Analyzes of three common thrombophilic gene mutations in German women with recurrent abortions

BACKGROUND: Several etiological factors have been proposed as a cause for recurrent fetal abortions. Changes in blood coagulation during pregnancy may play an important role in the occurrence of recurrent abortions (RA). METHODS: The aim of this study was to investigate the prevalence of factor V Leiden, factor II prothrombin, and methylenetetrahydrofolate reductase (MTHFR) mutations in women with recurrent abortions (> or =2 abortions) in the German population. The mean number of abortions was 3 (range 2-8). RESULTS: Frequencies of the factor V Leiden mutation and the prothrombin G20210A mutation were equally high in the patient group compared with our control group (for factor V Leiden: 11/101 vs. 9/122; p-value: 0.348; for prothrombin G20210A: 2/101 vs. 3/122; p-value: 0.81). Moreover, in both the patient and control groups, 15 of the women were homozygous for the MTHFR C677T allele (15/101 vs. 15/122; p-value: 0.635). The occurrence of FV Leiden, FII and MTHFR mutations was not significantly increased in the patient group compared with our control group. CONCLUSION: The results of the present study reveal no relationship between these common three thrombophilic mutations and recurrent abortions for the German population, and further studies are essentially recommended on whether a thrombophilia evaluation should be performed in patients with recurrent abortions.     

高龄妊娠宫内死胎原因分析

目的探讨高龄妊娠孕妇发生宫内死胎的原因。 方法本研究采用回顾性研究方法对2009年1月1日至2014年12月31日因宫内死胎(单胎)在广州医科大学附属第三医院妇产科住院治疗的339例患者临床资料进行分析,根据孕妇分娩年龄分为高龄组(≥35岁)和非高龄组(20～34岁),比较两组孕妇宫内死胎的原因。采用独立样本t检验、χ²检验或Fisher精确概率法对数据进行统计学分析。 结果高龄妊娠宫内死胎率为1.66%(61/3 670)比非高龄组1.10%(278/25 227)高,χ²＝8.670,P＝0.003;两组宫内死胎各种病因发生率的比较,差异均无统计学意义(P均>0.05);高龄组不明原因宫内死胎发生率27.87%(17/61)明显比非高龄组7.55%(21/278)高,χ²＝20.74,P＝0.000)。 结论高龄妊娠孕妇发生宫内死胎风险比非高龄者高,需加强对高龄妊娠人群孕期母胎监测。     

Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody

Effects of therapy, antibody titer, and pregnancy history on pregnancy outcome were evaluated in pregnancies of women with antiphospholipid antibody. Prior fetal death and a high antiphospholipid antibody titer (greater than 40 IgG phospholipid units) contributed independently, in an additive manner, to current fetal loss. Twenty-one pregnancies occurred in asymptomatic women who had both prior fetal death and a high IgG antiphospholipid antibody titer. In this very high-risk group, 9 of 11 (82%) of pregnancies treated with prednisone, 10 to 60 mg/day, ended in fetal death, compared with 5 of 10 (50%) not treated with prednisone (p approximately 0.01, life-table analysis). Of pregnancies treated with aspirin, 80 mg/day, 9 of 14 (64%) treated and 5 of 7 (71%) not treated with prednisone had a fetal death (difference not significant). Prednisone does not improve, and may worsen, current fetal outcome in asymptomatic pregnant women with a high antiphospholipid antibody titer and prior fetal death.     

Thrombophilia and antithrombotic therapy in women with recurrent spontaneous abortions

OBJECTIVE: To investigate the association between thrombophilia and recurrent spontaneous abortions (RSAs) and to evaluate the efficacy of anticoagulant treatment. STUDY DESIGN: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. RESULTS: All couples with a history of RSAs were studied by immunologic tests and determination of coagulation factors. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy were used in 29 selected cases with acquired and inherited thrombophilia. The control group included 23 women with a history of RSAs and tests positive for thrombophilia who declined to receive medication during pregnancy. CONCLUSION: All couples with RSAs require screening for thrombophilia. Low-molecular-weight heparin and low-dose aspirin daily during pregnancy appear to have a favorable effect on pregnancy outcome in selected women with RSAs and acquired or inherited thrombophilia.     

