易栓症与不良妊娠结局的病理改变

妊娠期血液处于高凝状态是生理性的血栓前状态,遗传性和获得性易栓症增加了孕妇血栓形成的几率。虽然易栓症与胎盘介导的妊娠期并发症相关,但是否为直接原因仍未证实。妊娠期易栓症不具备特征性的胎盘病变,故易栓症及妊娠不良结局与胎盘异常病理之间的关系值得进一步研究。     

Inherited thrombophilia and pregnancy with fetal loss

Maternal thrombophilia (inherited and acquired) has recently been identified as a major cause of thrombembolism (TE), but it may also contribute to adverse pregnancy outcomes and recurrent pregnancy loss. If the acquired thrombophilia is a well-established factor in etiology of fetal loss, the contribution of specific inherited thrombophilic genes is still controversial. The most common inherited traits are deficiency of antithrombin, protein C or protein S; Factor V Leiden; prothrombin G20210A; MTHFR C677T This review focuses on association of recurrent fetal loss with specific gene thrombophilic defects. Overall 52% of women with obstetric complication other than TE carry thrombophilic gene defects. The role of specific genes is different in etiology of early and late pregnancy loss. Inherited thrombophilia is now view as multicausal model; clinical manifestation can be heterogeneous result of gene-gene and gene-environment interactions. Therefore the criteria for genetic screening affected women with history of fetal loss should not be very stringent. The implication of screening for thrombophilic mutations allow to find women at risk of thrombosis and vascular gestational abnormalities in which antithrombotic drugs may have potential therapeutic benefit.     

Inherited thrombophilia and poor pregnancy outcome

Gestational vascular complications are a major cause of maternal and fetal morbidity.A growing body of evidence suggests a significant role for inherited thrombophilia in the development of gestational vascular complications. While the majority of women with thrombophilia will have an uneventful gestation, case-control studies demonstrated that thrombophilia is more prevalent in cohorts of women with pregnancy loss and early-onset pre-eclampsia. Placental abruption and severe intrauterine growth restriction (IUGR) may also be associated with thrombophilia. Placental pathological findings in women with thrombophilia are hallmarked by thrombosis and fibrin deposition potentially to a greater degree than in normal pregnancy. Preliminary non-randomized studies suggest a benefit for prophylaxis with unfractionated and low-molecular-weight heparin (LMWH), and prospective randomized trials are in progress to define whether LMWH is effective in preventing pregnancy loss and other gestational vascular complications in women with thrombophilia and previous fetal wastage.     

Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions

OBJECTIVE: To investigate the association between thrombophilia and recurrent spontaneous abortions (RSAs) and to evaluate the efficacy of anticoagulant treatment. STUDY DESIGN: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. RESULTS: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. CONCLUSION: All couples with RSAs require screening for thrombophilia. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy appear to have a favorable effect on pregnancy outcome in selected women with RSAs and acquired or inherited thrombophilia.     

Thrombophilia and pregnancy complications

OBJECTIVE: This systematic review examines the strength of the association between thrombophilia and recurrent pregnancy loss and other serious obstetric complications.Study design Electronic databases and manual bibliography searches were used to identify studies evaluating the association between thrombophilia and pregnancy loss, preeclampsia, fetal growth retardation, and placental abruption. RESULTS: Thrombophilic disorders are associated with an increased risk of fetal loss in the majority of case control and cohort studies. The risk is increased throughout pregnancy, but may be higher in the second and third trimester. The common pathologic finding of placental infarction suggests unexplained fetal loss may result from uteroplacental insufficiency and thrombosis. Thrombophilic disorders are not consistently associated with preeclampsia, fetal growth retardation, or placental abruption. Preliminary data suggest prophylactic anticoagulation may improve outcome in thrombophilic women with unexplained recurrent fetal loss. CONCLUSION: Women with thrombophilia have an increased risk of pregnancy loss and possibly other serious obstetric complications, although definition of the magnitude of risk will require prospective longitudinal studies. Preliminary data suggesting prophylactic anticoagulation may improve gestational outcome provide a rationale for prospective randomized trials in thrombophilic women with unexplained recurrent fetal loss.     

