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The objective of this study is to investigate the prevalence of elevated factor VIII activity among women with severe complications of pregnancy. The study group included 49 patients with a previous history of pregnancy complications: severe preeclampsia (n = 9); intrauterine fetal death (IUFD) (n = 9); severe intrauterine fetal growth restriction (IUGR) (n = 12); IUGR and preeclampsia (n = 7); preeclampsia and placental abruption (n = 2); IUFD and IUGR (n = 5); and abruptio placenta (n = 5). The control group included 49 healthy women who had had at least one normal pregnancy. Seventeen women of the study group (34.6%) had elevated factor VIII activity compared to one woman (2.1%) in the control group (P < 0.05). The mean level of factor VIII was 159 ± 52% and 88 ± 17.4% of normal activity (mean  ±  SD, t-test, P < 0.05). Importantly, 10 women of the study group (20.4%) had only elevated factor VIII activity with no other known thrombophilia compared to one woman (2.1%) in the control group (P < 0.05). Elevated plasma activity of factor VIII might be a risk factor for severe pregnancy complications.

Objectives: The aim of this study was to investigate the effect of low molecular weight heparin (LMWH) on incidence of adverse outcome in women with thrombophilias and previous severe pregnancy complications., Materials and Methods: The study included 116 women with history of severe preeclampsia, fetal growth restriction (FGR)  ≤5th percentile, severe placental abruption and stillbirth  >20 weeks carrying factor V Leiden or prothrombin mutations, or protein S or C deficiency. Eighty-seven women referred to us for follow-up were treated with LMWH starting from weeks 5-15 (study group, A). Twenty-nine non-treated women referred only for delivery in our institution constituted the control group (B)., Results: The incidence of severe pregnancy complications in previous pregnancies was similar in both groups. Following treatment with LMWH, the incidence of severe preeclampsia was 4.6% in group A compared to 21% in group B, p = 0.007. The incidence of FGR was 2.3% in group A compared to 21% in group B, p = 0.03. The incidence of stillbirth or placental abruption was 0% in group A compared to 7% in group B, p = 0.06. The total incidence of adverse outcome was 7% in group A compared to 55% in group B, p = 0.0001., Conclusion: LMWH treatment of women with previous severe pregnancy complications and thrombophilias significantly reduces the rate of recurrence.

Background: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined., Methods: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%)., Results: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group., Conclusion: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.

Preeclampsia, intrauterine growth restriction and placental abruption greatly contribute to maternal and fetal morbidity and mortality. Thrombophilia is an inherited or acquired condition that predisposes individuals to venous and/or arterial thrombosis. Recently, three important inherited thrombophilias have been discovered. An inherited mutation in the gene coding for coagulation factor V (factor V Leiden), and a mutation in prothrombin that is associated with higher plasma levels of prothrombin. Both mutations result in an increased susceptibility to develop venous thrombosis. Hyperhomocysteinemia, which is associated with mutations in the gene for methylenetetrahydrofolate reductase, is a risk factor for venous and arterial thrombosis. The presence of antiphospholipid antibodies, an acquired thrombophilic condition, is associated with venous and arterial thrombosis. The term placental vasculopathy, is used to describe pathological placental changes that have been associated with preeclampsia, intrauterine growth restriction, placental abruption and fetal loss. The known thrombotic nature of the placental vasculopathy and the increased thrombotic risk with the presence of thrombophilias suggest, a cause-and-effect relationship between inherited and acquired thrombophilias and a number of severe obstetric complications. Testing patients with these complications for thrombophilias may have therapeutic implications for future pregnancies.

Background: We investigated whether hereditary thrombophilia is more prevalent in women with recurrent IVF-embryo transfer failures., Methods: This case-control study was conducted in an academic tertiary care hospital and compared 45 women with a history of four or more failed IVF cycles (group A) with 44 apparently healthy women matched for age and ethnic origin (group B). All participants were tested for inherited thrombophilias: mutations of prothrombin, factor V Leiden and methylene tetrahydrofolate reductase (MTHFR), and protein C, protein S and antithrombin III deficiencies., Results: Excluding homozygotic MTHFR, the incidence of thrombophilia in group A, was 26.7% compared with 9.1% in group B (P = 0.003; odds ratio 2.9; 95% confidence interval 1.02-8.4). The incidence of thrombophilia in women with unexplained infertility in group A was 42.9% (9/21), compared with 18.2% in group B (P < 0.002)., Conclusions: These data suggest that inherited thrombophilia may play a role in the aetiology of repeated IVF failures, particularly in the subgroup with unexplained fertility.

