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.     

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.     

Recurrent Miscarriage - Outcome After Supportive Care in Early Pregnancy

One hundred and thirty three couples were investigated at a recurrent miscarriage clinic. In their next pregnancy 42 women (Group 1) with unexplained recurrent miscarriage were managed with a programme of formal emotional support and close supervision at an early pregnancy clinic. Two women were seen in 2 pregnancies (44 supervised pregnancies); 86% (38 of 44) of these pregnancies were successful. Four of the 6 miscarriages had an identifiable causal factor. Nine women (Group 2), also with unexplained recurrent miscarriage, acted as a control group. After initial investigation they were reassured and returned to the care of their family practitioner and did not receive formal supportive care in their subsequent pregnancy; 33% (3 of 9) of these pregnancies were successful (p = 0.005; Fishers Exact Test). Whilst acknowledging that there is a significant spontaneous cure rate in this condition, emotional support seems to be important in the prevention of unexplained recurrent miscarriage, giving results as good as any currently accepted therapy.     

Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women

Aim: Genetic thrombophilias are known to contribute to adverse pregnancy outcomes. Studies in Western populations show that 5, 10-methylenetetrahydrofolate reductase (MTHFR) 677C>T and Factor V (F5) 1691G>A (Leiden) polymorphisms are commonly associated with pre-eclampsia and recurrent spontaneous pregnancy loss. The objective of this study was to investigate the association of MTHFR 677C>T (rs1801133); 1298A>C (rs1801131) and F5 1691G>A (rs6025); 4070A>G (rs1800595) polymorphisms with pre-eclampsia and recurrent pregnancy loss among Sinhalese women in Sri Lanka. Material and Methods: Genotype and allele frequencies at each polymorphic site in the MTHFR and F5 genes and the haplotypes defined by them were determined in 175 Sinhalese women with pre-eclampsia, 171 normotensive controls, 200 Sinhalese women with two or more recurrent pregnancy losses and 200 controls with two or more living children and no pregnancy losses. Genotyping was done by polymerase chain reaction/restriction fragment length polymorphism. Odds ratios and χ(2) -testing were performed to compare genotype/haplotype frequencies at each polymorphic site for both cases and controls. Results: The genotype frequencies at each polymorphic site in the MTHFR 677C>T; 1298A>C; F5 1691G>A and 4070A>G genes and the haplotypes defined by them were not significantly associated with either pre-eclampsia or recurrent pregnancy loss. There was no significant association of genetic thrombophilia with either early or late pregnancy losses. Conclusions: The MTHFR and F5 polymorphisms and the haplotypes defined by them were not significantly associated with either pre-eclampsia or recurrent pregnancy loss in this group of Sinhalese women.     

Factor XII deficiency in women with recurrent miscarriage

Congenital thrombophilia is known to cause significant maternal complications, and possibly has an adverse effect on normal fetal development. The aim of this study was to assess the prevalence of factor XII (FXII) deficiency in women with a history of recurrent miscarriage. Two hundred and forty-one consecutive Japanese women with a history of two or more recurrent miscarriages were prospectively assessed for their etiology by conventional screening methods. Seven women were found to have reduced FXII activity (19. 2-46.1%) and prolonged activated partial thromboplastin time (33. 3-51.3 s). Of these 7 women, 6 had experienced early pregnancy losses, while 1 woman had experienced repeated mid-trimester fetal losses with coincidental gestational thrombocytopenia. In 241 women with a history of recurrent miscarriage, the prevalence of FXII deficiency was 2.9%.     

Habitueller Abort – genetische Ursachen

Genetic factors play an etiologic role in sporadic and recurrent miscarriage. Fetal chromosomal anomalies are the main cause of sporadic miscarriages, whereas in recurrent miscarriages, the rate of fetal chromosomal anomalies is inversely correlated to the number of miscarriages. An abnormal karyotype is present in 3–5% of women with a diagnosis of recurrent miscarriage and their partners. Specific polymorphisms are also associated with an increased risk for recurrent miscarriage. Genetic thrombophilia conferred by carrying the factor V Leiden polymorphism is of clinical relevance for women with recurrent miscarriage due to possible treatment with heparin. Another genetic factor associated with recurrent miscarriage is skewed X-chromosome inactivation, defined as a selective inactivation of paternal or maternal X chromosomes. In addition, androgenetic anomalies such as sperm aneuploidy and sperm DNA fragmentation have been described as etiologic factors in recurrent miscarriage.     

