In the United States as well as the developed world, pregnancy-related venous thromboembolism is the most common cause of venous thromboembolism death.1,2 Compared with the nonpregnant state, the risk of venous thromboembolism increases fourfold to fivefold during pregnancy. The overall incidence of venous thromboembolism during pregnancy is estimated at 2 per 1,000 deliveries.3,4
One risk factor for venous thromboembolism in pregnancy is thrombophilia.4,5 Almost half the cases of pregnancy-related venous thromboembolism occur in women with an inherited or acquired thrombophilia.6 The Leiden mutation is the most common inherited thrombophilia, with a heterozygous carrier prevalence ranging from 3–7% in the United States and European populations.7 In its heterozygous form, it is associated with as much as an eightfold increase in thrombotic risk.8 Homozygous inheritance, however, confers around a 30-fold increase in relative risk of thrombosis.8
Universal screening for factor V Leiden has not been considered cost-effective given the relatively high prevalence of inherited thrombophilias and the rarity of venous thromboembolism; nearly 8,000 women would need to be screened for factor V Leiden to detect 400 mutations to prevent 1 episode of venous thromboembolism.9 Selective thrombophilia screening has been advocated in women with a personal or family history of venous thromboembolism to identify those at increased risk of thrombotic complications during and outside of pregnancy.10 Despite the widespread acceptance of this recommendation, limited evidence exists on the reliability of family history to detect the most common thrombophilic defects.11–13
To date, no study has evaluated the utility of a family history of venous thromboembolism as a screening tool to identify women at risk for factor V Leiden during pregnancy. The objective of this study was to estimate the sensitivity and positive predictive value of a positive family history of venous thromboembolism for factor V Leiden mutation among gravid women without a personal history of thrombosis.
MATERIALS AND METHODS
This is a secondary analysis of the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Maternal–Fetal Medicine Units Network factor V Leiden study. The factor V Leiden study was a prospective observational multicenter study of 5,168 women with a singleton pregnancy. Women with current or planned anticoagulation therapy, known factor V Leiden status, antiphospholipid syndrome, prior thrombosis, fetal demise, or planned pregnancy termination were excluded. Institutional review board approval was obtained from the University of North Carolina. The primary objective was to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden mutation without a personal history of thromboembolism. Full details on the study design, data collection, and results have been reported previously.14
The outcome of interest in this study was factor V Leiden heterozygous carriage in women who reported a positive family history (first- or second-degree relative) of a thromboembolic event in this cohort of women. In this registry, the presence of a positive family history of venous thromboembolism was based on self-report at the time of study enrollment. Women reported the presence or absence of a family history of venous thromboembolism. If present, women then identified the affected family member, and this relationship was documented in the study record. A family history was regarded as positive if venous thromboembolism was reported in at least one first-degree relative or second-degree relative or both. Sensitivity, specificity, and positive and negative predictive values of family history to predict factor V Leiden carrier status and likelihood ratios were calculated by first-degree and first- or second-degree relative history. With 140 factor V Leiden carriers, there was a sufficient sample size to estimate sensitivity with a 95% confidence interval (CI) half-width no more than 8.3%. Likewise, with more than 4,700 noncarriers, the precision in terms of 95% CI half-width was 1.5%.
Continuous variables were analyzed using the Wilcoxon rank sum test, and categorical variables were analyzed using the χ2 test. The association between factor V Leiden mutation carriage and family history of venous thromboembolism were assessed using Pearson's χ2 test, and 95% CIs for proportions were calculated. A value of P<.05 was considered significant.
A total of 5,168 women without a personal history of venous thromboembolism had factor V Leiden DNA results available and were included in this analysis. Factor V Leiden mutation heterozygous carrier status was identified in 140 women (2.7% [95% CI 2.3–3.2%]). Positive family history of venous thromboembolism was reported in 412 women (8.0% [95% CI 7.3–8.7%]). Of those who reported a positive family history, 23 women were found to be carriers of the factor V Leiden mutation. None of the 23 women found to be carriers of the factor V Leiden mutation developed venous thromboembolism. Maternal demographic characteristics based on family history are listed in Table 1. Women with a positive family history were more likely to be white, smoke cigarettes, and have higher education levels in comparison with women with a negative family history.
Women with a positive family history of venous thromboembolism were more likely to be factor V Leiden carriers than women with a negative family history (23 of 412 [5.6%] compared with 117 of 4,756 [2.5%], P<.001). Sensitivity, specificity, and positive and negative predictive values of family history to predict factor V Leiden carrier status and likelihood ratios are listed in Table 2. For patients with a positive family history of venous thromboembolism, the probability of having factor V Leiden, the positive predictive value of the test is 5.6% (95% CI 3.6–8.3%) (Table 2). The positive predictive value was similar regardless of whether a first- or second-degree relative experienced venous thromboembolism (5.0% [95% CI 2.3–9.3%] and 5.6% [95% CI 3.6–8.3%], respectively).
Among white women, the prevalence of factor V Leiden was 6.1% (95% CI 5.0–7.4%). The sensitivity of a first- or second-degree relative to predict factor V Leiden mutation was 22.7% (95% CI 14.8–32.3%), the specificity was 84.3% (95% CI 82.4–86.1%), and the likelihood ratio for positive family history of venous thromboembolism was 1.4 (95% CI 1.0–2.1). The positive predictive value remained poor (8.6% [95% CI 5.4–12.7%]).
