Is thrombophilia a risk factor for placental vascular disorders?

First trimester recurrent fetal loss and severe second or third trimester placental vascular disorders are still frequently unexplained. Acquired biological thrombophilia (antiphospholipid syndrome, essential thrombocythemia) are known risk factors. Genetic thrombophilia may represent a new risk factor for placental vascular diseases, but reported data are conflicting. Combined hereditary thrombophilias are indeed a moderate risk factor, but even in these cases most pregnancies are normal giving healthy live birth children. Whether hereditary thrombophilia is associated with recurrent severe placental vascular disorders is unknown.     

Preventing adverse obstetric outcome in women with thrombophilia

Thrombophilia may represent a new risk factor for placental vascular disorders. Thromboprophylaxis with low doses of heparin and aspirin may be discussed in order to reduced adverse obstetric outcomes. No randomized controlled trials are currently published in the literature. Thromboprophylaxis may be unwarranted in asymptomatic women because of the lack for an association between thrombophilia and pregnancy outcome. Women with antiphospholipid syndrome are at high risk for pregnancy loss and maternal complications. Pregnancy in women with antiphospholipid syndrome appears to be improved by thromboprophylaxis, but adverse obstetric outcome may occur despite treatment. Thromboprophylaxis is recently reported in women with previous poor obstetric outcomes. These preliminary observational studies are still insufficient to recommend a large diffusion for thromboprophylaxis. Prevention for adverse outcomes with a low fixed dose of heparin may only be discussed in women with previous late fetal loss or intrauterine fetal death.     

Thrombophilia and fetal loss

A large body of evidence obtained during the last 6 years suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. Case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss. Other complications such as preeclampsia, placental abruption, and intrauterine growth retardation may also be associated with thrombophilia. Placental pathologic findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition. Preliminary case-control studies suggest that low-molecular-weight heparins are effective in preventing pregnancy loss in women with thrombophilia and previous fetal wastage.     

Thrombophilia related issues in women and children

Women experience increased thrombotic risk at pregnancy and puerperium as well as during hormonal therapy with oral contraceptives or hormone replacement therapy. Physiological and anatomical changes in pregnancy contribute to the hypercoagulable situation. Women with thrombophilia have an increased risk for venous and arterial thromboembolism as well as for gestational vascular complications including fetal loss, pre-eclampsia, placental abruption, and fetal growth restriction. Children are at increased thrombotic risk, particularly at the neonatal period, and may express thrombosis often in association with thrombophilia. This article will focuses on the clinical association, pathogenesis, and treatment of thrombophilia-related issues in women and children.     

Inherited thrombophilia and fetal loss

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.     

Embryogenesis and gene targeting of coagulation factors in mice

Genetic or acquired thrombophilia of the pregnant mother has been associated with the occurrence of gestational vascular disease and recurrent fetal loss and may contribute to the aetiology of pre-eclampsia. This chapter reviews insights into this link between thrombophilia and pregnancy complications that were gained from the study of genetically altered mice. These studies strongly support the notion of a cause-effect relationship between altered function of the thrombomodulin-protein C pathway and adverse pregnancy outcome. Analysis of the mouse models highlights unique aspects of vascular structure and function at the feto-maternal interface, and exposes new biological functions of natural anticoagulant pathways in pregnancy. These roles are unrelated to the maintenance of vascular patency and may be mediated through specific signalling pathways activated by coagulation factors. Abnormal signalling by placental trophoblasts at the feto-maternal interface is suggested as a hitherto unrecognized mechanism that may underlie adverse pregnancy outcome associated with haemostatic disorders.     

