Acquired and inherited thrombophilia disorders in pregnancy

Thromboembolism is the leading cause of antepartum and postpartum maternal mortality. The presence of antiphospholipid antibodies is responsible for many pregnancy losses and other morbidities in pregnant women, and is the most prevalent and treatable cause of acquired thrombophilia in pregnancy. There is also evidence that women with thrombophilia are at increased risk not only of pregnancy-related venous thromboembolism but other vascular pregnancy complications. Many studies have examined the association between thrombophilia and pregnancy complications. This article reviews the most up-to-date knowledge of prevalence, pathogenesis, and diagnosis of acquired and inherited thrombophilias and their relationship and association with pregnancy complications.     

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.     

Low molecular weight heparin treatment and impact of inherited thrombophilia type in pregnancies with previous adverse outcome

Objective: To assess the impact of low molecular weight heparin (LMWH) treatment in 50 pregnancies of women with inherited thrombophilia and adverse pregnancy outcome (APO) in previous untreated pregnancies. The impact of “Conventional” (FVL, PT, AT, PC, PS) and “Novel” (MTHFR, PAI-1, ACE) thrombophilias on APO was investigated.

Methods: The primary outcomes (PO) were: early and late pregnancy loss (EPL, LPL), preterm birth (PTB) or term birth (TB) compared to the last untreated pregnancies of the same women. Secondary outcomes (SO) were APO in LMWH treated and last untreated pregnancies ended with birth. PO and SO were compared in relation to the thrombophilia type.

Results: LMWH decreased EPL and LPL rate and improved TB rate compared with last untreated pregnancies (p?<?0.001). There were less PTB (p?=?0.019) and no cases of intrauterine fetal death (IUFD) (p?=?0.0019) in LWMH-treated pregnancies. The division to Conventional and Novel thrombophilias showed: (a) difference between pregnancy losses and birth rate (p?=?0.0069) and (b) no difference in the prevalence of APO in untreated pregnancies ended with birth.

Conclusions: LMWH treatment improves pregnancy outcome in women with inherited thrombophilia and APO in previous pregnancies. Novel thrombophilias have the equal impact on the pregnancy outcome compared to the Conventional thrombophilias.     

Screening and management of inherited thrombophilias in the setting of adverse pregnancy outcome

Inherited thrombophilic conditions are associated with adverse pregnancy outcomes, including severe pre-eclampsia, fetal loss, abruptio placentae, and intauterine growth restriction. Although the prevalence of these complications is approximately 8% in the general population, their presence is associated with a significantly increased recurrence risk. Thrombophilic conditions most strongly associated with adverse pregnancy outcome include factor V Leiden, prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin. Other thrombophilic conditions, such as protein Z deficiency, also appear to be associated with an increased risk of pregnancy complications. Antenatal administration of heparin to prevent pregnancy complications has shown promise in small studies, but a randomized, placebo-controlled trial is necessary to determine whether heparin administration is beneficial in preventing adverse pregnancy outcome.     

Single inherited thrombophilias and adverse pregnancy outcomes

INTRODUCTION: Inherited thrombophilia is believed to be a multiple gene disease with more than one defect. We aimed to determine the association between single thrombophilic patterns and a variety of pregnancy diseases. METHODS: 284 pregnant women were recruited for the present study and were divided in two groups: A group (176 controls) and B group (108 cases). Patients belonging to the B group had one of the following: severe pre-eclampsia, hemolysis, hepatic enzymes increase, hypertension and low platelet count (HELLP) syndrome, gestational hypertension, fetal growth restriction, intrauterine death, abruptio placentae and disseminated intravascular coagulopathy. To detect methylenetetrahydrofolate reductase (MTHFR) A1298C, MTHFR C677T, factor V Leiden, PAI-1, mutant prothrombin G20210A, an inverse hybridization technology was used. Plasma homocysteine, antithrombin (AT) III and protein S were determined. A modified functional activated protein C resistance was detected. RESULTS: MTHFR C677T and hyperhomocysteinemia were more prevalent than other thrombophilias. Deficiency in AT III was significantly linked with pre-eclampsia (relative risk 0.88; 95% CI 0.83-0.94). Activated protein C resistance (APCR) was significantly related to the abruptio placentae (relative risk 0.71; 95% CI 0.61-0.82). COMMENTS: Apart from the linkage between AT III deficiency and the occurrence of pre-eclampsia, and apart from the increased risk of abruptio placentae in pregnant women with altered APCR, we obtained findings in contrast with some of the published literature. In our case series, no association of pre-eclampsia with factor V Leiden or with prothrombin gene mutation was found.     

