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Keywords:

  • factor V Leiden;
  • pregnancy;
  • prothrombin gene 20210GA polymorphism;
  • thrombophilia;
  • venous thrombosis

Summary.

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Background:  Pregnancy is associated with a 10-fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy-related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms.

Materials and Methods:  The study comprised 377 155 women with 613 232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material.

Results:  The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1–8.3] and 9.4 (95% CI 2.1–42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy-related VT occurred in 1.1/1000 non-carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively.

Conclusions:  Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy-related VT was low.


Introduction

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

In developed countries, venous thrombosis (VT) continues to be one of the leading causes of maternal morbidity and death during pregnancy and puerperium [1]. The incidence of VT is approximately 1/1000 pregnancies, with the highest incidence at, and early after, delivery [2–5]. Identification of risk factors for VT related to pregnancy may therefore have potential for risk stratification to help clinicians in their management of pregnant women.

Several factors are of importance for the development of pregnancy-related VT. These include clinical, acquired and genetic risk factors [5–8]. The factor (F)V Leiden and the prothrombin gene G20210A polymorphisms (hereafter called FV Leiden and the prothrombin polymorphism) are the two most commonly inherited causes of thrombophilia in Caucasians [9]. Several studies have shown that these polymorphisms increase the risk of VT associated with pregnancy, with the highest risk among homozygous and combined heterozygous carriers [10–20]. A weakness of these studies is that they have included small numbers of women. However, a meta-analysis suggested that the risk is approximately eight-fold higher for FV Leiden heterozygotes and seven-fold higher for heterozygous carriers of the prothrombin polymorphism than that in pregnant women without these polymorphisms [21].

We have previously reported that there are different clinical risk factors for antenatal and postnatal VT [5,6]. The purpose of the present study was to investigate the association of FV Leiden and the prothrombin polymorphism with VT during pregnancy and within 14 weeks postpartum. Furthermore, we wanted to estimate the probability of VT among pregnant women with these polymorphisms, to assess the usefulness of screening for FV Leiden and the prothrombin polymorphism in pregnant women.

Materials and methods

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Selection of cases and controls

The selection of cases and controls has been described and reported earlier [22]. In short, we searched the Norwegian Patient Registry for selected ICD-9 and ICD-10 codes to identify women with a diagnosis of VT in pregnancy or within 14 weeks postpartum at 18 Norwegian hospitals during 1990–2003. We included women who had completed 23 weeks of pregnancy. The diagnosis of VT was validated through review of medical records, using strict objective criteria [6]. In total, 559 cases were identified.

From the Norwegian Medical Birth Registry, we selected four women who gave birth at Oslo University Hospital at Ullevål (formerly Ullevål University Hospital) at the same time as a case as possible controls. We utilized the two first listed women as controls. If their medical records were not retrievable, we included the third or fourth selection [6,22]. In total, 1229 women were identified.

After exclusion of cases and controls who were foreign, had emigrated, or were dead, the remaining cases (n = 531) and controls (n = 1092) were invited to donate a blood sample and to answer a detailed questionnaire (Fig. 1). The final study population of the present study comprised 313 cases and 353 controls naïve for VT prior to index pregnancy [22].

image

Figure 1.  Flowchart for selection of the study population.

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Clinical variables

From the medical record, we collected information on clinical variables of index pregnancy. Conception by assisted reproduction technique comprised in vitro fertilization and intracytoplasmatic sperm injection. Intrauterine fetal growth restriction was defined as gestational age-adjusted birth weight below the 2.5 percentile. Delivery mode was categorized as vaginal delivery, either spontaneous or by vacuum extraction or forceps, and Cesarean section, either planned or by emergency. In the current study, we compared any Cesarean section with any mode of vaginal delivery. Postnatal hemorrhage was estimated as blood loss >1000 mL as reported in the medical record by the attending midwife or physician. Cigarette smoking was divided into four groups by number of cigarettes per day at start of pregnancy, irrespective of whether or not the women stopped during pregnancy (0, 1–4, 5–9, and 10–30). Women with missing data for smoking were categorized as non-smokers. In the current study, we compared heavy smokers (10–30) with non-smokers. Antenatal immobilization was defined as strict bed rest for 1 week or more prior to delivery or prior to the diagnosis of VT [6].

