Genital Mycoplasmas in Pregnancy and Obstetric Outcome

Summary: This prospective study was conducted to determine the incidence of genital mycoplasma carriage in an antenatal pregnant population in Singapore, and to study the association of genital mycoplasma with preterm labour, prelabour rupture of membranes (PROM) and low birth-weight babies.
Genital mycoplasma was isolated in 26.3% of 312 pregnant women. The carrier rate was twice as high in women between 28 and 34 weeks (37.9%) compared with women at <28 weeks (23.8%) (p <0.05). In the individual women, the carriage of genital mycoplasmas was not persistent throughout pregnancy even without treatment, and a negative swab did not exclude colonization later on in pregnancy.
Our study does not support an association between genital tract colonization with genital mycoplasmas (Mycoplasma hominis or Ureaplasma urealyticum) and prematurity (8.5% in carriers compared with 8.3% in noncarriers), PROM (3.7% in carriers compared with 4.8% in noncarriers) or low birth-weight babies (2.4% in carriers compared with 5.6% in noncarriers).     

遗传性易栓症与不良妊娠结局的研究进展

近年研究发现妊娠期易栓症的发生呈增加趋势。易栓症分为遗传性易栓症和获得性易栓症,遗传性易栓症主要与凝血基因突变所致的蛋白表达异常有关,包括因子VLeiden(FVL)、凝血酶原基因G20210A、亚甲基四氢叶酸还原酶(MTHFR)基因突变以及蛋白S(PS)、蛋白C(PC)和抗凝血酶(AT)缺乏等。凝血、抗凝及纤溶系统功能失调可引起胎盘灌注不良,不良妊娠结局如子痫前期(PE)、胎盘早剥、胎儿生长受限(FGR)和习惯性流产等可能与此有关。但遗传性易栓症是否是造成不良妊娠结局的直接因素以及预防性抗凝是否可以改善妊娠结局仍需进一步探讨。综述遗传性易栓症与不良妊娠结局的关系,评估预防性抗凝的必要性,为临床诊断和治疗提供思路。     

Prothrombotic gene mutations in women with recurrent abortions and intrauterine fetal death

AIM: The factor V Leiden mutation (FVL) and the G20210 prothrombin gene mutation (FII G20210A) are well-established risk factors for venous thromboembolism. In the recent years many scientific reports have suggested that these defects are associated with an increased risk of intrauterine fetal death. The aim of our study was to investigate the prevalence of these molecular defects in subjects with history of unexplained pregnancy loss. METHODS: One-hundred and fifty women, 99 with history of unexplained recurrent pregnancy loss (between the 13th and the 20th week of gestation) and 51 with history of unexplained fetal death (pregnancy loss after the 20th week of gestation) were studied for hereditary thrombophilia. Physiologic coagulation inhibitors (antithrombin III, protein C, protein S) were in the normal range. RESULTS: The prevalence of FVL and FII G20210A mutations was compared in patients with recurrent pregnancy loss and in a control group of 115 healthy women, without history of pregnancy loss (6.1% and 8.1% for FVL and FII G20210A respectively vs 2.6% for both mutations in the control group, P=0.36 for FVL and P=0.13 for FII G20210A). FVL and FII G20210A mutations were significantly more prevalent in women with fetal death (19.6%, P=0.001 for both mutations). CONCLUSIONS: Our data suggest that the screening for the FVL and FII G20210A mutations is useful in the setting of unexplained early and late pregnancy loss. Further studies are necessary in order to clarify the real impact of prothrombotic molecular defects on the pregnancy outcome and then to evaluate the appropriate therapeutic approach.     

Risk of thrombophilia in carriers of thrombophilic genetic factors in unsuccessful assisted reproduction

The aim of this study was to evaluate an association of carrier status of common inherited thrombophilic genetic mutations and implantation failure after assisted reproduction (ART): IVF and ICSI. Sixty seven women with failure of embryo implantation and ninety six controls--women without obstetric complication were investigated for carriage of factor V Leiden (FVL), G20210A prothrombin gene mutation, genetic variant C677T in methylentetrahydrofolate reductase gene (MTHFR) and polymorphism A2 in platelet glycoprotein IIb/IIIa (GIPr IIb/IIIa). A significantly higher prevalence of polymorphism A2 in GIPr IIb/IIIa was found in women with implantation failure in ART compared to controls (respectively 26.1% and 12.5%; OR: 2.571, 95% CI: 1.066-6.258, p = 0.033). A higher but not significant prevalence of G20210A prothrombin gene mutation carriage was found inpatients compared to controls (respectively 5.8% and 3.13%, OR: 1.968, 95% CI 0.356-11.539). The carriage of FVL was a little but not significantly higher in controls. The carriage of genetic variant C677T in MTHFR was the same in both groups. These data suggest that polymorphism A2 in GIPr IIb/IIIa and G20210A prothrombin gene mutation could be play a role in the etiology of IVF failures and the carriers of GIPr IIb/IIIa A1/A2 and G20210A prothrombin gene mutation are at higher risk of implantation failure and not successful ART outcome. The carriage of these two genetic defects should be investigated in women undergoing IVF and the antithrombotic or anticoagulant prophylaxis should be indicated for carriers of these two factors.     