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

Pregnancy is hypercoagulable state. The field of thrombophilia; the tendency to thrombosis, has been developed rapidly and has been linked to many aspects of pregnancy. It is recently that severe pregnancy complications such as severe preeclampsia intrauterine growth retardation abruptio placentae and stillbirth has been shown to be associated with thrombophilia. Recurrent miscarriage and has also been associated with thrombophilia. Finally, thromboembolism in pregnancy as in the non-pregnant state is linked to thrombophilia. In this review all aspects of thrombophilia in pregnancy are discussed, and also all prophylactic and therapeutic implications.

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.

Severe obstetric complications, including preeclampsia, intrauterine growth retardation, abruptio placentae, and stillbirth, constitute a major cause of maternal and perinatal morbidity and death. The etiology of these severe obstetric complications is still unknown. However, the frequent finding of structural and thrombotic changes in placental capillaries, which lead to inadequate fetomaternal circulation and decreased placental perfusion, and the high prevalence of heritable or acquired risk factors for thrombosis found in women with these complications strongly suggest a cause-and-effect relationship. This review describes the recent findings on the association between these obstetric complications and the various thrombophilias, and recent therapeutic approaches. Aspirin, which was regarded as the drug of choice for the prevention of such obstetric complications, has proved to be ineffective in a large clinical trial. The encouraging observations on the efficacy of low-molecular-weight heparins, which are also included in the recently published guidelines of The American College of Chest Physicians, are summarized in this review. However, controlled clinical trials are still necessary to allow the development of better clinical standards.

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.

Objective: To determine the risk of thrombophilias in women with unexplained intrauterine fetal deaths (IUFD)., Methods: All women with IUFD at 27 weeks' gestation or greater were initially assessed during a period of 26 months. Subjects with multiple pregnancies, congenital anomalies, intrauterine infection, chorioamnionitis, immune hydrops, diabetes mellitus, previous thromboembolism, and severe hypertensive disease were excluded. The remaining 40 women with unexplained IUFD (study group) were matched for age and ethnicity with 80 healthy women who had at least one normal pregnancy (control group). All participants were tested at least 2 months after delivery for mutations of factor V Leiden, prothrombin gene, methylenetetrahydrofolate reductase, and for deficiencies of protein S, protein C, and antithrombin III. They were also tested and found to be negative for anticardiolipin antibodies., Results: The gestational age at delivery and birth weight were significantly lower in the study group. The prevalence of inherited thrombophilias was 42.5% in the study group compared with 15% in the control group (odds ratio 2.8, 95% confidence interval 1.5, 5.3, P =.001). The prothrombin mutation and protein S deficiency rates were significantly higher in the study group (odds ratio 2.3, 95% confidence interval 1.3, 4.0, and odds ratio 3.2, 95% confidence interval 2.4, 4.1, respectively)., Conclusion: Third-trimester IUFD is significantly associated with thrombophilias. These findings suggest that thrombophilia work-ups should be part of IUFD investigations and may have therapeutic and prognostic implications in future pregnancies.

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.

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., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: To evaluate the benefit of combined low-molecular-weight (LMW) heparin and aspirin for prophylaxis in women carriers of thrombophilia who had previously suffered from severe obstetric complications., Methods: The 33 studied women had an earlier pregnancy complicated by severe preeclampsia, abruptio placentae, intrauterine growth retardation, or intrauterine fetal death. All were subsequently diagnosed as carrying inherited thrombophilias. In their subsequent pregnancy, prophylactic therapy consisting of LMW heparin 40 mg/day (Enoxaparin, Rhone-Poulenc-Rorer, France) and aspirin was administered. Patients who were found to be homozygotes for the methylenetetrahydrofolate reductase mutation also received folic acid supplementation throughout their pregnancy., Results: Low-molecular-weight heparin was well tolerated and none of the women or the newborns developed any hemorrhagic complications. Only three (9.1%) of the women developed pregnancy complications. The mean gestational age and the mean birth weight at delivery in the previously complicated pregnancies were 32.1 +/- 5.0 weeks and 1175 +/- 590 g, respectively, compared to 37.6 +/- 2.3 weeks and 2719 +/- 526 g, respectively, in the treated pregnancies (p < 0.001)., Conclusions: This uncontrolled trial suggests that patients with obstetric complications and an inherited thrombophilia may benefit from treatment with combined LMW heparin and aspirin in subsequent pregnancies. However, this needs to be verified by controlled trials before considering clinical application.