Recurrent early pregnancy loss and consanguinity

The present authors have studied the possible relationship between recurrent miscarriage and consanguinity in the Qatari population, where the prevalence of first cousin marriage is 47%. The maternal of three or more early pregnancy losses were compared with those of 92 non-consanguineous women from the same population and with the same obstetrical history, matched for maternal age. The retrospective investigation showed no difference in the rate of previous pregnancy loss and maternal disorders, including diabetes, thyroid dysfunction and immunity, abnormal uterine and ovarian anatomy or thrombophilia. There was also no evidence of familial clustering of recurrent miscarriage in both groups. The prospective study showed no difference in the rate of subsequent pregnancy loss and the median gestational age and fetal weight at delivery in ongoing pregnancies. The absence of a relationship between recurrent miscarriage and consanguinity in Qatar could be due to the particular characteristics of the native Qatari population, in which rare recessive genes are uncommon, or overall to the absence of an association between recurrent miscarriage and consanguinity.     

Risk factors associated with a new pregnancy loss and perinatal outcomes in cases of recurrent miscarriage treated with lymphocyte immunotherapy

Objective: To assess the perinatal outcomes and risk factors for further pregnancy loss in patients with recurrent miscarriage treated with lymphocyte immunotherapy (LIT).

Methods: We performed a retrospective observational study of women with a history of two or more consecutive miscarriages who underwent LIT. All patients had undergone investigation of the etiology of the pregnancy losses according to a specific protocol. These etiologic factors were compared between those whose pregnancy outcome was successful and those who had a further miscarriage. The comparison between the groups was performed by Kruskal–Wallis, Fisher exact and Chi-square tests. Perinatal outcome data were collected for the successful pregnancies.

Results: One-hundred six patients were included. The mean number (±SD) of previous pregnancies, deliveries and miscarriages in all patients were 2.73?±?0.8, 0.19?±?0.4 and 2.54?±?0.6, respectively. A successful pregnancy outcome after lymphocyte therapy occurred in 82 patients (group I), while 24 (22.6%) sustained a further miscarriage (group II). There was no statistical difference in the genetic, anatomic and hormonal causes of miscarriage between the groups (p?>?0.05). Antinuclear (ANA) and antithyroglobulin (TgAb) autoantibodies occurred more frequently in group II (p?=?0.0010 and p?=?0.0024, respectively). Of those with successful pregnancies, 11 women (13.4%) had a preterm delivery. The mean birth weight was 3036.4?±?498.6?g.

Conclusion: In patients with recurrent miscarriage treated with LIT, the presence of ANA and TgAb was a risk factor for further pregnancy loss. Perinatal outcomes in those whose pregnancies continued were favorable.     

The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation

Objective To observe the effect of thrombophylaxis on pregnancy in women with a history of unexplained recurrent pregnancy loss also carrying the factor V Leiden mutation.
Methods Between 1 January and 31 December 1996, activated protein C (APC) resistance and factor V Leiden mutation were prospectively measured in 56 nonpregnant women, with a history of two or more unexplained recurrent pregnancy losses. During the same study period, seven women carrying the factor V Leiden mutation conceived, and were subsequently followed throughout their pregnancy. Subcutaneous low molecular weight heparin (LMWH, enoxaparin, 40 mg/day) and oral low dose aspirin (100 mg/day) were administered throughout the pregnancies, starting at early first trimester. Ultrasound and Doppler umbilical and fetal middle cerebral arterial flow studies were performed in the second and third trimesters, and the course and outcome of the pregnancies were documented.
Results Activated protein C resistance and factor V Leiden were found in 20 (36%) and 12 (21%) women of the study, respectively. Five of the seven pregnancies occuring progressed uneventfully to term with normal fetal growth, normal Doppler flow studies and uneventful neonatal outcome. Two of the seven women had early missed abortions.
Conclusions Thrombophylaxis, beginning in early pregnancy, in women with unexplained recurrent pregnancy loss associated with factor V Leiden mutation, seems to be safe and allow normal fetal development and good neonatal outcome. To prove the efficacy of thrombophylaxis by LMWH and low dose aspirin in this setting prospective controlled studies seem to be justified.     

