Looking for Trouble

Educational Objectives

The goals of this program are to improve the detection and management of pregnant women with thrombophilias and to clarify strategies for prenatal genetic screening. After hearing and assimilating this program, the clinician will be better able to:

1.   List adverse pregnancy outcomes associated with thrombophilias.

2.   Identify pregnant women who warrant testing for thrombophilias.

3.   Discuss recommendations for prevention of thrombophilias.

4.   Discuss the pros and cons of prenatal genetic screening strategies.

5.   Counsel patients about the most appropriate prenatal genetic screening strategy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgments

Dr. Silver was recorded at the 39th Annual Ob/Gyn Spring Symposium, and sponsored by the Medical University of South Carolina, and held March 31 to April 2, 2008, in Charleston, SC. Dr. Norton was recorded at Antepartum & In­trapartum Management, sponsored by the University of California, San Francisco, School of Medicine, held June 5-7, 2008, in San Francisco, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

Thrombophilias in Obstetrics

Robert M. Silver, MD, Professor and Chief, Maternal-Fetal Medicine, University of Utah Health Sciences, Salt Lake City, UT

General considerations: thrombophilias heterogeneous group of conditions predisposing individual to venous thromboembolism (VTE); significant cause of maternal mortality in pregnancy; associated with stillbirth, severe in­trauterine growth restriction (IUGR), severe preeclampsia, and placental abruption; procoagulant and anticoagulant imbalance (excess clotting factor or insufficient anticlotting proteins); pregnancy and hemostasis  —  increased risk for clotting in pregnancy; large increase in procoagulant factors and decrease in anticoagulant factors (eg, increase in PA1-1, decrease in protein S); resistance to activated protein C; impaired fibrinolysis

Hereditary thrombophilias: protein C pathway mutations  —factor V Leiden ; protein C deficiency; protein S defi­ciency; prothrombin G20210A mutation  —  involves upregulation of procoagulant protein; antithrombin (AT) III deficiency  —(anticoagulant protein deficiency); hyperhomocysteinemia (HHC)  —  weaker association with venous thromboembolism or obstetric complication; methylenetetrahydrofolate reductase (MTHFR) mutation most com­mon cause of HHC; factor V Leiden mutation  —  most common mutation; factor V activated in clotting cascade; in­activated in presence of protein C and protein S complexes; impaired anticoagulation; autosomal dominant condition; prothrombin mutation  —  second most common thrombophilia; mutation in promotor of prothrombin gene (causes increase in procoagulate protein); protein C and protein S deficiencies  —  different subtypes; autoso­mal dominant condition; AT III deficiency  —  less common, but most thrombogenic disorder; multiple mutations based on decreased protein, decreased function, or both;  HHC  —   increased risk for myocardial infarction; related to neural tube defect; data associating elevated levels with thromboembolism less clear; strong association with cystathionine-b-synthase (CbS) mutation (1 in 200    000 people); mild to moderate risk for HHC if patient heterozy­gous for CbS or homozygous for MTHFR mutation (40% of people heterozygous for MTHFR, but almost none have HHC); 11% of patients homozygous for MTHFR (most do not have HHC); speaker therefore recommends testing for homocysteine levels, rather than for HHC gene mutations

Prevalence in population: factor V Leiden  —  in whites, 5% to 9%; thrombosis in 20% to 40%; prothrombin gene mutation  —3%; thrombosis in 6% to 15%; protein C, protein S, and AT III deficiencies  —  much smaller proportion of general population and smaller proportion of people with thrombosis; elevated homocysteine  —  in 5%; thrombo­sis may be 5% as well; lifetime prevalence of thromboembolism  —  factor V Leiden and prothrombin gene mutation, »30%; protein C and protein S deficiencies, »50%; AT III deficiency most thrombogenic, »100%; MTHFR muta­tion homozygous at baseline; thromboembolism in pregnancy  —  1 per 1000 pregnancies; with thrombophilia, 8-fold increase in risk (overall); dramatic increase in risk with >1 thrombophilia (compound heterozygote); relative risk for thromboembolism (Gerhardt et al study of women with previous VTE)  —  factor V Leiden 7-fold increase, prothrombin gene 20–fold increase, and AT III »10-fold increase relative to control; no difference with MTHFR mutation; absolute risk for thromboembolism low (»1 in 400 with factor V Leiden), except in compound heterozy­gotes (5% risk)

