• abortion;
  • fetal loss;
  • pre-eclampsia;
  • pregnancy;
  • stillbirth;
  • thrombophilia


  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References

Summary.  Pregnancy complications are still a challenge for physicians, because knowledge of pathomechanisms and prophylactic measures is still limited. In recent years thrombophilia as a risk factor for pregnancy complications has gained much attention in the scientific community. However, data on this topic in the literature are conflicting. Besides an established association between antiphospholipid antibodies and pregnancy loss, available data suggest additional associations for antithrombin deficiency, hyperhomocysteinemia and also for factor (F)V Leiden, prothrombin G20210A variation, and protein S-deficiency. The contribution of thrombophilia to the risk of pre-eclampsia is less well established and recent studies did not confirm earlier data suggesting an association between thrombophilia and pre-eclampsia. A limited number of prospective studies have failed to reveal an increased risk of pregnancy complications in unselected women with thrombosis risk factors. Low-molecular weight heparin (LMWH) seems to have a positive effect on pregnancy outcome after single or recurrent abortions, however, data from only one controlled trial are available. Experience in the prevention of pre-eclampsia by prophylactic heparin is very limited, and in addition, data on pregnancy complications in women with known heritable thrombophilia or a history of thrombosis are inconsistent. These women will usually have a favorable pregnancy outcome referring to the European Prospective Cohort on Thrombophilia Study. In conclusion, thrombophilia screening might be justified in women with pregnancy loss and treatment with LMWH might be considered in those with pregnancy loss and thrombophilia. Further prospective studies and controlled interventional trials are urgently needed.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References

Mortality and morbidity of bleeding complications of pregnancy and delivery have been dramatically reduced by advances in medicine and obstetric care. Venous thromboembolism (VTE), pre-eclampsia, and pregnancy loss are still important complications of pregnancy. Heritable prothrombotic factors lead to an increased risk of thromboembolism and are also believed to significantly impair the outcome of pregnancy and to play a substantial role in the pathogenesis of spontaneous abortions. Recurrent abortion involves more than 500 000 women in the United States per year [1] and is an established risk factor for depressive disorders [2,3]. For instance, around a three times higher overall relative risk (RR) for an episode of a major depressive disorder was reported for miscarrying in comparison with community women and around a five times higher RR for childless women compared with women with children [2]. Conceiving again and the birth of a living child lessens grief [4] and thus prevention of thrombophilia-induced miscarriage or other pregnancy complications by the use of safe anticoagulants is a fascinating prospect.

Within the past 10 years interest in associations between thrombophilia and complications of pregnancy has increased remarkably. Thrombophilia is present in at least 15% of the Western population and is found in up to 50% of individuals with VTE (Table 1). Apparently it would appear to play a critical role in the development of pregnancy-related deep vein thrombosis and pulmonary embolism. Thrombotic processes may also be involved in other serious obstetric complications, such as recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction (IUGR), and placental abruption by impairment of placental perfusion. Pregnancy itself induces a physiologic hypercoagulable state [5–9] that might be aggravated by inherited or acquired thrombophilia. Interestingly, results of studies on pregnancy complications in women with thrombophilia have been conflicting. However, a recently completed interventional trial employing anticoagulants for the prevention of pregnancy complications has shown promising results [10].

Table 1.  Incidence of hereditary thrombophilia in the general population and in patients with venous thromboembolism (VTE)
 Frequency (%) in the general populationFrequency (%) in patients with VTE
  1. Information obtained from Ref. [98–105].

Antithrombin deficiency (type I)0.02–0.171.1
Protein C-deficiency0.14–0.53.2
Protein S-deficiencyUnknown2.2
Factor V Leiden (heterozygous)3.6–6.021
Factor V Leiden (homozygous)0.1–0.022
Hyperhomocysteinemia5–10 10–25
Prothrombin G20210A variation1–4  2–8

Pregnancy loss

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References

The terms of abortion, miscarriage, and stillbirth are used to discern between pregnancy loss that occurs within different periods of pregnancy. Abortion and miscarriage are defined as pregnancy loss before the week 20 of gestation (calculated by sonography or on the first day of the last period) or when the fetus weighs <500 g [11]. Sensitive assays for human chorionic gonadotropin (HCG) reveal that approximately 50% of pregnancies are lost after implantation, but only a minority of these are diagnosed clinically [11]. About 60% of first trimester spontaneous abortions are associated with an abnormal karyotype of the fetal tissue, which contrasts with figures of as low as 30% of second trimester abortions and 3% of stillbirths [11]. Systemic illnesses have not been associated clearly with an increased risk of abortion, but infections and chemotherapeutic agents can cause abortion especially during early gestation. Certain environmental factors are also associated with a higher risk of abortion, e.g. cigarette smoking, alcohol, and heavy coffee consumption. Habitual or recurrent (repetitive) pregnancy loss is defined as three consecutive pregnancy losses before the week 20 of gestation [11]. As the probability of one clinically evident spontaneous abortion is normally about 20%, that of two consecutive losses should be 4%, and that of three consecutive losses 0.8%. Thus, recurrent abortion in normal women is a rare finding and the most common gynecologic causes of recurrent first trimester abortions are a luteal phase defect or uterine abnormalities.

