Thrombophilia in pregnancy: Whom to screen, when to treat
Despite extensive research on testing and prophylaxis, a cautious approach is warranted
IN THIS ARTICLE
Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.
Why thrombophilia matters
During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.3
Pulmonary embolism is the leading cause of maternal death in the United States.1 Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.
Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.
Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.4
Thrombophilias are inherited or acquired
Prevalence of thrombophilias in women with normal pregnancy outcomes
Factor V Leiden mutation
Prothrombin gene mutation
Protein C and S deficiencies
* Combined rate
Link to adverse pregnancy outcomes
During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,2-6 which include the following maternal effects:
- Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
- Arterial thrombosis (peripheral, cerebral)
- Severe preeclampsia
Placental and fetal abnormalities include:
- Thrombosis and infarcts
- Abruptio placenta
- Recurrent miscarriage
- Fetal growth restriction
Preeclampsia and thrombophilia
The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.
An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.7 Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.7-25 Their findings range from:
- Factor V Leiden: 3.7% to 26.5%
- Prothrombin gene mutation: 0 to 10.8%
- Protein S deficiency: 0.7% to 24.7%
- MTHFR variant: 6.7% to 24.0%
A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.5 However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.
Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.8 This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.
Preeclampsia and APA syndrome
In 1989, Branch et al26 first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.26 Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.
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.
Incidence of thrombophilias in women with intrauterine growth restriction
FACTOR V LEIDEN (%)
PROTHROMBIN GENE MUTATION (%)
Kupferminc et al50
Infante-Rivard et al30
Verspyck et al51
McCowan et al52
Dizon-Townson et al*10
* <5th percentile
** 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
Incidence of factor V Leiden mutation in women with recurrent pregnancy loss
95% CONFIDENCE INTERVAL
Grandone et al53
≥2 unexplained fetal losses, other causes excluded
Ridker et al54
Recurrent, spontaneous abortion, other causes not excluded
Sarig et al55
≥3 first- or second-trimester losses or ≥1 intrauterine fetal demise, other causes excluded*
* Excluded chromosomal abnormalities, infections, anatomic alterations, and endocrine dysfunction
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.
How women with a previous adverse outcome fare on anticoagulation therapy
PREVIOUS ADVERSE PREGNANCY OUTCOME
OUTCOME IN CURRENT PREGNANCY
Riyazi et al9
LMWH and low-dose aspirin
Decreased recurrence of preeclampsia (85% to 38%) and IUGR (54% to 15%)
≥3 first-trimester recurrent pregnancy losses with thrombophilia
Higher live birth rate compared with historical controls (75% vs 20%)
Ogueh et al48
Previous adverse pregnancy outcome plus history of thromboembolic disease, family history of thrombophilia
No significant mprovement
Kupferminc et al38
Thrombophilia with history of preeclampsia or IUGR
LMWH and low-dose aspirin
With treatment, 3% recurrence of preeclampsia
Grandone et al53
Repeated pregnancy loss, gestational hypertension, HELLP, or IUGR
UFH or LMWH
90.3% treated with LMWH had good obstetric outcome
Paidas et al3
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.