Thrombophilia-associated pregnancy wastage

OBJECTIVE: To critically review the literature regarding inherited thrombophilia and recurrent fetal loss. DESIGN: English-language literature review. PATIENT(S): Women who experienced repeated pregnancy wastage. INTERVENTION(S): Aspirin, glucocorticoids, heparin, and IV immunoglobulin for the prevention of miscarriage. MAIN OUTCOME MEASURE(S): Live birth, miscarriage, preeclampsia, and pregnancy loss. RESULT(S): Recurrent fetal loss and other placental vascular pathologies of pregnancy have long been associated with antiphospholipid syndrome, an acquired autoimmune thrombophilic state. The number of known heritable thrombophilic disorders has grown rapidly in recent years with the identification of activated protein C resistance, factor V Leiden mutation, and hyperhomocysteinemia as major causes of thrombosis. Data accumulated over the past 2 years suggest that heritable thrombophilia is associated with an increased risk of fetal loss and preeclampsia. The present review discusses potential pathogenetic mechanisms for this association and evaluates reported therapeutic regimens for the prevention of fetal loss in women with thrombophilia. CONCLUSION(S): Placental thrombosis may be the final common pathophysiologic pathway in most women with habitual abortions and repeated pregnancy wastage. Prophylactic antithrombotic therapy is indicated in women with heritable thrombophilia and antiphospholipid syndrome and probably is more effective than the previously used modalities of prednisone, aspirin, and IV immunoglobulin.     

Thrombophilia and adverse maternal-perinatal outcome: controversies in screening and management

A recent review of the literature on thrombophilia and adverse pregnancy outcome reveals contradictory findings. There are retrospective and prospective studies that recommend testing for genetic and acquired markers of thrombophilia for those with the enumerated adverse pregnancy outcome. Based on our review, routine screening for thrombophilias in women with a history of adverse pregnancy outcome (preeclampsia, abruptio placenta, intrauterine growth restriction, and fetal loss) is not justified. Based on data from observational studies and few randomized trials with inadequate number of subjects, there is consensus that women with true antiphospholipid antibody syndrome should receive low-dose aspirin plus adjusted-dose heparin in subsequent pregnancies. Some authors also recommend heparin prophylaxis in subsequent pregnancies in women with genetic thrombophilia with previous adverse pregnancy outcome. However, this recommendation is not based on randomized trials. Hence, a randomized double-blind, controlled trial is urgently needed to evaluate the benefit of heparin during pregnancy in women with a history of adverse pregnancy outcome in association with genetic thrombophilia.     

Thrombophilia and adverse maternal-perinatal outcome

A recent review of the literature on thrombophilia and adverse pregnancy outcome (APO) reveals contradictory findings. We have limited our review of literature mostly to the most recent decade. On the basis of our review, screening for thrombophilias with a history of APO (preeclampsia, abruptio placenta, intrauterine growth restriction, and fetal loss) is not clear. There are retrospective and prospective studies that recommend testing for genetic and acquired markers of thrombophilia for those with the enumerated APO. The rationale for such recommendation is to use heparin prophylaxis in subsequent pregnancies. However, this recommendation is not based on randomized trials. Hence, a randomized double-blinded controlled trial is urgently needed to evaluate the benefit of heparin during pregnancy in women with a history of APO in association with thrombophilia.     

Inherited thrombophilias

Many inherited thrombophilias have been detected and the pathophysiologic insight has increased tremendously during the last decades. Despite, however, the overwhelming observational evidence on the association between inherited thrombophilia and several women's health issues, including VTE, thus far the implications for clinical practice are uncertain. Although there is firm epidemiologic evidence that is helpful in counseling women who have inherited thrombophilia to prevent a first or recurrent VTE, the uncertainty is particularly present for women who have other pregnancy complications, such as recurrent pregnancy loss and pre-eclampsia. For this group, well-designed placebo-controlled trials to assess the harm-benefit ratio are urgently needed.     

How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.

OBJECTIVE: To determine whether inherited and acquired thrombophilias are associated with adverse obstetric complications. STUDY DESIGN: A systematic review; studies where women with adverse obstetric complications were tested for one or more acquired and inherited thrombophilias were included. MAIN OUTCOME MEASURES: Prevalence of thrombophilia in women with severe pre-eclampsia/eclampsia, severe placental abruption, intrauterine growth restriction or unexplained stillbirth. RESULTS: Compared with controls, placental abruption was more often associated with homozygous and heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homocysteinaemia, activated protein C resistance or anticardiolipin IgG antibodies. Women with pre-eclampsia/eclampsia were more likely to have heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T mutation, protein C deficiency, protein S deficiency or activated protein C resistance compared with controls. Unexplained stillbirth, when compared with controls, was more often associated with heterozygous factor V Leiden mutation, protein S deficiency, activated protein C resistance, anticardiolipin IgG antibodies or lupus anticoagulant. Women with intrauterine growth restriction had a higher prevalence of heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T gene mutation, protein S deficiency or anticardiolipin IgG antibodies than controls. There was wide heterogeneity in the prevalence of thrombophilia between the studies. CONCLUSIONS: Women with adverse pregnancy outcome are more likely to have a positive thrombophilia screen but studies published so far are too small to adequately assess the true size of this association. Screening for thrombophilia should not become standard practice until clear evidence emerges that thromboprophylaxis during pregnancy improves perinatal outcome. Further research into the link between the observed association, causality and heterogeneity is required.     

