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Obstetrics & Gynecology 2002;100:332-336
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Use of Selective Factor V Leiden Screening in Pregnancy to Identify Candidates for Anticoagulants

Pelle G. Lindqvist, MD, PhD, Per Olofsson, MD, PhD and Björn Dahlbäck, MD, PhD

From the Departments of Obstetrics and Gynecology, and Coagulation Disorders, Lund University, University Hospital, Malmö, Sweden.

Address reprint requests to: Pelle Lindqvist, MD, Department of Obstetrics and Gynecology, University Hospital, Malmö, S-20502 Malmö, Sweden; E-mail: pelle.lindqvist{at}obst.mas.lu.se.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To improve identification of gravidas at risk for thrombosis. Venous thromboembolic complications are a major cause of maternal mortality during pregnancy. Factor V Leiden, which causes activated protein C resistance, is the most prevalent thrombophilia in white populations. However, selective screening for factor V Leiden has not been evaluated previously for identifying women who might benefit from anticoagulant prophylaxis during pregnancy.

METHODS: We constructed a risk score based on major risk factors such as overweight, family history of thrombosis, previous thrombosis, cesarean delivery, and preeclampsia. A cohort of 2384 women with known factor V Leiden status was studied. Using the risk score and its distribution, we explored possible strategies of doing selective testing for factor V Leiden and their consequences.

RESULTS: During the postpartum period, but not antepartum, there is a possibility of identifying women at similar risk as those with a history of thrombosis. Women with a risk score of 2 (4% of women, 0.2% risk of thrombosis) would be screened for factor V Leiden, and those with a resulting risk score of at least 3 (ie, 1.2% risk of thrombosis) would be treated for 6 weeks. Theoretically, for every 83 women treated at this risk level, one thrombotic episode might be prevented.

CONCLUSION: By using a risk score, a subgroup of women who could benefit from selective factor V Leiden screening were identified postpartum.

Thromboembolic complications are a major cause of maternal mortality and morbidity during pregnancy.1,2 The incidence of deep venous thrombosis related to pregnancy (ie, deep venous thrombosis or pulmonary embolism occurring during or up to 6 weeks after delivery) is 13 in 10,000 pregnancies in Sweden, equally distributed between the antepartum and postpartum periods.3 Maternal obesity, family history of thrombophilia, cesarean delivery, and preeclampsia are major risk factors traditionally associated with thrombosis during pregnancy. Each of these factors exposes a woman to approximately a five-fold increased risk of de novo thrombosis during pregnancy.3,4 Activated protein C resistance caused by the Leiden mutation (factor V Leiden or factor V: Q506) has been identified as the most prevalent heritable thrombophilia in whites.5–7 Factor V Leiden is present in 3–15% of the general white population and in 15–50% of individuals with thrombosis.8 Women heterozygous for factor V Leiden run a five-fold to ten-fold increased risk of thrombosis,4 and homozygous women a ten-fold to 75-fold increased risk.9,10 A general screening for factor V Leiden before starting oral contraceptives or in early pregnancy has been suggested but has not proven effective.4,11 A third category of women at risk are those with previous venous thromboembolic complications; they run a 10–15% risk of rethrombosis related to pregnancy.12,13 These women are routinely prescribed anticoagulant prophylaxis during pregnancy and the postpartum period.