Thrombophilia and adverse pregnancy outcome

This article focuses on the clinical evaluation and management of women who have thrombophilia-related placental vascular complications, including fetal loss, pre-eclampsia, intrauterine fetal growth restriction, and placental abruption. All are major causes of maternal and fetal adverse outcomes.     

Thrombophilia and adverse pregnancy outcome

This article focuses on the clinical evaluation and management of women who have thrombophilia-related placental vascular complications, including fetal loss, pre-eclampsia, intrauterine fetal growth restriction, and placental abruption. All are major causes of maternal and fetal adverse outcomes.     

Thrombophilia and adverse pregnancy outcome

The hemostatic system plays an important role in three crucial stages of pregnancy: ovulation, implantation, and placentation. A thrombophilic defect is an abnormality in the coagulation pathways that predisposes an individual to thrombosis. Pregnancy is a hypercoaguable state and interest has focused on the potential role that thrombophilic defects may play in the etiology not only of recurrent miscarriage but also of late pregnancy complications. Maternal intervillous blood flow does not develop to any significant extent before 8 weeks of gestation and thrombophilic defects are therefore unlikely to contribute to pregnancy loss before this time. Retrospective studies have reported a similar prevalence of genetic thrombophilic defects among women with recurrent first-trimester miscarriage and controls but an increased prevalence among those with second-trimester miscarriage and later pregnancy complications. There is a paucity of data documenting the prospective outcome of untreated pregnancies among women with thrombophilic defects and of the placental histology in these pregnancies. Until these issues have been addressed, routine thromboprophylaxis during pregnancy cannot be recommended for women with thrombophilic abnormalities.     

Thrombophilia and adverse pregnancy outcome

PURPOSE OF REVIEW: Recent case-control studies and metaanalyses have attempted to quantify the risks associated with individual thrombophilic defects and adverse clinical events in pregnancy, including fetal loss, preeclampsia, placental abruption and intrauterine growth restriction. This review has examined the evidence. RECENT FINDINGS: The literature is in general agreement that thrombophilia increases the risk of venous thromboembolism and adverse pregnancy outcomes, including pregnancy loss, preeclampsia, placental abruption and intrauterine growth restriction in pregnancy. However, the size of the estimated risks varies between individual studies due to heterogeneity in study design. Low-molecular-weight heparin has been shown to be the superior choice, on the grounds of safety and effectiveness, in preventing venous thromboembolism and improving pregnancy loss. Large-scale, randomized controlled studies are required, however, to confirm these findings. Although selective thrombophilia screening based on prior venous thromboembolism history has been shown to be marginally more cost-effective than universal screening in pregnancy, the overall clinical and economic benefit of universal and selective screening is unsupported. SUMMARY: Despite the growing evidence in the literature, there are still gaps in our knowledge of thrombophilia and pregnancy. In particular, accurate estimates are required of the risks of venous thromboembolism and adverse pregnancy outcomes associated with some thrombophilias and the relative clinical and cost-effectiveness of different anticoagulation therapies in the prevention of venous thromboembolism and pregnancy loss. More large-scale studies are required to better inform clinicians and help determine optimum management and prevention strategies of thrombophilia and associated adverse clinical events in pregnancy.     