Second-trimester maternal serum alpha-fetoprotein (MSAFP) is elevated in women with adverse pregnancy outcome associated with inherited thrombophilias

Obstetric complications, such as severe pre-eclampsia, fetal growth restriction, abruptio placentae, or stillbirth are associated with abnormally elevated second-trimester maternal serum alpha-fetoprotein (MSAFP) and beta subunit of human chorionic gonadotrophin (betahCG). This has been attributed to placental abnormalities. Women with thrombophilias have been shown to have abnormalities of the placenta resulting in adverse pregnancy outcome in these patients. The purpose of the present study was to evaluate whether women with pregnancy complications and inherited thrombophilias have abnormally elevated second-trimester MSAFP or betahCG. Sixty-two women with pregnancy complications were tested for inherited thrombophilias several months after delivery. The thrombophilia group included 29 women with pregnancy complications and an inherited thrombophilia and the control group included 33 other patients without thrombophilia. Patients in the thrombophilia group had a higher median MoM MSAFP compared to the controls (1.337 vs. 1.086, p=0.0516). The incidence of abnormally elevated MSAFP (>2.5 MoM) was also significantly higher in the thrombophilia group compared to controls (21% vs. 3%, p=0.04). Neither the median MoM betahCG nor the incidence of abnormally elevated betahCG were significantly different between the groups. We conclude that second trimester MSAFP, but not betahCG, is abnormally elevated in patients with thrombophilia and obstetric complications.     

Thrombophilia and early pregnancy loss

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol.     

High frequency of congenital thrombophilia in women with pathological pregnancies?

The obstetrical complications preeclampsia, intrauterine growth restriction (IUGR), placental abruption and fetal loss are major causes of maternal and fetal morbidity and mortality. Much recent research has focused on to what extent congenital thrombophilia contributes to these obstetrical complications. Combined with the hypercoagulable state of pregnancy, thrombophilia has the potential to induce placental thrombosis and cause placental insufficiency with subsequent obstetrical complications. This article aims to review and discuss published clinical studies of the relationship between congenital thrombophilia and preeclampsia, IUGR, placental abruption and fetal loss. In addition, the few published clinical trials of prophylactic antithrombotic treatment to prevent severe obstetrical complications in thrombophilic women are discussed. The studies have shown variable results evaluated mainly as a result of the limited number of case reports published. However, the strongest association was found to be between congenital thrombophilia and preeclampsia and late fetal loss. Early fetal loss was not found to be associated with congenital thrombophilia. At present, the question remains open as to whether IUGR and placental abruption is directly associated with thrombophilia or mediated through preeclampsia. In conclusion, the associations between congenital thrombophilia and preeclampsia, IUGR, placental abruption and fetal loss only reaches evidence grade 4. Present recommendations and clinical guidelines are thus based on weak scientific proof.     

Perinatal outcome in women with severe pregnancy complications and multiple thrombophilias

Hypercoagulability leading to placental thrombosis has been implicated in severe pregnancy complications. We compared the perinatal outcome in women with severe preeclampsia, intrauterine growth retardation (IUGR) and severe abruptio placentae and multiple acquired and inherited thrombophilias (study group, n=22) to matched women with similar complications and single thrombophilia (control group, n=22). Gestational age at delivery and birth weight were significantly lower in the study group compared to the control group (p<0.01) and among the study women with severe preeclampsia and IUGR. Severe pregnancy complications may occur earlier during pregnancy and more seriously affect perinatal outcome in women with multiple thrombophilias.     

Anticoagulant prophylaxis in women affected by thrombophilia and previous obstetric complications

Pregnancy is a condition of excessive clotting due to a decrease of some coagulation factors and a reduction of anticoagulant proteins, such as protein S. It is known that the causes of congenital or acquired thrombophilia may be associated with an increased risk of venous thromboembolism during pregnancy and/or obstetric complications, such early or late fetal loss, intrauterine fetal deaths, pre-eclampsia, fetal growth restriction. During pregnancy the use of a prophylaxis with antithrombotic drugs is considered at present a promising opportunity to significantly reduce the prevalence of thromboembolic complications, improving maternal and fetal outcomes. This article is a review to most recent evidence of pregnant anticoagulant prophylaxis in women with previous thromboembolic events.     

