AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

5,10-methyltetrahydrofolate reductase mutations, MTHFR mutations, C677T, hyperhomocysteinemia, PAI-1 elevation / polymorphisms, protein S deficiency, prothrombin G20210A, protein C deficiency, antithrombin deficiency, heparin cofactor II deficiency, tissue plasminogen activator deficiency, TPA deficiency, lipoprotein (a), immune vasculitis, annexin-V, annexin V, placental anticoagulant protein, dalteparin, Fragmin

INTRODUCTION

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• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Background

Recurrent miscarriage syndrome (RMS) is a common obstetric problem, affecting over 500,000 women in the United States per year¹; infertility, although less well defined epidemiologically, is also a common clinical problem.

For excellent patient education resources, visit eMedicine's Women's Health Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Miscarriage, Threatened Miscarriage, and Infertility.

Related eMedicine topics:
Abortion, Complete
Abortion, Incomplete
Abortion, Inevitable
Abortion, Missed
Abortion, Threatened
Infertility
Infertility, Male

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CME/CE Eating Chocolate May Decrease Risk for Preeclampsia
CME "Fertility Diet" May Improve Fertility Outcomes in Women
CME Miscarriage Risk Minimal After Normal First Antenatal Visit
CME The Role of Thyroid Autoimmunity in Fertility and Pregnancy

Pathophysiology

RMS due to blood protein or platelet defects may come about through 2 mechanisms: (1) those disorders that are associated with a hemorrhagic tendency or (2) those defects that are associated with a thrombotic tendency. Hemorrhagic (bleeding) defects that are associated with RMS are rare, whereas thrombotic or hypercoagulable/thrombophilic defects are extremely common.^{2, 3} The hemorrhagic defects associated with fetal wastage syndrome presumably lead to inadequate fibrin formation, thus precluding adequate implantation of the fertilized ovum into the uterus.

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Frequency

United States

RMS affects more than 500,000 women in the United States per year.¹

Race

Females of any race can be affected by RMS.

Sex

Only females are affected by RMS.

Age

Females of childbearing age

CLINICAL

Section 3 of 10  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

History

Patients have a history of 2 or more miscarriages. They may or may not have a history of bleeding (see Workup, Lab Studies).

Physical

The physical examination is usually normal, unless maternal thrombosis is present.

Causes

Blood coagulation protein and platelet defects

The hemorrhagic defects associated with fetal wastage syndrome include factor XIII deficiency or polymorphism,^{3, 4, 5} factor XII defects,⁶ factor X deficiency,⁷ factor VII deficiency,⁸ factor V deficiency,⁹ factor II (prothrombin) deficiency,¹⁰ von Willebrand syndrome, and carrier state for hemophilia and fibrinogen defects (including afibrinogenemia), and those dysfibrinogenemias associated with hemorrhage and others.^{11, 12, 13, 14, 15, 16, 17}

Management of these patients is generally plasma substitution therapy or, in appropriate disorders, DDAVP (vasopressin) therapy.^{1, 2} Hemorrhagic or bleeding defects are rare causes of recurrent miscarriage relative to thrombotic or thrombophilic disorders.^{1, 2, 18}

The thrombotic defects associated with fetal wastage occur due to thrombosis of early placental vessels, with peak fetal wastage in the first trimester, but small peaks also occur in the second and third trimesters.^{1, 19} The earlier the pregnancy, the smaller the placental and uterine vessels and, therefore, the greater the propensity to undergo partial or total occlusion by thrombus formation. Thrombotic occlusion of placental vessels, both venous and arterial, preclude adequate nutrition and, thus, viability of the fetus.^{1, 2}

The thrombotic hemostasis defects associated with recurrent miscarriage syndrome include lupus anticoagulants and anticardiolipin antibodies (these 2 comprise the antiphospholipid syndromes [APLSs] that are associated with fetal wastage syndrome),^{20, 21, 22} factor XII deficiency,²³ dysfibrinogenemias associated with thrombosis,²⁴ protein C defects,²⁵ protein S defects, antithrombin deficiency,²⁶ heparin cofactor II deficiency,²⁷ and fibrinolytic defects that are associated with thrombosis (including plasminogen deficiency,²⁸ tissue plasminogen activator [t-PA or TPA] deficiency, elevated plasminogen activator inhibitor type 1 [PAI-1],²⁹ and PAI-1 polymorphisms³⁰).

