magnitude of the association between inherited thrombophilias and fetal loss varies according to type of fetal loss and type of thrombophilia [55]. The association between thrombophilia and late pregnancy loss has been consistently stronger than for early pregnancy loss. In this meta-analysis, factor V Leiden was associated with recurrent first-trimester fetal loss (OR 2.01, 95 % CI 1.13–3.58), recurrent fetal loss after 22 weeks (OR 7.83, 95 % CI 2.83–21.67), and nonrecurrent fetal loss after 19 weeks (OR 3.26, 95 % CI 1.82–5.83). Activated protein C resistance was associated with recurrent first-trimester fetal loss (OR 3.48, 95 % CI 1.58–7.69). The G202310A prothrombin gene mutation was associated with recurrent first-trimester fetal loss (OR 2.32, 95 % CI 1.12–4.79), recurrent fetal loss before 25 weeks (OR 2.56, 95 % CI 1.04–6.29), and late nonrecurrent fetal loss (OR 2.3, 95 % CI 1.09–4.87).
Similarly, another meta-analysis of 16 case-control studies reported that carriers of factor V Leiden or the G20210A prothrombin gene mutation have doubled the risk of experiencing recurrent miscarriage compared to women without these thrombophilic mutations [56].
Prospective data on the outcome of untreated pregnancies in women with such thrombophilias are scarce. One small study of six hereditary thrombophilias reported no adverse effects on the live birth rate of women with recurrent miscarriage [57]. In contrast, two small prospective studies reported an increased risk of miscarriage in untreated pregnancies for women with recurrent miscarriage who carry the factor V Leiden mutation compared to those with a normal factor V genotype [58, 59].
The importance of the fetal genetic thrombophilia status in governing pregnancy outcome has not been explored in large studies. Dizon-Townson et al. reported that fetal carriage of the factor V Leiden mutation is associated with a significantly increased risk of miscarriage. This area of research demands further attention [60].
While some centers advocate the use of thromboprophylactic therapy – typically LDA in combination with heparin – for those with recurrent miscarriage and hereditary thrombophilias, there is little evidence base for this. Indeed the Habenox study, a multicenter randomized study, reported no difference in live birth rates among those with an inherited thrombophilia who were treated with heparin, heparin and LDA, or LDA alone [61]. The results of this study however have to be treated with some caution as the sample population was small (26 women with thrombophilia, including 17 women with factor V Leiden and 5 with prothrombin G20210A) and the study was stopped prematurely due to slow recruitment.
The TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) compared antepartum versus no antepartum dalteparin for the prevention of placenta-mediated pregnancy complications, including sever pre-eclampsia, small-for-gestational-age infants, and placental abtuption, in pregnant women with thrombophilia. The investigators postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. There were 146 and 143 women randomized to the dalteparin and no dalteparin arms respectively, between 2000 and 2014; 16 % of the women randomized to dalteparin had three or more miscarriages at <10 weeks’ gestation, 8 % had two or more fetal losses at 10–16 weeks gestation, and 19 % had one or more fetal losses at ≥16 weeks gestation; and 14, 10 and 23 % to the no dalteparin arm respectively. Dalteparin did not reduce the incidence of the primary composite outcome in both intention-to-treat analysis and on-treatment analysis in this trial, and was associated with an increased risk of minor bleeding [62] Limitations of this study include that the trial design permitted commencement of dalteparin up to 20 weeks gestation (approximately 27 % at <8 weeks, 27 % at 12 weeks, and 9 % at 12–20 weeks), therefore potentially excluding women with thrombophilia at higher risk of miscarriage. In addition, statistical power calculations are based on an aggregate of adverse outcomes, and thus the study may be underpowered as regards the assessment of the results in women within the individual clinical groups.
7.3 Tests of Global Haemostasis and Coagulation Activation
Conventional hemostasis tests are expensive, time-consuming, and take no account of the fact that hemostasis in vivo is a dynamic process that involves the interaction of coagulation and fibrinolytic pathways together with cellular elements such as endothelial cell surfaces. Hence, the measurement of individual coagulation factors is of limited use in establishing an individual’s thrombotic risk, particularly during pregnancy. These limitations have prompted us to investigate the value of global tests of hemostasis in the investigation and treatment of women with recurrent miscarriage.
7.3.1 Thrombin-Antithrombin Complexes
We studied levels of thrombin-antithrombin (TAT) complexes, a marker of thrombin generation, in nonpregnant women with recurrent miscarriage, with and without aPL [8]. TAT concentrations were significantly raised in both aPL-positive and aPL-negative women with a history of recurrent miscarriage compared with normal controls. There was no significant difference in TAT values between aPL-positive and aPL-negative women or between women with early or late miscarriage. This study of 130 women demonstrated that even outside of pregnancy there is a cohort of women with recurrent miscarriage who have an identifiable prothrombotic state [8].
Related posts:
Systemic Thromboembolism in Pregnancy: Heritable and Acquired Thrombophilias
Inherited Bleeding Disorders in Pregnancy: Platelet Defects
Acquired Bleeding Disorders in Pregnancy: Obstetric Hemorrhage
Peri-delivery Analgesia and Anesthesia in Women with Hemostatic or Thrombotic Disorders
Inherited Bleeding Disorders in Pregnancy: von Willebrand Disease, Factor XI Deficiency, and Hemophilia A and B Carriers
Antithrombotic Therapy for Cardiac Disorders in Pregnancy
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
