Thrombophilia and the risk for venous thromboembolism during pregnancy, delivery, and puerperium

The main inherited thrombophilias (antithrombin deficiency, protein C and S deficiency, FVL, the prothrombin gene variant, and MTHFR C677T homozygotes) have a combined prevalence in Western European populations of 15% to 20%. One or more of these inherited thrombophilias is usually found in approximately 50% of women who have a personal history of VTE. Obstetricians must therefore be aware of the interaction between thrombophilias and the procoagulant state of pregnancy and should have an understanding of additional risk factors that may act synergistically with thrombophilias to induce VTE. Such knowledge combined with the appropriate use of thromboprophylaxis and treatment in women who have objectively confirmed VTE continue to improve maternal and perinatal outcomes.     

Immunomodulation in Recurrent Miscarriage

There are many etiological factors responsible for recurrent abortions. However, no explanation can be identified in approximately 40–50 % of women with recurrent miscarriage (RM). Several studies demonstrated that successful pregnancy is dependant on shifting of maternal immune response from (proinflammatory) Th1 toward (anti-inflammatory) Th2 phenotypes. It was suggested that unexplained RM might be due to immunologic factors. Recently, there is improved understanding regarding the role of the different immune cells and proteins that are important at each stage of a normal pregnancy. Various immune-based therapies with variable clinical evidences have been reported in women with RM with variable efficacy. Still there is lack of information about the mode of action and possible adverse effects of the treatment and a reliable marker for patient selection for immunopotentiation. Adequately powered placebo-controlled studies are required to study and treat couples with the so-called idiopathic recurrent miscarriage.     

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.     

Evidence-based care of recurrent miscarriage

Between 0.5 and 1.0% of couples experience recurrent pregnancy loss (RPL), which is defined as three or more consecutive miscarriages. Losses are classified as pre-embryonic (<5 weeks), embryonic (5-10 weeks) or fetal (>10 weeks). Genetic abnormalities are responsible for RPL in 2-4% of these couples. Inadequate progesterone production has been proposed a cause of RPL and progesterone is given to prevent miscarriage, despite a lack of supportive evidence. The factor V Leiden and prothrombin G20210A mutations are common inherited thrombophilias also associated with RPL. Antenatal thromboprophylaxis is sometimes recommended although no data exist regarding efficacy. Antiphospholipid syndrome is known to cause RPL and antenatal thromboprophylaxis reduces the risk of miscarriage. Uterine abnormalities might also result in RPL. About 50% of cases of RPL have no identifiable cause. Alloimmune incompatibility has been proposed as a cause for RPL in these women. The concept of alloimmune-related RPL has not been scientifically validated.     

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.     

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.     

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.     

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.     

Cervical fetal fibronectin as a predictor of first trimester pregnancy outcome in unexplained recurrent miscarriage

OBJECTIVE: To determine whether cervical fetal fibronectin is a reliable predictor of first trimester pregnancy outcome in patients with unexplained recurrent miscarriage. STUDY DESIGN: A prospective observational study was carried out on 49 pregnant women with a history of unexplained recurrent miscarriage. In all participants the presence of fetal fibronectin in the cervical secretion was determined with a qualitative rapid immunoassay. The outcome of the first trimester pregnancy was recorded a successful outcome was a pregnancy that progressed beyond 12 weeks of gestation; a miscarriage referred to a pregnancy loss in the first 12 weeks. RESULTS: Of the 49 subjects screened, fetal fibronectin was positive in 17 and negative in 32. Overall, 14 pregnancies resulted in fetal loss before the 12th week of gestation. Fetal cervical fibronectin was positive in 6 of the 14 patients who miscarried and in 11 of the 35 in whom outcome was successful. As predictor of first trimester pregnancy outcome the test had a sensitivity and a specificity of 43% and 69% and positive and negative predictive values of 35%, and 75%, respectively. Subgroup analysis by number of previous miscarriages and maternal age gave similar values. CONCLUSION: This study examines the possible value of cervical fetal fibronectin in predicting first trimester pregnancy outcome. We conclude that the occurrence of positive or negative fetal cervical fibronectin test has only limited predictive value and therefore its use cannot be considered for clinical application.     