Objective: To determine whether severe preeclampsia is associated with genetic thrombophilic mutations or other types of thrombophilia., Methods: A case-control study compared 63 consecutive women with severe preeclampsia evaluated at our institution between November 1997 and April 1999 with 126 control women matched for age and ethnicity. All of these women were tested several months after delivery for mutations of factor V Leiden, methylenetetrahydrofolate reductase, and prothrombin gene; for deficiencies of protein C, protein S, and antithrombin-III; and for the presence of anticardiolipin antibodies., Results: Thirty-five study women (56%) had a thrombophilic mutation compared with 24 control women (19%), P <.001. Seven other study women (11%) had other thrombophilias, compared with one control woman (0.8%), P <.01. Within the study group, women with thrombophilia delivered at an earlier gestational age, and their neonates' birth weights were lower compared with those of women without thrombophilia., Conclusion: Because thrombophilia was found in 67% of women with severe preeclampsia, we suggest that women who have severe preeclampsia should be tested for thrombophilia.

Background and Purpose: The aim of our study was to investigate the association of transient ischemic cerebrovascular events during pregnancy and inherited thrombophilias., Methods: The study group comprised previously healthy pregnant women who had their first ischemic event during pregnancy (n=12). The control group included 24 healthy women matched with the study women for age, ethnicity, and smoking status. All women were evaluated for factor V Leiden mutation, methylenetetrahydrofolate reductase C677T gene mutation, the G20210A mutation in the prothrombin gene, and deficiencies of plasma proteins C and S and antithrombin III., Results: Inherited thrombophilia was detected in 83% of women with transient neurological manifestations compared with 17% of the control group (P<0.001)., Conclusions: Transient cerebrovascular ischemic events during pregnancy are associated with a high rate of inherited thrombophilias. Pregnant women with focal neurological symptoms should be evaluated for thrombophilia.

Background: Obstetrical complications such as severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth are associated with intervillous or spiral-artery thrombosis and inadequate placental perfusion. Whether these complications are associated with an increased frequency of thrombophilic mutations is not known., Methods: We studied 110 women who had one of the above-mentioned obstetrical complications and 110 women who had one or more normal pregnancies. The women were tested several days after delivery for the mutation of guanine to adenine at nucleotide 1691 [corrected] in the factor V gene (factor V Leiden), the mutation of cytosine to thymine at nucleotide 677 in the gene encoding methylenetetrahydrofolate reductase, and the mutation of guanine to adenine at nucleotide 20210 in the prothrombin gene. Two to three months after delivery the women were tested for deficiency of protein C, protein S, or antithrombin III and for the presence of anticardiolipin antibodies., Results: The mutation at nucleotide 1691 [corrected] in the factor V gene was detected in 22 of the women with obstetrical complications and in 7 of the women with normal pregnancies (20 percent and 6 percent, respectively; P=0.003). Twenty-four women with complications, as compared with nine women without complications, were homozygous for the C677T mutation in the gene encoding methylenetetrahydrofolate reductase (22 percent and 8 percent, respectively; P=0.005). The G20210A mutation in the prothrombin gene was found in 11 women with complications as compared with 3 women without complications (10 percent and 3 percent, respectively; P=0.03). Overall, 57 women with obstetrical complications had a thrombophilic mutation, as compared with 19 women with normal pregnancies (52 percent and 17 percent, respectively; P<0.001). Deficiency of protein S, protein C, or antithrombin III or anticardiolipin antibodies were detected in an additional 14 women with complications, as compared with 1 woman with a normal pregnancy (13 percent and 1 percent, respectively; P<0.001)., Conclusions: Women with serious obstetrical complications have an increased incidence of mutations predisposing them to thrombosis and other inherited and acquired forms of thrombophilia.