Abstract

There is strong evidence that the incidence of venous thromboembolism (VTE) is increased during pregnancy. However, it is unknown whether and to which extent pregnancy influences the risk for recurrent VTE in women with previous thrombosis. To investigate whether pregnancy temporarily increases the risk for recurrent thrombosis, we retrospectively evaluated the recurrence rate in 109 women who had at least one pregnancy after an episode of VTE by comparing the time period during pregnancy with the nonpregnant period. Forty-three women had a first recurrence during a total observation time of 1014 years. Eight events (73 observation years) occurred during pregnancy, and 35 events (941 observation years) occurred outside pregnancy. Recurrence rates per 100 patient-years were 10.9% during and 3.7% outside pregnancy. Relative risk during pregnancy was 3.5 (95% confidence interval, 1.6-7.8; P = .002). Our data suggest that pregnancy leads to a temporary increase in the risk for recurrent thrombotic events.

Introduction

Venous thromboembolism (VTE) occurs infrequently but is a leading cause of maternal death.1 Debate is ongoing about whether pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation therapy. Estimates of the rate of recurrent VTE during pregnancy vary; in retrospective studies, rates as high as 12% have been found.2 In a recent prospective study, Brill-Edwards et al3 found a low risk for recurrent antepartum VTE despite withholding prophylactic anticoagulation, and they concluded that antepartum prophylaxis should be considered only in patients with idiopathic thrombosis and those with thrombophilia.

In the general population, pregnancy increases the risk for VTE approximately 5-fold.4 No data in the literature show how pregnancy influences the risk for recurrent VTE in women with previous thrombosis. To investigate whether pregnancy temporarily increases the risk for recurrent thrombosis, we studied women with a history of VTE and evaluated their risk for recurrence during pregnancy in comparison with durations when they were not pregnant.

Study design

Patients

Nine hundred seventy-three consecutive women with a history of objectively confirmed VTE that had occurred when they were between the ages of 13 and 45 years were investigated, between 1985 and 1998, for risk factors for thrombosis, and they were invited for reinvestigation in 1999. Five hundred seven women accepted. Blood samples were drawn, and the women underwent standardized interviews on their history of thrombosis and pregnancy-associated complications.5 One hundred nine women had at least one pregnancy (in total, 180 pregnancies) without thrombosis prophylaxis after a single VTE and were included in the study. The median age was 38 years (range, 22-76 years) at inclusion and 24 years (range, 14-42 years) at first VTE. At first thrombosis, 94 women had at least one temporary risk factor: oral contraceptive (OC) use, 56; surgery, 14 (5 with additional OC); trauma, 11 (6 with OC); pregnancy, 5; delivery, 15; immobilization, 7 (5 with OC); other conditions, 2. Fifteen women had no temporary risk factor at first event. Thrombosis risk factors in the patients were determined as previously described5 and are listed in Table1. Recurrent thrombotic events were categorized as definite when they were objectively confirmed by ultrasonography, phlebography, ventilation-perfusion lung imaging, or computed tomography and as probable when clinical symptoms were typical and led to anticoagulation.

Table 1.

Laboratory risk factors for thrombosis in 109 women with a history of VTE

Risk factors Abnormality/total Percentage 
None 39 of 101* 39.0 
Heterozygous factor V:R506Q 38 of 109 35.0  
Homozygous factor V:R506Q 5 of 109 4.6  
Heterozygous G20210A prothrombin 8 of 107 7.5  
Antithrombin deficiency 2 of 109 1.8  
Protein C deficiency 5 of 109 4.6  
Protein S deficiency 5 of 109 4.6  
Hyperhomocystinemia 11 of 101 11.0  
Elevated factor VIII 12 of 102 12.0  
Lupus anticoagulant 3 of 109 2.8  
Of these   
 Two risk factors combined 13 of 101* 13.0  
 Three risk factors combined 3 of 101* 3.0 
Risk factors Abnormality/total Percentage 
None 39 of 101* 39.0 
Heterozygous factor V:R506Q 38 of 109 35.0  
Homozygous factor V:R506Q 5 of 109 4.6  
Heterozygous G20210A prothrombin 8 of 107 7.5  
Antithrombin deficiency 2 of 109 1.8  
Protein C deficiency 5 of 109 4.6  
Protein S deficiency 5 of 109 4.6  
Hyperhomocystinemia 11 of 101 11.0  
Elevated factor VIII 12 of 102 12.0  
Lupus anticoagulant 3 of 109 2.8  
Of these   
 Two risk factors combined 13 of 101* 13.0  
 Three risk factors combined 3 of 101* 3.0 
*

In 101 women, all risk factors were determined.