Participants with both parents from either Austria, Belgium, Denmark, Germany, Iceland, Ireland, Luxemburg, the Netherlands, Norway, Poland, Sweden or UK. were classified as being from north-western Europe, and the remainder as being from outside north-western Europe.

Blood sampling and analyses

Blood samples were collected from fasting women throughout the year 2006. Blood was collected in 5 mL Vacutainer tubes (Becton-Dickinson, Meylan-Cedex, France) containing 0.5 mL of buffered citrate (0.129 mol L−1), in Vacutainer tubes containing ‘serum gel’, and in Monovette tubes (Sarstedt, Nümbrecht, Germany) containing EDTA anticoagulant. Tubes with citrate were kept at ambient room temperature, and centrifuged at 2000 × g for 15 min within 1 h. Plasma and serum aliquots were frozen and kept at − 70 °C until being assayed. DNA was extracted using DNA isolation kit I large volume (Roche Diagnostics, Basel, Switzerland) with Magna Pure (Roche Diagnostics). FV Leiden and the prothrombin polymorphism were detected with Factor V Leiden Mutation Detection and Prothrombin Mutation Detection kits (Roche Diagnostics), respectively, run on a real-time polymerase chain reaction analyzer (LightCycler 2.0; Roche Diagnostics). All analyses were performed examiner blind at the Haematological Research Laboratory at the Department of Haematology, Oslo University Hospital at Ullevål.

Estimation of the frequency of FV Leiden and the prothrombin polymorphism

The 313 cases originated from a population of 377 155 women with 613 232 pregnancies over the 14-year study period. The control population was selected from only one hospital over the same period. By applying the observed frequencies of women with FV Leiden and the prothrombin polymorphism to the total study population, we estimated the probability of VT among pregnant women carrying either or both polymorphisms. We used woman as the unit for calculations, which means that the probability of VT was calculated over one to three pregnancies. As none of the control women was homozygous for either polymorphism, we estimated the frequencies of homozygous carriers in the normal population on the basis of the allele frequencies of heterozygous carriers (Hardy–Weinberg equilibrium).

Estimation of numbers needed to be screened and numbers needed to be treated

The numbers needed to be treated to prevent one pregnancy-related VT were calculated from the estimated numbers of heterozygous or homozygous carriers of a polymorphism in the source population divided by the actual numbers of heterozygous or homozygous cases for either polymorphism. For these calculations, we assumed that testing for a polymorphism would identify all heterozygous and homozygous individuals with 100% sensitivity and 100% specificity, and that thromboprophylaxis would always be given and be 100% effective. In the calculations for the two polymorphisms separately, we did not include the double heterozygous women, but in the case of screening for both polymorphisms we included the estimated numbers of heterozygous, homozygous and double heterozygous women in the calculations.

To calculate the numbers needed to screen, the numbers needed to be treated were divided by the estimated fraction of women in the source population with the polymorphism, that is, the numbers needed to be tested to find the numbers needed to be treated to prevent one pregnancy-related VT.

Statistical analyses

Data were reported as percentages, probabilities, or odds ratio (ORs) with 95% confidence interval (CIs). All data were analyzed with spss version 16.0 (SPSS, Chicago, IL, USA).

Approvals

The study (http://www.clinicaltrials.gov identifier number NCT00856076) was approved by the Regional Committee for Research Ethics in Health Region East, Norway. The committee granted two reminders when inviting participants to the study. Authorization for the use of data retrieved from medical records for research purposes was obtained from the Norwegian Ministry of Health and Social Affairs. The Norwegian Data Inspectorate approved processing of data with sensitive personal health information and merging of clinical data and register data by using the unique 11-digit personal identification number given to all Norwegian citizens at birth or immigration. All attending women gave written consent.

Results

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The final case population comprised 313 women with a first lifetime VT, 155 during pregnancy and 158 in the puerperium. The majority (73.5%) of the women had experienced deep vein thrombosis (DVT), 23.6% had experienced pulmonary embolism (PE), and 2.9% had experienced clinically combined DVT and PE. PE occurred more frequently after delivery (43.1% of all postnatal VTs) than during pregnancy (9.6% of all antenatal VTs). Among the controls, 90.1% had parents who were both from north-western Europe, and 95.8% of the cases had parents who were both from north-western Europe (Table 1). None of the study subjects with one or both parents from outside north-western Europe had the prothrombin polymorphism. The frequency of FV Leiden (homozygous or heterozygous) was 7.2% among the controls from north-western Europe, and 6.1% among the controls from outside north-western Europe. Clinical risk factors were fairly equally distributed between cases and controls who agreed or did not agree to participate, but the controls who participated in the study were older and of lower parity at time of index pregnancy than controls who did not agree to participate, as reported earlier [22].

