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.     

Preconception counseling for women with thrombophilia

Inherited thrombophilias are a heterogeneous group of coagulation disorders that predispose individuals to thromboembolic events. This group of conditions is the major risk factor for thromboembolism during pregnancy and the puerperium. In addition, thrombophilias have been associated with several adverse obstetric events, including pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. An increased risk for these obstetric complications has prompted many authorities to recommend screening and treating pregnant women for thrombophilias. Optimal obstetric management, however, is controversial as thrombophilias are common and many affected individuals are asymptomatic. Indeed, pregnancy outcome in most women with thrombophilias is normal. The most commonly identified inherited thrombophilias are the factor V Leiden and prothrombin G20210A gene mutations. More rare thrombophilias include protein C and S deficiencies, antithrombin III deficiency. Although relatively common, the association between hyperhomocysteinemia and associated mutations (such as the C677 T methylenetetrahydro-folate reductase) and obstetric complications is controversial.     

Inherited thrombophilias and adverse pregnancy outcome: screening and management

Inherited thrombophilias are a heterogenous group of conditions which have been implicated in a variety of pregnancy complications. Evidence is mounting that implicates these inherited disorders in a range of pregnancy outcomes, including recurrent miscarriage, late fetal loss, preeclampsia, abruptio placentae, and intrauterine growth restriction. The most commonly identified inherited thrombophilias consist of Factor V Leiden and the prothrombin gene mutation G20210A. Rarer inherited thrombophilic conditions include deficiencies of protein S, C and antithrombin. More recently, deficiency of protein Z has been linked to pregnancy complications, including preterm delivery. Clinical manifestations often are associated with the presence of more than one inherited thrombophilia, consistent with their multigenic nature. Some, but not all, studies investigating the use of heparin to prevent adverse pregnancy outcome have demonstrated a benefit. However, an adequate randomized trial is required to definitively determine whether heparin anticoagulation is the best prevention option in patients who harbor one or more inherited thrombophilias and are at risk for adverse pregnancy outcome. This review will summarize the association of thrombophilic conditions and obstetrical complications.     

Double versus single thrombophilias during pregnancy

Objective: The primary objective of this study was to evaluate whether women with double thrombophilias have a greater risk for obstetric complications as compared with women who have single thrombophilias.

Study design: This is a retrospective cohort study of all patients in a single practice with a clinically significant inherited thrombophilia and treated with anticoagulation between 2005 and 2013. Thrombophilias evaluated include: factor V Leiden, prothrombin G20210A gene mutation, protein S deficiency, protein C deficiency, and antithrombin III deficiency. Double thrombophilia was defined as the presence of two thrombophilias or homozygosity for factor V Leiden or prothrombin Gene Mutation. Demographic and obstetrical outcome data were collected. Data on all patients with double thrombophilias who met inclusion criteria was reported. Data was then compared between the patients with double thrombophilias and single thrombophilias with singleton gestations. The data was analyzed with Pearson’s chi-squared or Student’s t-test as appropriate with p value <.05 used for significance.

Results: Eighteen patients with clinically significant double thrombophilias who met inclusion criteria were identified. Most patients delivered full term (88.9%) and appropriate for gestational age (77.8%) infants. One hundred thirty-two patients with single thrombophilias and 14 patients with double thrombophilias with singleton gestations were then compared. Demographic characteristics were not significantly different between the two groups. There were no significant differences in obstetrical outcomes between patients.

Conclusions: There were no significant differences in obstetrical outcomes for patients with clinically significant double thrombophilias versus single thrombophilias when treated with anticoagulation.     

Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia

Objective To investigate the association between severe mid-trimester IUGR, whose causes are unknown in most cases, and maternal thrombophilias.
Design Case–control study.
Setting Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel Aviv University.
Population Twenty-six women with severe mid-trimester (22–26 weeks of gestation) IUGR (birthweight  <3rd centile  ) and 52 matched multiparous women with normal pregnancies (controls).
Methods After excluding pregnancies with vascular maternal disease, chromosomal and structural aberrations and cytomegalovirus infection, 26 women out of 35 with severe mid-trimester IUGR remained and composed the study group. Each was matched for age, ethnicity and smoking status with two healthy women who had normal pregnancies. All the women were tested for genetic and acquired thrombophilias at least eight weeks after delivery.
Main outcome measures Prevalence of maternal thrombophilias.
Results The frequency of thrombophilias was 69% in the study group compared with 14% in the control group [odds ratio (OR) 4.5; 95% confidence interval (CI) 2.3–9, P  < 0.001  ]. The frequencies of factor V Leiden mutation, prothrombin gene mutation and protein S deficiency were significantly increased in the study group compared with the control group. The frequency of multiple thrombophilias was 33% in the study group versus none among the controls. Of the 26 pregnancies with severe mid-trimester IUGR, 13 ended in intrauterine fetal death before 25 weeks of gestation: 10 of these women had thrombophilia.
Conclusion Women with mid-trimester severe IUGR have an increased prevalence of inherited and acquired thrombophilias.     

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.     

Efficacy of family history in determining thrombophilia risk

STUDY OBJECTIVE: This retrospective study sought to examine the importance of family history of cardiovascular disease (CVD) or venous thromboembolism (VTE) in predicting risk for an inherited thrombophilia. DESIGN/METHODS: A cohort of 88 adolescent females who had a thrombophilia panel in the last three years was identified for this retrospective chart review. Family history data of CVD or VTE were collected in addition to laboratory results from the thrombophilia screen. SETTING: Adolescent patients who had a thrombophilia screen within the last three years at University OB-GYN Associates, Louisville, KY. RESULTS: Within the cohort (n=88), 21% of patients were found to have a documented thrombophilia. At least 47% of individuals diagnosed with thrombophilia had more than one screening abnormality. A family history of VTE was noted to have a positive predictive value (PPV) of 40% and a negative predictive value (NPV) of 88% for detection of thrombophilia. Patients with a family history of CVD alone carried a PPV of 24% and NPV of 100%. Finally, among individuals with both family history risk factors, PPV was strengthened at 52% while NPV remained unchanged. CONCLUSIONS: Within the last decade, inherited thrombophilias have gained more clinical interest. While thrombophilia disease prevalence data is available for the adult population, there remains a paucity of data in adolescents. Our results reinforce the importance for screening adolescent females, prior to contraceptive administration, if family history risk factors exist.     

Inherited thrombophilias are not increased in "idiopathic" small-for-gestational-age pregnancies

OBJECTIVE: The purpose of this study was to determine (1). whether the inherited thrombophilias (the factor V Leiden and prothrombin gene mutations and the methylenetetrahydrofolate reductase [C677T] polymorphism) are increased in women with "idiopathic" (normotensive) small-for-gestational-age pregnancies and/or in their babies and (2). whether fetal carriage of a thrombophilia is associated with abnormal umbilical Doppler studies. STUDY DESIGN: This was a case-controlled study of normotensive women who were delivered of a singleton small-for-gestational-age baby (birth weight, <10th percentile adjusted for sex) with no clinical evidence of chromosomal or congenital abnormality. Control subjects were healthy women who were delivered of appropriate-for-gestational-age babies. RESULTS: One hundred forty-five women with small-for-gestational-age pregnancies and 290 control subjects were recruited. Small-for-gestational-age babies were born at an earlier gestational age (38 +/- 3.0 weeks) and with a lower birth weight (2373 +/- 521 g) than control babies (39.7 +/- 1.3 weeks and 3606 +/- 423 g, P <.01). There were no differences in the rates of factor V Leiden (2.8% vs 3.8%; relative risk, 0.79; 95% CI, 0.34-1.85), prothrombin gene mutation (2.8% vs 3.1%; relative risk, 0.92; 95% CI, 0.40-2.09), and methylenetetrahydrofolate reductase C677T polymorphism (13% vs 9%; relative risk, 1.27; 95% CI, 0.87-1.84) between mothers with small-for-gestational-age babies and control subjects, respectively. Inherited thrombophilias were not increased in small-for-gestational-age babies compared with control babies. Of small-for-gestational-age babies with abnormal umbilical artery Doppler studies (n = 25), 21% had a thrombophilia compared with 11% with normal umbilical artery Doppler studies (n = 68; relative risk, 1.75; 95% CI, 0.81-3.81). CONCLUSION: The rates of these inherited thrombophilias are not increased in normotensive women with small-for-gestational-age pregnancies. Further studies are required to determine whether thrombophilias are increased in small-for-gestational-age babies with abnormal umbilical Doppler study results.     

