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%.     

Future of prenatal cytogenetic studies: rapid aneuploidy testing or full karyotype

Thrombophilia is a congenital or acquired disorder of haemostatic imbalance leading to clot formation. Congenital thrombophilia is a result of different genetic polymorphisms in the genes coding for particular elements in coagulation and fibrinolysis processes and is connected with excessive readiness to thrombosis in the carriers the mutated alleles. A higher coagulation activity has been observed in case of pregnant women who are carriers of congenital thrombophilia, when compared to the pre-pregnancy activity. These changes concern first of all utero-placental circulation, and may lead to many complications during pregnancy such as: recurrent miscarriages, intrauterine fetal death in second and third trimester, preeclampsia/eclampsia, intrauterine growth restriction and placental abruption. Numerous research indicates that anticoagulation prophylaxis in pregnant women with the abovementioned complications in medical history might prevent a similar condition in the following pregnancies. What is more, it underlines that administration of low molecular weight heparin and acetylsalicylic acid may improve perinatal outcome in thrombophilic women. However, the notion whether anticoagulant prophylaxis should be applied in women with preeclampsia, fetal hypotrophy or fetal loss remains disputable. Furthermore, the question of when the prophylaxis should start and of its duration remains unanswered. The following summary focuses on congenital thrombophilia in pregnant women with burdened anamnesis and suggested pattern of anticoagulation prophylaxis.     

Inheritance and perinatal consequences of inherited thrombophilia in Greece.

OBJECTIVE: To investigate the impact of inherited thrombophilic factors on the gestational outcome of unselected pregnant women. METHOD: A total of 392 women with spontaneous pregnancy were investigated for Factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations. Adverse pregnancy outcomes were recorded. RESULTS: Thrombophilic genotypes were significantly higher in women with placental abruption. Heterozygocity for Factor V Leiden increased the risk for placental abruption 9.1 times. The MTHFR T677T genotype increased the risk for placental abruption 4.8 times despite folate supplements, and normal serum folate and B(12) levels. Women with inherited thrombophilia and previous obstetric complications were at significant risk for complications in a subsequent pregnancy (P<0.05). CONCLUSION: Women with placental abruption should be screened for thrombophilic factors and plasma homocysteine should be measured. Subgroups of women with inherited thrombophilia and obstetric complications might benefit from prophylactic anticoagulation in subsequent pregnancies.     

Preventing adverse obstetric outcomes in women with genetic thrombophilia

OBJECTIVE: To improve fetomaternal outcomes in women with obstetric complications and inherited causes of thrombophilia. DESIGN: Clinical trial. SETTING: Thrombophilic women with previous unexplained adverse outcomes. PATIENT(S): Twenty-five women with previous severe obstetric complications were treated during and after pregnancy. INTERVENTION(S): Low fixed dose of heparin or aspirin. MAIN OUTCOME MEASURE(S): Fetomaternal outcome. RESULT(S): Low fixed dose of heparin were administered to 24 pregnant women, aspirin to 7. Overall, among 31 treated pregnant women, 28 (90.3%) compared to 4 of 58 (6.9%) in previous pregnancies had a good obstetric outcome. Two fetal losses <14 weeks gestation and a fetal growth restriction were registered. All newborns, except one, were in the tenth centile or above. All babies were discharged in good clinical status. In the treated pregnancies, no thrombosis or pharmacological side effect was recorded. CONCLUSION(S): Heparin prophylaxis at fixed low doses and possibly aspirin could be efficacious in preventing adverse outcomes in women carrying inherited thrombophilia with previous poor obstetric outcomes.     

