Approach Considerations
Because fetal loss associated with clotting 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 recurrent miscarriage syndrome (RMS) due to thrombophilia; rather, we use low-dose aspirin 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. [75] However, the authors remain concerned and continue to advocate low-dose aspirin as the preconception antithrombotic therapy in most instances. [1, 59, 6]
The regimen of a postconception addition of fixed, low-dose heparin at 5000 units every 12 hours is empirical, but higher doses seem to be associated with bleeding and a lower success rate. [76] 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 antiphospholipid syndrome (APLS) and other types of thrombosis, wherein the corticosteroid use could be shown to lower antiphospholipid antibody titers but failed to abort thrombotic events. [1, 6, 7, 8, 23, 24, 25] In addition, steroid use in patients with APLS is considered possibly detrimental. [28]
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, [77] Perino et al reported a 93% failure rate in untreated women, [78] and Many et al also reported a similar failure rate in untreated patients. [79]
Lubbe and Liggins noted an 80% successful term pregnancy rate in a small group of women with use of prednisone and aspirin [80] ; a similar success rate with this regimen was noted by Lin. [81] Cowchuck et al noted a 75% success rate with prednisone alone or with aspirin alone, but the investigators also noted more undesirable effects in the prednisone-treated population. [82] Landy et al, reported a 90% success rate in a small population with either aspirin alone or with prednisone alone. [83] However, Many et al only noted a 43% successful term pregnancy rate with aspirin and prednisone, [79] and Semprini et al noted only a 14% success rate with prednisone alone. [84]
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) heparin [76] ; 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 aspirin plus dose-adjusted SC heparin [85] ; the mean heparin dose was 26,000 U/d. Many et al reported that patients treated with prednisone plus aspirin and heparin at 5000 U twice a day had a better outcome (69%) than did those who were treated with aspirin plus prednisone (43%) or with prednisone alone (7%). [79]
The authors' results suggest that fixed low-dose heparin is more effective than high-dose, dose-adjusted regimens [1, 6] ; 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.
In a meta-analysis of 19 trials involving 2391 patients with a history of recurrent miscarriage with or without thrombophilia and 543 patients with APS for patients with or without thrombophilia, low molecular weight heparin therapy had the greatest probability of live births; for patients with APS, the combination of unfractionated heparin and aspirin was the superior treatment. [86]
Parke reported on the combination of low-dose heparin used in conjunction with intravenous immunoglobulin (IVIG). [87] Her success rate, however, was only 27%, suggesting that IVIG has little role in antiphospholipid fetal wastage syndrome.
Treatment with hydroxychloroquine proved beneficial in a preliminary study of 170 pregnancies in 96 women with persistent antiphospholipid antibodies. Compared with a control group of 65 women who received conventional treatment, the 31 women who received hydroxychloroquine for at least 6 months before pregnancy and throughout gestation had a higher rate of live births (67% vs 57%; P = 0.05) and lower rates of antiphospholipid antibody–related pregnancy morbidity (47% vs 63%; P = 0.004), miscarriage at > 10 weeks of gestation (2% vs 11%; P = 0.05), and placenta-mediated complications (2% vs 11%; P = 0.05). Hydroxychloroquine-treated women also had longer pregnancy duration and a higher rate of spontaneous vaginal labor. [88]
Evaluation and Treatment Protocol
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, 5, 6] This protocol is presented in the image below.
In all instances, women with RMS and infertility are first seen by an obstetrician or reproductive specialist. 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 two 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 found to have a hemostasis defect is 92% (322 of 351). See Table 1, below.
Table 1. Characteristics of the First 351 Women Referred for Hemostasis Evaluation (Open Table in a new window)
Patient Characteristics (All 351 Patients) |
Mean |
Standard Deviation |
Maximum |
Minimum |
Age, y |
33.3 |
5.63 |
49 |
18 |
Number of Miscarriages |
2.9 |
2.39 |
9 |
2 |
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, 10 (3%) had a bleeding disorder: three (1%) with platelet dysfunction, one (0.3%) with factor XIII deficiency, three (1%) with von Willebrand disease, and three (1%) with Osler-Weber-Rendu syndrome.
The remainder of the patients had a thrombophilia, as follows:
-
Antiphospholipid syndrome (APLS): 195 patients (60%)
-
Sticky platelet syndrome: 64 (20%)
-
5,10-Methyltetrahydrofolate reductase: (5,10-MTHFR) mutation: 38 (12%)
-
Plasminogen activator inhibitor type 1 (PAI-1) polymorphism (most commonly polymorphisms [4G/5G or 4G/4G]): 23 (7.1%)
-
Protein S deficiency: 12 (3.7%)
-
Factor V Leiden: 12 (3.7%)
-
Antithrombin deficiency: Three (1%)
-
Heparin cofactor II deficiency: Three (1%)
-
Tissue plasminogen activator (tPA) deficiency: Three (1%)
-
Protein C deficiency: Six (2%)
A total of 364 defects were found in the 312 patients with thrombophilia; thus, several had two, and a few had three, separate defects.