The investigation of hereditary and acquired thrombophilia risk factors in the development of complications in pregnancy in Croatian women

Objectives: To investigate the genetic and acquired thrombophilic risk factors in pregnancy-associated complications and venous thromboembolism (VTE) and evaluate the association between particular thrombophilic risk factors and thromboembolic complications.

Methods: In this study, pregnant women with pregnancy complications and VTE (N?=?101) were the study group, and the control group were women with normal pregnancy (N?=?102). All women underwent testing for factor V Leiden mutation (FVL), mutation of the coagulation factors II (FII20210), methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor-1, antithrombin III (ATIII), protein C (PC) and protein S, lupus anticoagulant (LAC) antibodies, anticardiolipin antibodies and anti-beta-2-glycoprotein-1.

Results: In this study group, mutations of the FVL was 15.8% (16/101), FII20210 5.9% (6/101) and the MTHFR at locus 677 was TT in 19.8% (20/101). Deficiency of ATIII and PC were rare: 3.0% and 1.0%, respectively. LAC were significantly higher in the study group than in the control group: 32.7% versus 3.9%; p?<?0.0005. Pregnant women with VTE have been more frequent for FVL (41.7%; p?<?0.005), PC deficiency (25.0%; p?<?0.005) and LAC (33.3%; p?<?0.005). Combination of FVL and MTHFR mutation was related to the risk of recurrent fetal death and habitual abortion.

Conclusion: The inherited and the acquired thrombophilic risk factors were found to be up to 10 times more common in the study group than in the control group.     

Inherited thrombophilias in pregnant patients: detection and treatment paradigm

Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with an increased risk of certain adverse pregnancy outcomes including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events and those with these characteristic adverse pregnancy events should be evaluated for thrombophilias. The most common, clinically significant, inherited thrombophilias are heterozygosity for the factor V Leiden and prothrombin G20210A mutations. The autosomal-dominant deficiencies of protein C and protein S are of comparable thrombogenic potential but are far less common. Homozygosity for the 4G/4G mutation in the type-1 plasminogen activator inhibitor gene and the thermolabile variant of the methylenetetrahydrofolate reductase gene, the leading cause of hyperhomocysteinemia, although relatively common, confer a low risk of thrombosis. In contrast, autosomal-dominant antithrombin deficiency and homozygosity or compound heterozygosity (ie, carriers of one copy of each mutant allele) for the factor V and prothrombin mutations are very rare but highly thrombogenic states. Regardless of their antecedent histories, pregnant patients with these highly thrombogenic conditions are at very high risk for both thromboembolism and characteristic adverse pregnancy outcomes, require full therapeutic heparin therapy throughout pregnancy, and need at least 6 weeks of postpartum oral anticoagulation. There is also compelling evidence that patients with the less thrombogenic thrombophilias and a history of venous thrombotic events or characteristic adverse pregnancy outcomes require prophylactic anticoagulant therapy during pregnancy and, in the case of prior thromboembolism, during the puerperium. Antepartum anticoagulation does not appear warranted among patients with less thrombogenic thrombophilias who are without a history of venous thromboembolism, characteristic adverse pregnancy outcomes, or other high risk factors for venous thrombosis.     

Umbilical artery Doppler in relation to placental pathology and FV Leiden in pregnant women and their offspring

Abstract

Objective: Abnormal umbilical artery blood flow has been implicated in pregnancy complications and fetal demise. Its relation to histopathological changes in the placenta and to maternal or fetal thrombophilia is less well understood. The aim of this study was to evaluate the relation between umbilical artery Doppler findings, placental histopathology, and maternal and fetal coagulation factor V Leiden (FVL) status.

Methods: Two previous studies on FVL in pregnancy made the placentas of 25 women with maternal FVL carriership and 43 randomly selected non-carriers available for a histopathological examination. Umbilical artery Doppler velocimetry was performed on 54 women in late pregnancy.