It has been known for over 20 years that antiphospholipid antibodies are recognized risk factors for pregnancy loss [12]. However, in 1993 an association between another thrombosis risk factor, namely hyperhomocysteinemia and pregnancy loss has been described [13]. As that time antiphospholipid antibodies have been established convincingly as major risk factors, especially for second trimester pregnancy loss and stillbirth. In 1996, the first reports of an association between other forms of thrombophilia and recurrent pregnancy loss were published [14–16]. As then numerous case–control studies investigating the impact of pregnancy loss and thrombophilia have been reported [17–24]. In most of these studies factor (F)V Leiden (FV 1691 G/A), prothrombin 20210 A/G and the methylene tetrahydrofolate reductase (MTHFR) gene 677 C/T variation were investigated. Some studies also included other classical markers of thrombophilia, such as antithrombin, protein C- and S-deficiency and antiphospholipid antibodies [17,25]. The largest study was performed by Rai et al. [26], who investigated the association between FV Leiden and recurrent pregnancy loss in 1111 consecutive Caucasian women. It is interesting to mention that this study did not demonstrate an association between recurrent miscarriage with FV Leiden, but found a significantly higher number of women with acquired activated protein C resistance (APC) resistance in the recurrent miscarriage group in comparison with control women. It is also interesting to note that studies by different groups from the same geographic area have produced conflicting results. Whereas Kupferminc et al. [17] and Younis et al. [21] found a clear association between thrombophilia and pregnancy loss in a population from Israel, Carp et al. [27] were unable to confirm these results. However, these latter authors employed a further approach by studying subsequent pregnancies in women with recurrent miscarriage and compared the outcome of pregnancies in women with and without thrombophilia. Thrombophilia did not adversely affect the live birth rate in women with thrombophilia namely 43% in comparison to those without (live birth rate 31%).

Several meta-analyses have summarized and analyzed data on pregnancy loss and thrombophilia [28–30] and all have reported increased odds ratios (OR) of approximately two or more for recurrent fetal loss in carriers of FV Leiden. Rey et al. [30] separately analyzed women with early recurrent fetal loss (OR = 2.0), non-recurrent fetal loss (OR = 1.7), and fetal loss after 19 weeks of gestation (OR = 3.3). Similarly high OR were calculated for carriers of prothrombin 20210 G/A variation (OR = 2.0 for recurrent fetal loss [30]). Homozygous MTHFR variation was not confirmed as a risk factor in this meta-analysis [30]. The highest OR (7.3) was determined for protein S-deficiency, however, data of only three studies were analyzed in the calculation of this OR. A small number of studies have been performed in women from populations in which the FV Leiden mutation was rare or even not existing. Not surprisingly FV Leiden was not identified in women either with recurrent fetal loss or in controls [31].

Currently information on two population-based prospective cohort studies with a large number of participating women is available [32,33]. A total of 3020 women (1643 primigravida) were included in the two studies and FV Leiden was detected in 283 (9.4%). Neither the proportion of second trimester abortions, pre-eclampsia nor intrauterine growth restriction (IUGR) was significantly higher in carriers of FV Leiden than in controls (Table 2). An analysis of first trimester abortion was not possible, because observations started after the first trimester in a significant proportion of the women.

Table 2.  Frequencies of pregnancy-associated complications in factor V Leiden-positive and -negative women – analysis of data from two prospective studies [32,33]
 Factor V LeidenOR (95% CI)
Positive (n = 283), n (%)Negative (n = 2737), n (%)
  1. *Abortion within second or third trimester.

  2. OR, odds ratio; CI, confidence interval.

Late spontaneous abortion*6 (2.1)40 (1.5)1.4 (0.6–3.5)
Pre-eclampsia5 (1.8)56 (2.0)0.9 (0.3–2.2)
Intrauterine growth restriction9 (3.2)88 (3.2)1.0 (0.5–2.0)

Prevention of recurrent pregnancy loss by treatment with anticoagulants has been evaluated in a number of studies. Usually heparin was administered, but in some women aspirin was given in addition [21,34–38]. An improved outcome, in comparison with historical controls or the previous pregnancy, was noted in all studies and data from one randomized-controlled trial have been published [10]. In this trial, women designated with either FV Leiden, the prothrombin 20210 G/A variation or protein S-deficiency with a single pregnancy loss after the ninth week of gestation were included. Those with unexplained loss before the week 10 of gestation and with other explained pregnancy losses were excluded. Eighty women received 40 mg of enoxaparin s.c. and the same number of women (controls) received 100 mg of aspirin once daily. Sixty-nine of the 80 pregnancies (86%) of women treated with heparin were successful in comparison with 23 of 80 pregnancies (29%) of women treated with aspirin. These results reveal an OR of 16 (95% CI: 7–34) in favor of treatment with heparin. The observed rate of successful pregnancies of women treated with aspirin, who had mild thrombophilia (FV Leiden or prothrombin variation) and a history of a single abortion, is much lower than it would have been expected from other studies. A life birth rate of 72% was reported in women with recurrent abortion and antiphospholipid antibodies treated with aspirin alone [39] and a rate of 65% was described in women from the general population with a history of recurrent pregnancy loss [40]. In another study only seven of 61 women (11%) with previous pregnancy loss had a recurrent abortion [41]. Other authors reported successful pregnancies in 47 of 59 women (80%) with abortion in their previous sole pregnancy [42]. The cohort of women studied in this report was quite similar to that in the study of Gris et al. [10] except that no data on thrombophilia were available in these women.