As has been found by most other investigators, the most common defect found in RMS has been APLS; however, unlike some groups, the authors assess for all phospholipid antibody subgroups, including the following:
-
Antiphosphatidylserine
-
Antiphosphatidylethanolamine
-
Antiphosphatidylglycerol
-
Antiphosphatidic acid
-
Antiphosphatidylcholine
-
Antiphosphatidylinositol
-
Anti–annexin-V antibody
-
B2GP1
-
Hexagonal phospholipid
-
Lupus anticoagulant (by dilute Russell viper venom test [dRVVT], with correction by nonplatelet-derived phospholipid to avoid false-positive results)
-
Anticardiolipin antibody (all three idiotypes: IgG, IgA, IgM)
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 were not performed. Interestingly, this finding is about the same as that noted in young-age patients (< 51 y) with thrombotic stroke. [89]
The particulars of the patients with APLS in the authors' population, with demonstration of the idiotypes found, are summarized in Table 2, below.
Table 2. Clotting Disorders Found in the Authors' Population (Open Table in a new window)
Antiphospholipid Found |
Patients With APLS, % |
ACLA-IgG only |
32.6 |
ACLA-IgM only |
23.4 |
ACLA-IgA only |
7 |
ACLA-IgG + IgM |
3 |
ACLA-IgG + IgA |
1 |
ACLA IgA + IgM |
0 |
Lupus anticoagulant only |
2 |
ACLA + lupus anticoagulant |
2 |
Subgroup Only (No ACLA or lupus anticoagulant present) |
|
Antiphosphatidylserine |
4 |
Antiphosphatidylinositol |
2 |
Antiphosphatidylethanolamine |
5 |
Antiphosphatidic acid |
5 |
Antiphosphatidylcholine |
7 |
Antiphosphatidylglycerol |
1 |
Anti-annexin-V |
5 |
B2GP1 |
0 |
Hexagonal phospholipid |
0 |
Total |
|
(9 Patients had ACLA + a subgroup antibody) |
|
Total with only a subgroup antibody |
|
APLS patients with only a subgroup antibody, % |
29 |
Treatment of thrombophilia
All patients with a thrombophilic defect were treated with preconception aspirin at 81 mg/d, and at documentation of conception, the women were treated with the addition of subcutaneous (SC) unfractionated heparin at 5000 U q12 hours by self-injection (first 120 patients) or SC low–molecular-weight (LMW) heparin (dalteparin [Fragmin], 5000 U q24 h by self-injection; subsequent 192 patients). Both drugs (aspirin and 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 the following:
-
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)
-
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.
Patients receive the following instructions about self-administration of SC medication:
-
The anterior or lateral thighs are the ideal injection sites
-
Injection sites should be rotated with every injection
-
Each injection is likely to produce a bruise about 0.5-4.0 cm in diameter
-
Injection pain, 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:
-
Aspirin: 81 mg/d, start preconception (time of diagnosis)
-
Heparin: 5000 U SC q12h immediately postconception (added to aspirin, both to term) or Dalteparin: 5000 U SC q24h immediately postconception (added to aspirin, 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 (anti–factor Xa method) weekly for 4 weeks; then CBC/platelet count and heparin level 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
Clinicians considering the use of LMW heparin in pregnancy should be made aware of the US Food and Drug Administration (FDA) safety alert warning regarding the use of enoxaparin (Lovenox) in pregnancy and women of childbearing age.
Outcomes
All of the authors' 315 patients with a thrombophilic defect were treated with the aforementioned regimen of preconception low-dose aspirin plus postconception thromboprophylactic (low-dose) SC heparin or dalteparin. Patients with MTHFR mutations were also treated with folic acid at 5 mg/d plus pyridoxine at 50 mg/d.
Four pregnancy losses (2.6%) occurred in patients receiving antithrombophilic prophylaxis. One loss was during the second trimester and accompanied a cholecystectomy, and one loss was during the first trimester in a patient with APLS and a fetal chromosomal defect; neither of these were considered treatment failures. However, two patients suffered first-trimester loss, and placental thrombi and infarcts were present. Thus, those two 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 two 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.
-
Defects causing recurrent miscarriage.
-
Dallas/Fort Worth Metroplex (DFW Metroplex) flow protocol.
Tables
Patient Characteristics (All 351 Patients) |
Mean |
Standard Deviation |
Maximum |
Minimum |
Age, y |
33.3 |
5.63 |
49 |
18 |
Number of Miscarriages |
2.9 |
2.39 |
9 |
2 |
Antiphospholipid Found |
Patients With APLS, % |
ACLA-IgG only |
32.6 |
ACLA-IgM only |
23.4 |
ACLA-IgA only |
7 |
ACLA-IgG + IgM |
3 |
ACLA-IgG + IgA |
1 |
ACLA IgA + IgM |
0 |
Lupus anticoagulant only |
2 |
ACLA + lupus anticoagulant |
2 |
Subgroup Only (No ACLA or lupus anticoagulant present) |
|
Antiphosphatidylserine |
4 |
Antiphosphatidylinositol |
2 |
Antiphosphatidylethanolamine |
5 |
Antiphosphatidic acid |
5 |
Antiphosphatidylcholine |
7 |
Antiphosphatidylglycerol |
1 |
Anti-annexin-V |
5 |
B2GP1 |
0 |
Hexagonal phospholipid |
0 |
Total |
|
(9 Patients had ACLA + a subgroup antibody) |
|
Total with only a subgroup antibody |
|
APLS patients with only a subgroup antibody, % |
29 |
