Recurrent Miscarriage: Causes, Evaluation, and Treatment

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Disclosures

Medscape General Medicine. 1998;1(3) 

In This Article

Blood Coagulation Protein or Platelet Defects

The coagulation protein and platelet defects associated with fetal wastage include factor XIII[9] and factor XII[10] defects; dysfibrinogenemia[11]; antiphospholipid syndrome,[12] including both anticardiolipin antibodies (ACLA) and lupus anticoagulant (LA); plasminogen defects[13]; other fibrinolytic system defects, such as elevated plasminogen activator inhibitor type 1 (PAI-1) or low-tissue plasminogen activator (t-PA)[14,15]; congenital protein S defects; and sticky platelet syndrome.

Factor XIII defects, as well as most cases of dysfibrinogenemia or other hereditary or acquired hemorrhagic defects, lead to inadequate fibrin-induced implantation of the fertilized ovum into the decidua. However, antiphospholipid syndrome, plasminogen defects, fibrinolytic system defects, some cases of dysfibrinogenemia, and other hypercoagulable blood protein and platelet defects are associated with thrombosis of the early placental vessels, precluding viability of the implanted ovum or fetus. It may be postulated, however, that any blood protein or platelet defect associated with hypercoagulability and thrombosis could be associated with placental vascular thrombosis and recurrent fetal loss.[16]

The differential diagnosis of RFL due to blood coagulation protein or platelet defects includes the occurrence of 2 or more unexplained, spontaneous abortions (usually in the first trimester) and a high index of suspicion based on clinical judgment and awareness of the syndrome, followed by appropriate clinical and laboratory evaluation. We have previously reported our experience, including identification and management of women who have had RFL due to blood protein or platelet defects.[16]

Evaluation of Patients with RFL Suspected to Have Blood Protein or Platelet Defects

Given that about 50% to 60% of patients with recurrent miscarriages harbor a coagulation defect and that identification of the defect, followed by appropriate therapy, will lead to normal-term delivery in 98%, the cost of evaluation (about $1200) can be justified. To contain costs of evaluation, patients who are suspected of having blood protein or platelet defects should be evaluated in 2 stages. Stage I consists of a complete history and physical examination, a routine complete blood count, and a panel of those blood protein and platelet defects commonly associated with RFL. If the first panel of blood protein and platelet defect tests is normal, a second panel (stage II) should be considered, consisting of those blood protein defects thought to be more rarely associated with RFL.[16]

Based on our prevalence studies (Table I),[16] a list of stage I blood-protein and platelet-defect assays was generated. A complete outline of panel I and panel II defect assays may be found in Table II.[17] If all tests in panel I are negative, panel II assays should be considered. All abnormal hemostasis results should be repeated at least once for confirmation. Preferred methodologies for these assays are discussed elsewhere in the literature.[16]

Treatment Considerations

All patients found to have a blood-protein or platelet defect associated with recurrent fetal loss caused by hypercoagulability and thrombosis (thrombosis/vasculitis) of placental vessels are treated preconception with low-dose aspirin at 81mg/day. The aspirin is initiated immediately upon (1) diagnosis of recurrent fetal loss; (2) association with a blood protein/platelet defect related to thrombosis; and (3) desire for subsequent pregnancy. To inhibit coagulation factor Xa, which can lead to placental thrombi during pregnancy, a fixed low dose of subcutaneous porcine heparin at 5000 units every 12 hours until term is added to the daily aspirin regimen immediately postconception.[16]

To make administration more comfortable for the patient, the injection volume of heparin should be small (20,000 units/mL), with a high drug concentration. Patients must be instructed as to the proper methods for self-administration of subcutaneous heparin. Both aspirin and heparin are used to term.

Following delivery, patients harboring a defect associated with hypercoagulability and thrombosis usually require ongoing antithrombotic therapy of some type. Therapeutic options depend on the nature of the thrombotic defect and on the patient's history, if any, of thrombosis.[16] For patients placed on heparin, the plasma heparin levels are monitored by heparin anti-Xa assay.[16]

Recurrent fetal loss due to blood-protein or platelet defects may come about by 2 mechanisms: disorders associated with either a hemorrhagic tendency or a thrombotic tendency.

Hemorrhagic Defects

Recurrent fetal loss associated with hemorrhagic disorders comes about due to interference with adequate fibrin formation, thereby disrupting implantation of the fertilized ovum into the uterine lining. The hemorrhagic defects associated with recurrent fetal loss include factor XIII, factor X, factor VII, factor V, and factor II (prothrombin) deficiencies, as well as fibrinogen defects including afibrinogenemia and those dysfibrinogenemias associated with hemorrhage. All of these defects are rare; management is generally plasma-substitution therapy.