Also, although sticky platelet syndrome has been known for over a decade and leads to a wide variety of arterial and venous events, only in the past several years has it become apparent that this defect is a common cause of RMS.¹⁹ In addition, like other new defects (including factor V Leiden; 5,10-methyltetrahydrofolate reductase mutations [5,10-MTHFR], and prothrombin G20210A gene mutation), sticky platelet syndrome should be added to the prothrombotic disorders that are associated with RMS.² As new procoagulant factor mutations associated with hypercoagulability and thrombosis are discovered, they, too, are anticipated to be found associated with placental thrombosis and RMS in many cases.

The following list summarizes the bleeding disorders which may give rise to recurrent RMS or infertility; these are very rare causes as compared with prothrombotic disorders.

Bleeding disorders that are associated with RMS (rare) include the following:

• Factor XIII deficiency
• von Willebrand disease
• Factor X deficiency
• Factor VII deficiency
• Factor V deficiency
• Factor II deficiency
• Hypofibrinogenemia
• Dysfibrinogenemia
• Hemophilia A carrier status

Thrombotic disorders associated with RMS (common) include the following: 

• APLSs
• Sticky platelet syndrome
• MTHFR mutations
• Hyperhomocysteinemia
• PAI-1 elevation/polymorphisms
• Protein S deficiency
• Factor V Leiden
• Prothrombin G20210A
• Protein C deficiency
• Antithrombin deficiency
• Heparin cofactor II deficiency
• TPA deficiency
• Elevated lipoprotein (a)
• Immune vasculitis

APLS is clearly the most common thrombotic defect leading to fetal wastage syndrome, infertility, or both, and various treatment programs have been advocated.³¹ One difficulty in evaluating these programs has been that some populations have addressed primarily patients with secondary APLS and fetal wastage, in particular those with underlying systemic lupus erythematosus or other autoimmune disorders. Only a few investigators have addressed populations with primary APLS who have no known underlying disease.

APLS has long been recognized as a cause of miscarriage and infertility; it has also long been recognized that treatment for this condition is often successful.³² Many clinicians consider APLS to be the most common prothrombotic disorder among both hereditary and acquired defects, as well as the most common thrombotic disorder causing recurrent miscarriage.^{1, 2, 20, 21, 33, 34, 35, 36, 37}

When assessing causes of infertility alone, APLS is thought to account for about 30% of infertility cases; however, in one series, abnormal CD56+/CD16 cell ratios were the single most common defect found (40%) in infertility patients.³⁸ In another series, only 21% of patients with RMS had APLS; however, when assessing historically women with APLS, 80% had suffered at least one miscarriage.^{39, 31}

In a series reported by Granger and Farquharson, 387 unselected patients were assessed for APLS. Of these, 16% harbored APLS, and of those with APLS, 56% had a term delivery with low-dose aspirin (ASA).⁴⁰ Borelli et al found that 60% of their studied patients with "habitual" unexplained miscarriage had APLS.⁴¹ Although the great majority of cases of APLS are clearly acquired,^{20, 36} familial APLS that is associated with RMS has been reported.⁴² Clearly, however, screening for APLS is indicated in patients with RMS.^{1, 2, 20, 21, 33, 34, 36, 43}