Labor induction in intrauterine fetal death

The particulars of 78 patients with fetal demise of the last 14 years were evaluated retrospectively. The most important reason of fetal death was hypoxaemia or anoxaemia. 31 patients were delivered by cesarean section or had spontaneous uterine contractions. Induction of 47 abortions were started with oxytocin or prostaglandins. Within 12 hours 54% of the oxytocin and 67% of the prostaglandin group succeeded in spontaneous delivery. In both groups there were 5 management failure of therapy, so that alternative medication or a cesarean section lead to delivery.     

Lymphocyte immunization generates immunosuppressive factors in women with recurrent abortions

Women with recurrent spontaneous abortions of unknown etiology were treated with injection of their partner's lymphocytes. The effect of lymphocyte immunization is evaluated by various immunological tests. The results demonstrate the appearance of immunosuppressive factors, especially P4 protein, present in normal pregnancy, which inhibits cellular cytotoxicity.     

Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death

OBJECTIVE: Genetic polymorphisms associated with vascular diseases have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). The Nos3 gene is known to regulate vascular tone via the endothelial nitric oxide synthase/nitric oxide pathway. STUDY DESIGN: In a multicenter case-control study, we evaluated two Nos3 polymorphisms (exon 7 Glu298Asp and a 27bp-repeat in intron 4) in 92 women with IUFD and 92 healthy control women. RESULTS: The investigated Nos3 polymorphisms were not associated with the occurrence of IUFD. In the subgroup of pregnancies affected by IUFD, women with at least one mutant allele of the Nos3 intron 4 polymorphism were diagnosed with IUFD at a significantly earlier gestational age (31.8 [standard deviation (S.D.) = 4.9] weeks versus 34.6 [S.D. = 4.8] weeks, p = 0.02) and showed a significantly reduced birth weight (2113 g [S.D. = 1028] versus 1571 g [S.D. = 568], p = 0.03). CONCLUSION: We are the first to report on Nos3 polymorphisms and IUFD. While not being associated with the incidence of IUFD overall, the intron 4 Nos3 polymorphism might modulate the timing of IUFD in affected pregnancies.     

Prenatal diagnosis of ALPL gene mutations in recurrent fetal skeletal dysplasia

ObjectiveOne multiparity women had recurrent pregnancies of skeletal dysplasia. The karyotype and array-comparative genomic hybridization were unremarkable. Thus, trio whole exome sequencings were suggested.Case reportThe ALPL gene mutations were identified. Maternal heterozygous deletion on Chr1: 21880592 (GRCh37) TA->T, paternal heterozygous insertion on Chr1 21894597, 21894598 (GRCh37) G->GC, T->TAA, and the compound heterozygous mutation were noted on her third pregnancy. The prenatal ultrasound findings and ALPL variants were compatible with the diagnosis of hypophosphatasia. Sanger sequencings were performed and found their normal phenotype daughter carried the same heterozygous mutation with her mother. The mother was then incidentally found her fourth pregnancy; unfortunately, the fetus was prenatally diagnosed of hypophosphatasia with the compound heterozygous mutations.ConclusionThe whole exome sequencing could assist to find the disease-causing variants, which may not be identified through routine prenatal diagnosis. With the precise diagnosis, we could provide the counseling for prenatal or pre-implantation diagnosis.     

Sex differences of abortuses and neonates in women with allo-immune recurrent abortions

To investigate the possible association of recurrent spontaneous abortions (RSA) of immune aetiologies with neonatal sex differences, karyotyping of abortuses from allo-immune RSA and epidemiological studies on the sex differences of neonates from sporadic aborters was carried out. Allo-immune disorders, as diagnosed by an increased number of shared HLA class II loci and reduced blocking activity of the woman's serum in mixed lymphocyte reaction, were found almost twice (54.9%) as often as auto-immune disorders (29.9%) among a total of 244 women with RSA. Of 33 abortuses karyotyped from women with RSA, 69.7% showed normal female karyotypes, while only 6.1% had normal male karyotypes, indicating that female fetuses are more prone to abort than males. Epidemiological studies revealed that boys were born at a significantly greater incidence of 58.1% in 221 women with a history of sporadic abortion than 47.6% in 893 women with no history of abortion. Moreover, the proportion of women giving birth to boys only was consistently and significantly higher, regardless of repeated deliveries, in sporadic aborters (36.7%) than in women with no history of abortion (19.6%), showing that more boys were born than girls to women with sporadic abortion. It is concluded that male fetuses are more likely to survive than females in allo-immune RSA due to allo-immune reproductive wastage of chromosomally normal female concept in early human pregnancy, and that allo-immune RSA makes up the highest proportion of unexplained RSA.     