Three main questions arise from a study of the literature on thrombophilia and pregnancy loss.

  • 1
    How can conflicting results from case–control studies in comparable ethnic groups be explained?
  • 2
    Why do prospective studies not confirm an increased risk of pregnancy complications in women with thrombophilia?
  • 3
    If FV Leiden has such an adverse impact on human reproduction (only 29% successful pregnancies after a single abortion), why is the proportion of carriers of the mutation not rapidly declining in the Caucasian population?

It is accepted practice that we have to make our treatment recommendations on the basis of the available data in the literature. However, without any doubt, further randomized-controlled (blinded) trials are needed urgently to prove a positive effect of heparin on the outcome of pregnancies in women with pregnancy loss, both with and without known thrombophilia. Until we have clearer evidence, it is difficult to decide whether or not treatment with heparin should be recommended in women with previous pregnancy loss. Prophylactic doses usually do not harm mother or fetus and heparin significantly reduces the risk of thromboembolic events during pregnancy, which is especially meaningful for women with thrombophilia. Alternative treatment with proven efficacy is not available thus far.

Pre-eclampsia and IUGR

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References

Pre-eclampsia is a unique and serious disorder of human pregnancy [43] characterized by hypertension and proteinuria and with an incidence of approximately 5% in a Caucasian population [44]. The term severe pre-eclampsia is used when a blood pressure above 160/110 mmHg is recorded in two measurements at least 6 h apart and proteinuria of more than 5 g during 24 h occurs. Hypertension of pregnancy and pre-eclampsia are considered to have a strong genetic background [45] and pre-eclampsia itself may lead to a widespread organ damage of kidneys, brain, and placenta. Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome is thought to be an atypical form of pre-eclampsia. Maternal mortality associated with pre-eclampsia is due to placental abruption, hepatic rupture or eclamptic seizures.

In 1994, the WHO study on the risk of thrombosis associated with oral contraception reported that women who later develop venous thrombosis are more likely to have a history of pre-eclampsia [46]. A subsequent finding was that women with pre-eclampsia have a higher risk of subsequently developing VTE [47] and this finding is supported further by the possible association between pre-eclampsia and thrombophilia. First reports on a higher incidence of thrombotic risk factors in women with pre-eclampsia and/or HELLP syndrome were published in 1996 [48,49]. AS then numerous studies, mostly with a case–control design, have been published [17,19,50–66], notably van Pampus et al. [57] who found a very high incidence of thrombophilia (40%) in women with a history of severe pre-eclampsia. In this study tests for thrombophilia included not only genetic polymorphisms but also tests for APC resistance, hyperhomocysteinemia, and anticardiolipin antibodies.

Meta-analyses have been performed to determine an association between thrombophilia and pre-eclampsia [66–68]. The large meta-analysis by Kosmas et al. focused on FV Leiden [66] and included data on almost 3000 women with pregnancy-associated hypertension and normotensive controls led to an OR of 2.3 (95% CI: 1.5–3.4) being calculated. However, results of studies included in this meta-analysis were contradictory and in addition, statistically significant heterogeneity in the results of the different studies was found. Three of the four large studies which included more than 200 women with pre-eclampsia [56,63,68] did not find an association with FV Leiden, whereas only one [57] did so. Interestingly, no study published since 2000 has found a positive association, and a recently published investigation with 157 pre-eclamptic women and 157 controls confirmed a lack of association for six genetic polymorphisms including FV Leiden and prothrombin 20210 G/A variation [69]. In a recent meta-analysis Kosmas et al. [67] specifically addressed whether or not the C677T polymorphism in the MTHFR gene had an impact on the development of pre-eclampsia. A moderately increased risk in carriers of the T allele (MTHFR 667 CT and TT) in comparison with homozygous carriers of the C allele (MTHFR 667 CC) was found (OR 1.3, 95% CI: 1.0–1.4). However, data from the studies included in this analysis were very contradictory, as was seen before in the meta-analysis of FV Leiden reports. Moreover, no studies published between 2001 and 2003 reported a significant association (OR 1.3, 95% CI: 0.8–2.2). In a recently published prospective study of 1874 women [70] hyperhomocysteinemia detected in the early second trimester of pregnancy did not allow the prediction of pre-eclampsia or IUGR. In conclusion, the FV Leiden defect, the MTHFR 677 C/T polymorphism and other hereditary thrombosis risk factors may increase moderately the risk of pre-eclampsia during pregnancy, however, the evidence linking thrombophilia to pre-eclampsia is weak and routine screening of pregnant women is not recommended.