Statistical analysis

To compare the risk for recurrent VTE during pregnancy with the risk outside pregnancy, we evaluated the incidence of thrombosis when the women were pregnant and when they were not. Observation started with the cessation of oral anticoagulant treatment after the first VTE (usually 4-6 months) or, if anticoagulant treatment was stopped earlier, 3 months after the first event, and it ended at first recurrence. Observation of patients who did not experience recurrent VTE was censored at the time of the interview. To calculate the recurrence rate per-patient year, the number of recurrent VTEs was related to the total observation time in years.6 This was calculated separately for the total observation time during and outside pregnancy. Cox regression analysis7 was used to estimate the relative risk for VTE from pregnancy. In this analysis, a time-dependent prognostic factor was considered that described the various states of patients (pregnant or not pregnant) during observation. We allowed for temporary exclusions from the risk set if patients were temporarily not evaluable for the event of interest. This was the case when pregnant patients were administered thrombosis prophylaxis. Patients were also excluded from the risk set for 6 weeks after each pregnancy because, during this period, the risk for recurrent thrombosis is unpredictably high and thrombosis prophylaxis is recommended.

Results and discussion

Forty-three of the 109 women had a first recurrent event during a total observation period of 1014 years—73 years during and 941 outside pregnancy. Eight events (5 deep leg vein thrombosis, 1 deep arm vein thrombosis, and 2 pulmonary embolisms) occurred during pregnancy. All events were objectively documented (definite). Five events occurred during the first, 2 during the second, and one during the third trimester. No additional triggering factors, such as trauma, surgery, or immobilization occurred. Four women had detectable abnormalities (4 were heterozygous for factor V:R506Q, 2 of whom also had hyperhomocystinemia), and 4 had normal laboratory test results (Table2). In all women with recurrence during pregnancy, a temporary risk factor (OC in 7, additional trauma in 3, surgery in 1) had been present at the first event. Thirty-five women had recurrence while not being pregnant (25 definite, 10 probable). Twenty-five recurrent events occurred without a temporary risk factor; 2 occurred while on OCs, 2 after trauma, and 2 during immobilization; and 4 occurred after surgery. Recurrence rates per patient year were 10.9% during pregnancy and 3.7% in the nonpregnant period. Using Cox regression analysis, the estimated relative risk during pregnancy was 3.5 (95% confidence interval, 1.6-7.8; P = .002).

Table 2.

Recurrent VTE during pregnancy and risk factors at first event in 109 women with a history of VTE

Temporary risk factor No Yes No Yes  
Laboratory risk factor Yes Yes No No  
Women (n) 9.0 55.0 6.0 39.0  
Recurrence (n) 0.0 4.0 0.0 4.0  
Recurrence rate (%) 0.0 7.3 0.0 10.3 
Temporary risk factor No Yes No Yes  
Laboratory risk factor Yes Yes No No  
Women (n) 9.0 55.0 6.0 39.0  
Recurrence (n) 0.0 4.0 0.0 4.0  
Recurrence rate (%) 0.0 7.3 0.0 10.3 

Temporary risk factors: OC use, pregnancy, surgery, trauma, immobilization.

Laboratory risk factors: antithrombin-, protein C– or S–deficiency, factor V:R506Q, G20210A prothrombin gene variation, hyperhomocystinemia, elevated factor VIII, lupus anticoagulant.

The main question is whether women with previous thrombosis should receive prophylaxis not only after delivery but also during pregnancy. The low risk for pregnancy-associated recurrent VTE in the recently published prospective study3 prompted the authors of the Sixth ACCP Consensus Conference on Antithrombotic Therapy1 to recommend 2 general approaches—(1) active prophylaxis with heparin or (2) clinical surveillance and investigation if symptoms suspicious of deep vein thrombosis or pulmonary embolism (PE) during pregnancy occur without routine prophylactic anticoagulation. In the prospective study published by Brill-Edwards et al,3 the recurrence rate was low (3 events during 125 pregnancies); a comparison with periods outside pregnancy was not performed. Although the study had a prospective design, there are several limitations. The enrollment of most patients was after the first trimester, and the mean duration of pregnancy at enrollment was 15 ± 6 weeks. It might be suggested that thromboembolic events occurring during the first and the second trimesters were missed. Furthermore, no information on the duration and outcome of pregnancy is provided. Data on abortion, stillbirth, and premature delivery and, therefore, a shortened period at risk are not given. Thus, it might be that in this prospective study the recurrence rate is underestimated. Our retrospective study covered the whole period of pregnancy and takes into consideration pregnancies that ended prematurely. As a result, an exact estimate of the recurrence per patient-year could be performed.