Evidence-based indications for thrombophilia screening

Thrombophilic defects have been shown to be associated with an increased risk of venous thrombosis, fetal loss, and gestational complications. The knowledge about the clinical relevance of thrombophilic defects is increasing, and evidence-based indications for thrombophilia screening are therefore discussed in this review. Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism is more cost-effective than universal screening in all patient groups evaluated. In the majority of patients with acute venous thrombosis, the results of thrombophilia screening do not influence the duration of oral anticoagulation. The only patient population who clearly profits from thrombophilia screening in this situation are patients with a newly diagnosed antiphospholipid syndrome, because prolonged anticoagulation can avoid the high incidence of recurrence in this patient population. Because of the increased risk of venous thrombosis during pregnancy and the puerperium, thrombophilia screening is indicated in selected patients with a previous history of venous thrombosis or a positive family history. Significant associations with early and late pregnancy loss are observed for carriers of the heterozygous factor V Leiden mutation, the heterozygous prothrombin-mutation G20210A and anticardiolipin antibodies, while protein S deficiency is significantly associated with late pregnancy loss. Antithrombotic drugs like UFH, LMWH or low-dose aspirin may have a potential therapeutic benefit in patients with recurrent pregnancy loss and thrombophilia, but placebo-controlled, multicenter trials are urgently needed to clarify this issue. Although a supra-additive effect for the risk of venous thrombosis is observed between oral contraceptives and some thrombophilias, the absolute incidence of venous thromboembolism is low in premenopausal women and mass screening strategies are therefore unlikely to be effective. While antiphospholipid antibodies are known to be associated with arterial thrombosis, screening for heritable thrombophilias is not useful in arterial thrombosis, although subgroup analysis indicates that they may play a role particularly in young patients and children.     

Vascular placental pathology in high-risk groups: definition and synopsis

The vascular placental pathology (VPP) is associated with many etiologies. Some are the consequence of a maternal genetic or acquired predisposition. Others are associated with a chronic maternal disease (hypertension, lupus, obesity, diabetes, ...). Finally, some others are associated with placental implantation leading to fetal ischemia (multiple pregnancy, chorioangioma, primiparity, feto-placental hydrops) or to environmental (altitude) or nutritional factors (famine and specific alimentary depressions). We classify these factors into three categories according to the risk level (moderate, significant and elevated). While any of these factors can increase the risk of VPP, no one is sufficiently sensitive or specific in predict inevitable onset of VPP. In most cases VPP results from a combination of two (or more) risk factors. The risk factors of VPP classified as moderate include age (> or = 35 years), increased blood pressure during the second trimester of pregnancy, a new paternity, dietetic factors or environmental factors, smoking and controlled diabetes (class B, C), or inactive systemic diseases. Risk is significantly elevated among obese (BMI > or = 25), primiparous women, women with a past familial history (first degree) of preeclampsia or eclampsia, cocaine use or association of tobacco and caffeine use, increased placental mass (associated with twin pregnancy, fetal hydrops or molar pregnancy), uncontrolled diabetes, lupus, active scleroderma. Risk is considered to be high among patients with chronic hypertension, women with a past history of preeclampsia, diabetes (class D, F, R), patients with active systemic disease or with antiphospholipid antibodies or women with lupus or renal lesions and/or proteinuria as well as chronic kidney disease resulting in proteinuria, hypertension and renal insufficiency. Finally, the risk of VPP is considered to be increased in the presence of acquired thrombophilia. It remains moderate in the presence of isolated genetic thrombophilia, except in forms presenting with multiple genetic mutations or associated with an hyperhomocysteinemia. A "high-risk group" is defined among women with past history of deep venous thromboembolic events outside pregnancy, or with a past history of placental vascular pathology (intra-uterine death, placental abruptio, severe and precocious placental, intra-uterine growth retardation, early and repetitive fetal loss) and who, in addition, present with acquired thrombophilia (antiphospholipid antibodies, thrombocytemia), unique homozygous genetic thrombophilia, amultiple genetic thrombophilia or unique heterozygous genetic thrombophilia associated with hyperhomocysteinemia. Prophylactic treatment of acquired thrombophilia and of the multiple genetic forms or associated with hypercysteinemia is a logical rationale, particularly among women with a past history of placental vascular pathology, or with a past history of venous thromboembolic events. On the contrary, prophylaxis using low-molecular-weight heparin in the event of asymptomatic genetic thrombophilic mutations and for women without a past history of deep venous thromboembolism or vascular placental pathology remains controversial.     