Combined thrombophilic factors among women with late recurrent spontaneous abortions

The aim of this study was to assess the role of combined thrombophilic factors carrier status for development of late recurrent pregnancy loss (RPL). The polymorphism 4G/5G (PL 4G/5G) - genotype 4G/4G in plasminogen activator inhibitor type 1 (PAI-1), Factor V Leiden (FVL) and prothrombin (FII) gene mutation 20210 G>A in 52 women with recurrent pregnancy loss between 10 and 20 weeks of gestation and in 125 healthy women with at least one uncomplicated full-term pregnancy was investigated. Combined carrier status for thrombophilic factors was more pronounce among women with RPL (7.7%) compared to control subjects (3.2%), (OR=2.52, 95% CI (0.5- 12.62), p-ns). The most common association was between FVL and PL 4G/5G (5.8% compared to 0.8% in patients and controls, OR=7.59, 95% CI (0.68 - 191.04), p-ns). Because of relatively small size of the study, the difference in carrier status between women with RPL and control subjects did not rich statistical significance. A weak association between double carrier status for inherited thrombophilic factors and RPL was established. The strong determination in larger studies of the relation between combined inherited thrombophilic status and RPL development could better specify anticoagulant prophylaxis in further pregnancy     

Coagulopathy associated with dilatation and evacuation for intrauterine fetal death

Dilatation and evacuation was reported recently to be a safe and effective method for the treatment of intrauterine fetal death. The current authors have treated ten cases of intrauterine fetal death with dilatation and evacuation. Five patients (50%) developed coagulopathy, one of whom also developed endometritis. Patients who developed coagulopathy were significantly older than those who did not. Previous pregnancy also was associated with the development of coagulopathy. Five of six multigravidas developed coagulopathy, whereas none of the four primigravidas developed this complication. Other factors that may have contributed to the development of coagulopathy are discussed. The authors conclude that dilatation and evacuation for midtrimester intrauterine fetal death may not be as safe as has been reported.     

Restricted fetal growth in sudden intrauterine unexplained death

BACKGROUND: Unexplained antepartum stillbirth is a common cause of perinatal death, and identifying the fetus at risk is a challenge for obstetric practice. Intrauterine growth restriction (IUGR) is associated with a variety of adverse perinatal outcomes, but reports on its impact on unexplained stillbirths by population-based birthweight standards have been varying, including both unexplained and unexplored stillbirths. AIM: We have studied IUGR, assessed by individually adjusted fetal weight standards, in antepartum deaths that remained unexplained despite thorough postmortem investigations. METHODS: Antenatal health cards from a complete population-based 10-year material of 76 validated sudden intrauterine unexplained deaths were compared to those of 582 randomly selected liveborn controls. Birthweight <10th percentile of the individualized standard adjusted for gestational age, maternal height, weight, parity, ethnicity, and fetal gender was defined as growth restriction. RESULTS: 52% of unexplained stillbirths were growth restricted, with a mean gestational age at death of 35.1 weeks. Suboptimal growth was the most important fetal determinant for sudden intrauterine unexplained death (odds ratio 7.0, 95% confidence interval 3.3-15.1). Concurrent maternal overweight or obesity, high age, and low education further increase the risk. Overweight and obesity increase the risk irrespective of fetal growth, and while high maternal age increases the risk of the normal weight fetus, it is not associated to growth restriction as a precursor of sudden intrauterine unexplained death. CONCLUSIONS: IUGR is an important risk factor of sudden intrauterine unexplained death, and this should be excluded in pregnancies with any other risk factor for sudden intrauterine unexplained death.     