Women with a single risk factor of thrombosis might only run a slightly increased risk, but women with multiple risk factors could have a risk similar to those currently prescribed prophylactic anticoagulants. Women at risk of thrombosis, where an additional five-fold increased risk would warrant a change in clinical treatment, might benefit from factor V Leiden testing (selective screening). The value of selective screening has not previously been investigated. With the aim of constructing an improved model for identifying women who might benefit from anticoagulant prophylaxis, we introduced selective screening for factor V Leiden on the basis of a risk score and its distribution.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
During a 17-month period, pregnant women in Malmö were approached to participate in the study. Of the 2496 gravidas who entered the study, 112 were excluded; 96 women had had abortions (63 early spontaneous abortions [before 13 weeks’ gestation], 19 late abortions [at 13 to 27 weeks], and 14 induced abortions, in eight cases on fetal indications [three cases of chromosomal aberrations, two of central nervous system defects, and three of structural anomalies]); three women (one of whom had factor V Leiden) were delivered at home, 11 were delivered abroad, one could not be identified from the interview form (reference number inadvertently omitted), and one died of meningococcal septicemia during pregnancy. Of the remaining 2384 women, 1899 were delivered at University Hospital, Malmö, and 485 at other Swedish hospitals. Thus, 2384 women were included in the study. At their first routine visit to the Maternal Health Care Services, they were interviewed, and blood was drawn for factor V Leiden testing. The study was approved by the Ethics Committee of the University of Lund, and informed written consent was obtained from all participants.

Carriership of factor V Leiden was defined as either heterozygous or homozygous. Blood samples were centrifuged and stored in a -70C freezer, and factor V Leiden analyses were done no earlier than 3 months after each woman had delivered. A modified functional activated protein C resistance test using factor V-deficient plasma, Coatest activated protein C resistance-V (Chromogenix; Göteborg, Sweden), was performed as previously described.14 Individuals with a ratio below 1.86 were tested with polymerase chain reaction (PCR)-based analysis for the presence of factor V Leiden.14 Women with a ratio of 1.86 or higher were assumed to be noncarriers, a conclusion supported by the results of parallel analysis with the activated protein C resistance-V assay and PCR analyses. The latter was performed in 415 women, of whom 257 carried the factor V Leiden genotype. All women with a normal factor V genotype had a ratio of 1.67 or higher, and all those with factor V Leiden had a ratio of 1.64 or lower. In three women with a previous history of venous thromboembolism, the presence of factor V Leiden status was already known. Eight women with a history of thrombosis and two women with a solid family history of thrombosis were scheduled for anticoagulant prophylaxis.

Thrombosis was defined as a deep venous thrombosis, pulmonary embolism, or cerebral thromboembolism occurring in pregnancy or during the first 3 months postpartum. A family history of thrombosis was defined as one or more thromboses in a first-degree relative (father, mother, or sibling) occurring before age 60 years. Maternal weight and height were recorded at the first antenatal visit. Overweight was defined as a body mass index (BMI [kg/m2]) exceeding 27.6 (ie, more than one standard deviation above the mean for the series, see Table 1Go). Preeclampsia was defined as pregnancy-induced hypertension and proteinuria of 0.3 g/L or higher (Albustix, Boehringer, Mannheim, Germany). Pregnancy-induced hypertension was defined as a resting diastolic blood pressure greater than 90 mm Hg, measured on two consecutive occasions with an interval of at least 5 hours, and developing after 20 weeks’ gestation in a previously normotensive woman.


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  		Table 1. Clinical Characteristics of the Study Population (n 3 2384)
 
The following risk factors were each roughly estimated to entail a five-fold increased risk of thrombosis: overweight (odds ratio [OR] 5.2),4 family history of thrombosis (OR 7.6),4 heterozygous factor V Leiden (OR 4.6),4 cesarean delivery (OR 4.9),3 and preeclampsia (OR 3.0).3 Women were assigned a risk score of 1 for each condition. Homozygous carriers of factor V Leiden were assigned a risk score of 2, and women with a history of thrombosis a risk score of 4 (the score closest to 5% risk). Preeclampsia and cesarean delivery were considered as risk factors only during the postpartum period.3 The factor V Leiden status was included in the risk score but not in the anamnestic risk score. The risk score (denoted by the letter n) thus represents a 5n-fold increased risk of thrombosis, compared with the baseline incidence of thrombosis, ie, having a risk score of 0 or without major risk factors. Thus, a risk score of 2 represents a 52 (5 x 5 = 25-fold) increased risk, a score of three represents a 53 (125-fold) increased risk.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The clinical characteristics of study subjects are shown in Table 1Go. The distribution of the anamnestic risk score in the antepartum period is shown in Table 2Go and for the postpartum period in Table 3Go. The eight women with an antepartum risk score of at least 4 all had a history of thrombosis (Table 2Go). The testing for factor V Leiden mutation revealed that 10.6% (n = 252) of the population was heterozygous and 0.2% (n = 5) homozygous for the mutation. Tables 2Go and 3Go also show the distribution of risk scores after inclusion of factor V Leiden status.