Study of Thrombophilia in Recurrent Pregnancy Loss

Objectives

Recently, it has been found that women who have thrombophilia have increased risk of fetal loss. This study was designed to corroborate the association of elevated factor VIII level, protein C and protein S deficiencies, and the presence of LAC in women with recurrent pregnancy loss.

Materials and Methods

53 patients with history of two or more pregnancy losses and 47 healthy age-matched subjects with no history of pregnancy loss and who have delivered at least one term infant without any complication were enrolled into the study.

Results

Thrombophilic defect was present in 64.15 % of patients of study group. Protein S deficiency (50.94 %) was the most common thrombophilic defect observed. Spontaneous abortion (SA), preterm birth (PTB), and intrauterine growth retardation (IUGR) were the most important pregnancy complications observed. The strongest associations of pregnancy complications were observed with protein S deficiency (87.5 %) and with elevated factor VIII (66.66 %) level.

Conclusion

This study observed strong association of thrombophilia with unexplained recurrent pregnancy loss.     

Study of the frequency of occurrence of genetic and acquired thrombophilia in infertile women prior IVF

Abstract

This study of infertile women prior in vitro fertilization (IVF) is focused at the genetic and acquired thrombophilia before the IVF program, the identification of the frequency of occurrence of thrombophilia in them, the impact of thrombophilia of the offensive, the course and outcome of pregnancies, to improve the quality of cycles in terms of a pregnancy and childbirth. Forty-five women with infertility were examined. Thirty-two (71%) were identified thrombophilia: genetic thrombophilia in 32 cases (100%), among them a combination of several forms of genetic thrombophilia – 21 (63%) of them, other forms of thrombophilia (genetic and acquired) – in 5 of them (16%). In IVF 23 (72%) women became pregnant. In 87% of pregnancies ended in spontaneous birth, in 13% of cases of preterm birth.     

Thromboembolism in pregnancy

PURPOSE OF REVIEW: Venous thromboembolism is the leading cause of maternal death in the UK. Thrombophilia underlies many thrombotic disorders in pregnancy. The high prevalence of thrombophilic defects in the population, the association of defects with venous thromboembolism and the special considerations for management make it a widely debated subject. RECENT FINDINGS: A limited number of studies measuring the risk of venous thromboembolism in pregnancy with thrombophilia have been conducted within the last year. Studies confirm that heritable thrombophilias are associated with increased risk of venous thromboembolism in pregnancy. However, estimated risks vary between individual studies. The risk of venous thromboembolism with acquired thrombophilia remains unclear. Guidelines have been published to guide clinicians in preventing and treating venous thromboembolism in pregnancy; however, large-scale, randomized controlled trials need to be conducted to establish the effectiveness of administering antithrombotic agents in pregnancy. Although selective thrombophilia screening based on prior history of venous thromboembolism has been proposed, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Due to the lack of studies, gaps still exist in our knowledge of the risk of pregnancy-related venous thromboembolism associated with thrombophilia. In particular, accurate estimates are required for the risks of acquired thrombophilias. Furthermore, the true effectiveness of anticolagulants in pregnancy needs to be established through well-conducted studies and randomized controlled trials. These studies will inform clinicians and help to determine the optimum management and prevention strategies for thrombophilia and venous thromboembolism in pregnancy.     

Fetale Thrombophilie

Recent findings suggest that inherited or acquired maternal thrombophilic disorders lead to recurrent fetal loss, preeclampsia, intrauterine growth restriction and placental abruption. On the fetal side, there is a growing body of evidence that fetal thrombophilia is closely related to catastrophic perinatal events, such as stroke (resulting in cerebral palsy) or limb ischemia via arterial thrombosis, cerebral sinus venosus thrombosis or renal vein thrombosis. Furthermore, an association between fetal thrombophilia and adverse pregnancy outcome has been reported. Fetal thrombotic vasculopathy has been assumed to be a plausible underlying cause for placental lesions and neonatal sequelae. This review aims to tabulate and discuss the findings regarding the weight of fetal thrombophilic factors and the potential association with obstetric and neonatal complications derived from the current literature.     

Prenatal screening for thrombophilia: the background and the approach

Coagulation is a normal response to blood vessel injury and involves the interaction of endothelium, platelets and clotting factors. Coagulation is altered by pregnancy and may be further altered by thrombophilia, an acquired or inherited predisposition to develop thrombosis. An overview of coagulation is provided as background for understanding thrombophilia. Both acquired and genetic risk factors for thrombosis are discussed. Thrombosis may affect not only the maternal circulation, but the utero-placental-fetal circulation as well. The literature documenting the association between maternal thrombosis and thrombophilia is summarized, as is the recent data linking thrombophilia and poor pregnancy outcome. An approach to screening for thrombophilia is outlined and strategies for thromboprophylaxis are provided.