Adenosine deaminase activity and its isoenzyme pattern in women with recurrent spontaneous abortions

Normal pregnancy is characterized by suppressed cell-mediated immunity. Adenosine deaminase (ADA) is a purine metabolic enzyme enriched in trophoblast cells of the placenta. It is an early marker of trophoblast cell differentiation. Also, the activation of ADA gene expression in the placenta is crucial and essential for proper fetal development. The activity of ADA shows changes in diseases characterized by the alteration of cell-mediated immunity. The purpose of this study was to assess the possible role of the alteration of cell-mediated immunity in women with recurrent spontaneous abortions (RSA) as a cause of changes in tADA activity, and also to evaluate the extent of the contribution of ADA1 and ADA2 to changes of tADA activity in serum and peripheral blood lymphocytes (PBLs). We measured in serum and in PBLs activities of tADA, ADA1 and ADA2 of 25 married women with RSA (group A) and of 28 healthy non-pregnant women (group B). According to our results in women with RSA, mean serum tADA, ADA1 and ADA2 activities were significantly higher than those of non-pregnant women (p < 0.001, p < 0.05 and p < 0.05 respectively). In women with RSA, mean PBLs tADA, ADA1 and ADA2 activities were significantly higher than those of non-pregnant women (p < 0.001, p < 0.05 and p < 0.05 respectively). The findings of this study show a marked increase of serum and PBLs ADA activities, which is derived from an increase of ADA2 and ADA1 activity in women with RSA. These changes reflect cell-mediated immunological changes.     

双胎之一胎死宫内的诊治

随着促排卵技术和辅助生殖技术的发展，多胎妊娠发生率逐年增多。与单胎妊娠相比，多胎妊娠围产儿病死率更高。双胎之一胎死宫内属于双胎妊娠的严重并发症，一胎死亡后会对存活胎儿有潜在、长期的影响，可引起存活胎儿死亡、神经系统损伤、早产及相关后遗症等，因此，孕期应加强母儿监护。及时诊断和处理是改善围产儿结局的关键。     

Mechanism of recurrent spontaneous abortions in women with mosaicism of X-chromosome aneuploidies

OBJECTIVE: To investigate the mechanism of recurrent miscarriages in women with mosaicism of X-chromosome aneuploidies. DESIGN: Prospective case-control study. SETTING: University-based reproductive clinic housed in a medical center with genetic laboratories. PATIENT(S): Eighteen women who experienced recurrent miscarriages and had mosaicism of X-chromosome aneuploidies; two control groups, one with a balanced structural autosomal rearrangement and the other without chromosomal abnormalities. INTERVENTION(S): Criteria were established for the diagnosis of low-grade X-chromosome mosaicism by using peripheral blood lymphocytes. Patients were evaluated for the pathogenesis of recurrent miscarriages. Their abortion rate was assessed, and each abortus was karyotyped. MAIN OUTCOME MEASURE(S): Abortion rate and karyotype of the abortus. RESULT(S): In comparison with patients with X-chromosome mosaicism with a balanced structural autosomal rearrangement, patients with X-chromosome mosaicism without a balanced autosomal structural rearrangement had a significantly higher incidence of diminished ovarian reserve (DOR) and had a somewhat higher prevalence of uterine anomalies. In comparison with controls without chromosomal abnormalities, the patients with a balanced autosomal structural rearrangement also had higher incidence of both conditions, but the differences were not statistically significant. At least two factors are implicated in recurrent miscarriages in women with X-chromosome mosaicism. Among them, DOR is the most prevalent (occurring in 44.4% of cases), followed by uterine anomalies (16.7% of cases). Cases with DOR had a higher abortion rate than did those without (68.6% vs. 44.1%). Cases with DOR also had a slightly higher rate of abnormal karyotypes in the abortus than did those without (73.7% vs. 42.9%). CONCLUSION(S): The oocytes of women with X-chromosome mosaicism are in a suboptimal state of development and are prone to embryonic lethality.     

A piece in the puzzle of intrauterine fetal death: Pathological findings in placentas from term and preterm intrauterine fetal death pregnancies

Objective.?To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine fetal death (IUFD).

Study design.?A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was made between placentas from term and preterm (<37 weeks' gestation) pregnancies complicated by IUFD. A second analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks' gestation. Uteroplacental insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor vascularity of the chorionic villi, intravascular thrombi and vascular occlusion.

Results.?During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were noted. When comparing gross and microscopic findings in term and preterm (<37 weeks) IUFD placentas, higher rates of calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks' gestation, higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks. Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third of both term and preterm placentas demonstrated histological chorioamionitis.

Conclusions.?A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.