Pregnancy complications: thrombosis in uteroplacental circulation causes infarction; decreased blood flow to fetus causes abnormal placentation, placental insufficiency, abruption, pregnancy loss and preeclampsia; study data  —  40% of women with placentas showing >10% infarction had factor V Leiden mutation compared to only few per­cent in controls (Dizon-Townson et al); study (Kupferminc et al)  —  women with various obstetric complications; significant odds ratio of 8.2% for thrombophilia with severe preeclampsia, IUGR, stillbirth, or abruption; remains significant when broken down individually by obstetric complication and specific thrombophilic mutation; women with fetal death had higher rate for factor V Leiden and prothrombin gene mutations; MTHFR mutation not associ­ated with increased risk for fetal death (Martinelli et al); factor V Leiden, prothrombin, and protein S deficiency gene mutations associated with recurrent loss and late sporadic loss (Rey et al); studies support association between thrombophilias and fetal death >20 wk, but not with recurrent first-trimester miscarriage (Kutteh); no association between thrombophilias and IUGR (Infante-Rivard et al); no association between regular preeclampsia, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, or preeclampsia with IUGR and thrombophilias (Livingston); summary  —  fetal death has consistent, but not uniform, association with most thrombophilias other than MTHFR mutation; some association with APS and first-trimester miscarriage (speaker does not believe first-trimester miscarriage associated with factor V Leiden or prothrombin gene mutations); mixed results for pre­eclampsia, IUGR, and abruption; evidence supports risk for adverse pregnancy outcome in patient with thrombo­philia; however, patients with thrombophilia and no history of adverse obstetric outcome have no greater risk for future adverse outcomes than women without thrombophilia (ie, they have normal pregnancy outcomes); 2-hit hypothesis  —thrombophilia and adverse event (eg, stillbirth, thrombosis) different from thrombophilia alone

Testing recommendations: history of VTE  —  testing for factor V Leiden and prothrombin gene mutation most cost-effective; if negative, test for anticardiolipin antibodies (antiphospholipid antibodies); if negative, test for rarer con­ditions (eg, protein C, protein S, and AT III deficiencies);  family history of VTE; test for AT III, protein C, and pro­tein S mutations; obstetric complications  —  data show abnormal thrombophilia screen in 53% of women tested at 10 wk postpartum, compared to 39% of women with normal pregnancies (significant, but possibly not clinically significant); poor obstetric history likely better than laboratory tests in predicting adverse outcomes; history of un­explained fetal death (possibly); testing not recommended for first-trimester loss; severe preeclampsia and severe IUGR and abruption unclear, but testing recommended for recurrent cases

Tests: factor V Leiden, prothrombin gene mutation, antiphospholipid antibodies, anticardiolipin, and lupus anticoag­ulant; AT III, protein S, and protein C deficiencies rare and testing expensive (highly penetrant and autosomal dom­inant, but reasonable with family history); use caution in testing for MTHFR or other antiphospholipid antibodies; when testing for HHC, obtain fasting homocysteine; some tests affected by anticoagulation, acute thrombosis and pregnancy; tests for factor V Leiden and prothrombin gene mutations can be performed at any time; antithrombin functional assay altered by acute thrombosis and heparin; protein C and protein S functional assay altered by preg­nancy, oral contraceptives, warfarin, and acute thrombosis; protein S also altered by inflammatory states; unclear what course to take when positive test results obtained; selection bias with retrospective studies; increased relative risk, but low absolute risk; theoretic risk vs risk and cost of interventions