Outcome of pregnancy in women with hereditary thrombophilia.

OBJECTIVES: The aims of this study are to review the outcome of pregnancy in women with thrombophilia, and investigate the possible beneficial effect of heparin therapy in these women. METHODS: We reviewed the hospital records of 126 women who were referred to the high-risk obstetrical hematology clinic between June 1996 and December 1999. The placental histology and outcome of 39 pregnancies in 24 women with hereditary thrombophilia were studied, and pregnancies which were treated with heparin were compared with those without treatment. RESULTS: An adverse pregnancy outcome occurred in 54% of the pregnancies. All seven miscarriages (18%) occurred in pregnancies that were not treated with heparin. However, heparin treatment did not prevent the development of obstetric complications in later pregnancies (odds ratio=0.955, 95% C.I.=0.255-3.577, Fisher's exact test). Excluding miscarriages, 28% of the placentas had thrombotic lesions, and the pregnancies with placental thrombotic lesions were more likely to have complications than those pregnancies without placental abnormalities (P=0.023, C.I.=1.257-5.197, Fisher's exact test). CONCLUSIONS: Pregnancy complications in cases of hereditary thrombophilia may be related to placental abnormalities. Heparin therapy is likely to be useful in preventing miscarriage in cases of hereditary thrombophilia.     

The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage

OBJECTIVE:To investigate the association between the C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR), serum homocysteine levels, and idiopathic recurrent miscarriage in a Middle-European white population.METHODS:In a case control study, we investigated 133 women with a history of three or more consecutive pregnancy losses before 20 weeks' gestation and 74 healthy controls with at least two live births and no history of pregnancy loss. A DNA extraction and polymerase chain reaction followed by restriction fragment length polymorphism analysis were used to genotype women for the presence of the MTHFR C677T polymorphism. Serum homocysteine levels were assessed by a fluorescence polarization immunoassay.RESULTS:The MTHFR allele frequencies in women with idiopathic recurrent miscarriage and controls were 34.6% and 21.6%, respectively, for the T allele (mutant) and 65.4% and 78.4%, respectively, for the C allele (wild type) (P =.007, odds ratio 1.9, 95% confidence interval 1.2, 3.1). The MTHFR genotype frequencies in women with idiopathic recurrent miscarriage and controls were: 17.3% (T/T), 34.6% (C/T), 48.1% (C/C) and 5.4% (T/T), 32.4% (C/T), 62.2% (C/C), respectively (P =.03, odds ratio 3.7, 95% confidence interval 1.2, 11.8 [T/T versus C/T and C/C]). Serum concentrations of homocysteine were significantly higher in carriers of a MTHFR mutant allele compared with women with no mutant allele (mean 7.4 +/- 2.4 micromol/L [T/T + C/T] versus 6.5 +/- 2.6 micromol/L [C/C], P =.05).CONCLUSION:Carriage of the mutant allele of the MTHFR C677T polymorphism is associated with elevated serum levels of homocysteine and idiopathic recurrent miscarriage.     