Management of Obstetric Antiphospholipid Syndrome

Recurrent early miscarriages (excluding chromosomal anomalies), late fetal loss, and maternal thrombosis are characteristic of obstetric antiphospholipid syndrome (APS). Obstetric complications such as preeclampsia, fetal growth restriction, premature delivery, and fetal death also occur in higher frequency in APS patients than in the general population. A high-risk obstetric center is needed for proper evaluation of and intervention with pregnant women with APS. Association with lupus carries additional risk of thrombosis when antiphospholipid antibodies (aPLs) are present. Gestational results with live births are improved to about 80% when antithrombotic therapy is used, but failure in 20% to 30% of the cases despite correct treatment with low-dose aspirin with or without heparin reveals new pathways for pregnancy loss in APS and unmet needs. At the moment, there is no recommendation to investigate patients with infertility for the presence of aPLs.     

Thrombophilia in pregnancy: a systematic review

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.     

Clinical management of thrombophilia-related placental vascular complications

Pregnancy is a hypercoagulable state with an increased thrombotic risk throughout gestation and the postpartum period. Women with thrombophilia may have a further increased risk of placental vascular complications, including pregnancy loss, preeclampsia, intrauterine growth restriction, and placental abruption. Preliminary data suggest that maternal antithrombotic prophylaxis may result in improved gestational outcome. Randomized trials are under way and hopefully will optimize maternal and neonatal outcome.     

Preventing thrombophilia-related complications of pregnancy

Pregnancy is associated with an increased risk of venous thromboembolism (VTE) and approximately half of all pregnancy-related VTEs are associated with thrombophilia. Recent studies suggest that there is a link between thrombophilia and other adverse pregnancy outcomes, such as fetal loss, preeclampsia, placental abruption and intrauterine growth restriction. However, the associations reported are modest, and high quality data are limited. Although the most compelling data derive from pregnant women with antiphospholipid antibodies, the use of anticoagulants for the prevention of pregnancy complications other than VTE in women with heritable thrombophilias is becoming more frequent. In this article, we review the impact of the various thrombophilias on pregnancy and its outcome, the evidence for therapies aimed at prevention of thrombophilia-related pregnancy complications, and briefly discuss the role of screening for thrombophilia in pregnancy.     

Pregnancy failure and heritable thrombophilia

Heritable thrombophilia is associated with an increased risk for pregnancy failure, defined as sporadic and recurrent miscarriage, late fetal loss, and other vascular pregnancy complications such as preeclampsia and intrauterine growth retardation. The pathogenesis is likely to include effects on trophoblast differentiation and not solely hypercoagulability. This is in line with the observation that most recurrent miscarriages occur early. Therapeutic options include aspirin as well as low-molecular-weight heparin. However, in women with heritable thrombophilia and unexplained recurrent pregnancy loss, evidence is not available as published trials have not used an adequate comparator (no treatment or placebo). Currently, randomized controlled trials with no treatment or placebo are being carried out and results should be awaited before implementing a potentially harmful intervention in pregnant women with heritable thrombophilia and a history of pregnancy failure. Both infertility and pregnancy failure are extremely distressing for couples with the desire to have children. Pregnancy failure comprises (recurrent) early miscarriage, as well as late pregnancy loss. The role of heritable thrombophilia in pregnancy failure is reviewed, with a focus on recurrent miscarriage, in terms of epidemiology, etiology, and potential therapeutic implications.     

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.     

Assessment of uterine placental circulation in thrombophilic women

Thrombophilia is associated with several complications of pregnancy including first and second trimester fetal loss, intrauterine fetal death, intrauterine growth restriction, preeclampsia, and placental abruption. Few studies have documented thrombotic lesions observed on the pathologic examination of the placenta in women with severe pregnancy complications. Moreover, a significantly higher rate of factor V Leiden and prothrombin G20210A gene mutations have been found in placentas with thrombotic events compared with normal placentas. In addition, clinical studies have been performed, using Doppler ultrasonography, to assess the uterine placental circulation in women with thrombophilia. Doppler studies of the umbilical artery in cases of intrauterine growth retardation have shown a high systolic to diastolic ratio (S/D) ratio, suggesting an increase in the resistance of the placental small vessels. When these placental vessels were examined after delivery, significant differences were found in comparison with placental vessels of normal pregnancies. Most of the Doppler studies of the umbilical and uterine arteries in pregnancies with thrombophilia were performed in women with antiphospholipid antibodies. The other pathologic conditions associated with thrombophilia and complications of pregnancy were published only recently. These few studies have demonstrated abnormal umbilical and uterine arteries blood flow in complicated pregnancies. Finally, few Doppler studies also suggest improved uterine placental circulation when women with thrombophilia received thromboprophylaxis.     