One study has suggested that monitoring miscarriage patients with APLS by use of prothrombin fragment 1.2 may predict preclinical placental thrombi⁴⁴; if this finding is confirmed, it may preclude the necessity of frequent sonograms, which is the current mode of careful monitoring for pregnant patients who have had RMS and who are on therapy. In addition, because APLS is very common and because many of the hereditary thrombophilias, such as factor V Leiden, are very prevalent in North America, it is not unexpected that some women with RMS have APLS in combination with other procoagulant defects. Aznar et al reported a case of RMS that was complicated by deep venous thrombosis (DVT) and thrombotic stroke in a patient with APLS, factor V Leiden, and congenital protein S deficiency.⁴⁵

Many mechanisms have been proposed whereby APLS interferes with the hemostasis system and predisposes to thrombosis.^{1, 2, 3, 20, 21, 33, 34, 35, 36, 43} However, some investigators have proposed mechanisms that are specific for RMS. These proposed mechanisms have included the proposal that APLSs induce acquired activated protein C resistance (APC-R),⁴⁵ as well as interferes with prothrombin (factor II), protein C and protein S, tissue factor, factor XI,⁴⁶ and the tissue factor/tissue factor pathway inhibitor (TF/TFPI) system.⁴⁷ Another study also found that patients with APLS harbored antibodies to prothrombin, protein C, and protein S.⁴⁸ Other investigators have proposed these patients may also develop antibodies to "thromboplastin" and thrombin.⁴⁹

Another proposed mechanism is that APLSs interfere with annexin-V (also referred to as placental anticoagulant protein, serine only).⁵⁰ Three studies demonstrated immunoglobulin (Ig) fractions of antiphospholipid antibody (APLA) or beta2-glycoprotein-1 (B2GP1) decrease trophoblastic annexin-V^{50, 51, 52}, but several studies have shown this anti–annexin-V activity to be limited to the antiphosphatidylserine subgroup antibody idiotype.^{53, 54} On rare occasions, APLS may be inherited (this author has seen 3 such families) and others have been reported,⁴² suggesting that a positive maternal history may warrant evaluation at first pregnancy, as should a history of familial thrombosis.

Patients with other congenital or acquired thrombophilic states are also at high risk for placental thrombosis and RMS. In a study that assessed a variety of these defects in 46 selected women with RMS (anatomic and hormone defects were ruled out before the hemostasis assessment), the following was found: 76% had anticardiolipin antibodies (void of lupus anticoagulants), 3% had a lupus anticoagulant (void of anticardiolipin antibodies), 11% had congenital protein S deficiency (3 quantitative; 1 dysfunctional), 6.5% had sticky platelet syndrome (2 with type I; 1 with type II), 3% had dysfibrinogenemia, and 3% had congenital TPA deficiency.¹⁹

In a study that assessed the prevalence of hereditary and acquired defects in patients with RMS, 9.4% had isolated factor XII deficiency and 7.4% had APLS; fibrinolytic system defects, leading to hypofibrinolysis and hypercoagulability, were found in 42.6% of patients.⁵⁵ This study concluded that von Willebrand disease, fibrinogen deficiency, antithrombin deficiency, protein C and protein S deficiency, TPA deficiency, and PAI-1 defects played no role in RMS.⁵⁵

However, in a similar study assessing hereditary hemostasis defects in 125 patients with RMS, quite different results were noted, and factor V Leiden mutation was found in 14%.⁵⁶ However, in another study of 50 patients with RMS, it was concluded that factor V Leiden, prothrombin G20210A mutation, and 5,10-MTHFR mutations were not causes of RMS.⁵⁷ Bokarewa et al also noted in their study that although factor V Leiden was responsible for a greater than 3-fold risk of DVT, there was no association with miscarriage.⁵⁸

Yet Brenner et al revealed that factor V Leiden was responsible for 48% of recurrent miscarriages,⁵⁹ and Rai et al reported that factor V Leiden was associated with a high incidence of second-trimester miscarriages in their series.⁶⁰ An additional 2 studies clearly showed an association between factor V Leiden mutation and recurrent miscarriages.^{61, 62} Thus, the preponderance of evidence certainly strongly suggests that heterozygous factor V Leiden mutation is a significant risk factor for recurrent miscarriage and increases the risk for miscarriage by at least 3.3-fold.⁵⁹