Pregnancy outcome in patients with a history of recurrent spontaneous miscarriages and documented thrombophilias

The aim of this study was to evaluate the effect of treatment in patients analyzed for recurrent spontaneous miscarriage with a diagnosis of a hereditary thrombophilia, the presence of antiphospholipid and/or autoimmune antibodies, and/or hyperhomocystinemia (HHC) with or without methylenetetrahydrofolate reductase (MTHFR) polymorphisms. In total, 76 women with 2 or more embryonic or fetal losses were analyzed. Of these, 49 (64.4%) women were found to have one or more thrombophilias and/or autoimmune antibodies, and 33 (43.4%) women were found to have a MTHFR polymorphism and/or HHC. Since completion of the recurrent miscarriage analysis, 39 women conceived again. All women with a thrombophilia were treated with low-dose aspirin plus low molecular weight heparin. All women with previously diagnosed HHC and/or MTHFR polymorphisms were treated with folate and vitamin B(6) and B(12) supplementation. In the thrombophilia group, 27 women conceived resulting in 20 successful pregnancies (74.1%) and 7 pregnancy losses (2 trisomy 16, 1 ectopic pregnancy and 4 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 14.8%. In the HHC/MTHFR group 22 women conceived, resulting in 17 successful pregnancies (77.3%) and 5 pregnancy losses (1 trisomy 16, 1 Turner syndrome and 3 unexplained miscarriages), i.e. an unexplained pregnancy loss rate of 13.6%.     

The role of T-helper cytokines in human reproduction

OBJECTIVE: To explore the role of maternal periimplantation endometrial T-helper-1 (TH-1) and T-helper-2 (TH-2) cytokines in the success or failure of human reproduction and their relation to the endocrine system and subsequent pregnancy outcome. DESIGN: Controlled, prospective study. SETTING: A tertiary care hospital with a university-based reproductive medicine clinic. PATIENT(S): Healthy women and women with recurrent miscarriage who had no history of infertility or autoimmune disease. INTERVENTION(S): Measurement of qualitative cytokine expression by RT-PCR and quantitative by ELISA, also hormone levels and pregnancy outcome. MAIN OUTCOME MEASURE(S): Expression of TH-1 and TH-2 cytokines and correlation with hormone levels and subsequent pregnancy outcome. RESULT(S): Levels of TH-1 cytokines were significantly greater and higher in women with recurrent miscarriage compared with controls, whereas levels of TH-2 cytokine interleukin-6 were significantly lower in women with recurrent miscarriage than in controls. There was no correlation between cytokine expression and serum hormone levels, and periimplantation cytokine levels were not predictive of subsequent pregnancy outcome in women with recurrent miscarriage. CONCLUSION(S): This study demonstrated in vivo that women with recurrent miscarriage exhibit primarily TH-1 cytokines, whereas healthy women exhibit decreased TH-1 cytokines and increased TH-2 cytokines. This suggests a potential role for a dichotomous T-helper response in the mediation of subsequent reproductive events. This maternal T-helper response appears to operate independently of hormonal factors in influencing the success or failure of human reproduction, as no correlation was evident between serum hormone levels and cytokine levels. An attempt to use periimplantation TH-1 and TH-2 cytokine profiles as a predictor of subsequent pregnancy outcome (live birth or no live birth) was limited by the small number of patients studied.     

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.     

High frequency of thrombophilic disorders in women with recurrent fetal miscarriage

OBJECTIVES: Our purpose was to examine whether genetic thrombophilias are etiological factors for recurrent fetal miscarriage or not. STUDY DESIGN: We compared the rate of thrombophilic anomalies in women with unexplained recurrent fetal miscarriages to the rate of age-matched women with successful pregnancies as a case-control study. RESULTS: A total of 101 consecutive patients with 102 age-matched controls were included in the study. The rate of Factor V (FV) Leiden mutation, Factor (F) II mutation, protein S, protein C, antithrombin III deficiencies and overall thrombophilia in patients with recurrent fetal loss was significantly higher than the frequencies in control patients. CONCLUSION: Women with recurrent fetal miscarriages have an increased incidence of thrombophilia. Genetic thrombophilias may be one of the major etiological factors for recurrent abortion and fetal demise.     

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.     