Results: Abnormal umbilical artery Doppler velocimetry was associated with an approximately sevenfold increased risk of fetoplacental thrombotic vasculopathy (odds ratio [OR]: 7.5, 95% confidence intervals [CI]: 1.3–44.3), ischemic lesions (OR: 7.5, 95% CI: 1.2–46.1) and fetal carriership of FVL (OR: 8.2, 95% CI: 1.5–43.5), but not maternal FVL. Fetal FVL carriership was also associated with a sevenfold increased risk of ischemic lesions (OR: 6.7, 95% CI: 1.3–35).

Conclusions: Our results indicate that the fetal – not the maternal – FVL carriership matters regarding the umbilical artery blood flow and placental pathology, which might explain some of the heterogeneity of studies.     

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.     

Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?

BACKGROUND: Major concern was raised by an earlier study regarding oral contraceptive use in women with the factor V Leiden mutation. A more than 30-fold increase in relative risk for venous thromboembolism was reported; for homozygotes, the relative risk was as much as 100-fold or more. OBJECTIVE: To replicate the reported risk estimates with a new population-based case-control study. METHODS: Eighty women with a diagnosis of venous thromboembolism were consecutively identified and compared with population-based controls (n = 406). Factor V Leiden mutation was identified by genotype analysis. The evaluation was performed with conditional logistic regression (matched for 5-year age group). RESULTS: Matched, adjusted odds ratios (OR) for idiopathic venous thromboembolism in women without and with the factor V Leiden mutation who used oral contraceptives were 4.1 (95% confidence interval (CI) 2.1-7.8) and 10.2 (95% CI 1.2-88.4), respectively. The adjusted OR for factor V Leiden carriers was 2.0 (95% CI 1.0-4.4). The OR for women with the factor V Leiden mutation and oral contraceptive use versus no factor V Leiden mutation and no oral contraceptive use was 10.2 (95% CI 3.8-27.6). CONCLUSION: The results confirm the increased relative risk of idiopathic venous thromboembolism for users of oral contraceptives and factor V Leiden carriers. However, we suspect that the true risk for women who are factor V Leiden carriers may be increased two- to four-fold rather than seven-fold or more, and that the risk for the combination of factor V Leiden and oral contraceptive use may be increased in the order often- to 15-fold rather than over 30-fold.     

Frequency of selected thrombophilias in women with placental abruption

OBJECTIVE: There is a growing view that inherited or acquired thrombophilia may predispose a woman towards an adverse pregnancy outcome. The aim of this study was to investigate whether risk factors for placental abruption because of such thrombophilias (such as carriership of factor V Leiden (FVL), prothrombin G20210A gene mutation and homozygous MTHFR C677T) might be used as a predictor for placental abruption. METHODS: A retrospective case-control study conducted at the University Hospital, Palacky University, Olomouc, Czech Republic. One hundred and eighty women with placental abruption out of 20,175 deliveries (0.79%) were compared to 196 unselected gravidae. A detailed medical history was taken with special reference to factors related to hypercoagulation and blood was drawn for polymerase chain reaction analysis. The prevalence of FVL, prothrombin G20210A and MTHFR C677T was related to placental abruption. RESULTS: The heterozygous form of FVL was present in 20of 142 cases (14.1%) in the placental abruption group, compared to ten of 196 (5.1%) in the control group (odds ratio 3.0, 95% confidence interval 1.4-6.7). CONCLUSIONS: We found that factor V Leiden is a significant risk factor for placental abruption.     

Antithrombotic therapy and pregnancy: consensus report and recommendations for prevention and treatment of venous thromboembolism and adverse pregnancy outcomes

Venous thromboembolism and adverse pregnancy outcomes are potential complications of pregnancy. Numerous studies have evaluated both the risk factors for and the prevention and management of these outcomes in pregnant patients. This consensus group was convened to provide concise recommendations, based on the currently available literature, regarding the use of antithrombotic therapy in pregnant patients at risk for venous thromboembolic events and adverse pregnancy outcomes.     

Factor V Leiden mutation: the most commonly inherited risk factor for venous thromboembolism

Factor V Leiden mutation is a common genetic risk factor for venous thrombosis. It has been documented in up to 65% of patients with unexplained venous thromboembolism. This genetic mutation is now known to be the most common inherited cause of activated protein C (APC) resistance. Recently, FV Leiden mutation has been associated with adverse pregnancy outcomes (including recurrent fetal loss, severe preeclampsia, placental abruption, intrauterine growth restriction and stillbirth), in addition to venous thromboembolic disorders. In this article, we discuss the genetic basis, diagnosis and clinical significance of FV Leiden mutation. Awareness of the clinical manifestations associated with FV Leiden mutation should ensure screening of appropriate populations and prophylaxis against thromboembolic disease when indicated.     