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  		Table 2. Distribution of Antepartum Risk Score, Without and With the Factor V Leiden Mutation
 

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  		Table 3. Distribution of Postpartum Risk Score, Without and With the Factor V Leiden Mutation
 
Three pregnant women had antepartum thrombosis, and three parturients had postpartum thrombosis, for an overall uncorrected incidence of six per 2384 subjects (25 of 10,000) in the series. Three of these six women were carriers of factor V Leiden. The three women with antepartum thrombosis had risk scores of 4, 2, and 0, and the three with postpartum thrombosis 2, 2, and 2. These figures were comparable to the theoretically estimated number of thromboses in each subgroup (Table 4Go).


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  		Table 4. Estimated Number of Expected Thromboses in the Series During Pregnancy and Postpartum
 
To estimate the baseline incidence of thrombosis (ie, the thrombosis incidence among those with risk score 0), one could transform the distribution of risk to number of women with risk score 0 (ie, one woman with risk score 1 equals the risk of five women with risk score 0, etc). By combining these figures with the average thrombosis incidence (6.5 per 10,000 antepartum and 6.5 per 10,000 postpartum), the baseline incidence of thrombosis can be calculated (baseline incidence per 10,000 = 2384 x 6.5/number of women with risk score 0 per 10,000). In the antepartum period, 1735 women had a risk score of 0, 572 a risk score of 1 (ie, equals 572 x 5 = 2860 at risk score 0), 63 had a risk score of 2 (ie, equals 63 x 5 x 5 = 1575 at risk score 0), five had a risk score 3 (ie, equals 5 x 5 x 5 x 5 = 625 at risk score 0), and nine had a risk score of at least 4 (ie, equals 9 x 5 x 5 x 5 x 5 = 5500 risk score 0, see Table 2Go). These figures might be added (1735 + 2860 + 1575 + 625 + 5625 = 12,420) to total 12,420. Thus, 12,420 women with risk score 0 will have the same thrombosis incidence as the 2384 women in our study population (ie, 6.5 per 10,000). The baseline incidence of antepartum thrombosis is estimated to be (2384/ 12,420) x 6.5/10,000 = 1.2 per 10,000.

The respective calculations for the postpartum period are 1581 women with a risk score of 0, 627 with a risk score of 1 (ie, equals 627 x 5 = 3135 risk score 0), 146 with a risk score of 2 (ie, equals 146 x 5 x 5 = 3650 risk score 0), 21 with a risk score of 3 (ie, equals 21 x 5 x 5 x 5 = 2625 risk score 0), and nine with a risk score of at least 4 (ie, equals 9 x 5 x 5 x 5 x 5 = 5625 risk score 0) (see Table 3Go). These figures might be added (1581 + 3135 + 3650 + 2625 + 5625 = 16,616) to total 16,616. Thus, 16,616 women with a risk score 0 will have the same thrombosis incidence as the 2384 women in our study population (ie, 6.5 per 10,000). The baseline postpartum thrombosis incidence is estimated to be (2384/16,616) x 6.5/10,000 = 0.93 per 10,000.3 Women with postpartum risk scores of 1, 2, and 3, respectively, would thus have a 0.05%, 0.2%, and 1.2% incidence of thrombosis (Table 4Go).