Inherited thrombophilia: treatment during pregnancy

OBJECTIVE: Inherited thrombophilia is associated with thromboembolic events and/or poor obstetric outcome. We evaluated the pregnancy outcome in women with inherited thrombophilia treated with low-molecular-weight heparin (LMWH). METHODS: 38 thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome were treated during their 39 consecutive pregnancies with LMWH from pregnancy verification until 4-6 weeks in puerperium. A fixed dose of enoxaparin 4,000 IU/day (except 1 case who required nadroparin 0.3 ml/day) was administered in most cases, adopting a higher dose (6,000 IU/day to 6,000 IU twice a day) in those with previous thromboembolic events. RESULTS: In the treated women, all had a good obstetric outcome, whereas in the previous untreated pregnancies (n = 78), the rate of fetal loss (early and late) was 76.9%, only 12 live infants survived (66.6%). Moreover, birth weight resulted significantly higher in live infants born to treated pregnancies in comparison to that of previous untreated pregnancies (p = 0.009). No maternal thrombosis or major bleeding complications were recorded. CONCLUSIONS: The treatment with LMWH improved pregnancy outcome resulting effective and safe in thrombophilic women with a history of thromboembolic events and/or poor obstetric outcome.     

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.     

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.     

Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage

OBJECTIVE: To assesses the live birth rate without treatment in women with hereditary thrombophilia who have recurrent miscarriage and women without thrombophilia who have recurrent miscarriage. DESIGN: Prospective observational study. SETTING: Tertiary referral unit in university hospital. PATIENT(S): One hundred twenty women with thrombophilia and 65 women without thrombophilia. MAIN OUTCOME MEASURE(S): Number of live births or repeated miscarriages. RESULTS: Of the 185 patients, 44 with thrombophilia and 26 without thrombophilia have conceived. Nineteen of the 44 pregnancies (43.2%) in thrombophilia patients have terminated in live births, compared with 8 of 26 pregnancies (30.8%) in patients without thrombophilia. This difference is not statistically significant. CONCLUSIONS: Hereditary thrombophilia did not seem to affect the live birth rate in women with recurrent miscarriage.     

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.     

The effect of anticoagulation on antenatal ultrasound findings in pregnant women with thrombophilia.

OBJECTIVE: To assess whether treatment with heparin alters ultrasound findings in pregnant women with inherited thrombophilia. METHODS: This was a retrospective study of a cohort of patients referred for pregnancy complications who were found to have genetic thrombophilia. Ultrasounds were reviewed in treated and untreated pregnancies for the presence of growth restriction, oligohydramnios or abnormal Doppler results. RESULTS: There were a total of 178 pregnancies in 51 patients. The overall percentage of abnormal ultrasounds was significantly greater in the untreated compared with treated pregnancies (52.8% vs. 27.9%; p = 0.024.) Growth restriction and abnormal Doppler results were more common in untreated pregnancies. There was a significantly decreased risk of oligohydramnios with treatment (27.3% vs. 7%; p = 0.03). Overall outcomes were significantly improved with the use of anticoagulation ( p < 0.0001). CONCLUSIONS: Treatment markedly improves ultrasound parameters of growth, fluid and feto-placental blood flow in patients with thrombophilia. The presence of abnormalities despite treatment reinforces the need for close antenatal surveillance.     

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.     

Is thrombophilia a risk factor for placenta-mediated pregnancy complications?

Purpose

To determine if thrombophilia is a risk factor for placenta-mediated pregnancy complications (PMPC) (i.e., preeclampsia, intrauterine growth restriction (IUGR), placental abruption, intrauterine fetal death and recurrent pregnancy loss).

Methods

A 5-year retrospective cohort study. Ongoing pregnancies in women with an antecedent PMPC with thrombophilia were compared with the pregnancies in similar women without thrombophilia. The main outcome measures were mean birth weight deviations, corrected for gestational age, and recurrence of PMPC. Low-molecular-weight heparin (LMWH) was employed for thromboprophylaxis only. Mann?CWhitney??s, Fisher??s and Chi-square tests were employed for comparison.

Results

PMPC recurred in 10/43 (23?%) in the thrombophilia group and in 7/41 (17?%) in the non-thrombophilia group, P?P?Conclusion Thrombophilia does hardly increase the risk of IUGR/PMPC or if so, it can be prevented by LMWH.     