Sperm DNA fragmentation is a novel biomarker for early pregnancy loss

Research questionSpontaneous pregnancy loss affects 10–15% of couples, with 1–2% suffering recurrent pregnancy loss and 50% of miscarriages remaining unexplained. Male genomic integrity is essential for healthy offspring, meaning sperm DNA quality may be important in maintaining a pregnancy. Does sperm DNA fragmentation measured by alkaline Comet assay act as a biomarker for early pregnancy loss?DesignSperm DNA fragmentation was measured by alkaline Comet test in 76 fertile donors and 217 men whose partners had recently experienced miscarriage. Couples were divided into five groups for analysis: one miscarriage after spontaneous conception; two or more miscarriages after spontaneous conception; one miscarriage after fertility treatment; two or more miscarriages after fertility treatment and biochemical pregnancy.ResultsReceiver operator characteristic curve analysis was used to determine ability of the average Comet score (ACS), low Comet score (LCS) and high Comet score (HCS) to diagnose miscarriage and develop clinical thresholds comparing men whose partners have miscarried with men with recently proven fertility. Male partners of women who had miscarried had higher sperm DNA damage (ACS 33.32 ± 0.57%) than fertile men (ACS 14.87 ± 0.66%; P < 0.001). Average Comet score, HCS and LCS all have promise as being highly predictive of sporadic and recurrent miscarriage using clinical thresholds from comparisons with fertile men's spermatozoa: receiver operating characteristic curve AUC for ACS ≥26%, 0.965; LCS ≤70%, 0.969; HCS ≥2%, 0.883; P <0.0001.ConclusionsSperm DNA damage measured by the alkaline Comet has promise as a robust biomarker for sporadic and recurrent miscarriage after spontaneous or assisted conception, and may provide novel diagnoses and guidance for future fertility pathways.     

孕前“极简式”腹腔镜下宫颈环扎术的临床应用

目的:探讨"极简式"腹腔镜下宫颈环扎术(simplified laparoscopic cervical cerclage,SLCC)预防既往经阴道宫颈环扎失败的女性中期流产、早产的效果,并评价手术安全性。方法:分析2010年12月—2015年8月首都医科大学附属复兴医院收治的153例有经阴道宫颈环扎术失败史,实施孕前SLCC的患者临床资料。患者术前孕中期流产平均次数为(2.7±1.2)次,孕周为13~27周,平均孕周(20.0±3.5)周。结果:153例SLCC患者手术顺利,平均手术时间(33.0±1.3)min,术中平均出血量(9.7±8.3)m L,无严重手术并发症。术后共117例患者妊娠,其中8例妊娠2次,总妊娠次数125次;其中包括20次早期流产,2次异位妊娠,1次葡萄胎;截至2015年8月,正在妊娠中19例,已知妊娠结局83例,活产率为96.4%(80/83),平均终止妊娠孕周为(37.2±2.2)周。结论:对于既往经阴道宫颈环扎失败的宫颈机能不全患者,SLCC是一种简单、安全、有效的治疗方法。     

亚甲基四氢叶酸还原酶、凝血因子V和凝血酶原基因多态性与原因不明复发性早期流产的关系

目的探讨亚甲基四氢叶酸还原酶（MTHFR）基因C677T突变、凝血因子V（FV）基因G1691A突变和凝血酶原（PT）基因G20210A突变与原因不明复发性早期流产（URESA）的关系。方法应用聚合酶链反应．限制性片段长度多态性（PCR-RFLP）技术分析112例URESA患者（病例组）和100例健康妇女（对照组）MTHFR、FV和PT3种基因多态性。结果（1）MTHFR基因的T／T基因型和T等位基因频率,病例组[分别为38．4％（43／112）和59．8％（134／224）]高于对照组[分别为18．0％（18／100）和43．0％（86／200）],两组分别比较,差异均有统计学意义（P＜0．01）。病例组与对照组比较,T／T基因型者发生URESA的相对风险增加（OR=2．8390,95％CI为1．5022～5．3661）。（2）病例组和对照组妇女Fv基因和PT基因均为G／G基因型（即正常带型）。结论MTHFR基因C677T位点多态性与URESA发病密切相关,T／T基因型是其发病的危险因素。FV和PT基因的突变率在中国妇女人群中极低。     

Estrogen receptor beta gene polymorphisms and risk of recurrent pregnancy loss: a case–control study