The number of months of anticoagulant prophylaxis needed to prevent one thrombotic episode in the antepartum and postpartum periods can be calculated. Presently, in women with a history of thrombosis (ie, at 5% [one in 20] risk of thrombosis), we recommend prophylaxis for 6 months antepartum and 1.5 months postpartum. Thus, in this category 120 months of antepartum prophylaxis are needed to prevent one thrombotic episode (6 months treatment of 20 women). Using similar calculations, the number of months of prophylaxis needed to prevent one thrombotic event in women at risk score 3 can be calculated. In the antepartum period with a thrombosis risk of 1.6% (one in 63), 378 months (63 x 6) of prophylaxis is required to prevent one thrombotic event. In the postpartum period, these women have a risk of 1.2% (one in 83), and so 125 months (83 x 1.5) of prophylaxis would be needed.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this unselected series of gravidas, 18.6% had at least one anamnestic risk factor that exposed them to higher risk of thrombosis in pregnancy, and 26.2% were at similar risk in the postpartum period. After addition of the factor V Leiden test result to the anamnestic risk score, the risk figures increased to 27.2% antepartum and 33.7% postpartum.

We constructed a risk score based on major risk factors for thrombosis and have presented the distribution of risk scores with and without factor V Leiden status. Our aim was to explore strategies for selective screening for factor V Leiden to improve the identification of women requiring anticoagulant prophylaxis. The development of a risk score is based on the following assumptions: 1) a multiplicative relationship exists between risk factors and thrombosis risk; 2) some women may run the same risk as those currently prescribed thrombosis prophylaxis; and 3) women at risk of thrombosis, where a five-fold additional risk of thrombosis would change their clinical treatment, might benefit from selective screening for factor V Leiden.

There seems to be a multiplicative relationship between risk factors (ie, the measurements of relative risk can be multiplied to obtain the resulting relative risk).10,15 The assumption of a multiplicative relationship is supported, at least in part, by the risk scores of those who developed thrombosis in our population. A drawback of our study is that multiple relationships have not been shown for all included risk factors. However, because the selected variables are major risk factors, they will presumably help to improve identification of gravidas at high risk even if their relationship is additive. In Sweden, women with earlier thromboembolic complications routinely are prescribed anticoagulants during pregnancy and for the first 6 weeks postpartum. Without anticoagulant treatment, these women would have a roughly 10% incidence of rethrombosis (5% antepartum and 5% postpartum).12,13

In the antepartum period, the subgroup with a risk score of 2, representing 0.9% of the series (22 of 2384), is notable (Table 2Go). One-fifth (five of 22) of these women were carriers of factor V Leiden, making them a high-risk group for thrombosis. This subgroup, with a risk score of 3 and comprising 0.2% of the total series, are at 1.6% risk of thrombosis (Table 4Go). However, this risk is lower than the risk of those being treated today with anticoagulant therapy (5.0% risk).

In the postpartum period, women with a risk score of 3, comprising 0.3% of the total series, would run a similar risk per month as those currently receiving anticoagulants during pregnancy. A possible strategy would be to test women with an anamnestic risk score of 2 (4% of the total series) for factor V Leiden. The aim would be to treat those with a resulting risk score of at least 3 (1.2% risk of thrombosis) for 6 weeks postpartum. Thus, the 0.9% of the population at this risk level (of whom 0.6% [14 of 2384] might be identified through selective factor V Leiden screening) would continue on prophylaxis for 6 weeks.

A second treatment option would be to differentiate the duration of prophylaxis. The risk of thrombosis is greatest immediately peripartum.16 Therefore, women with two anamnestic risk factors who were screened for factor V Leiden might benefit from a single dose or short-term treatment with anticoagulants. However, it remains to be determined whether this treatment is effective.

Because approximately one-third of all women have a postpartum risk score of at least 1, we do not believe that routine thrombosis prophylaxis is indicated for all heterozygous carriers of factor V Leiden, as suggested elsewhere.17 Absent other risk factors, these women run a five-fold higher risk above the baseline risk (5 x 0.9/10,000); ie, they have a 0.05% incidence of postpartum thrombosis. This means that about 2000 women would need to be treated to protect one woman from thrombosis. Because the effectiveness of thrombosis prophylaxis is not 100%, the number of women requiring prophylaxis would be even larger.