While large interventional trials have studied the effect of aspirin on the recurrence rate of pre-eclampsia, only limited data are available regarding low-molecular weight heparin (LMWH). In two prospective trials [71,72], no benefit in pregnancy outcome was observed following treatment with aspirin compared to placebo in women with a history of pre-eclampsia. In a small study from the Netherlands, the recurrence rate of pre-eclampsia was similar in 26 women with thrombophilia following treatment with LMWH and 32 women receiving aspirin. Ongoing prospective studies are investigating the recurrence rate of pre-eclampsia in women receiving LMWH.

Data on the risk of IUGR in individuals with thrombophilia are conflicting as well. Hereditary thrombophilic defects were described in up to 70% of women with IUGR [17,73–75]. However, in a large case–control study, no association of FV Leiden or prothrombin 20210 G/A variation with IUGR was found [76]. In contrast, hyperhomocysteinaemia and acquired APC resistance were linked to IUGR and significantly lower birth weight, respectively [77–79]. According to our data neonates of women with a history of VTE have a slightly but significantly lower birth weight than neonates from the general population [80]. On the contrary, IUGR was equally frequent in women with and without FV Leiden in two large prospective studies [32,33]. Because of this conflicting data in the literature, a definite conclusion on the impact of thrombophilia on IUGR cannot be drawn.

Pregnancy outcome in women with thrombophilia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References

Women with a history of thromboembolism or known thrombophilia have an increased risk for pregnancy-associated recurrent thromboembolism [81–84]. Nonetheless, retrospective and prospective studies have revealed a relatively favorable outcome of pregnancies in women with a history of venous thrombosis regardless of heparin prophylaxis during pregnancy [85–87]. Women with antiphospholipid antibodies are an important exception: they have a high risk of thrombosis, pregnancy loss, and pre-eclampsia [88,89]. Only a limited number of studies of pregnancy outcome in women with a history of VTE or known thrombophilia have been published (Tables 3 and 4). Preston et al. [14] reported an increased risk of stillbirth (defined as intrauterine death after and including the week 28 of gestation) in women with antithrombin- and protein S-deficiency and combined defects, whereas the risk was not significantly increased in women with protein C-deficiency and FV Leiden. There was no significant increase in the risk of miscarriage (fetal loss up to and including the week 27 of gestation) associated with various deficiency states except a borderline increased risk in antithrombin-deficient women (OR 1.7, 95% CI: 1.0–2.8). Data from this study including the control group are listed in Tables 3 and 4. Sanson et al. [16] also reported in 1996 an increased risk for fetal loss in antithrombin-, protein C- or protein S-deficient women compared to relatives without these deficiencies (Table 4). Meinardi et al. [90] found an increased frequency of fetal loss, especially by miscarriage, in women carrying the FV Leiden mutation in comparison with unaffected relatives (Table 3), whereas Tormene et al. [91] described an increased risk of stillbirth, but not miscarriage, in women with FV Leiden compared with non-carrier relatives. In a multicenter study [85], we evaluated retrospectively pregnancy outcome in 64 women with the homozygous FV Leiden mutation in comparison with 52 matched control women (Table 4). The proportion of pregnancies ending in stillbirth was higher in the patient group (3.3%) than in controls (1.7%), however, the difference was not statistically significant. With respect to miscarriages of affected women, numbers were almost equal in homozygous carriers compared with controls. The only prospective and controlled observational study addressing specifically hereditary thrombophilia and fetal loss was performed by the European Prospective Cohort on Thrombophilia (EPCOT) Study Group [92]. No significant increase in risk for fetal loss was found in 48 women with antithrombin-, protein C- or protein S-deficiency of FV Leiden in comparison with 60 controls from the general population (Table 3).

Table 3.  Pregnancy complications in women with thrombophilia or a history of VTE and controls
AuthorsPatients/controlsWomen (n)Fetal loss, n (%)Severe pre-eclampsia, n (%)
  1. AT, antithrombin deficiency; PC, protein C-deficiency; PS, protein S-deficiency; FVL, factor V Leiden; NA, not available; VTE, venous thromboembolism.

  2. *Number of homozygous individuals not given.

  3. 15 homozygous.

Preston et al. [14]AT10834 (31.5)NA
PC16248 (29.6) 
PS14542 (29.0) 
FVL*14138 (26.9) 
Controls39593 (23.5) 
Meinardi et al. [90]FVL22872 (31.6)NA
Controls (relatives)12127 (22.3) 
Pabinger et al. [80]History of VTE395103 (26.1)12 (3.0)
With thrombophilia21452 (24.3)5 (2.3)
Controls31377 (24.6)4 (1.3)
Vossen et al. [92]AT, PC, PS, FVL4810 (20.8)NA
Controls6010 (16.7) 
Table 4.  Fetal loss (based on number of pregnancies) in women with thrombophilia and controls
AuthorsPatients/controlsWomen (n)Pregnancies (n)Fetal loss, n (%)
  1. AT, antithrombin deficiency; PC, protein C-deficiency; PS, protein S-deficiency; FVL, factor V Leiden.