Table 1.   Ancestry of the study participants
 All participants, no. (%)
North-western EuropeOutside north-western EuropeMissing
Controls (n = 353)318 (90.1)33 (9.3)2 (0.6)
Cases (n = 313)300 (95.8)11 (3.5)2 (0.6)

The frequencies of FV Leiden and the prothrombin polymorphism and the ORs for VT are given in Table 2. FV Leiden was found in 34.9% and in 24.2% of antenatal and postnatal cases, respectively, and in 7.1% of controls. The prothrombin polymorphism was found in 8.4% and in 6.3% of antenatal and postnatal cases, respectively, and in 1.2% of controls. Double heterozygosity for the mutations was found in 5.2% of antenatal and in 1.3% of postnatal cases, respectively, and in 0.6% of controls. Homozygous carriers of both polymorphisms were rare and found only among cases.

Table 2.   Numbers, odds ratios (ORs) and 95% confidence intervals (CIs) of antenatal and postnatal and total venous thromboses (VTs) for different genotypes of factor V Leiden and the prothrombin polymorphism
PolymorphismGenotypeCasesControlsOR95% CI
nN%nN%
  1. NA.

Antenatal VT
 FV Leiden onlyHeterozygous4115526.5233536.56.13.5–10.6
Homozygous51553.203530NANA
 Prothrombin polymorphism onlyHeterozygous51553.223530.68.51.6–44.5
Homozygous0155003530NANA
 CombinedHeterozygous81555.223530.613.62.8–65.0
 NormalNo polymorphism9615561.932635392.41.0Ref.
Postnatal VT
 FV Leiden onlyHeterozygous3315820.9233536.54.22.4–7.4
Homozygous31581.903530NANA
 Prothrombin polymorphism onlyHeterozygous71584.423530.610.22.1–49.8
Homozygous11580.603530NANA
 CombinedHeterozygous21581.323530.62.90.4–10.9
 NormalNo polymorphism11215870.932635392.41.0Ref.
Antenatal and postnatal VT
 FV Leiden onlyHeterozygous7431323.6233536.55.03.1–8.3
Homozygous83132.603530NANA
 Prothrombin polymorphism onlyHeterozygous123133.823530.69.42.1–42.4
Homozygous13130.303530NANA
 CombinedHeterozygous103133.223530.67.81.7–36.1
 NormalNo polymorphism20831366.532635392.41.0Ref.

Table 3 gives tables of interactions between clinical risk factors for pregnancy-related VT [6] and heterozygous FV Leiden. The number of women who were heterozygous for FV Leiden in combination with a clinical risk factor was low, and OR estimates were uncertain, with wide CIs. The combination of a clinical risk factor, for example, heavy smoking and heterozygous FV Leiden tended to increase the risk for VT. Analysis of interaction with homozygous FV Leiden or heterozygous or homozygous prothrombin polymorphism was not possible, because of the low number of individuals.

Table 3.   Interaction between clinical risk factors for pregnancy-related venous thrombosis and heterozygous factor V Leiden
 Risk factorFV LeidenCase, NControl, NOR (95% CI)
  1. CI, confidence interval; NA; OR, odds ratio.

Risk factor – antenatal VT
 Intrauterine fetal growth restriction933221 (Ref.)
+38235.7 (3.2–10.1)
+342.6 (0.6–11.8)
++30NA
 Artificial reproduction technique893181 (Ref.)
+36235.6 (3.2–9.9)
+783.1 (1.1–8.6)
++50NA
Risk factor – postnatal VT
 Any Cesarean section642591 (Ref.)
+20165.1 (2.5–10.3)
+48672.9 (1.8–4.6)
++1377.5 (2.9–19.6)
 Postnatal bleeding >1000 mL933201 (Ref.)
+27224.2 (2.3–7.8)
+19610.9 (4.2–28.1)
++6120.6 (2.5–173)
Risk factor – all VT
 Antenatal immobilization ≥ 1 week1903241 (Ref.)
+71225.5 (3.3–9.2)
+18215.3 (3.5–66.9)
++315.1 (0.5–49.5)
 Smoking 10–30 cigarettes d−11672941 (Ref.)
+61205.4 (3.1–9.2)
+15102.6 (1.2–6.0)
++726.2 (1.3–30.0)