The risk level at which to initiate anticoagulant prophylaxis is open to debate and might be higher or lower than that used in Sweden. However, we believe that our figures of risk distribution, together with the strategy for selective testing, might be used in clinical treatment independent of the chosen risk level.

The information about risk factors, both for anamnestic risks and factor V Leiden, was gathered prospectively; therefore, all recall bias can be excluded. Because women entered prospectively early in the study, we believe the risk of selection bias is low.

An uncertainty in our discussion of strategies is the effectiveness of anticoagulant prophylaxis during pregnancy, which is not well proven. Further studies are urgently needed. Assuming 70% protection with anticoagulant therapy, in order to estimate the efficacy of prophylactic treatment on women predicted to have a 5% risk of developing thrombosis, as measured by a two-sided statistical test, a 5% significance level, and a power of 80%, it would be necessary—according to our strategy for selective screening in a randomized trial—to include 400 women in each group. Thus, multicenter studies are probably needed.


   Footnotes
 
This study was supported by University Hospital, Malmö, research funds.

PII S0029-7844(02)02092-6

Received October 16, 2002. Received in revised form March 22, 2002. Accepted April 11, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Report on confidential enquiries into maternal deaths in the United Kingdom, 1985–87. London: HMSO, 1991.

2. Högberg U, Innala E, Sandström A. Maternal mortality in Sweden, 1980–1988. Obstet Gynecol 1994;84:240–4.[Abstract/Free Full Text]

3. Lindqvist P, Dahlbäck B, Marsal K. Thrombotic risk during pregnancy: A population study. Obstet Gynecol 1999;94:595–9.[Abstract/Free Full Text]

4. Lindqvist PG, Svensson PJ, Marsal K, Grennert L, Lutherkort M, Dahlbäck B. Activated protein C resistance (FV: Q506) and pregnancy. Thromb Haemost 1999;81:532–7.[Medline]

5. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993;90:1004–8.[Abstract/Free Full Text]

6. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–7.[Medline]

7. Dahlbäck B. Blood coagulation. Lancet 2000;355: 1627–32.[Medline]

8. Lindqvist PG. Risk estimation and prediction of preeclampsia, IUGR, and thrombosis in pregnancy. Thesis Department of Obstetrics and Gynecology, Malmö: University of Lund. Available at: http://www.lub.lu.se/luft/diss/med377_transit.html. Accessed July 1, 2002.

9. Svensson PJ, Zöller B, Mattiasson I, Dahlbäck B. The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis. J Intern Med 1997; 241:379–85.[Medline]

10. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85: 1504–8.[Abstract/Free Full Text]

11. Palareti G, Legnani C, Frascaro M, Flamigni C, Gammi L, Gola G, et al. Screening for activated protein C resistance before oral contraceptive treatment: A pilot study. Contraception 1999;59:293–9.[Medline]

12. Tengborn L, Bergqvist D, Matzsch T, Bergqvist A, Hedner U. Recurrent thromboembolism in pregnancy and puerperium. Is there a need for thromboprophylaxis? Am J Obstet Gynecol 1989;160:90–4.[Medline]

13. Badaracco MA, Vessey MP. Recurrence of venous thromboembolic disease and use of oral contraceptives. Br Med J 1974;1:215–7.

14. Zöller B, Dahlbäck B. Linkage between inherited resistance to activated protein C and factor V gene mutation in venous thrombosis. Lancet 1994;343:1536–8.[Medline]

15. Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deepvein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995;346:1593–6.[Medline]

16. Salonen Ros H, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001;12: 456–60.[Medline]

17. De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: Clinical implications. Semin Thromb Hemost 1998;24:367–79.[Medline]




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Thromboembolism: Reducing maternal death and disability during pregnancy
Br. Med. Bull., December 1, 2003; 67(1): 177 - 190.
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