Thrombophilia in pregnancy: Whom to screen, when to treat
Despite extensive research on testing and prophylaxis, a cautious approach is warranted
IN THIS ARTICLE
No need to screen women with abruptio placenta
The placental circulation is comparable to venous circulation, with low pressure and low flow velocity rendering it susceptible to thrombotic complications at the maternal–placental interface and consequent premature separation of the placenta.
It is difficult to confirm an association between thrombophilia and abruptio placenta because of confounding variables such as chronic hypertension, cigarette and cocaine use, and advanced maternal age.3 Studies reviewing this association are scarce, and screening for thrombophilia is discouraged in pregnancies marked by abruptio placenta.
Kupferminc et al28 found that 25%, 20%, and 15% of thrombophilia patients with placental abruption had mutations in factor V Leiden, prothrombin gene, and MTHFR, respectively. In contrast, Prochazka et al29 found 15.7% of their cohort of patients with abruptio placenta to have factor V Leiden mutation.
A large prospective, observational study of more than 5,000 asymptomatic pregnant women at multiple centers found no association between abruptio placenta and factor V Leiden mutation.8 Nor were there cases of abruptio placenta among 134 women who were heterozygous for factor V Leiden.
And no routine screening in cases of IUGR
Routine screening for thrombophilias in women with intrauterine growth restriction (IUGR) is not recommended. One reason: The prevalence of thrombophilias in these women ranges widely, depending on the study cited: from 2.8% to 35% for factor V Leiden and 2.8% to 15.4% for prothrombin gene mutation (TABLE 3). In addition, in contrast to earlier studies, a large case-control trial by Infante-Rivard et al30 found no increased risk of IUGR in women with thrombophilias, except for a subgroup of women with the MTHFR variant who did not take a prenatal multivitamin.
A recent meta-analysis of case-control studies by Howley et al31 found a significant association between factor V Leiden, the prothrombin gene variant, and IUGR, but the investigators cautioned that this strong association may be driven by small, poor-quality studies that yield extreme associations. A multicenter observational study by Dizon-Townson et al8 found no association between thrombophilia and IUGR in asymptomatic gravidas.
TABLE 3
Incidence of thrombophilias in women with intrauterine growth restriction
| STUDY | FACTOR V LEIDEN (%) | PROTHROMBIN GENE MUTATION (%) | ||
|---|---|---|---|---|
| IUGR | CONTROLS | IUGR | CONTROLS | |
| Kupferminc et al50 | 5/44 (11.4) | 7/110 (6.4) | 5/44 (11.4) | 3/110 (2.7) |
| Infante-Rivard et al30 | 22/488 (4.5) | 18/470 (3.8) | 12/488 (2.5) | 11/470 (2.3) |
| Verspyck et al51 | 4/97 (4.1) | 1/97 (1) | 3/97 (3.1) | 1/97 (1) |
| McCowan et al52 | 4/145 (2.8) | 11/290 (3.8) | 4/145 (2.8) | 9/290 (3.1) |
| Dizon-Townson et al*10 | 6/134 (4.5) | 233/4,753 (4.9) | NR | NR |
| Kupferminc**34 | 9/26 (35) | 2/52 (3.8) | 4/26 (15.4) | 2/52 (3.8) |
| * | ||||
| ** Mid-trimester severe intrauterine growth restriction | ||||
| IUGR=intrauterine growth restriction, NR=not recorded | ||||
| SOURCE: Adapted from Clin Obstet Gynecol. 2006;49:850–860 | ||||
Fetal loss is a complication of thrombophilia
One in 10 pregnancies ends in early death of the fetus (before 20 weeks), and 1 in 200 gestations ends in late fetal loss.32 When fetal loss occurs in the second and third trimesters, it is due to excessive thrombosis of the placental vessels, placental infarction, and secondary uteroplacental insufficiency.2,33 Women who are carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are (TABLE 4).
Fetal loss is a well-established complication in women with thrombophilia, but not all thrombophilias are associated with fetal loss, according to a meta-analysis of 31 studies.33 In women with thrombophilia, first-trimester loss is generally associated with factor V Leiden, prothrombin gene mutation, and activated protein C resistance. Late, nonrecurrent fetal loss is associated with factor V Leiden, prothrombin gene mutation, and protein S deficiency.33
TABLE 4
Incidence of factor V Leiden mutation in women with recurrent pregnancy loss
| STUDY | PATIENT SELECTION | PATIENTS (%) | CONTROLS (%) | ODDS RATIO | 95% CONFIDENCE INTERVAL |
|---|---|---|---|---|---|
| Grandone et al53 | ≥2 unexplained fetal losses, other causes excluded | 7/43 (16.3) | 5/118 (4.2) | 4.4 | 1.3–14.7 |
| Ridker et al54 | Recurrent, spontaneous abortion, other causes not excluded | 9/113 (8) | 16/437 (3.7) | 2.3 | 1.0–5.2 |
| Sarig et al55 | ≥3 first- or second-trimester losses or ≥1 intrauterine fetal demise, other causes excluded* | 96/145 (66) | 41/145 (28) | 5.0 | 3.0–8.5 |
| * Excluded chromosomal abnormalities, infections, anatomic alterations, and endocrine dysfunction | |||||
History of adverse outcomes? Offer screening
It is well established that women with a history of fetal death, severe preeclampsia, IUGR, abruptio placenta, or recurrent miscarriage have an increased risk of recurrence in subsequent pregnancies.3,30,34-36 The rate of recurrence of any of these outcomes may be as high as 46% with a history of 2 or more adverse outcomes, even before any thrombophilia is taken into account.3 Although there are few studies describing the rate of recurrence of adverse pregnancy outcomes in women with thrombophilia and a previous adverse outcome (TABLE 5), it appears to range from 66% to 83% in untreated women.3,37
Based on these findings, some authors recommend screening for thrombophilia in women who have had adverse pregnancy outcomes3,9,38 and prophylactic therapy in subsequent pregnancies when the test is positive. Therapy includes low-dose aspirin with or without subcutaneous heparin, as well as folic acid and vitamin B6 supplements, according to the type of thrombophilia present as well as the nature of the previous adverse outcome.