  2. *Number of homozygous individuals not given.

  3. 15 homozygous.

Preston et al. [14]AT10826050 (19.2)
PC16243073 (17.0)
PS14537862 (16.4)
FVL*14141048 (11.7)
Controls3951019124 (12.2)
Meinardi et al. [90]FVL228654107 (16.4)
Controls (relatives)12135232 (9.1)
Pabinger et al. [85]FVL (all homozygous)6421232 (15)
Controls5211814 (12)
Tormene et al. [91]FVL6519131 (16.2)
Controls (relatives)4412113 (10.7)
Sanson et al. [16]AT, PC, PS6018842 (22.3)
Controls (relatives)6920223 (11.4)

The most compelling association between thrombophilia and pregnancy loss is that afforded by antiphospholipid antibodies. Women with antiphospholipid antibodies have a high risk of thrombosis, pregnancy loss, and pre-eclampsia [89,93] and hypothetical explanations for this association include placental thrombosis and end-stage infarction. Recently, it has been proposed that the occurrence of sudden fetal death, especially after the week 12 of gestation, results from interference with spiral artery remodeling during secondary trophoblast invasion [94]. Rai et al. have reported a randomized-controlled trial, in which the pregnancy outcome in women with antiphospholipid antibodies and previous recurrent fetal loss was markedly improved by combined treatment with 75 mg aspirin (once daily) and 5000 units unfractionated heparin every 12 h [95]. The life birth rate of women treated with aspirin and heparin was 71% and 42% in those treated with aspirin alone. A similar observation was made by Kutteh [96] although it should be mentioned that in this study women with lupus anticoagulant were excluded. In contrast to previous studies, Farquharson et al. [39] were unable to confirm a significantly better outcome after treatment with aspirin plus heparin. Life birth rate was 78% in 51 women treated with aspirin plus heparin and 72% in women treated with aspirin alone (Table 5). However, it must be emphasized that these women were recruited rather late during their pregnancy. Finally, in a small randomized-controlled trial in women with antiphospholipid antibodies and recurrent pregnancy loss, treatment with aspirin was compared with a placebo. Live infants were delivered in more than 80% of women in each group and there was no statistically significant difference [97].

Table 5.  Randomized trials comparing treatment with heparin or LMWH plus aspirin and aspirin alone in women with recurrent pregnancy loss and antiphospholipid antibodies
AuthorsEvent rate underRR (95% CI)
Heparin/LMWH plus aspirin, n/n (%)Aspirin, n/n (%)
  1. Kutteh [96] and Rai et al. [95] administered unfractionated heparin 5000 units twice daily whereas Farquharson et al. [39] dalteparin 5000 units once daily.

  2. LMWH, low-molecular weight heparin; RR, relative risk; CI, confidence interval.

Kutteh [96]5/25 (20)14/25 (56)0.36 (0.15–0.84)
Rai et al. [95]13/45 (29)26/45 (58)0.50 (0.30–0.84)
Farquharson et al. [39]11/51 (22)13/47 (28)0.78 (0.39–1.57)

As a number of randomized studies have led to differing conclusions, it remains unclear, if indeed a treatment regimen of LMWH plus aspirin is superior to aspirin alone with respect to pregnancy outcome in women with antiphospholipid antibodies. Another approach for investigating whether or not thrombophilia has an impact on pregnancy outcome was chosen by our group [80]. Pregnancy outcome was studied in 345 women with a history of objectively confirmed VTE and in 313 healthy female controls from the same population without a history of VTE (Table 3). Women in the patient group had a statistically significant more incident history of pregnancy-induced hypertension but no significant tendency toward severe pre-eclampsia. The rate of miscarriage and stillbirth was equally distributed between the two groups, furthermore, we did not find an increased risk based on a laboratory diagnosis of thrombophilia.