Recurrent miscarriage: pathophysiology and outcome

PURPOSE OF REVIEW: This article reviews new concepts in the aetiology of recurrent miscarriage, presents new outcome data and evaluates new modalities of treatment for unexplained recurrent miscarriage. RECENT FINDINGS: Preimplantation genetic diagnosis has been considered an option for couples who have structural chromosomal abnormalities or unexplained recurrent miscarriage. The association between thrombophilias and adverse pregnancy outcome is further reviewed. In relation to this, there is increasing support for the use of thromboprophylaxis in improving pregnancy outcome in women with inherited thrombophilias. Nonrandomized studies have shown that the reduction in insulin levels with metformin in insulin-resistant individuals may reduce miscarriage risk by restoring normal haemostasis and improving the endometrial milieu. With respect to immunological concepts there is now evidence to suggest that, in addition to a suppression of maternal cell-mediated immunity, some elements of the innate immune system are activated in successful pregnancies. SUMMARY: With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.     

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.     

Dalteparin and Low-Dose Aspirin in the Prevention of Adverse Obstetric Outcomes in Women With Inherited Thrombophilia

ObjectiveTo evaluate the benefit of treatment with dalteparin and low-dose aspirin (ASA) in the prevention of obstetric complications in women with inherited thrombophilia.MethodsA retrospective chart review identified women who had had at least one pregnancy complicated by severe early-onset preeclampsia, placental abruption, fetal growth restriction (FGR), or fetal death. The following inherited thrombophilias were included: deficiencies of antithrombin, protein C, or protein S, and mutations of factor V Leiden (G1691A), factor II (G20210A), or methylenetetrahydrofolate reductase C677T.ResultsThe records of 43 women with 110 pregnancies were included in the study. Anticoagulant prophylaxis was administered using dalteparin in 13 pregnancies, ASA with dalteparin in 26, and ASA alone in 11. Dalteparin alone and ASA alone showed equivalent effects in preventing preeclampsia and FGR. Combined dalteparin and ASA significantly decreased the risk of preeclampsia (odds ratio [OR] 0.80; 95% confidence intervals [CI] 0.70–0.91, P = 0.001) and FGR (OR 0.70; 95% CI 0.60–0.82, P = 0.001).ConclusionData from this retrospective cohort study suggest that combined treatment with dalteparin and ASA decreases the risk of preeclampsia by 20% and the risk of FGR by 30% in women with inherited thrombophilia.     

Thrombophilias and recurrent miscarriage

Inherited and acquired thrombophilias have been associated with recurrent pregnancy loss. Over recent years our ability to detect protein and genetic abnormalities responsible for thrombotic tendency has improved. We are now left with the task of deciphering which of these thrombophilias carries an increased risk for recurrent pregnancy loss. Acquired thrombophilias including lupus anticoagulant and anticardiolipin antibodies have been linked to recurrent pregnancy loss. However the evidence for the role of inherited thrombophilias such as, heterozygosity for the factor V Leiden, prothrombin G20210A mutation, the methylenetetrahydrofolate reductase (C677T MTHFR) mutation, as well as deficiencies of antithrombin, protein C and protein S is less clear. The methods for diagnosis and the evidence for their associations are discussed in this paper. Treatment modalities independent of those needed to prevent thrombotic events in pregnancy have generally not been studied. Given the present available data, there is insufficient evidence to include inherited thrombophilias in the initial evaluation of RPL. It is important to look for other, more common, causes of recurrent miscarriage in the evaluation of these patients.     