Prophylaxis and treatment of thrombophilia in pregnancy

PURPOSE OF REVIEW: This review addresses the prophylaxis and treatment of thrombophilia in pregnancy, which is associated with increased risk of venous thromboembolism and placental vascular complications. RECENT FINDINGS: Topics include preventing deep vein thrombosis recurrence in pregnant women with constitutional thrombophilias, using prophylactic heparins throughout pregnancy and postpartum anticoagulants. Cases of thrombosis still occur in the postpartum period and other therapeutics should be tested. Primary prophylaxis is acceptable for high-risk thrombophilias. Early pregnancy losses (before the 10th week) are not associated with constitutional thrombophilias. The natural prognosis of embryonic losses associated with current thrombogenic polymorphisms is good, unlike fetal losses associated with the same thrombophilias: in this case, a prophylactic low-molecular-weight heparin given from the beginning of the 8th week is more efficient than low-dose aspirin. Data are lacking on the prevention of severe preeclampsia, placental abruption, or intrauterine growth restriction in women with constitutional thrombophilias; preliminary results indicate that low-molecular-weight heparin may have some preventive effect. Specific studies are needed. SUMMARY: Recent studies have shown the limits of available procedures for women with constitutional thrombophilia and have helped define the clinical situations in thrombophilia-related placental insufficiency in which prophylactic low-molecular-weight heparin may be indicated.     

Grossesse et syndrome des antiphospholipides

Antiphospholipid syndrome (APS) is associated with a risk of obstetrical complications, affecting both the mother and the fetus. Obstetrical APS is defined by a history of three consecutive spontaneous miscarriages before 10 weeks of gestation (WG), an intra-uterine fetal death after 10 WG, or a premature birth before 34 WG because of severe pre-eclampsia, eclampsia or placental adverse outcomes (intrauterine growth retardation, oligohydramnios). Pregnancy in women with a diagnosis of obstetric APS is at increased risk for placental abruption, HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome and thrombosis that may be part of a catastrophic antiphospholipid syndrome (CAPS). A previous thrombosis and the presence of a lupus anticoagulant are risk factors for pregnancy failure. A multidisciplinary approach, associating the internist, the anesthesiologist and the obstetrician, is recommended for these high-risk pregnancies. Preconception counseling is proposed to identify pregnancy contraindications, and to define and adapt the treatment prior and during the upcoming pregnancy. Heparin and low-dose aspirin are the main treatments. The choice between therapeutic or prophylactic doses of heparin will depend on the patient's medical history. The anticoagulant therapeutic window for delivery should be as narrow as possible and adapted to maternal thrombotic risk. There is a persistent maternal risk in the postpartum period (thrombosis, HELLP syndrome, CAPS) justifying an antithrombotic coverage during this period. We suggest a monthly clinical and biological monitoring which can be more frequent towards the end of pregnancy. The persistence of notches at the Doppler-ultrasound evaluation seems to be the best predictor for a higher risk of placental vascular complications. Treatment optimization and multidisciplinary antenatal care improve the prognosis of pregnancies in women with obstetric APS, leading to a favorable outcome most of the time.     