Our analysis shows that a positive family history with at least one first- or second-degree relative with venous thromboembolism is a poor predictor of factor V Leiden mutation carrier status in gravid women without a personal history of thrombosis. Although this association between a positive family history and factor V Leiden carriage is significant, a positive family history does not appear to be a reliable screening method for factor V Leiden.
A personal history of thrombosis and the presence of a thrombophilia7 are two of the risk factors with the highest association with venous thromboembolism.5 Thrombophilia is present in up to 50% of women who experience venous thromboembolism during pregnancy and postpartum.15 Although factor V Leiden is the most common inherited form of thrombophilia, universal screening is not recommended.10 To identify those women who are at increased risk of thrombotic complications during and outside of pregnancy, selective screening based on personal and family history has been suggested by some.10
Currently, no consensus exists on the value of family history for the selection of patients who should be screened for an inherited thrombophilia. Our finding of a poor sensitivity and positive predictive value of a positive family history is consistent with available literature regarding nonpregnant individuals.11–13 Cosmi et al12 prospectively evaluated 479 thrombosis-free women before the initiation of oral contraceptives. In this study, the sensitivity and positive predictive value for a positive family history of a first-degree relative to predict factor V Leiden carrier status were 6.7% (95% CI 0–32%) and 3.1% (95% CI 0–16%), respectively. When first- or second-degree relatives were combined, the sensitivity and positive predictive value for a positive family history to predict factor V Leiden carrier status were similar, 6.7% (95% CI 0–32%) and 2.1% (95% CI 0–11%), respectively.12 Our results may actually overestimate the association, as there may have been women who enrolled in the factor V Leiden study motivated to participate in the study because of a relative with a prior venous thromboembolism and underlying thrombophilia.
There are several limitations to our study that warrant discussion. Family history of venous thromboembolism was self-reported and not confirmed through objective documentation in medical records. Family history of venous thromboembolism was not further defined to distinguish between superficial or deep vein thrombosis or pulmonary embolism. Age and the number of affected family members were also not taken into account. We considered a family history as positive when only one first- or second-degree relative was reported to have had a venous thromboembolism. Although second-degree relatives were included in the analysis, they were not analyzed separately. Second-degree and more distant relatives likely have a lower baseline risk of venous thromboembolism through a dilution of effect of other inherited predispositions.16 To date, a uniform definition of a positive family history has not been established.
In this analysis, our interest was the use of a positive family history of venous thromboembolism as a screening tool to identify carriers of factor V Leiden, the most common inherited thrombophilia. We further evaluated the role of a positive family history among whites, given its highest prevalence in this racial category, and found similar results when compared with the entire cohort of women. Other thrombophilias, such as the prothrombin G20210A mutation, protein C deficiency, and protein S deficiency, were not included in this analysis and therefore the utility of family history to determine risk for these inherited thrombophilias cannot be extrapolated from our data.
How should these findings be incorporated into clinical practice? This study was prompted by the question of whether clinicians can identify gravid women who should be screened for factor V Leiden on the basis of a positive family history of venous thromboembolism. The results indicate that selective screening for factor V Leiden based on family history fails to identify a substantial number of women who are carriers of this common thrombophilia. Given the high specificity, women with a negative family history can be reassured it is unlikely they are carriers of the factor V Leiden mutation. As the risk of thromboembolic events in untreated heterozygotes for the factor V Leiden mutation without evident risk factors for thrombosis is low, neither universal nor selective screening based on a positive family history for the factor V Leiden mutation is warranted during pregnancy.
1. Berd CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancy-related mortality in the United States, 1991–1997. Obstet Gynecol 2003;101:289–96.
2. Marik PE, Planta LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025–33.
3. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ III. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697–706.
4. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311–5.
5. James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol 2009;29:326–31.
6. Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353:1258–65.
7. Price DR, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 1997;127:895–903.
8. Roberston L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132:171–96.
9. Clark P, Twaddle S, Walker ID, Scott L, Greer IA. Cost-effectiveness of screening for the factor V Leiden mutation in pregnant women. Lancet 2002;359:1919–20.
10. Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, et al. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol Assess 2006;10:1–110.
11. Cosmi B, Legnani C, Bernard F, Coccheri S, Palareti G. Value of family history in identifying women at risk of venous thromboembolism during oral contraception: observational study. BMJ 2001;322:1024–5.
12. Cosmi B, Legnani C, Bernardi F, Coccheri A, Palareti G. Role of family history in identifying women with thrombophilia and higher risk of venous thromboembolism during oral contraception. Arch Intern Med 2003;163:1105–9.
13. Schambeck CM, Schwender S, Haubitz I, Geisen UE, Grossman RE, Keller F. Selective screening for the Factor V Leiden mutation: is it advisable prior to the prescription of oral contraceptives? Thromb Haemost 1997;78: 1480–3.
14. Dizon-Townson D, Miller C, Sibai B, Spong CY, Thom E, Wendel G Jr, et al. The relationship of the factor V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet Gynecol 2005;106:517–24.
15. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80.
16. Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review. Thromb Haemost 2003;90:17–26.
Figure. No caption available.