Another common thrombophilic disorder, prothrombin G20210A gene mutation, was described by Poort and associates in 1996.⁶³ Although Kutteh et al found no association between this mutation and RMS,⁵⁷ a study by Brenner et al found an increased 2.2-fold risk of recurrent miscarriage in women with this genetic procoagulant defect.⁶⁴

Another hereditary defect that leads to hypercoagulability and thrombosis is 5,10-MTHFR C677T mutation. Although Kutteh et al found no association between this defect and recurrent miscarriage,⁵⁷ Brenner et al showed a clear association between heterozygosity for this mutation and recurrent miscarriage, with those who harbor the mutation having a 2-fold enhanced risk of miscarriage.⁶⁴

Finally, although hypofibrinolysis in general has been shown to be associated with recurrent miscarriage,²⁹ only recently has the role of PAI-1 elevation and PAI-1 polymorphism or polymorphisms been shown as a cause of RMS.³⁰ Potential and proposed mechanisms of antiphospholipid antibody-induced thrombosis (APL-T) are summarized in the list below.

Proposed mechanisms of thrombosis APL-T syndromes include the following:

• Interference with endothelial phospholipids and, thus, prostacyclin release
• Inhibition of prekallikrein and, thus, inhibition of fibrinolysis
• Inhibition of thrombomodulin, thus, protein C/S activity
• APC-R (nonmolecular)
• Interaction with platelet membrane phospholipids
• Inhibition of endothelial TPA release
• Direct inhibition of protein S
• Inhibition of annexin-V, or placental anticoagulant protein (serine only), a cell-surface protein that inhibits tissue factor
• Induce release of monocyte tissue factor 

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DIFFERENTIALS

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Other Problems to Be Considered

A coagulation defect is the single, most common cause of recurrent miscarriage (2 or more miscarriages), after hormonal defects and anatomic defects have been eliminated as the cause. Recurrent miscarriage, based upon the available literature and our experience, is generally due to well-defined defects, as follows¹:

• About 15% are due to hormonal abnormalities (progesterone, estrogens, diabetes, or thyroid disease)
• About 10% are due to anatomic abnormalities
• About 7% are secondary to chromosomal abnormalities
• About 6% cannot be explained
• The remainder, about 55-62%, are due to blood coagulation protein/platelet defects.

The approximate prevalence of causes of RMS and infertility is summarized in Image 1.¹ These are in contrast to first-time miscarriage, which in most cases, is due to a chromosomal defect and may affect up to 25% of first-time pregnancies.¹

WORKUP

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Lab Studies

• If the patient has a history of bleeding, the following tests should be ordered:
• • Platelet count
  • Prothrombin time (PT)
  • Activated partial thromboplastin time (aPTT)
  • Platelet function testing (aggregation)
  • von Willebrand evaluation
  • Factor XIII function and antigen
• If there is no history of bleeding, an antiphospholipid panel should be ordered.

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TREATMENT

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Medical Care

Because fetal loss associated with bleeding disorders is thought to occur due to interference with adequate fibrin formation for implantation of the fertilized ovum into the uterine lining, the authors choose not to use vigorous preconception antithrombotic therapy in those patients with thrombophilia; rather, we use low-dose ASA at 81 mg/d. This issue may be of theoretical concern only, in view of the report by Sher et al, who used preconception low-dose heparin with a high success rate for in vitro fertilization techniques.⁶⁵ However, the authors remain concerned and continue to advocate low-dose ASA as the preconception antithrombotic therapy in most instances.^{1, 4, 19}