American College of Obstetricians and Gynecologists (ACOG) recommendations: full anticoagulation for preg­nant women with  —  AT III deficiency, homozygous for factor V Leiden or prothrombin mutations, compound het­erozygotes, or antiphospholipid syndrome with previous thrombosis; full anticoagulation or thromboprophylaxis for pregnant women with  —  history of thrombosis, protein C or protein S deficiencies, heterozygous for factor V Leiden or prothrombin mutations, MTHFR, and HHC (speaker disagrees and would not treat patients with MTHFR or HHC); thromboprophylaxis or no treatment for pregnant women with no personal history of thrombosis, but  —  inherited thrombophilia and strong family history of thrombosis; consider postpartum anticoagulation (speaker does not treat women without personal history, but considers with significant family history); course uncertain in women with no personal or family history of thrombosis and heterozygous for factor V Leiden, prothrombin muta­tion, protein C or protein S deficiency, or MTHFR (speaker believes best not to test these women); all women at risk for thrombosis should receive postpartum anticoagulation for 6 wk (no supporting data); consider prophylaxis for cesarean delivery in high-risk cases; asymptomatic women with history of obstetric complications and thrombophilia  —  little reliable data upon which to base management, and expert opinion varies; treatment experi­mental; consider recurrent cases; study looking at thrombophilias and pregnancy loss showed 70% rate of recurrent pregnancy loss in study participants receiving aspirin, compared to »10% in women receiving low-molecular-weight heparin (LMWH); survival rate for small for gestational age fetus »30% in aspirin group and 10% in LMWH group; odds ratio for live birth in group taking LMWH, 15%; similar results for each thrombophilia; lower birth weight in aspirin group and higher in heparin group (Gris et al); similar data from uncontrolled trials; no ob­served difference between live birth rates in patients treated with thromboprophylaxis and those not (Warren et al); heparin not recommended yet; one study suggests heparin may be beneficial for thrombophilia and unexplained fe­tal death; consider adverse effects and cost of treatment; consider prevalence in normal individuals and look for al­ternative causes of adverse outcomes in previous pregnancies

Wading Through the Maze of Prenatal Genetic Testing

Mary E. Norton, MD, Clinical Professor, Obstetrics, Gynecology and Reproductive Science, University of Cal­ifornia, San Francisco, School of Medicine; Regional Director, Perinatal Genetic Service, Kaiser Permanente, San Francisco

Advances in genetic testing: more available testing options; lower procedure-related loss rates; more advanced cost-effectiveness analysis; emphasis on patient autonomy and decision-making; addition of inhibin A to triple test im­proves detection rate for Down syndrome; detection rate better in women >35 yr of age with triple screen and qua­druple screen (but higher screening positive rate); quadruple screening now standard of care (SOC); increase in nuchal translucency (NT) (layer of fluid at back of fetal neck) associated with chromosome problem or other birth defect; combined NT ultrasonography and biochemical screening improves detection

First-trimester biochemistry: PAPP-A (decreased when fetus has Down syndrome) and hCG (free  b  or total, in­creased in Down syndrome); first-trimester screen  —  NT and biochemistry done between 11 and 14 wk; detection rate »87%; blood test can be performed before, or at same time as, NT; serum screening not valid in triplet or higher order multiples; protocol that involves NT most sensitive; NT screening best at evaluating risk in twin preg­nancy and, discriminating between one twin and another