Inherited thrombophilias and anticoagulation in pregnancy

Thromboprophylaxis, primary or secondary, should be considered in selected pregnant women with inherited thrombophilias; such women may be divided into high-, medium- and low-risk categories on the basis of the specific thrombophilic defect and any personal or family history of venous thromboembolism (VTE). Women at high risk of VTE should receive treatment doses of low-molecular-weight heparin (LMWH) throughout pregnancy and should remain on anticoagulation for 6 weeks postpartum, or, where appropriate, long-term. Women at moderate risk should be treated with prophylactic fixed-dose LMWH throughout pregnancy and for 6 weeks postpartum. Women at low risk should receive prophylactic fixed-dose LMWH for 6 weeks postpartum, and low-dose aspirin LDA should be considered during pregnancy. LWMH offers important advantages over unfractionated heparin (UFH); heparin-induced thrombocytopaenia (HIT) and osteopaenia are rarely seen. For treatment doses of LMWH, dosage adjustment based on anti-Xa levels is usually required as pregnancy progresses. Warfarin should be avoided throughout pregnancy. LMWH, UFH and warfarin are safe for breast-feeding mothers.     

Thromboembolism and thrombophilia in pregnancy

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and postpartum and the acute management of VTE when it occurs during pregnancy.The thrombophilias, both heritable and acquired are becoming increasingly recognised as a cause of morbidity and mortality both within and outside pregnancy. There has been recent increased interest in the thrombophilias and their link with recurrent miscarriage, pre-eclampsia, abruption and intrauterine growth restriction. The relationship between the thrombophilias and adverse pregnancy outcome is addressed in detail with reference to the current literature available on this evolving subject.     

Inherited thrombophilia and stillbirth

Thrombophilias are inherited or acquired conditions that predispose individuals to thromboembolism. New inherited thrombophilias are recognized each year. Some, but not all, studies have found an association between inherited thrombophilias and adverse pregnancy outcomes, including fetal loss. The controversy regarding the clinical implications of thrombophilias in pregnancy is clouded by differences in study populations, the number of thrombophilias tested, interactions between thrombophilias, and the retrospective nature of most studies, just to name a few factors. The lack of adequately designed studies also extends to clinical management. Clear evidence to determine when to test, whom to test, which thrombophilias to test for, when to treat, and what to treat with is not available. Further studies to investigate these questions are urgently needed.     

Thromboembolism and thrombophilia in pregnancy

Venous thromboembolism (VTE) is one of the leading causes of maternal mortality worldwide and is also the cause of significant maternal morbidity. This article discusses the risk factors for VTE in pregnancy, the management of the pregnant woman at risk both antenatally and post-partum, and the acute management of VTE when it occurs during pregnancy.The thrombophilias, both heritable and acquired, are becoming increasingly recognised as a cause of morbidity and mortality both within and outside pregnancy. There has been a recent increased interest in the thrombophilias and their link with recurrent miscarriage, preeclampsia, abruption and intrauterine growth restriction. The relationship between the thrombophilias and adverse pregnancy outcome is addressed in detail, with reference to the current literature available on this evolving subject.     

Association between inherited thrombophilias,antiphospholipid antibodies,and lipoprotein A levels and venous thromboembolism in pregnancy

The objective of this study is to evaluate the association between venous thromboembolism (VTE) in pregnancy with thrombophilic factors. Thirty pregnant women with VTE were compared with 30 pregnant women matched by age and race without VTE and evaluated for risk factors and thrombophilia. Statistical analysis used two-tailed Fisher's exact test. VTE distribution was 30% in first trimester, 9% in 2nd trimester, 26% in 3rd trimester and 35% postpartum. Seventeen (57%) of VTE cases versus 2 (7%) of control cases had specific thrombophilia diagnosis ( p <0.001). The results were: Factor V Leiden mutation (27 vs. 3%) p = 0.026, MTHFR homozygous 677 mutation (10 vs. 44%) p = 0.017, prothrombin gene mutation (11 vs. 0%), protein C deficiency (7 vs. 0%), antiphospholipid antibodies (27 vs. 3%) p = 0.026, mean lipoprotein levels 49 versus 23 mg/dL, p = 0.008, mean homocysteine levels 7.8 versus 7.1 umol/L. An association is suggested between thromboembolic events in pregnancy and thrombophilia, especially Factor V Leiden gene mutation and elevated antiphospholipid antibodies. A new finding is the association of elevated lipoprotein A levels with thromboembolic events in pregnancy.     