Factor V Leiden as a risk factor for miscarriage and reduced fertility

The Leiden mutation is a recent discovery. It is the main cause of inherited thrombophilia and has been found in 20-60% of deep vein thrombosis cases. More recently it has been found in a significant number of cases of obstetric complications attributable to placental thrombosis. Current patient management practice for dealing with the Leiden mutation is based mainly on information about deep vein thrombosis because there is little information on pregnancy complications. There are no prospective studies examining the risk of developing pregnancy complications for Leiden mutation carriers. The aim of this study is to do that by comparing the frequency of unfavourable pregnancy outcomes among carriers with those among controls. The number of women developing miscarriages, intrauterine deaths, or infertility problems among 128 Leiden mutation carriers was compared with the number among 461 controls. The risk of having at least one miscarriage or infertility problems was 1.5 times greater for Leiden mutation carriers than controls. This result was statistically significant (95% CI 1.2, 2.7). The risk of having at least two miscarriages or infertility problems was 2.5 times greater for Leiden mutation carriers than controls. This was also statistically significant (95% CI 1.2, 5.13).     

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.     

Two successful pregnancies following eight miscarriages in a patient with antithrombin deficiency

Inherited thrombophilias are associated with an increased risk of maternal thromboembolism and certain adverse pregnancy outcomes, including second- and third-trimester fetal loss, placental abruption, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Pregnant patients with severe thrombophilias, especially antithrombinopathies are at very high risk for both thromboembolism and adverse pregnancy outcomes. A case of a patient with antithrombin deficiency is reported, who had two successful pregnancies after eight miscarriages. Our case shows that a combined treatment with antithrombin substitution and a prophylactic, body-weight-adjusted dose of low-molecular-weight heparin may be successful in preventing pregnancy loss and thromboembolism in antithrombin deficiency during pregnancy, although other complications, such as preeclampsia and intrauterine growth restriction cannot always be prevented.     

Anticoagulants

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Sample bias among women with retained DNA samples for future genetic studies

OBJECTIVE: To evaluate whether women who agree to future use of their biologic specimens for genetic studies reflect the larger study population from which they are derived. METHODS: Women were questioned as to the future disposition of their maternal and fetal DNA samples upon enrollment in a multicenter, observational study originally designed to identify factor V Leiden mutation carriers and prospectively ascertain the estimated rate of pregnancy-related venous thromboembolism and adverse pregnancy outcome. Univariate and multivariate analyses was carried out on the 5,003 of 5,188 enrolled women who indicated their desire regarding future disposition of their DNA samples. RESULTS: Among these 5,003 women, 20.1% desired that their samples be discarded and not available for future genetic studies. Multivariate analysis demonstrated that women who agreed to subsequent use of samples were less likely African-American (odds ratio [OR] 0.6, 95% confidence interval [CI] 0.4-0.7) or Hispanic (OR 0.4, 95% CI 0.3-0.5), and more likely to use tobacco (OR 1.2, 95% CI 1.0-1.6) than those who desired that their samples be discarded. CONCLUSION: Genetic samples from women agreeing to their use in a sample repository may not be representative of the index study cohort. This should be considered in their subsequent interpretation and generalizability. LEVEL OF EVIDENCE: III.     

Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units

OBJECTIVES: This study was undertaken to determine the frequencies of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes. STUDY DESIGN: This was a prospective observation of pregnancy outcomes among 462 women with pregestational diabetes mellitus (White classes B-F) and singleton pregnancies who were enrolled in a multicenter trial to compare low-dose aspirin with placebo for preeclampsia prevention. The main outcome measures were preeclampsia and neonatal outcomes. RESULTS: Among 462 women with pregestational diabetes, 92 (20%) had preeclampsia. Preeclampsia frequency rose significantly with increasing severity of diabetes according to White classification (class B, 11%; class C, 22%; class D, 21%; class R plus class F, 36%; P <.0001). Preeclampsia was also more common among women who had proteinuria at baseline (28% vs 18%; odds ratio, 1.75; 95% confidence interval, 1.02-3.01). Frequency of preterm delivery at <35 weeks' gestation rose greatly with increasing severity of diabetes (P =.0002). Women with proteinuria at baseline were significantly more likely to be delivered at <35 weeks' gestation (29% vs 13%; odds ratio, 2.6; 95% confidence interval, 1.5-4.6) and to have small-for-gestational-age infants (14% vs 3%; odds ratio, 5. 4; 95% confidence interval, 2.7-17.7), and they were less likely to have large-for-gestational-age infants (14% vs 40%; odds ratio, 0.2; 95% confidence interval, 0.1-0.5). CONCLUSION: Among women with pregestational diabetes mellitus, the frequency of preeclampsia rose with increasing severity of diabetes. Proteinuria early in pregnancy was associated with marked increases in adverse neonatal outcomes independent of preeclampsia development.