The regimen of a postconception addition of fixed, low-dose porcine mucosal heparin at 5000 units (U) every (q) 12 hours is empirical, but higher doses seem to be associated with bleeding and a lower success rate.⁶⁶ However, it may be that even lower doses of heparin might suffice. The authors do not advocate using corticosteroid therapy in this patient population, based upon the negative experience of others in fetal wastage syndrome and the authors' own experience of using steroids in conjunction with antithrombotics in patients with APLS and other types of thrombosis, wherein the corticosteroid use could be shown to lower APLA titers but failed to abort thrombotic events.^{1, 19, 20, 21, 34, 35, 36} In addition, it is thought that steroid use in patients with APLS may be detrimental.³²

Various treatment programs have been used for women with APLS (anticardiolipin antibodies or lupus anticoagulants) and fetal wastage syndrome; however, many of these studies have examined only very small populations or failed to distinguish between primary or secondary APLS in the information provided. Brown reported a 90% failure rate (miscarriage) among untreated women,⁶⁷ Perino et al reported a 93% failure rate in untreated women,⁶⁸ and Many et al also reported a similar failure rate in untreated patients.⁶⁹

Lubbe and Liggins noted an 80% successful term pregnancy rate in a small group of women with use of prednisone and ASA⁷⁰; a similar success rate with this regimen was noted by Lin.⁷¹ Cowchuck et al noted a 75% success rate with prednisone alone or with ASA alone, but the investigators also noted more undesirable effects in the prednisone-treated population.⁷² Landy et al, reported a 90% success rate in a small population with either ASA alone or with prednisone alone.⁷³ However, Many et al only noted a 43% successful term pregnancy rate with ASA and prednisone,⁶⁹ and Semprini et al noted only a 14% success rate with prednisone alone.⁷⁴

Several studies have assessed the role of postconception addition of heparin; however, most have used higher doses than used in the authors' population. Rosove et al reported a 93% success rate with dose-adjusted subcutaneous (SC) heparin⁶⁶; the mean heparin doses were about 25,000 U/d. Kutteh noted a success rate of 76% in a population of 25 patients treated with ASA plus dose-adjusted SC heparin⁷⁵; the mean heparin dose was 26,000 U/d. In Many et al's study, patients treated with prednisone plus ASA and heparin at 5000 U twice a day had a better outcome (69%) than did those who were treated with ASA plus prednisone (43%) or with prednisone alone (7%).⁶⁹

Based on the authors' results, it appears that fixed low-dose porcine heparin is more effective than the high-dose, dose-adjusted regimens^{1, 19}; more than 98% of the authors' RMS population with APLS or other prothrombotic propensity had a normal term delivery. Higher doses of heparin may somehow contribute to adverse outcomes, such as small periplacental hemorrhages. Parke reported on the combination of low-dose heparin used in conjunction with intravenous immunoglobulin (IVIG).⁷⁶ Her success rate, however, was only 27%, suggesting that IVIG has little role in antiphospholipid fetal wastage syndrome.

MEDICATION

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See the 2002 US-FDA Medwatch Alert regarding Lovenox. The alert is summarized below. 

Prosthetic Heart Valve Warnings

Lovenox Injection is not recommended for patients with prosthetic heart valves for thromboprophylaxis. Prosthetic heart valve thrombosis has been reported in these patients, some of whom were pregnant women in whom thrombosis led to maternal and fetal deaths. The thromboembolism risk may be higher in pregnant women with prosthetic heart valves (see Pregnancy Precautions, below).

Pregnancy Precautions

Teratogenic effects

Congenital anomalies in infants of women who received enoxaparin during pregnancy include cerebral anomalies, limb anomalies, hypospadias, peripheral vascular malformation, fibrotic dysplasia, and cardiac defect. The incidence is not higher than in the general population, and cause and effect are not established.

Nonteratogenic effects

Fetal deaths have occurred in pregnant women who received Lovenox Injection. A cause-and-effect relationship has not been established in these cases. Pregnant women who take anticoagulants, including enoxaparin, have a greater risk for bleeding at any site, which may lead to fetal or maternal death. Carefully monitor pregnant women on enoxaparin. Inform pregnant women and women with childbearing potential of the potential hazard of enoxaparin in pregnancy to the mother and fetus.