Table 4 displays the estimated probability of pregnancy-related VT per 1000 pregnant carriers of FV Leiden or the prothrombin polymorphism. The probabilities for VT among heterozygous carriers of FV Leiden and the prothrombin polymorphism and double heterozygotes were 5/1000, 9/1000, and 8/1000, respectively. Homozygous carriers of FV Leiden had an overall probability of 36/1000. As only one case and none of the controls were homozygous for the prothrombin polymorphism, the probability estimate for pregnancy-related VT in such women was meaningless.

Table 4.   Estimates for probability of venous thrombosis (VT) per 1000 pregnant carriers of factor V Leiden and the prothrombin polymorphism, naive for VT before pregnancy, with 95% confidence intervals (CI)
PolymorphismGenotypeStudy populationGeneral population
Cases, %Controls, %CasesWomen giving birthProbability of VT
Total (n)Estimated, nTotal, nEstimated, nn/100095% CI
  1. *Estimated from a 6.5% prevalence of heterozygous FV Leiden in the control population. †Estimated from a 0.6% prevalence of heterozygous prothrombin polymorphism in the control population.

NoneNormal66.592.4559371.7377 155348 4911.11.0–1.2
FV LeidenHeterozygous23.66.5559131.9377 15524 5155.44.5–6.3
Homozygous2.60.11*55914.5377 15539836.418.0–54.8
Prothrombin polymorphismHeterozygous3.80.655921.2377 15522639.45.4–13.4
Homozygous0.30.0009†5591.7377 1553.45000–1000
CombinedHeterozygous3.20.655917.9377 15522637.94.3–11.5

From the numbers in Table 4, we calculated the number of women needed to be screened and to be treated to prevent one pregnancy-related VT, in the hypothetical case of pregnant women being screened for FV Leiden, the prothrombin polymorphism, or both (Table 5). In the case of screening for both polymorphisms, we found that 2015 pregnant women would need to be tested and 158 women would need to receive anticoagulant prophylaxis to prevent one pregnancy-related VT, given that the tests identified both heterozygous and homozygous individuals and that thromboprophylaxis was fully effective. In the case of screening only for the prothrombin polymorphism, 16 470 women would need to be screened and 99 women would need to be treated to avoid one VT.

Table 5.   The numbers of pregnant women who need to be screened and who need to be treated to avoid one venous thrombosis
PolymorphismNumber who need to be screenedNumber who need to be treated
  1. *Double heterozygotes excluded.

Factor V Leiden*2576170
Prothrombin polymorphism*16 47099
Double heterozygosity21 070126
FV Leiden and/or prothrombin polymorphism2015157

Discussion

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

This population-based case–control study aimed to assess the risk of VT during pregnancy and puerperium associated with FV Leiden and the prothrombin polymorphism. Pregnancy-related VT is rare, and previous studies have included small numbers of women with this complication. Our study included the largest number of pregnancy-related VTs so far. We found that the risk of VT related to pregnancy or delivery was approximately five-fold higher for FV Leiden heterozygotes, nine-fold higher for prothrombin polymorphism heterozygotes and eight-fold higher for carriers of both polymorphisms than in women without these causes of thrombophilia. These numbers are in the same order as for the general Caucasian population [23]. Other studies have found ORs varying from 2 to 20 for heterozygous FV Leiden [10–20], and from 2 to 19 [10,13,14,17] for heterozygosity of the prothrombin polymorphism. The meta-analysis by Robertson et al. [21], however, found ORs in the same range as in the present study. Only few and inconclusive data are as yet available regarding the risk associated with double heterozygosity [13,24–27], and most studies have reported a high risk of VT in such women [13,25,26]. However, the recent study of Martinelli et al. [27] of 52 double heterozygotes found a similar low risk as in the present study. There are very limited data on the risk associated with homozygosity for these polymorphisms. Only 29 cases with homozygous FV Leiden have been reported [13,16,24,28]. Our study had too few homozygous cases of either polymorphism to show the risk of VT related to pregnancy. However, it is interesting that all of the eight women homozygous for FV Leiden were found among the cases, which is an indication of a very high risk for pregnancy-related VT in such women. One study has previously reported on homozygosity for the prothrombin polymorphism in two cases [10]. In our study, only one case and none of the controls were homozygous for the prothrombin polymorphism.