First plus second trimester: adding second-trimester biochemistry can further improve detection rate and lower false-positive rate; contingent screening  —  add second-trimester testing if first-trimester results borderline; inte­grated screening  —perform first- and second-trimester tests; no results until all completed; results put into one equation to calculate risk; lowest false-positive rate and best detection rate; sequential screening  —  first- and sec­ond-trimester tests done; patient gets result in first trimester; second result after second-trimester results completed; “stepwise sequential” results integrated; “independent” sequential results not integrated, but reported indepen­dently; contingent sequential  —  second-trimester test contingent on first-trimester results; diagnostic test offered with positive result; no further testing with negative result; borderline results get quadruple screen and integrate first- and second-trimester results; most cost-effective strategy, but complicated and rarely practiced; independent sequential screening  —  report first- and second-trimester screen separately; if first-trimester results not considered with calculation of second-trimester risk, results inaccurate; if first-trimester risk positive (and not considered), risk estimate too low; if first trimester risk negative, estimate will be too high; estimated detection rate high, but false-positive rate very high; least accurate; summary  —  first-trimester screening provides early results; 87% detection rate; integrated screening has best statistics, but results only available later; stepwise sequential ideal protocol (pro­vides excellent statistics); contingent screening most cost-effective, but most complicated to implement; indepen­dent screening should be avoided

ACOG recommendations:  tests considered confusing; no test endorsed over another; clinicians left without SOC or recommendation of what is practical; ACOG Practice Bulletin, January 2007  —  all women should be offered aneu­ploidy screening at <20 wk of gestation, regardless of maternal age; changes in recommendations for screening compared with diagnostic testing; moving away from maternal age-based dichotomizing of testing; option that in­cludes first- and second-trimester screening should be offered to women who present for care in first trimester; in­vasive diagnostic testing for aneuploidy should be available to all women, regardless of age; invasive testing with appropriate counseling should be made available to women <35 yr of age; invasive prenatal testing for aneuploidy  —invasive prenatal testing should be available to all women, regardless of age; pretest counseling should include discussion of risks and benefits of invasive testing compared with screening, how many women will have a positive result (and, of those, how many will have true positive result), detection rate of aneuploidies other than Down syndrome, and type and prognosis of aneuploidies likely to be missed by serum screening; difference between screening and diagnostic tests should be discussed with all women; speaker opines discussion with every patient not practical or realistic; discussion should focus on whether patient desires testing for birth defects and general discussion about difference between screening and diagnostic tests and their limitations

Summary: offer all pregnant women screening; discuss first- trimester testing options; find referral center for NT testing if not available, or do serum integrated approach; most tertiary centers have established protocol; avoid do­ing independent and separate first- and second-trimester testing

Suggested Reading

Alfirevic Z et al: Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 97(5 Pt 1):753, 2001; Barbour LA: ACOG Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin. Thromboembo­lism in pregnancy. Int J Gynaecol Obstet 75:203, 2001; Coppens M et al: Current practice of testing for inherited thrombo­philia. J Thromb Haemost. 5:1979, 2007; Dizon-Townson D et al: The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 106:517, 2005; Gerhardt A et al: Prothrombin and factor V muta­tions in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 342:374, 2000; Gris JC et al: Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 103:3695, 2004; Infante-Rivard C et al: Absence of association of thrombophilia polymorphisms with intra­uterine growth restriction. N Engl J Med 347:19, 2002; Kupferminc MJ et al: Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 340:9, 1999; Kutteh et al: Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 71:1048, 1999; Lindqvist PG et al: Activated protein C resistance (FV:Q506) and pregnancy. Thromb Haemost 81:532, 1999; Livingston JC et al: Maternal and fetal inher­ited thrombophilias are not related to development of severe preeclampsia. Am J Obstet Gynecol 185:153, 2001; Martinelli I et al: Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 343:1015, 2000; Norton ME: Genetic screening and counseling. Curr Opin Obstet Gynecol 20:157, 2008; Norton ME et al: First-trimester combined screening: experience with an instant results approach. Am J Obstet Gynecol 196:606, 2007; Rappaport VJ: Prenatal diagno­sis and genetic screening—integration into prenatal care. Obstet Gynecol Clin North Am 35:435, 2008. Rey E et al: Thrombo­philic disorders and fetal loss: a meta-analysis. Lancet 361:901, 2003; Warren JE et al: Thromboprophylaxis and pregnancy outcomes in asymptomatic women with inherited thrombophilias. Am J Obstet Gynecol 200:281, 2009.