In one clinical study of pregnant women with prosthetic heart valves, maternal and fetal death occurred in 2 of 7 women given enoxaparin (1 mg/kg bid) to reduce the risk of thromboembolism in whom clots formed that blocked their prosthetic heart valves. Prosthetic valve thrombosis has occurred in pregnant women with prosthetic heart valves who were taking enoxaparin for thromboprophylaxis, resulting in maternal death or surgical interventions. Lovenox Injection is not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves (see Prosthetic Heart Valve Warnings, above).

Adverse Reactions and Ongoing Safety Surveillance

Since 1993, more than 80 incidents of epidural or spinal hematoma formation have been reported with spinal/epidural anesthesia or spinal puncture in patients receiving Lovenox Injection.

MISCELLANEOUS

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Medical/Legal Pitfalls

Dallas/Fort Worth Metroplex Thrombosis Hemostasis Clinical Center Experience

Over the past 5 years, the authors have carefully assessed 351 women referred for thrombosis and hemostasis evaluation after recurrent miscarriages. In the Dallas/Fort Worth Metroplex (DFW Metroplex), composed of a population of about 6 million, a flow protocol is followed to maximize success and to keep the costs of evaluation for the etiology of RMS and infertility at a minimum while providing the best chances for defining an etiology and, thus, providing ideal therapy for a successful term-pregnancy outcome.^{1, 3, 19} This protocol is presented in Image 2.

In all instances, women with RMS and infertility are first seen by an obstetrician or reproductive specialist; at this stage, anatomic defects and hormonal defects are assessed and, if found, the workup stops at this point and treatment is initiated (about 25% of all women). If no anatomic or hormonal defect is found, the patient is then seen by referral for hemostasis evaluation; the positive yield among this selected population is about 92%. If these evaluation findings are negative (about 8%), then, if the patient desires, chromosomal evaluation is initiated (about a 7% yield).

Most of the obstetricians and reproductive specialists in the DFW Metroplex refer patients after 2 or more miscarriages; however, some specialists refer after one miscarriage in the face of a positive patient family history for miscarriage; occasionally, patients request a workup after only one miscarriage. The authors' practice has been to accommodate the desires of the patient after discussing the costs and other implications of evaluation. At the time of this writing, all 322 patients with a defect have been monitored for at least 15 months; their results have been analyzed in detail, with the summary presented below.

The mean age of the patients referred for a hemostasis evaluation is 33.3 years, the mean number of miscarriages before referral is 2.9 (range = 2-9), and the percentage who have been found with a hemostasis defect is 92% (322 of 351).

Table 1. Characteristics of the First 351 Women Referred for Hemostasis Evaluation

All patients underwent a thorough evaluation for thrombophilia and, when indicated, a hemorrhagic disorder. Of the 351 patients, 29 (8%) had no defect. Of the remaining 322 patients, 7 (2%) had a bleeding disorder, 3 (1%) with platelet dysfunction, 1 (0.3%) with factor XIII deficiency, 3 (1%) with von Willebrand disease, and 3 (1%) with Osler-Weber-Rendu syndrome.

The remainder of the patients had a thrombophilia as follows: 195 (60%) had APLS, 64 (20%) had sticky platelet syndrome, 38 (12%) had MTHFR mutation, 23 (7.1%) had PAI-1 polymorphism, 12 (3.7%) had protein S deficiency, 12 (3.7%) had factor V Leiden, 3 (1%) had antithrombin deficiency, 3 (1%) had heparin cofactor II deficiency, 3 (1%) had TPA deficiency, and 6 (2%) had protein C deficiency. There were a total of 364 defects found in the 312 patients with thrombophilia; thus, several had 2, and a few had 3, separate defects.