Although it is the largest study of pregnancy-related VT to date, our study still had insufficient power to investigate interactions between FV Leiden and clinical risk factors for pregnancy-related VT. The numbers in Table 3 do, however, indicate an increased risk for VT in women with both a clinical risk factor and FV Leiden.

When we extrapolated from our data to the entire population of pregnant women, we found that the probability of VT for pregnant women not carrying either polymorphism was 1.1 per 1000 women. Among women heterozygous for either FV Leiden or the prothrombin polymorphism or both, the probability for VT was low (5/1000, 9/1000, and 8/1000, respectively). As we used woman and not pregnancy as the unit for calculations [13], the actual probability in each pregnancy was slightly lower. Previous studies have reported that the probabilities of VT related to pregnancy are 0.2–1% and 0.3–0.5% in single heterozygous carriers of FV Leiden and the prothrombin polymorphism, respectively [13,17]. The overall low probability of VT in double heterozygotes in our study was similar to that reported by Martinelli et al. [27], who investigated family members of probands with either or both mutations. Other studies have found a higher probability of VT [13,24–26], but these studies may have important selection biases. The highest probability of VT was in homozygotes. We found that the probability of VT was 36/1000 in FV Leiden homozygotes, which is similar to that reported by Pabinger et al. [28]. Middeldorp et al. [29] reported a much higher probability of VT (17%) in a retrospective study, but they investigated the probability of VT in pregnant women with a first-degree relative with a history of VT, that is, an additional risk factor, which makes the results less valid for pregnant women in the general population.

On the basis of the current data, we estimated that 2015 women would need to be screened for both polymorphisms and 158 women would need to be given thromboprophylaxis to avoid one VT related to pregnancy or delivery, on the assumption that prophylaxis is 100% effective and that the sensitivity and specificity of both tests are 100%, both of which are highly unlikely. Our interpretation of these results is that general screening of pregnant women for FV Leiden or the prothrombin gene polymorphism is not justified, even though these are the most frequent inheritable risk factors for VT and pregnant women are at higher risk for VT than the general population.

The strengths of our study were the population-based approach, the large number of cases, the selection of only first lifetime VT, and the validation of diagnoses and cofactors. By reviewing all medical records of eligible women ahead of invitation and matching for time of delivery, we reduced the possibility of selection bias. The frequencies of FV Leiden and the prothrombin gene polymorphism among the controls were in the same range as previously reported for the Norwegian population [30], confirming the validity of the population-based approach. A weakness of our study is the selection of controls from only one hospital. However, as we are able to share information on the direction of this bias for major demographic, pregnancy-related and obstetric events and disorders, we consider control selection from one hospital to be a minor problem in calculating true estimates. For major risk factors, the incidence was higher in the control group than what is found in the background population [22]. Hence, this differential selection may have resulted in underestimation of the risk. There were somewhat more controls than cases from outside north-western Europe, but the frequencies of FV Leiden between the ancestral groups were similar.

In conclusion, FV Leiden and the prothrombin polymorphism increased the risk for both antenatal and postnatal VT. However, the probability of pregnancy-related VT with these polymorphisms was small.

Addendum

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

A. F. Jacobsen and P. M. Sandset designed the study. A. F. Jacobsen collected all data and blood samples. A. F. Jacobsen and A. Dahm performed the statistical analyses. All authors contributed to interpretation of data and writing up of the manuscript. A. F. Jacobsen and A. Dahm contributed equally to the manuscript (shared first authors). All authors had full access to the study and accept responsibility for the accuracy of the analyses.

Acknowledgements

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

We are grateful to M. Skogstad, who performed the analyses of FV Leiden and the prothrombin polymorphism.

The study was financially supported by grants from the Norwegian Research Council (fellowship to A. F. Jacobsen, grant no. 160805-V50), Oslo, Norway, the Norwegian South-Eastern Health Authorities, Hamar, Norway, and Oslo University Hospital Ullevål, Oslo, Norway. The study was planned, executed, analyzed and reported independently of these funders.

Trial registration: http://www.clinicaltrials.gov identifier number NCT00856076.

Disclosure of Conflict of Interests

  1. Top of page
  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The authors state that they have no conflict of interest.

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  2. Summary.
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
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