Management of essential thrombocythaemia during pregnancy

Essential thrombocythaemia is a rare myeloproliferative disorder that often presents with haemorrhagic or thrombotic complications. It may be detected incidentally in an asymptomatic younger adult and there are only a few case reports of essential thrombocythaemia in pregnant women. The risks posed by essential thrombocythaemia during pregnancy and its optimal management are uncertain. To determine if there is increased incidence of obstetric complications seen in women who have essential thrombocythaemia, we collected a large case series from a number of tertiary obstetric units in Australia and New Zealand. There were 30 pregnancies in 12 women who had essential thrombocythaemia. There were 17 live births (57%), 7 stillbirths (23%), 5 miscarriages (17%) and 1 ectopic (3%). Five pregnancies were complicated by placental abruption. When the outcomes of those women who received treatment with aspirin or interferon were compared to those that did not receive any treatment, there was a trend towards a higher livebirth rate (79% v. 38%, p = 0.06). Seven women were treated with aspirin and 5 had successful outcomes with no fetal complications. Four women were treated with alpha-interferon which reduced their platelet counts and all had successful outcomes with no fetal complication. These findings suggest that there is a high incidence of miscarriage, stillbirth and abruption in women with essential thrombocythaemia. Their pregnancies should be carefully monitored. Treatment with low dose aspirin and/or the use of alpha-interferon may be associated with an improved pregnancy outcome.     

Pathologic features of the placenta in women with severe pregnancy complications and thrombophilia.

OBJECTIVE: To compare placental pathology between women with and without thrombophilia who had severe preeclampsia, intrauterine growth retardation, severe abruptio placentae, or stillbirth. METHODS: After delivery, 68 women with singleton pregnancies with one of the above complications were evaluated for an inherited thrombophilia: factor V Leiden, methylenetetrahydrofolate reductase and prothrombin gene mutation, and deficiencies of protein S, protein C, and antithrombin III. Thirty-two women were thrombophilic (group A), and 36 women were not (group B). There was no difference in maternal age, parity, and type of pregnancy complication. A single pathologist examined each placenta. RESULTS: The gestational age at delivery, birth weight, and placental weight were significantly lower in group A. Three parameters showed significant differences between the groups: thrombophilic women had a higher number of villous infarcts (P <.01), more multiple infarcts (P <.05), and a higher incidence of placentas with fibrinoid necrosis of decidual vessels (P <.05). CONCLUSION: Placentas of women with severe complications and thrombophilia have an increased rate of vascular lesions.     

Inherited thrombophilia in women with recurrent miscarriages and pregnancy loss in anamnesis--own experience

Single nucleotide polymorphisms of the genes coding for coagulation factors are the cause of congenital thrombophilia which might lead to recurrent miscarriages and fetal loss in advanced pregnancy. The most frequent reasons of thrombophilia are the following: factor V Leiden (1691G>A), mutation 20210G>A of prothrombin gene, and 677C>T of 5, 10-methylenetetrahydrofoliate reductase gene. The following article briefly summarizes the administration of antithrombotic prophylaxis (low-molecular weight heparin, acetylsalicylic acid) which seems to be an effective course of action to prevent complications in next pregnancies. What is more, adverse events after long-term usage of low-molecular weight heparin and acetylsalicylic acid in prophylactic doses have not been observed. Due to lack of complete randomized investigation about the inclusion of antithrombotic prophylaxis in this group of pregnant women, common scheme of administration and optimal dosage is yet to be established.     

Routine antenatal thrombophilia screening in high-risk pregnancies: a decision analysis

Thrombophilias have been implicated in complications related to ischemic placental disease including recurrent pregnancy loss, intrauterine fetal demise, preeclampsia, fetal growth restriction, placental abruption, and preterm delivery. Maternal screening and treatment may lower the recurrence of these outcomes. Our objective was to estimate if antenatal screening for thrombophilias with the intention to offer treatment among women with a prior adverse pregnancy outcome (APO) is preferable to no screening. A decision-analytical model was constructed for pregnant women with prior APO, comparing screening for thrombophilia with intention to treat with no screening. Values obtained from previously published studies include probability of positive test: 0.3 (0.1 to 0.6); good outcome with treatment: 0.9 (0.3 to 0.99); no thrombophilia, good outcome: 0.75 (0.5 to 0.9); test negative, thrombophilia positive: 0.05 (0.01 to 0.1); test negative, thrombophilia positive, good outcome: 0.75 (0.5 to 0.9); thrombophilia/test negative, good outcome: 0.98 (0.5 to 0.99). Sensitivity analyses were run over a wide range of assumptions. Thrombophilia screening with intention to treat in women with prior APO associated with ischemic placental disease is the strategy of choice compared with no testing over a wide range of assumptions. Sensitivity analyses support this to be robust. Women with poor pregnancy history related to placental ischemic disease may benefit from thrombophilia screening and treatment in a subsequent pregnancy.     