Abstract

Estrogen might play a key role in the maintenance of pregnancy. We investigated the role of the ER-β gene +1730?G/A, +1082?G/A, and CA repeat polymorphisms in Korean patients with recurrent pregnancy loss (RPL). Genotyping was performed using the TaqMan assay in 305 patients with at least two unexplained consecutive spontaneous miscarriages before 20 weeks of gestation and 299 controls. The genotype distributions of the ER-β gene +1082?G/A and +1730?G/A polymorphisms in the RPL group did not differ from those in the control group. When the analysis was restricted to patients with three or more consecutive spontaneous miscarriages, there were also no differences in the genotype distribution between this subgroup and controls. The number of CA repeats was distributed from 13 to 28 with two large peaks at 18 and 23 in patients with RPL and controls. Using the two major peaks as cut-offs, the allele distributions were compared between patients and controls. However, the distribution of ER-β gene CA repeats did not differ between women with recurrent miscarriage and controls. Findings of the current study suggest that the ER-β gene polymorphisms are not major determinants of the development of RPL in Korean women.     

Preimplantation genetic diagnosis significantly improves the pregnancy outcome of translocation carriers with a history of recurrent miscarriage and unsuccessful pregnancies

Preimplantation genetic diagnosis (PGD) for translocations has been shown to significantly reduce the risk of recurrent miscarriage, but because the majority of embryos produced are unbalanced, pregnancy rate is relatively low since 20% or more cycles have no normal or balanced embryos to transfer. The purpose of this study was to evaluate whether PGD could improve pregnancy outcome in translocation carriers with a history of two or more consecutive miscarriages and no live births. PGD for translocations was offered to translocation carriers with two or more previous miscarriages (average 3.5) and no live births (0/117 pregnancies) using a combination of distal and proximal probes to the breakpoints. After PGD, only 18.3% of embryos were normal or balanced. Only 5.3% of pregnancies were lost after PGD compared with 100% before PGD (P < 0.001). The cumulative pregnancy rate was 57.6% and the cumulative ongoing pregnancy rate was 54.5% in the short period of time of 1.24 IVF cycles, or 46.3% and 43.9% respectively per cycle. In conclusion, PGD significantly reduced losses and increased the number of viable pregnancies (P < 0.001). IVF plus PGD are a faster method of conceiving a live child than natural conception, at least for translocation carriers with recurrent miscarriages and no previous live births.     

Thyroid antibody titer and avidity in patients with recurrent miscarriage

OBJECTIVE: To determine whether the titer and avidity of the thyroid peroxidase antibody differs between pregnant women in their first trimester who have a history of recurrent miscarriage and whose pregnancies continue to term and those whose pregnancies fail again later in the first trimester. DESIGN: Controlled clinical study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Pregnant women in their first trimester who had a history of recurrent miscarriage (> or = 3 miscarriages) and who were known to be positive for the thyroid peroxidase antibody. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Thyroid peroxidase antibody titer and avidity (i.e., the net binding strength between antibody and antigen). RESULT(S): At the time of presentation, thyroid peroxidase antibody titer and avidity was significantly higher in those women who later miscarried compared with those whose pregnancies continued. In those whose pregnancies continued to term, titer and avidity declined as the pregnancy progressed. CONCLUSION(S): Autoimmunity plays a role in recurrent miscarriage. Among a group of patients who had had recurrent miscarriages, there appeared to be differences in the humoral response to the pregnancy between those whose pregnancies continued to term and those whose pregnancies failed again.     

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.     

Combined inherited thrombophilia and adverse pregnancy outcome

Inherited thrombophilia has been suggested as a possible condition of increased susceptibility to adverse pregnancy outcomes. In our prospective study, we investigated the association between combined inherited thrombophilia and adverse pregnancy outcome in the South-Western Greek population. Three hundred and ninety-six healthy Greek women with spontaneous pregnancies were investigated for combinations of the three commonest thrombophilic mutations (Factor II G20210A, Factor V Leiden and MTHFR C677T) and followed for adverse pregnancy outcomes. Statistical analysis was performed by Pearson's chi-square test. Four women (1%) had the FV Leiden/MTHFR T677T double genotype and two women (0.5%) had the FII G20210A/MTHFR T677T double genotype. Although the small number of cases of combined inherited thrombophilia, it seems that the presence of FV Leiden/MTHFR T677T double genotype increases the risk for placental abruption.