Data in the literature are inconsistent with respect to pregnancy outcome in women with thrombophilia. Nowadays, it is widely accepted that women with a history of VTE but without antiphospholipid antibodies usually have a favorable pregnancy outcome. Data from one prospective study on women with a history of VTE are available, in which women with this history did not receive heparin prophylaxis [86]. The investigators found a low risk of recurrent thrombosis (approximately 3%), but unfortunately did not provide any information on other pregnancy complications. Further data on pregnancy outcomes in untreated women are needed urgently, because this could influence the decision whether or not to recommend heparin prophylaxis in women with a history of VTE.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Pregnancy loss
  5. Pre-eclampsia and IUGR
  6. Pregnancy outcome in women with thrombophilia
  7. Acknowledgement
  8. References
  • 1
    Bick RL. Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Miscarriage Syndrome Cooperative Group. Clin Appl Thromb Hemost 2000; 6: 11525.
  • 2
    Neugebauer R, Kline J, Shrout P, Skodol A, O'Connor P, Geller PA, Stein Z, Susser M. Major depressive disorder in the 6 months after miscarriage. JAMA 1997; 277: 3838.
  • 3
    Geller PA, Klier CM, Neugebauer R. Anxiety disorders following miscarriage. J Clin Psychiatry 2001; 62: 4328.
  • 4
    Cuisinier M, Janssen H, de Graauw C, Bakker S, Hoogduin C. Pregnancy following miscarriage: course of grief and some determining factors. J Psychosom Obstet Gynaecol 1996; 17: 16874.
  • 5
    Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 116670.
  • 6
    Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost 1984; 52: 17682.
  • 7
    Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68: 8815.
  • 8
    Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J 1969; 3: 3879.
  • 9
    Beller FK, Ebert C. The coagulation and fibrinolytic enzyme system in pregnancy and in the puerperium. Eur J Obstet Gynecol Reprod Biol 1982; 13: 17797.
  • 10
    Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 36959.
  • 11
    Sondheimer S. Abortion. Encyclopedia Reprod 1999; 1: 16.
  • 12
    Galli M, Barbui T. Antiphospholipid antibodies and pregnancy. Best Pract Res Clin Haematol 2003; 16: 21125.
  • 13
    Wouters MG, Boers GH, Blom HJ, Trijbels FJ, Thomas CM, Borm GF, Steegers-Theunissen RP, Eskes TK. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993; 60: 8205.
  • 14
    Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer FJ. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 9136.
  • 15
    Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated C resistance. Br J Haematol 1996; 92: 48990.
  • 16
    Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, Ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 1996; 75: 3878.
  • 17
    Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 913.
  • 18
    Gris JC, Ripart-Neveu S, Maugard C, Tailland ML, Brun S, Courtieu C, Biron C, Hoffet M, Hedon B, Mares P. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages. The Nimes Obstetricians and Haematologists (NOHA) Study. Thromb Haemost 1997; 77: 1096103.
  • 19
    Grandone E, Margaglione M, Colaizzo D, D'Addedda M, Cappucci G, Vecchione G, Scianname N, Pavonne G, Di Minno G. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77: 8224.
  • 20
    Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, Bozzo M, Mannucci PM. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 10158.
  • 21
    Younis JS, Brenner B, Ohel G, Tal J, Lanir N, Ben-Ami M. Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 315.
  • 22
    Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler CJ. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 2001; 46: 12431.
  • 23
    Alonso A, Soto I, Urgelles MF, Corte JR, Rodriguez MJ, Pinto CR. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002; 187: 133742.
  • 24
    Rasmussen A, Ravn P. High frequency of congenital thrombophilia in women with pathological pregnancies? Acta Obstet Gynecol Scand 2004; 83: 80817.
  • 25
    Gris JC, Quere I, Sanmarco M, Boutiere B, Mercier E, Amiral J, Hubert AM, Ripart-Neveu S, Hoffet M, Tailland ML, Rousseau O, Monpeyroux F, Dauzat M, Sampol J, Daures JP, Berlan J, Mares P. Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nimes Obstetricians and Haematologists Study – NOHA. Thromb Haemost 2000; 84: 22836.
  • 26
    Rai R, Shlebak A, Cohen H, Backos M, Holmes Z, Marriott K, Regan L. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16: 9615.
  • 27
    Carp H, Salomon O, Seidman D, Dardik R, Rosenberg N, Inbal A. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod 2002; 17: 16337.
  • 28
    Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91: 70011.
  • 29
    Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 2004; 164: 55863.
  • 30
    Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 9018.
  • 31
    Hashimoto K, Shizusawa Y, Shimoya K, Ohashi K, Shimizu T, Azuma C, Murata Y. The factor V Leiden mutation in Japanese couples with recurrent spontaneous abortion. Hum Reprod 1999; 14: 18724.
  • 32
    Lindqvist PG, Svensson PJ, Marsaal K, Grennert L, Luterkort M, Dahlback B. Activated protein C resistance (FV: Q506) and pregnancy. Thromb Haemost 1999; 81: 5327.
  • 33
    Murphy RP, Donoghue C, Nallen RJ, D'Mello M, Regan C, Whitehead AS, Fitzgerald DJ. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000; 20: 26670.