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.     

The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.

Venous thromboembolism is an important cause of maternal morbidity and mortality. The puerperium should be regarded as the period of greatest risk. However, fatalities in early pregnancy emphasise the need to assess thrombotic risk at all stages of pregnancy. In many cases those at increased risk are potentially identifiable on clinical grounds alone such as those with a personal or family history of venous thromboembolism, obesity, or surgery. Identification of women with multiple clinical risks for thrombosis during pregnancy remains the key to reducing the incidence of this condition. In women who present with a personal or family history of proven venous thromboembolism, thrombophilia screening should be performed in early pregnancy, since the results may influence subsequent management during pregnancy. The investigation and management of patients considered at increased risk of venous thrombosis during pregnancy requires close liaison between obstetricians and haematologists familiar with this rapidly expanding and complex field of thrombophilia.     

Psychiatric illness and adverse pregnancy outcome.

OBJECTIVES: To identify the adverse effect of psychiatric illness during pregnancy on pregnancy outcome. METHODS: A large population-based study of deliveries (1988--2005) was conducted that compared women with and without psychiatric illness. Stratified analysis included multiple logistic regression models. RESULTS: Out of 181,479 deliveries, 607 (0.3%) women reported psychiatric illness: depressive and anxiety disorders (39%), schizophrenia (11%), or other psychiatric illness (50%). The psychiatric patients were significantly older, with higher prevalence of diabetes and hypertensive disorders. Perinatal mortality rate, congenital malformations, low Apgar scores, and low birth weight (<2500 g) were significantly increased. Multivariable logistic regression models determined that psychiatric illness during pregnancy is an independent risk factor for perinatal mortality (odds ratio [OR] 2.4; 95% CI, 1.5-3.7, P<0.001) and congenital malformations (OR 1.4; 95% CI, 1.01-1.9, P=0.03). CONCLUSIONS: Psychiatric illness is an independent risk factor for congenital malformations and perinatal mortality, and prenatal care should be adjusted accordingly.     

Successful pregnancy outcome in the woman with thrombophilia and multiple miscarriages

OBJECTIVES: The case of a 25 year-old pregnant woman with a history of miscarriage (8 week) and a triple intrauterine fetal death (35, 25, 21 week) was reported. RESULTS: Personal and family history did not revealed any abnormalities. In the 25th week of gestation routine ultrasonographic examination showed abnormal pulsation indexes in the umbilical artery, as well as the right and left uterine artery. Also extremely high vascular resistance was confirmed in both uterine arteries (notch). The routine laboratory tests were normal. Because of high risks of stillbirth and preliminary pregnancy termination the screening tests for thrombophilia were performed. The presence of a heterozygous form of factor V Leiden mutation and C677T polymorphism of a methylenetetrahydrofolate reductase gene were confirmed. The low doses of LMWH (nadroparine) subcutaneously and aspirin (150 mg per day, orally) were administered until pregnancy termination. In the 35th week of gestation the pregnancy was terminated by cesarean section due to fetus intrauterine asphyxia (boy 1180 g, Apgar 1 min-6, Agar 5 min 9 points). Three months' follow-up after delivery did not revealed any complication in the mother or in the child. CONCLUSIONS: Successful pregnancy outcome in the woman with thrombophilia and multiple miscarriages confirms the necessity for both prophylactic anticoagulant treatment and detailed laboratory testing.     

Recurrent risk of adverse pregnancy outcome

It is an unfortunate fact that all pregnancies do not end with healthy babies and healthy mothers. Families who have experienced an adverse pregnancy outcome require accurate information about the risk of recurrence to plan future childbearing. This article examines the recurrence risk of four complications of pregnancy: gestational diabetes, preterm delivery, stillbirth, and preeclampsia. Combined, these four complications are responsible for approximately 24% of maternal and neonatal morbidity and mortality.