As has been found by most other investigators (discussed previously), the most common defect found in RMS has been APLS; however, unlike some groups, the authors assess for all phospholipid antibody subgroups, including antiphosphatidylserine, antiphosphatidylethanolamine, antiphosphatidylglycerol, antiphosphatidic acid, antiphosphatidylcholine, antiphosphatidylinositol, anti–annexin-V antibody, B2GP1, hexagonal phospholipid, and lupus anticoagulant (by dilute Russell viper venom test [dRVVT], with correction by nonplatelet-derived phospholipid to avoid false-positive results). The authors always assess for all 3 idiotypes of anticardiolipin antibody (IgG, IgA, and IgM). An incomplete evaluation continues to be made by many who evaluate these patients and who may leave out either the IgA or IgM idiotypes.

The most common defect we find is, again, APLS, followed by sticky platelet syndrome, then followed by MTHFR mutations, PAI-1 defects (most commonly polymorphisms [4G/5G or 4G/4G]), protein S deficiency, factor V Leiden, antithrombin deficiency, heparin cofactor II deficiency, TPA defects, and protein C deficiency. Of note, by including all antiphospholipid subgroups, 29% of patients are found to have a subgroup antiphospholipid antibody but no anticardiolipin antibody or lupus anticoagulant; thus, 29% of patients would remain undiagnosed if an assessment of these subgroups are not performed. Interestingly, this finding is about the same finding as that noted in young-age patients (<51 y) with thrombotic stroke.⁷⁷

The particulars of the patients with APLS in the authors' population, with demonstration of the idiotypes found, are summarized in Table 2 (platelet dysfunction = 3; von Willebrand factor = 3; Osler-Weber-Rendu = 3; factor XIII deficiency = 1).

Table 2. Clotting Disorders Found in the Authors' Population

All patients with a thrombophilic defect were treated with preconception ASA at 81 mg/d, and at documentation of conception, the women were treated with the addition of SC unfractionated porcine mucosal heparin at 5000 U q12 hours by self-injection (first 120 patients) or SC low–molecular-weight (LMW) heparin, dalteparin (Fragmin; Pfizer Inc, New York, NY, and Vetter Pharma-Fertigung, GmbH & Co. KG, Ravensburg, Germany), at 5000 U q24 hours by self-injection (subsequent 192 patients). Both drugs (ASA + unfractionated heparin or LMW heparin) are used to term.

All patients are instructed in the administration of heparin injections; they are also informed of all important side effects of heparin therapy and are extensively informed of the benefits and risks of heparin/LMW heparin therapy, including the fact that side effects, although rare, include heparin-induced thrombocytopenia (HIT) with and without paradoxical thrombosis/thromboembolism (HITT); osteoporosis; mild to moderate alopecia; skin and allergic reactions, including erythema and itching, at injection sites; eosinophilia (of little clinical consequence); and potential bleeding.

Patients are also informed that about 5-10% of patients develop a transient transaminasemia during heparin/LMW heparin therapy, but this is without any known adverse clinical consequences. They are also instructed that the ideal injection sites are the anterior or lateral thighs; injection sites should be rotated with every injection; each injection is likely to produce a bruise about 0.5-4.0 cm in diameter; and the pain of injection, if experienced, can usually be alleviated by applying a small piece of ice at the site for 20 seconds before and 20 seconds after the injection is given. All patients are instructed to return immediately if they note dark or black areas of the injection site, which are potentially indicative of skin necrosis. The methods of follow-up are summarized in the list below.