  • 34
    Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost 2003; 1: 4338.
  • 35
    Kupferminc MJ, Fait G, Many A, Lessing JB, Yair D, Bar-Am A, Eldor A. Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias. Hypertens Pregnancy 2001; 20: 3544.
  • 36
    Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 66872.
  • 37
    Tzafettas J, Mamopoulos A, Anapliotis A, Loufopoulos A, Psarra A, Klearchou N, Mamopoulos M. Thromboprophylaxis throughout pregnancy in women with previous history of recurrent miscarriages of unknown aetiology. Clin Exp Obstet Gynecol 2002; 29: 26770.
  • 38
    Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 6937.
  • 39
    Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 100: 40813.
  • 40
    Tulppala M, Palosuo T, Ramsay T, Miettinen A, Salonen R, Ylikorkala O. A prospective study of 63 couples with a history of recurrent spontaneous abortion: contributing factors and outcome of subsequent pregnancies. Hum Reprod 1993; 8: 76470.
  • 41
    Rud B, Klunder K. The course of pregnancy following spontaneous abortion. Acta Obstet Gynecol Scand 1985; 64: 2778.
  • 42
    Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ 1989; 299: 5415.
  • 43
    Magann EF, Martin JN Jr. Pre-eclampsia/eclampsia. In: KnobilE, NeillJD, eds. Encyclopedia of Reproduction Vol. 3. San Diego, USA: Academic Press, 1998: 96470.
  • 44
    Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R. Epidemiology of preeclampsia and eclampsia in the United States, 1979–1986. Am J Obstet Gynecol 1990; 163: 4605.
  • 45
    Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet 2001; 357: 536.
  • 46
    Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of cardiovascular disease and steroid hormone contraception. Lancet 1995; 346: 157582.
  • 47
    van Walraven C, Mamdani M, Cohn A, Katib Y, Walker M, Rodger MA. Risk of subsequent thromboembolism for patients with pre-eclampsia. BMJ 2003; 326: 7912.
  • 48
    Brenner B, Lanir N, Thaler I. HELLP syndrome associated with factor V R506Q mutation. Br J Haematol 1996; 92: 9991001.
  • 49
    Dizon-Townson DS, Nelson LM, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 175: 9025.
  • 50
    Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 45760.
  • 51
    Kobashi G, Yamada H, Asano T, Nagano S, Hata A, Kishi R, Kondo K, Fujimoto S. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Semin Thromb Hemost 1999; 25: 4879.
  • 52
    De Groot CJ, Bloemenkamp KW, Duvekot EJ, Helmerhorst FM, Bertina RM, Van Der Meer F, De Ronde H, Oei SG, Kanhai HH, Rosendaal FR. Preeclampsia and genetic risk factors for thrombosis: a case-control study. Am J Obstet Gynecol 1999; 181: 97580.
  • 53
    Grandone E, Margaglione M, Colaizzo D, Cappucci G, Scianname N, Montanaro S, Paladini D, Martinelli P, Di Minno G. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999; 81: 34952.
  • 54
    Horstkamp BS, Kiess H, Kramer J, Riess H, Henrich W, Dudenhausen JW. Activated protein C resistance shows an association with pregnancy-induced hypertension. Hum Reprod 1999; 14: 31125.
  • 55
    Mello G, Parretti E, Martini E, Mecacci F, La Torre P, Cioni R, Lucchetti R, Fedi S, Gori AM, Pepe G, Prisco D, Abbate R. Usefulness of screening for congenital or acquired hemostatic abnormalities in women with previous complicated pregnancies. Haemostasis 1999; 29: 197203.
  • 56
    O'Shaughnessy KM, Fu B, Ferraro F, Lewis I, Downing S, Morris NH. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort. Hypertension 1999; 33: 133841.
  • 57
    van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, von Blomberg BM, Buller HR. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999; 180: 114650.
  • 58
    Kupferminc MJ, Fait G, Many A, Gordon D, Eldor A, Lessing JB. Severe preeclampsia and high frequency of genetic thrombophilic mutations. Obstet Gynecol 2000; 96: 459.
  • 59
    Rigo J Jr, Nagy B, Fintor L, Tanyi J, Beke A, Karadi I, Papp Z. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase. Hypertens Pregnancy 2000; 19: 16372.
  • 60
    von Tempelhoff GF, Heilmann L, Spanuth E, Kunzmann E, Hommel G. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with preeclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets. Thromb Res 2000; 100: 3635.
  • 61
    Glueck CJ, Kupferminc MJ, Fontaine RN, Wang P, Weksler BB, Eldor A. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001; 97: 448.
  • 62
    Alfirevic Z, Mousa HA, Martlew V, Briscoe L, Perez-Casal M, Toh CH. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001; 97: 7539.
  • 63
    Kim YJ, Williamson RA, Murray JC, Andrews J, Pietscher JJ, Peraud PJ, Merrill DC. Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation. Am J Obstet Gynecol 2001; 184: 12117.
  • 64
    Livingston JC, Barton JR, Park V, Haddad B, Phillips O, Sibai BM. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol 2001; 185: 1537.
  • 65
    Mimuro S, Lahoud R, Beutler L, Trudinger B. Changes of resistance to activated protein C in the course of pregnancy and prevalence of factor V mutation. Aust N Z J Obstet Gynaecol 1998; 38: 2004.
  • 66
    Kosmas IP, Tatsioni A, Ioannidis JP. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 2003; 21: 12218.
  • 67
    Kosmas IP, Tatsioni A, Ioannidis JP. Association of C677T polymorphism in the methylenetetrahydrofolate reductase gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis. J Hypertens 2004; 22: 165562.