Thrombotic Defects

The thrombotic defects associated with fetal wastage are quite common and are due to thrombosis of early placental vessels (Fig. 5). Peak fetal loss occurs in the first trimester, but loss also occurs in the second and third trimesters. The thrombotic hemostasis defects associated with recurrent fetal loss include lupus anticoagulants and anticardiolipin antibodies (these 2 comprise the antiphospholipid syndromes associated with recurrent fetal loss),[18,19] factor XII deficiency, dysfibrinogenemias associated with thrombosis, protein C deficiency, antithrombin deficiency, heparin cofactor II deficiency, and fibrinolytic defects (plasminogen deficiency, tissue plasminogen activator deficiency, and elevated plasminogen activator inhibitor type 1).[14,15]

Figure 5. (click image to zoom) Multiple placental thrombi, as in this placenta from woman with antiphospholipid syndrome, is commonly associated fetal wastage.

Antiphospholipid syndrome is the most common thrombotic defect leading to RFL. A variety of treatment programs have been advocated for this syndrome. However, a difficulty in evaluating these regimens relates to the study methodologies: Some studies have primarily addressed patient populations with secondary antiphospholipid syndrome and fetal wastage (in particular those with underlying systemic lupus erythematosus or other autoimmune disorders), whereas only a few have addressed primary antiphospholipid syndrome. Primary antiphospholipid syndrome is at least 10 times more common in RFL than secondary antiphospholipid syndrome.

Fetal wastage associated with hemorrhagic disorders is likely to result from interference with adequate fibrin formation for implantation of the fertilized ovum into the uterine lining. For this reason, we choose not to treat vigorously with preconception antithrombotic therapy but rather with low-dose aspirin at 81mg/day. In contrast, Sher and colleagues[20]recently reported the successful use of preconception low-dose heparin for in vitro fertilization techniques. They continue to recommend caution, however, advocating low-dose aspirin as the preconception antithrombotic therapy of choice.

The postconception addition of fixed low-dose porcine mucosal heparin at 5000 units every 12 hours is empirical, as higher doses are associated with bleeding and a lower success rate. However, even lower doses might suffice. We do not advocate using corticosteroid therapy in patients with RFL as the result of antiphospholipid syndrome. This position is based on reports of other researchers and on our preliminary experience administering steroids in conjunction with antithrombotic agents. In patients with antiphospholipid syndrome and other types of thrombosis, corticosteroid use may lower antiphospholipid antibody titers, but they fail to stop thrombotic events.[18,19,21,22]

A variety of treatment programs have been used for women with antiphospholipid syndrome (anticardiolipin antibodies or lupus anticoagulants) and RFL; however, many of these studies have reported on only very small populations, or they have failed to distinguish between primary and secondary antiphospholipid syndrome. Brown[23] reported a 90% failure rate (miscarriage) among untreated women, Perino and colleagues [24] reported a 93% failure rate in untreated women, and Many and coworkers[25] reported a 93% failure rate in untreated patients. Lubbe and Liggins,[26] in a small group of women, noted a successful term pregnancy rate of 80% with use of prednisone and aspirin; a similar success rate with this regimen was noted by Lin.[27] Cowchock and associates[28] observed a 75% success rate with prednisone alone or aspirin alone, but they also noted more undesirable effects in the prednisone-treated population. Landy and colleagues,[29]in a small population, reported a success rate of 90% with either aspirin alone or prednisone alone. However, Many and coworkers[25] noted only a 43% successful term pregnancy rate with aspirin and prednisone. Semprini's team[30] reported only a 14% success rate with prednisone alone.

Several studies have assessed the role of the postconception addition of heparin; however, most have used higher doses than those used in our clinical practice.[16]Rosove and colleagues[31] reported a 93% success rate with dose-adjusted subcutaneous heparin, the mean heparin doses being about 25,000 units/day. Kuttah,[32] in a population of 25 patients, treated with aspirin plus dose-adjusted subcutaneous heparin, noting a success rate of 76% (mean heparin dose of 26,000 units/day). In the study by Many and colleagues,[25] patients treated with prednisone plus aspirin plus heparin at 5000 units twice a day had a better outcome (69%) than those treated with aspirin plus prednisone (43%) or prednisone alone (7%).

Based on the results of our study, it appears that fixed low-dose porcine heparin is more effective than the high-dose, dose-adjusted regimens. This was evidenced by the success rate of 100%, whereby all patients with antiphospholipid-syndrome-induced RFL had normal-term deliveries.[16] It may be that higher doses of heparin contribute to adverse outcomes, such as small periplacental hemorrhages. Parke[33]reported on the combination of low-dose heparin used in conjunction with intravenous immunoglobulin (IVIG). Her success rate for this regimen, however, was only 27%, suggesting that IVIG has little role in antiphospholipid recurrent fetal loss.

In our experience, sticky platelet syndrome (SPS) is the second most common prothrombotic defect contributing to RFL-associated blood coagulation protein/platelet defect. Other common causes include protein S deficiency, tissue plasminogen activator (TPA) deficiency, activated protein C resistance, and type 1 plasminogen activator (PAI-1) defects (Table I). Patients with SPS are treated the same as those with other prothrombotic defects, using preconception low-dose aspirin and immediate postconception addition of low-dose porcine heparin, with both agents being used to term delivery. It is unclear whether heparin is required in SPS patients; however, given the 100% success rate and lack of significant complications with this treatment regimen in our study,[16] it is recommended that heparin be administered to patients with RFL-associated SPS.

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