Thrombophilia in pregnancy: Whom to screen, when to treat
Despite extensive research on testing and prophylaxis, a cautious approach is warranted
IN THIS ARTICLE
TABLE 5
How women with a previous adverse outcome fare on anticoagulation therapy
| STUDY | PATIENTS | PREVIOUS ADVERSE PREGNANCY OUTCOME | ANTICOAGULANT | OUTCOME IN CURRENT PREGNANCY |
|---|---|---|---|---|
| Riyazi et al9 | 26 | Uteroplacental insufficiency | LMWH and low-dose aspirin | Decreased recurrence of preeclampsia (85% to 38%) and IUGR (54% to 15%) |
| Brenner37 | 50 | ≥3 first-trimester recurrent pregnancy losses with thrombophilia | LMWH | Higher live birth rate compared with historical controls (75% vs 20%) |
| Ogueh et al48 | 24 | Previous adverse pregnancy outcome plus history of thromboembolic disease, family history of thrombophilia | UFH | No significant mprovement |
| Kupferminc et al38 | 33 | Thrombophilia with history of preeclampsia or IUGR | LMWH and low-dose aspirin | With treatment, 3% recurrence of preeclampsia |
| Grandone et al53 | 25 | Repeated pregnancy loss, gestational hypertension, HELLP, or IUGR | UFH or LMWH | 90.3% treated with LMWH had good obstetric outcome |
| Paidas et al3 | 158 | Fetal loss, IUGR, placental abruption, or preeclampsia | UFH or LMWH | 80% reduction in risk of adverse pregnancy outcome, compared with historical controls (OR, 0.21; 95% CI, 0.11–0.39) |
| HELLP=hemolysis, elevated liver enzymes, and low platelets; IUGR=intrauterine growth restriction; LMWH=low-molecular-weight heparin; UFH=unfractionated heparin | ||||
| SOURCE: Adapted from Am J Perinatol. 2006;23:499–506 | ||||
No randomized trials on prophylaxis
We lack randomized trials evaluating thromboprophylaxis for prevention of recurrent adverse pregnancy outcomes in women with previous severe preeclampsia, IUGR, or abruptio placenta in association with genetic thrombophilia. Therefore, any recommendation to treat such women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies should remain empiric and/or prescribed after appropriate counseling of the patients regarding risks and benefits.
TABLE 6 summarizes the risk of thromboembolism in women with thrombophilia—both for asymptomatic patients and for those with a history of thromboembolism. These percentages should be used when counseling women about their risk and determining management and therapy.
TABLE 6
Risk of thromboembolism during pregnancy and postpartum in women with thrombophilia
| THROMBOPHILIA | RISK (%) | |
|---|---|---|
| ASYMPTOMATIC WOMEN | HISTORY OF VENOUS THROMBOEMBOLISM | |
| Factor V Leiden | ||
| Heterozygous | 0.2 | 10 |
| Homozygous | 1–2 | 15–20 |
| Prothrombin gene mutation | ||
| Heterozygous | 0.5 | 10 |
| Homozygous | 2.3 | 20 |
| Factor V Leiden and prothrombin gene mutation | 5 | 20 |
| Antithrombin deficiency | 7 | 40 |
| Protein C deficiency | 0.5 | 5–15 |
| Protein S deficiency | 0.1 | Unknown |
Prophylaxis for APA syndrome and recurrent pregnancy loss
Several randomized trials have described the use of low-dose aspirin and heparin in women with APA syndrome and a history of recurrent pregnancy loss, although the results are inconsistent (TABLE 7).39-45 The inconsistency may be due to varying definitions of APA syndrome and gestational age at the time of randomization, as well as the population studied (previous thromboembolism, presence or absence of lupus anticoagulant, level of titer of anticardiolipin antibodies, presence or absence of previous stillbirth). Nevertheless, we recommend that women with true APA syndrome (presence of lupus anticoagulant, high titers of immunoglobulin G, history of thromboembolism or recurrent stillbirth) receive prophylaxis with low-dose aspirin, with subcutaneous heparin added once fetal cardiac activity is documented.46
TABLE 7
Live births in women with APA and a history of fetal loss
| STUDY | TREATMENT | CONTROL | NO. OF LIVE BIRTHS (%) | |
|---|---|---|---|---|
| TREATED WOMEN | CONTROL GROUP | |||
| Cowchock et al39 | Aspirin/heparin | Aspirin/prednisone | 9/12 (75) | 6/8 (75) |
| Laskin et al40 | Aspirin/prednisone | Placebo | 25/42 (60) | 24/46 (52) |
| Kutteh41 | Aspirin/heparin | Aspirin only | 20/25 (80) | 11/25 (44) |
| Rai et al42 | Aspirin/heparin | Aspirin only | 32/45 (71) | 19/45 (42) |
| Silver et al43 | Aspirin/prednisone | Aspirin only | 12/12 (100) | 22/22 (100) |
| Pattison et al44 | Aspirin | Placebo | 16/20 (80) | 17/20 (85) |
| Farquharson et al45 | Aspirin/LMWH | Aspirin only | 40/51 (78) | 34/47 (72) |
| LMWH=low-molecular-weight heparin | ||||
Genetic thrombophilias
Few published studies describe prophylactic use of low-molecular-weight heparin with or without low-dose aspirin in women with genetic thrombophilia and a history of adverse pregnancy outcomes. All but 1 of these studies are observational, comparing outcome in the treated pregnancy with that of previously untreated gestations in the same woman.3,9,38,44,45,47 These studies included a limited number of women and a heterogeneous group of patients with various thrombophilias; they also involved different therapies (TABLE 7).3,9,38,41,48,49
Gris et al47 performed a randomized trial in 160 women with at least 1 prior fetal loss after 10 weeks’ gestation who were heterozygous for factor V Leiden or prothrombin G20210A mutation, or had protein S deficiency. Beginning at 8 weeks’ gestation, these women were assigned to treatment with 40 mg of enoxaparin (n=80) or 100 mg of low-dose aspirin (n=80) daily. All women also received 5 mg of folic acid daily.
In the women treated with enoxaparin, 69 (86%) had a live birth, compared with 23 (29%) women treated with low-dose aspirin. The women treated with enoxaparin also had significantly higher median neonatal birth weights and a lower rate of IUGR (10% versus 30%). The authors concluded that women with factor V Leiden, prothrombin gene mutation, or protein S deficiency and a history of fetal loss should receive enoxaparin prophylaxis in subsequent pregnancies.
History of severe preeclampsia, IUGR, or abruptio placenta. No randomized trials have evaluated thromboprophylaxis in women with this history who have genetic thrombophilia. For this reason, any recommendation to treat these women with low-molecular-weight heparin with or without low-dose aspirin in subsequent pregnancies remains empiric. Prophylaxis can be prescribed after an appropriate discussion of risks and benefits with the patient.
Unresolved questions keep management experimental
What is the likelihood that a woman carrying a gene mutation that predisposes her to thrombophilia will have a serious complication during pregnancy? And how safe and effective is prophylaxis?