  • 68
    Morrison ER, Miedzybrodzka ZH, Campbell DM, Haites NE, Wilson BJ, Watson MS, Greaves M, Vickers MA. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review. Thromb Haemost 2002; 87: 77985.
  • 69
    De Maat MP, Jansen MW, Hille ET, Vos HL, Bloemenkamp KW, Buitendijk S, Helmerhorst FM, Wladimiroff JW, Bertina RM, De Groot CJ. Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost 2004; 2: 158893.
  • 70
    D'Anna R, Baviera G, Corrado F, Ientile R, Granese D, Stella NC. Plasma homocysteine in early and late pregnancies complicated with preeclampsia and isolated intrauterine growth restriction. Acta Obstet Gynecol Scand 2004; 83: 1558.
  • 71
    Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, VanDorsten P, Landon M, Paul R, Miodovnik M, Meis P, Thurnau G. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998; 338: 7015.
  • 72
    CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet 1994; 343: 61929.
  • 73
    Kupferminc MJ, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 2000; 79: 9637.
  • 74
    Martinelli P, Grandone E, Colaizzo D, Paladini D, Scianname N, Margaglione M, Di Minno G. Familial thrombophilia and the occurrence of fetal growth restriction. Haematologica 2001; 86: 42831.
  • 75
    Kupferminc MJ, Many A, Bar-Am A, Lessing JB, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. BJOG 2002; 109: 13736.
  • 76
    Infante-Rivard C, David M, Gauthier R, Rivard GE. Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study. N Engl J Med 1991; 325: 10636.
  • 77
    Vollset SE, Refsum H, Irgens LM, Emblem BM, Tverdal A, Gjessing HK, Monsen AL, Ueland PM. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J Clin Nutr 2000; 71: 9628.
  • 78
    Clark P, Walker ID, Greer I. Acquired activated protein-C resistance in pregnancy and association with increased thrombin generation and fetal weight. Lancet 1999; 353: 2923.
  • 79
    Leeda M, Riyazi N, de Vries JI, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998; 179: 1359.
  • 80
    Pabinger I, Grafenhofer H, Kaider A, Ilic A, Eichinger S, Quehenberger P, Husslein P, Mannhalter C, Lechner K. Preeclampsia and fetal loss in women with a history of venous thromboembolism. Arterioscler Thromb Vasc Biol 2001; 21: 8749.
  • 81
    Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 2002; 100: 10602.
  • 82
    Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 1990; 63: 31920.
  • 83
    Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on natural inhibitors. Arterioscler Thromb Vasc Biol 1996; 16: 7428.
  • 84
    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: 904.
  • 85
    Pabinger I, Nemes L, Rintelen C, Koder S, Lechler E, Loreth RM, Kyrle PA, Scharrer I, Sas G, Lechner K, Mannhalter C, Ehrenforth S. Pregnancy-associated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden. Hematol J 2000; 1: 3741.
  • 86
    Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, Geerts W, Kovacs M, Weitz JI, Robinson KS, Whittom R, Couture G. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this Pregnancy Study Group. N Engl J Med 2000; 343: 143944.
  • 87
    Pabinger I, Grafenhofer H, Kaider A, Kyrle P, Quehenberger P, Mannhalter C, Lechner K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3: 94954.
  • 88
    Branch DW, Scott JR, Kochenour NK, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985; 313: 13226.
  • 89
    Triplett DA, Harris EN. Antiphospholipid antibodies and reproduction. Am J Reprod Immunol 1989; 21: 12331.
  • 90
    Meinardi JR, Middeldorp S, de Kam PJ, Koopman MM, van Pampus EC, Hamulyak K, Prins MH, Buller HR, van der Meer J. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 7369.
  • 91
    Tormene D, Simioni P, Prandoni P, Luni S, Innella B, Sabbion P, Girolami A. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost 1999; 82: 12379.
  • 92
    Vossen CY, Preston FE, Conard J, Fontcuberta J, Makris M, van der Meer FJ, Pabinger I, Palareti G, Scharrer I, Souto JC, Svensson P, Walker ID, Rosendaal FR. Hereditary thrombophilia and fetal loss: a prospective follow-up study. J Thromb Haemost 2004; 2: 5926.
  • 93
    Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995; 10: 33014.
  • 94
    Chamley LW, Duncalf AM, Mitchell MD, Johnson PM. Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death. Lancet 1998; 352: 10378.
  • 95
    Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 2537.
  • 96
    Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 15849.
  • 97
    Pattison NS, Chamley LW, Birdsall M, Zanderigo AM, Liddell HS, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol 2000; 183: 100812.
  • 98
    Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 647.
  • 99
    den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 75962.
  • 100
    Heijboer H, Brandjes DP, Buller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 15126.
  • 101
    Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 15036.
  • 102
    Miletich J, Sherman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 9916.
  • 103
    Pabinger I, Brucker S, Kyrle PA, Schneider B, Korninger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis 1992; 3: 54753.
  • 104
    Tait RC, Walker ID, Perry DJ, Islam SI, Daly ME, McCall F, Conkie JA, Carrell RW. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 10612.
  • 105
    Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 8793.