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Recurrent Miscarriage Evaluation/Coagulation Panel

Recurrent Miscarriage Evaluation/Coagulation Panel

Test Summary

Recurrent Miscarriage Evaluation/Coagulation Panel

  

Clinical Use

  • Identify thrombophilia-related causes of recurrent miscarriage

Clinical Background

Miscarriage or pregnancy loss is not uncommon, but only about 1% of women suffer 3 or more consecutive losses1; the probability of recurrence increases with maternal age and the number of previous pregnancy losses.2 Most expert groups agree that couples with 3 or more consecutive pregnancy losses should undergo thorough evaluation.3,4 However, many clinicians test for causative disorders after 2 consecutive losses, perhaps because couples often become distressed at this point.2 Although most (50% to 75%) cases of recurrent miscarriage remain unexplained, identifying the underlying cause can be a first step toward appropriate management.3

Recurrent miscarriage has many proposed causes but is most strongly associated with genetic, uterine, and thrombophilic abnormalities.3,5 Thus, initial evaluations may include parental cytogenetic analysis, a maternal pelvic ultrasound to detect uterine structural abnormalities, and karyotyping of products of conception to detect fetal aneuploidy.3,5 Women should be tested for antiphospholipid syndrome (APS), an acquired thrombophilic disorder that is associated with 5% to 15% of recurrent miscarriages.3-6 Screening for inherited thrombophilic disorders may also be useful; some studies suggest a stronger link with second- and third-trimester losses than with first-trimester losses.3,4

Thrombophilic disorders represent a potentially treatable cause of recurrent miscarriage, and accurate identification may help in designing therapeutic strategies. For example, combined aspirin and heparin therapy appears to improve pregnancy success in women with recurrent miscarriage associated with antiphospholipid antibodies.3,4 However, the benefit of antithrombotic therapy in recurrent miscarriage caused by inherited thrombophilia has not been established.4 The Recurrent Miscarriage Evaluation/Coagulation Panel helps to identify the most common acquired and inherited thrombophilic causes of recurrent miscarriage. The panel also detects several rarer, but important, thrombophilia-related causes (deficiencies in antithrombin III, protein C, and free protein S).

Individuals Suitable for Testing

  • Women who have had 2 consecutive, unexplained pregnancy losses

Because normal pregnancy is associated with elevated fibrinogen and factor VIII (which affects lupus anticoagulant test results) as well as reduced free protein S, the panel is not recommended for use in pregnant women.7

Method

  • Panel components are listed in the Table.

  • This test can be ordered with or without Coagulation Consultation.

Interpretive Information

The following Table shows and clinically significant values associated with thrombophilia-related causes of recurrent miscarriage.

Table. Interpretive Information for Recurrent Miscarriage Evaluation/Coagulation Panel Components
Assay Clinically
Significant Results
Miscarriage-
associated Disorder
Antithrombin III Activity <80% of normal Antithrombin III deficiency

Beta2-glycoprotein I

Antibody (IgG)a

>20 U APS

Beta2-glycoprotein I

Antibody (IgM)a

>20 U APS

Beta2-glycoprotein I

Antibody (IgA)

>20 U APS
Cardiolipin Antibody (IgG)a >40 U APS
Cardiolipin Antibody (IgM)a >40 U APS
Cardiolipin Antibody (IgA) >15 U  APS

Factor V (Leiden)b,c

Mutation detected

Activated protein C

resistance

Homocysteine (Cardiovascular) 10.4 μmol/L Hyperhomocysteinemia
Lupus Anticoagulant Evaluation with Reflexa,d LA detected APS

Phosphatidylserine

Antibody (IgG)

>20 U/mL APS

Phosphatidylserine

Antibody (IgM)

>35 U/mL APS
Protein C Activity <70% of normal Protein C deficiency
Protein S Antigen, Free <50% of normal Free protein S deficiency
Prothrombin Gene Analysisb,c Mutation detected Increased thrombosis risk because of elevated prothrombin levels

APS, antiphospholipid syndrome; LA, lupus anticoagulant.

a International consensus laboratory diagnostic criteria for APS.8

b This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.

c Additional assistance in interpretation of results is available from our Genetic Counselors by calling 1-866-GENE-INFO (1-866-436-3463).

d Includes partial thromboplastin time assay modified for lupus anticoagulant detection (PTT-LA) with reflex to hexagonal phase confirm and dilute Russell’s viper venom time (dRVVT) assay with reflex to dRVVT confirm and dRVVT mixing study. Reflex tests are performed at an additional charge and are associated with an additional CPT code.

Persistent detection (2 clinically significant results at least 12 weeks apart) of beta2-glycoprotein I IgG or IgM antibody, cardiolipin IgG or IgM antibody, or lupus anticoagulant identifies APS as a cause of recurrent miscarriage.8 Detection of IgA antibodies may indicate APS in symptomatic individuals who lack clinically significant IgG and IgM antibodies. Detection of non–first-line phospholipid antibodies such as phosphatidylserine antibodies in symptomatic individuals who lack beta2-glycoprotein I, cardiolipin, and lupus anticoagulant antibodies also suggests APS.3,9,10

Detection of any of the following is consistent with an inherited thrombophilic cause of recurrent miscarriage: prothrombin gene mutation (20210G>A) or factor V (Leiden) mutation (1691G>A; R506Q); elevated homocysteine levels; or deficiencies in antithrombin III, protein C, or free protein S.3,11

The panel does not identify non-thrombophilic causes of recurrent miscarriage.3 Test results are affected by methotrexate and warfarin as well as by liver disease, kidney disease, and disseminated intravascular coagulation.11,12

References

  1. Alberman E. The epidemiology of repeated abortion. In: Beard RW, Sharp F, eds. Early Pregnancy Loss: Mechanisms and Treatment. London: RCOG Press; 1988:9-17.

  2. Stirrat GM. Recurrent miscarriage I: definition and epidemiology. Lancet. 1990;336:673-675.

  3. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. Int J Gynaecol Obstet. 2002;78:179-190.

  4. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:844S-886S.

  5. Rai R, Regan L. Recurrent miscarriage. Lancet. 2006;368:601-611.

  6. Triplett DA. Antiphospholipid antibodies. Arch Pathol Lab Med. 2002;126:1424-1429.

  7. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol. 2003;16:153-168.

  8. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.

  9. Asherson RA. The primary, secondary, catastrophic, and seronegative variants of the antiphospholipid syndrome: a personal history long in the making. Semin Thromb Hemost. 2008;34:227-235.

  10. Hoppensteadt DA, Fabbrini N, Bick RL, et al. Laboratory evaluation of the antiphospholipid syndrome. Hematol Oncol Clin North Am. 2008;22:19-32.

  11. Girling J, de Swiet M. Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol. 1998;10:135-144.

  12. Van Cott EM, Laposata M. Laboratory evaluation of hypercoagulable states. Hematol Oncol Clin North Am. 1998;12:1141-1166.
     

Content reviewed 02/2013

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