Our data suggest that pregnancy leads to a temporary and a more than 3-fold increase in the risk for symptomatic recurrent thrombosis. Temporary risk factors at first event or the investigation for thrombosis risk factors seem not to differentiate clearly between women at high risk or low risk for pregnancy-associated recurrence. Probably prophylactic heparin can reduce the incidence of thrombosis during pregnancy. Possible disadvantages of prophylactic heparin during pregnancy are inconvenience for the woman, costs, and, though infrequent, bleeding, osteoporosis, or heparin-induced thrombocytopenia. However, based on a systematic review of 486 pregnancies,8 low-molecular–weight heparin (LMWH) can be regarded as safe. In the 486 pregnancies, there were no cases of clinically important bleeding or heparin-induced thrombocytopenia, 1 case of symptomatic osteoporosis, and 3 cases of VTE.

Because the study is retrospective, it has certain limitations. Thromboembolic events were objectively confirmed in each pregnancy-associated episode, but some of the events outside pregnancy were not confirmed. By not including these events, the relative risk during pregnancy would be even higher. Furthermore, our overall recurrence rate was not high in comparison with the results from most published studies on recurrence rates9-11 and was close to that observed in the prospective AUREC study in patients without elevated factor VIII levels, in whom a 5% likelihood of recurrence at 2 years was observed.12 

During pregnancy the recurrence rate was significantly higher (10.9 per 100 patient years). Recurrent VTE is a serious complication of pregnancy because it is potentially life threatening, and a recurrent thrombotic event increases the probability for a postthrombotic syndrome.9 The time of pregnancy and the postpartum period delineate a well-defined period of increased risk. Prophylactic administration of LMWH during pregnancy might reduce the risk for this pregnancy-associated thrombosis and thus the overall recurrence rate in this young patient population and probably does not have the disadvantage of high bleeding risk observed during oral anticoagulant treatment.13 However, it remains to be shown in well-designed randomized trials that prophylactic anticoagulation is definitely able to decrease the rate for pregnancy-associated recurrent VTE and to establish its safety.

Prepublished online as Blood First Edition Paper, May 24, 2002; DOI 10.1182/blood-2002-01-0149.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

References

References
1
Ginsberg
JS
Greer
I
Hirsh
J
Use of antithrombotic agents during pregnancy.
Chest.
119
2001
122S
131S
2
Tengborn
L
Bergqvist
D
Mätzsch
T
Bergqvist
A
Hedner
U
Recurrent thromboembolism in pregnancy and puerperium.
Am J Obstet Gynecol.
160
1989
90
94
3
Brill-Edwards
P
Ginsberg
JS
Gent
M
et al. 
Safety of withholding heparin in pregnant women with a history of venous thromboembolism.
N Engl J Med.
343
2000
1439
1444
4
National Institutes of Health Consensus Development Conference
Prevention of venous thrombosis and pulmonary embolism.
JAMA.
256
1986
744
5
Pabinger
I
Grafenhofer
H
Kaider
A
et al. 
Preeclampsia and fetal loss in women with a history of venous thromboembolism.
Arterioscler Thromb Vasc Biol.
21
2001
874
879
6
Marubini
E
Valsecchi
MG
Analyzing Survival Data from Clinical Trials and Observational Studies.
1995
John Wiley & Sons
New York, NY
7
Cox
DR
Regression models and life-tables (with discussion).
J R Stat Soc B.
34
1972
187
220
8
Sanson
BJ
Lensing
AWA
Prins
MH
et al. 
Safety of low-molecular-weight heparin in pregnancy: a systemic review.
Thromb Haemost.
81
1999
668
672
9
Prandoni
P
Lensing
AW
Cogo
A
et al. 
The long-term clinical course of acute deep venous thrombosis.
Ann Intern Med.
125
1996
1
7
10
Schulman
S
Riiedin
AS
Lindmarker
P
et al. 
A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.
N Engl J Med.
332
1995
1661
1665
11
Kearon
C
Gent
M
Hirsh
J
et al. 
A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.
N Engl J Med.
340
1999
901
907
12
Kyrle
PA
Minar
E
Hirschl
M
et al. 
High plasma levels of factor VIII and the risk for recurrent venous thromboembolism.
N Engl J Med.
343
2000
457
462
13
Palareti
G
Leali
N
Coccheri
S
et al. 
Bleeding complications of oral anticoagulant treatment: an inception–cohort, prospective collaborative study (ISCOAT): Italian study on complications of oral anticoagulant therapy.
Lancet.
348
1996
423
428

Author notes

Ingrid Pabinger, Department of Internal Medicine I, Division of Haematology and Blood Coagulation, Waehringer Guertel 18-20, A 1090 Vienna, Austria; e-mail: ingrid.pabinger@akh-wien.ac.at.