Testing for inherited thrombophilia in recurrent miscarriage

Approximately 1-5% of women trying to conceive experience recurrent miscarriage, and in 50% of these women, the cause of the preceding miscarriages is unknown. Inherited thrombophilias such as factor V Leiden mutation, prothrombin gene mutation (PT 20210A), and deficiencies of natural anticoagulants protein C, protein S, and antithrombin are associated with recurrent miscarriage. Knowledge of the association between inherited thrombophilia and recurrent miscarriage and of potential treatment options for improving chances of a live birth could tempt physicians to test for inherited thrombophilia in women with recurrent miscarriage. However, the strength of the association between inherited thrombophilia and recurrent miscarriage is not very strong, and more importantly, no evidence indicates that the use of anticoagulants improves the chance of live birth in these women. With the current state of evidence, testing for inherited thrombophilia should not lead to altered clinical management and therefore, should not be performed routinely in women with recurrent miscarriage but only in the context of scientific studies.     

The use of low-molecular-weight heparin for the management of venous thromboembolism in pregnancy

Thromboembolic disease is a rare, but important, complication of pregnancy that remains a leading non-obstetric cause of maternal death. The prevention and management of venous thromboembolism (VTE) in pregnant women is a complex area of medicine: a balance must be found between protecting the health of the mother and minimizing the risk to the unborn fetus. Until now, unfractionated heparin has been regarded as the drug of choice for the prevention and treatment of VTE during pregnancy. However, because of its significant side effects (osteoporosis and heparin-induced thrombocytopenia), the inconvenient mode of administration and need for monitoring, unfractionated heparin is now being replaced by low-molecular-weight heparin (LMWH). There is a convincing body of clinical evidence from well-designed studies and prospective case series that supports the efficacy and safety of LMWH in pregnant women. There are also encouraging observations on the efficacy of LMWH in the prevention of severe obstetric complications, which are frequently associated with inherited or acquired thrombophilias. The recently-published guidelines of The American College of Chest Physicians (ACCP), summarized in this review, allows the development of higher clinical standards. However, there is concern over the greater cost of LMWH compared with unfractionated heparin and oral anticoagulants, and cost-effectiveness studies are needed.     

Evaluation of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase gene mutations in patients with severe pregnancy complications in northern Finland

BACKGROUND: Thrombosis in placenta may lead to severe pregnancy complications. Most important inherited thrombophilias are factor V Leiden mutation, prothrombin mutation, and methylenetetrahydrofolate reductase mutation. The aim of our research was to evaluate the prevalence of inherited thrombophilias in severe pregnancy complications and in normal pregnancies. MATERIAL AND METHODS: The study subjects with severe preeclampsia, intrauterine growth restriction, placental abruption or fetal death were collected during the period 1999-2004 from Oulu University Hospital. We also collected during the same period voluntary parturients with normal pregnancy outcome as the control group. FVL, FII, and MTHFR gene mutations of the patients and controls were analyzed. RESULTS: We found a significant difference in the prevalence of FVL mutation between the groups. There were 9.5% FVL mutations in the study group compared to 1.8% in the control group; the observed difference between prevalences was 7.7% (95% CI 2.0-13.4). No statistical difference was found in the FII or MTHFR mutations between the groups. All FV and FII mutations were heterozygous and all the MTHFR mutations homozygous. CONCLUSION: Women with thrombophilia have a risk for severe pregnancy complications. Randomized controlled trials are needed to assess the influence of low-molecular-weight heparin in pregnant women with thrombophilia.