Unfractionated heparin and placental pathology in high-risk pregnancies: Secondary analysis of a pilot randomized controlled trial

Introduction

Heparin is often prescribed during pregnancy with the intention of improving perinatal outcomes on the basis that it exerts an anticoagulant action in the inter-villous space. Accumulating in-vitro and in-vivo evidence indicates that heparin's beneficial effects in pregnancy may result from ‘non-anticoagulant’ effects including the promotion of angiogenesis.

Methods

To study the effect of heparin within the placenta, we performed secondary analyses on a pilot trial where 32 women with negative thrombophilia screens and second-trimester evidence of placental insufficiency were randomized to standard care or antenatal self-administration of unfractionated heparin (UFH) 7500IU twice-daily. Serial placental ultrasound images were reviewed and compared with histo-pathologic findings following delivery.

Results

There were no differences between the two arms in either the evolution of abnormal placental lesions on ultrasound (p = 0.75) or evidence of maternal vascular under-perfusion on histopathology (p = 0.89). In pregnancies considered at increased risk for adverse pregnancy outcomes based on previous history or abnormal serum marker screen, early (second-trimester) placental ultrasound, reflecting developmental pathology had better test characteristics (sensitivity 77.8%; positive predictive value 80.8%) for predicting adverse pregnancy outcomes than third-trimester ultrasound that is reflective of placental thrombotic injury.

Conclusions

Administration of UFH did not prevent the development or evolution of abnormal placental lesions on placental ultrasound or evidence of maternal vascular underperfusion on placental histo-pathology. Second-trimester placental ultrasound may be of value in predicting those at greatest risk of adverse outcomes.     

Placental pathology,antiphospholipid antibodies,and pregnancy outcome in recurrent miscarriage patients

OBJECTIVE: To examine whether there are characteristic histological features in placentas from ongoing pregnancies of patients with a history of recurrent miscarriage, with and without primary antiphospholipid antibody syndrome, in relation to clinical pregnancy outcome. METHODS: Patients attending a recurrent miscarriage clinic were investigated and treated according to an established protocol. One hundred twenty-one consecutive patients achieving a potentially viable pregnancy (at least 24 completed weeks' gestation), including 60 primary antiphospholipid antibody syndrome-positive cases and 61 primary antiphospholipid antibody syndrome-negative cases were included. After delivery, placental pathologic examination was carried out by a pathologist unaware of the clinical details. Histological sections were examined by two pathologists independently. Pregnancy outcome and placental findings were reviewed in relation to the maternal antiphospholipid antibody status. RESULTS: Pregnancy outcome was similar in primary antiphospholipid antibody syndrome-positive and primary antiphospholipid antibody syndrome-negative groups regarding gestation at delivery and antepartum obstetric complications. Several histological placental abnormalities were identified in both groups, but most pregnancies were clinically uncomplicated, with no significant placental abnormalities. In cases with pregnancy complications, the placental pathology was primarily that of uteroplacental vasculopathy, such as placental infarction and preeclampsia, but there were no specific placental lesions or patterns of abnormalities characteristic of primary antiphospholipid antibody syndrome-positive patients. A small subgroup of primary antiphospholipid antibody syndrome-positive patients may be at increased risk of development of maternal floor infarction or massive perivillus fibrin deposition. CONCLUSION: There are no specific histopathologic placental abnormalities characteristic of treated patients with antiphospholipid antibody syndrome and poor reproductive history, but complications of uteroplacental disease are more common.