Association of reduced selenium status in the aetiology of recurrent miscarriage

Objective To determine whether recurrent miscarriage is associated with reduced selenium status.
Design Case–control study.
Setting Department of Obstetrics and Gynaecology, Glasgow Royal Infirmary and Glasgow Royal Maternity Hospital.
Population Twenty nonpregnant women with a history of unexplained recurrent miscarriage, and 47 nonpregnant parous women with a history of at least one successful pregnancy and no more than one miscarriage.
Methods A 7 mL blood sample from each woman was collected into lithium heparin 'vacutainer' tubes. Samples were centrifuged at 3000 g for 15 minutes, and plasma was extracted and stored at −20°C. Selenium concentrations were measured using a fluorescence spectrophotometer. The selenium concentrations in the two groups were compared and the differences examined using the Student's t test.
Main outcome measures Plasma selenium concentration (μg/L).
Results The mean selenium concentration for women with a history of unexplained recurrent miscarriage was 67.7 μg/L (SD 16.4). The selenium level for the women with no history of recurrent miscarriage was 70.3 μg/L (SD 12.7). There was no difference in selenium concentrations between the two groups (   P = 0.53  ).
Conclusions In this study there is no association between unexplained recurrent miscarriage and reduced selenium status, implying that reduced selenium status is not a factor in the pathogenesis of recurrent miscarriage. We can find no rationale for a trial of selenium therapy in women with a history of recurrent miscarriage.     

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.     

Preimplantation genetic diagnosis in early pregnancy loss✰

Miscarriage is a frequent outcome seen in obstetrics with 1 in 5 pregnancies ending in an early pregnancy loss. Aneuploidy is the most significant single factor affecting early pregnancy failure and miscarriage. The risk of aneuploidy increases significantly with increasing maternal age. There has been tremendous advancement in technology that has made preimplantation genetic testing for aneuploidy reliable and accessible. For women in their mid-to-late 30s there is great utility in the use of PGT-A to facilitate single embryo transfer, reduce the risk of clinical miscarriage and ongoing aneuploidy gestations. The current data supports use of preimplantation genetic testing for aneuploidy and single embryo transfer for this population of women. At this time, more prospective data is needed to determine the effect of preimplantation genetic testing for aneuploidy on rates of miscarriage in the recurrent pregnancy loss population.     

First trimester assessment of Pentraxin-3 levels in women with primary unexplained recurrent pregnancy loss

Objective

To evaluate the potential role of measuring first-trimester maternal Pentraxin-3 levels in patients with primary unexplained recurrent pregnancy loss.

Study design

A case control study was conducted in Ain Shams University Maternity Hospital. Cases included 45 women with primary unexplained recurrent pregnancy loss and early pregnancy failure admitted for medical or surgical termination of pregnancy. Controls (45 women) included a matched group of apparently healthy pregnant women who had at least one previous uneventful pregnancy with no previous obstetric history of adverse pregnancy outcomes. Maternal venous blood samples were collected for assay of Pentraxin-3 using enzyme-linked immunosorbent assay. The main outcome measure was the pregnancy outcome in women with elevated Pentraxin-3 levels.

Results

90 participants were statistically analyzed. In the patient group, the mean Pentraxin-3 level was 12.00 ± 4.07 ng/ml, while in the control group it was 1.69 ± 0.91 ng/ml. The difference was statistically significant (p < 0.001). In the patient group, Pentraxin-3 showed a significant positive correlation with the number of previous miscarriages (p = 0.038).

Conclusion

Abnormally elevated Pentraxin-3 levels indicate the presence of an abnormally exaggerated intrauterine inflammatory or innate immune response that may cause pregnancy failure in women with primary unexplained recurrent pregnancy loss.     

Interleukin-6 in pregnancy and gestational disorders

IL6 is a multifunctional cytokine with pivotal roles in the inflammatory response and in directing T cell differentiation in adaptive immunity. IL6 is widely expressed in the female reproductive tract and gestational tissues, and exerts regulatory functions in embryo implantation and placental development, as well as the immune adaptations required to tolerate pregnancy. Here, we summarise the current understanding of how membrane-bound and soluble receptors mediate IL6 signalling to regulate leukocytes and non-haemopoietic cells. We review the published literature regarding the expression and actions of IL6 in the uterus, decidua and placenta, and studies implicating this cytokine in pregnancy disorders. Elevated IL6 is frequently evident in the altered cytokine profiles characteristic of unexplained infertility, recurrent miscarriage, preeclampsia and preterm delivery. Notably, there is compelling evidence indicating altered systemic IL6 trans-signalling in women prone to recurrent miscarriage, with excessive IL6 bioavailability potentially inhibiting generation of CD4+ T regulatory cells required for pregnancy tolerance. Insufficient local IL6 may also contribute to fetal loss, since IL6 expression is reduced in the endometrium of women with recurrent miscarriage, and in the fetal-placental tissue of CBA×DBA/2 mice. Consistent with the role of IL6 in key reproductive events, Il6 null mutant mice exhibit elevated fetal resorption and delayed parturition. Investigation of the association between IL6 signalling components and T cell responses in pregnant women, as well as detailed analysis of the maternal immune response in IL6-deficient mice, is now required to define the mechanisms by which this cytokine exerts influence on reproductive success.