Perinatal aspects of inherited thrombophilia

The identified main causes of inherited thrombophilia are deficiencies of antithrombin, protein C and protein S, activated protein C (APC) resistance and the factor V Leiden mutation, mutant factor II, and inherited hyperhomocysteinemia. In women from symptomatic families these defects may be associated with an increased risk of venous thrombosis in pregnancy and recurrent fetal loss. Inherited thrombophilia is common and appears to be a multigene disorder. The thrombotic risk would seem to be greatest in women with antithrombin deficiency and more than one thrombophilia defect. The abnormalities that are now recognized represent only part of the genetic predisposition to thrombosis. In assessing thrombotic risk in pregnancy, acquired risk factors as well as genetic predisposition should be considered. Increasing age, obesity, immobility, and delivery by cesarean section are major risk factors. Pregnancy should be planned, and each patient should be managed on an individual basis. In pregnancy, heparin is the anticoagulant of choice, and as far as possible, treatment with warfarin should be avoided because of the risks to the fetus. When patients are on long-term treatment with warfarin, pregnancy should be avoided, and warfarin should be discontinued prior to embarking on a pregnancy or as soon as pregnancy is suspected and before 6 weeks' gestation. In women from symptomatic families with antithrombin deficiency, adjusted dose heparin throughout pregnancy is recommended and warfarin for at least 3 months post partum. In protein C and protein S deficiency, factor V Leiden, or mutant factor II, treatment can be based on personal and family history. Thromboprophylaxis in late pregnancy and post partum should be considered. Fetal loss may be increased in women with inherited thrombophilia. The risk appears greatest in women with antithrombin deficiency and women with more than one thrombophilia defect. A number of reports have claimed that prophylactic treatment with heparin during pregnancy has resulted in successful pregnancy in women with recurrent fetal death and inherited thrombophilia.     

Frequency of antiphospholipid antibodies and factor V (G1691A), prothrombin (G20210A) gene polimorphism among women with pregnancy complications

Thrombophilia these days is a subject of many medical research including obstetric and gynecology where causing feto-maternal complications. In women predispose to venous thromboembolism in high risk situation like pregnancy, puerperium, operation, prolonged bed rest or hormonal treatment. For fetal complication account miscarriages, intrauterine deaths, IUGR, and for maternal account premature placental separation and severe preeclampsia. Diagnostic panel include inherited factors like factor V Leiden and prothrombin mutation, activated protein C resistance and acquired like anticardiolipin antibodies, antibodies against beta2-glicoprotein 1 and lupus anticoagulant. The aim of this paper is estimation ofthrombophilia as a causative factor of pregnancy complications and attempt to establish screening criteria for thrombophilia. Material involved 36 women with pregnancy complications divided into three groups correlating with trimester when pregnancy loss occured. All patients had genetic, hormonal and anatomic tests done on purpose to exclude other possible causes of miscarriages. All women had done both types of tests for inherited and acquired thrombophilia. For factor V and II gene polimorphism we used PCR and RLFP method. Acquired protein C resistance and lupus anticoagulant was tested using chronometric method with the use of time measurement of optical density accompanying coagulation. Anticardiolipin antibodies and antibodies against beta2-glicoprotien 1 were measured in ELISA tests. Our current results present the frequency of at least one thrombophilic factor in 16.6% patients. The highest frequency rate was observed among women with pregnancy loss between 7th and 12th gestational week--19.04%. In this group we also noticed the highest number of miscarriages. In remaining two groups, with pregnancy loss between 12th and 22nd and after 22nd gestational week, one case of thrombophilia occurred in each group.     

Factor V Leiden in women: a thrombotic risk factor or an evolutionary advantage?

Factor V Leiden is a common gain-of-function gene mutation resulting in a genetic predisposition to thromboembolic complications. Growing evidence in the literature indicates an interaction between factor V Leiden thrombophilia and acquired prothrombotic conditions such as contraceptive use or hormone replacement therapy, resulting in an increased risk of venous thromboembolism (VTE). Similarly, when combined with the prothrombotic influence of pregnancy, women who are carriers of factor V Leiden are faced with an increased risk of adverse pregnancy outcomes, including VTE, pre-eclampsia, fetal loss, placental abruption, and fetal growth restriction. The results of the most important meta-analyses on the relationship between inherited (factor V Leiden) and acquired thrombophilia in women are analyzed in this review, along with the possible evolutionary role of this mutation.