The DFW Metroplex Cooperative RMS Group follow-up protocol for fetal wastage syndrome that is associated with hypercoagulable blood protein/platelet defects is as follows:

• ASA: 81 mg/d, start preconception (time of diagnosis) 
• Porcine heparin: 5000 U SC q12h immediately postconception (added to ASA, both to term), OR
• Dalteparin: 5000 U SC q24h immediately postconception (added to ASA, both to term)
• Calcium: 500 mg/d by mouth (PO)
• Prenatal vitamins
• Iron: 1 tab/d PO
• Folic acid: 1 mg/d PO

Laboratory assessment

• Complete blood cell (CBC) / platelet count and heparin level* q weekly for 4 weeks; then CBC/platelet count and heparin level q monthly to term
• Sonogram initially and frequently to term
• Fetal activity chart daily, starting at 28 weeks
• Biophysical profile and color Doppler flow ultrasonography of umbilical artery at 32, 34, 36, and 38 weeks
• Delivery at the discretion of the obstetrician
• At delivery (or loss), send the placenta for pathologic analysis and search for placental vascular thrombosis

*By anti-Xa method

Those clinicians considering the use of LMW heparin in pregnancy should be made aware of the US-FDA Medwatch Alert posted by the FDA in January of 2002 regarding the use of enoxaparin (Lovenox) in pregnancy and women childbearing age (see Medication).

Outcomes

All of the authors' 315 patients with a thrombophilic defect were treated with the aforementioned regimen of preconception low-dose ASA plus the addition of postconception thromboprophylactic (low-dose) SC porcine heparin or thromboprophylactic doses of dalteparin. Patients with MTHFR mutations were also treated with folic acid at 5 mg/d plus pyridoxine at 50 mg/d. There were a total of 4 losses (2.6%). One loss was during the second trimester and accompanied a cholecystectomy, and one loss was during the first trimester in an individual with APLS and a fetal chromosomal defect; both of these were not considered treatment failures (ASA + heparin/LMW heparin). However, 2 patients suffered first-trimester loss on ASA + heparin/LMW heparin, and placental thrombi and infarcts were present. Thus, 2 losses clearly represented treatment failure.

The overall success in treating patients with RMS with procoagulant/platelet defects in the authors' program is, therefore, 99% (313/315) with respect to normal term delivery. All patients were monitored for a minimum of 3 months after delivery. No patient sustained a thrombotic episode during the pregnancy, delivery, or postpartum period except the 2 patients who experienced treatment failures, both of whom had placental vascular thrombi. In addition, no patient developed HIT/thrombocytopenia, and none had a clinically significant hemorrhage.

Almost all patients developed small ecchymoses at the injection sites, but these findings were considered insignificant by both the patient and physician. Ten percent of patients developed eosinophilia, which had abated by 3 months postpartum, and 7% developed mild to moderate elevations of hepatic transaminases; these laboratory findings also returned to normal by 3 months postpartum. Per the obstetricians, reproductive medicine specialists, and involved pediatricians, no neonatal or pediatric problems were associated with the administered therapy. No patient sustained a fracture during or after treatment.

Patients with bleeding disorders were not treated. No patient had a significant hemorrhage during pregnancy or delivery. None required any blood product therapy.

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Specialty Site Hematology-Oncology
Specialty Site Pathology & Lab Medicine

Special Concerns

RMS and infertility are common problems in the United States. Recurrent miscarriage affects more than 500,000 US women annually. If the affected patients are properly screened through a cost-effective protocol as outlined earlier, the etiology is found in almost all women. The most common defect in women with RMS is a hemostasis defect, of which the most common is APLS—if a thorough evaluation for APLS is performed. Following APLS, other hereditary and acquired procoagulant defects are also commonly found, if they are looked for.

It is important to appropriately evaluate women with RMS, because if an etiology is found, most patients have positive outcomes with normal term delivery. Hemorrhagic defects are very rare hemostasis causes of RMS, but these conditions are also treatable in many instances and should be investigated in appropriate women. Treatment of the common procoagulant defects consists of preconception low-dose ASA at 81 mg/d, followed by the addition of immediate postconception low-dose unfractionated porcine heparin or dalteparin. Based on the authors' experience, LMW heparin may be a suitable alternative.

MULTIMEDIA

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

Media file 1:  Defects causing recurrent miscarriage.
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Media file 2:  Dallas/Fort Worth Metroplex (DFW Metroplex) flow protocol.
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REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• Multimedia
• References

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