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.     

History of biochemical pregnancy was associated with the subsequent reproductive failure among women with recurrent spontaneous abortion

Abstract

The aim of this study was to evaluate whether the presence of history of biochemical pregnancy (BP) was associated with clinical characteristics and the subsequent pregnancy outcome among women with recurrent spontaneous abortion (RSA). One-hundred and seventy-five RSA women with two or more clinical pregnancy losses were enrolled. The clinical characteristics were compared between 164 women with history of 0–1?BP (Group A) and 11 women with two or more BP (Group B). The frequency of previous pregnancy loss and history of in vitro fertilization and embryo transfer in Group B was higher than that in Group A; while frequency of secondary RSA in Group B was lower than Group A. The subsequent pregnancy outcome was assessed prospectively; and live-birth rate in Group A (72.9%) was higher (p?<?0.05) than that in Group B (41.7%). The incidence of reproductive failure (58.3%, p?<?0.05) and spontaneous abortion with normal chromosome (25.0%, p?=?0.050) in Group B was higher than those (27.1 and 5.9%, respectively) in Group A. RSA women with two or more BP had higher risk of reproductive failure and spontaneous abortion with normal chromosome together with lower chance of live-birth. The results of the present study involve important information and are helpful for clinical practitioners.     

Live birth rate varies with gestational history and etiology in women experiencing recurrent spontaneous abortion

OBJECTIVES: The aims of this study were to assess pregnancy outcome in relation to etiologic factors of recurrent spontaneous abortion (RSA). STUDY DESIGN: The pregnancies from consecutive 216 RSA women were assessed for live birth rates (LBR) according to etiology. The LBR in 110 pregnancies from RSA women with unexplained etiology was investigated according to various therapies. An attempt to karyotype the abortuses was made. RESULTS: Excluding pregnancies ending in abortion with abnormal karyotype, the LBR in primary recurrent spontaneous aborters (68.8%) who experienced three or more abortions was significantly lower than that in primary repeated aborters (82.4%) who experienced two abortions. The LBR ranged from 50 to 100% according to the etiology. In RSA women with unexplained etiology, the LBR in those undergoing massive intravenous immunoglobulin (MIVIg) therapy (100%) was significantly higher than those with low dose aspirin (57.1%) and luteal support therapy (67.3%). CONCLUSIONS: Excluding pregnancies ending in abortion with abnormal karyotype, we found that LBR varied with abortion history and etiologic factors of RSA.     

监测反复自然流产者血清HCMVIgM抗体及其绒毛组织DNA的研究

采用酶联免疫吸附测定法（ＥＬＩＳＡ）对８５例反复自然流产（ＲＳＡ）妇女及１０７例无流产史早孕妇女的血清进行ＨＣＭＶＩｇＭ、ＨＣＭＶＩｇＧ检测，应用ＰＣＲ技术检测部分绒毛组织ＤＮＡ，直接法制备绒毛细胞染色体。结果显示：ＲＳＡ组ＨＣＭＶＩｇＭ阳性率（５８．８２％），明显高于对照组（１５．８９％）（Ｐ＜０．０１）。说明孕妇原发性ＨＣＭＶ感染与ＲＳＡ有相关性；ＨＣＭＶＩｇＭ阳性与流产次数有密切关系；ＨＣＭＶ可以通过胎盘屏障感染胎儿，导致流产     

Lymphocyte immunotherapy and its probable mechanism in the maintenance of pregnancy in women with recurrent spontaneous abortion

Introduction Most women with alloimmune cause of recurrent spontaneous abortion (RSA) includes increased sharing of human leukocyte antigens (HLA) that may prohibit the mother from making anti-paternal cyto-toxic antibodies (APCA), anti-idiotypic antibodies (Ab2) and mixed lymphocyte reaction blocking antibodies (MLR-Bf). Overactivity of T helper-1 (Th-1) cytokines and natural killer (NK) cells have been also reported to be the major alloimmune cause of recurrent spontaneous abortion (RSA). It was revealed from extensive updated analysis of this subject that paternal lymphocytes immunotherapy may play a significant role in the prevention of alloimmune cause of fetal loss in women with RSA. These alloimmune parameters are found to be suppressed in successful immunotherapy, which is comparable to normal pregnancy.Review and discussion Various studies represented that paternal lymphocyte immunotherapy was attributed to the high expression of APCA, Ab2, MLR-Bf and inhibition of Th-1 pattern of cytokines and NK cell activity in women with alloimmune cause of RSA. Present updated randomized clinical trials demonstrated that women with RSA of study group who have been treated with paternal lymphocyte immunotherapy had more successful outcomes (68%) as compared to women with RSA of control group who either received autologous lymphocytes/third party lymphocytes/normal saline or no therapy (54%), (p<0.02). However, when the results of the randomized and nonrandomized studies were pooled together it was observed that 67% of women with RSA of study group who received paternal lymphocyte immunotherapy showed successful pregnancy outcome in comparison to 36% success in women with RSA of control group who either received autologous lymphocytes/third party lymphocytes/normal saline or no therapy (p<0.05).Conclusion These results advocate the role of paternal lymphocyte immunotherapy for the maintenance of pregnancy in women with RSA.     

Polymorphisms in the fibrinolytic pathway genes and the risk of recurrent spontaneous abortion

Impaired fibrinolytic activity is implicated in the pathogenesis of recurrent spontaneous abortion (RSA). This case-control study assessed the prevalence of polymorphisms in fibrinolytic system genes in RSA. Cases comprised 202 Sinhalese women who had experienced at least two first-trimester spontaneous abortions and had no living children; controls were 202 women with no history of spontaneous abortion and two or more living children. The groups were matched for age and ethnicity. DNA was genotyped using the Sequenom MassARRAY system. The PLAUR rs4251923 A (OR 95% CI 2.3 [1.3 to 4.0]), SERBP2 rs6098 A (OR 95% CI 1.4 [1.1 to 1.9]) and SERBP2 rs6103 C alleles (OR 95% CI 1.4 [1.1 to 1.9]) were increased in the RSA group compared with controls. The prevalence of PLAUR rs4251923/ SERBP2 rs6098/ SERBP2 rs6103 GG/AA/CC (OR 95% CI 2.4 [1.2 to 4.9], GA/GA/GC(OR 95% CI 3.9 [1.3 to 11.2]), GA/AA/CC (OR 95% CI 2.9 [1.0 to 8.6] and GA/GG/GG (OR 95% CI 21.3 [1.1 to 410.3]) genotypes were also increased in cases. Polymorphisms in the fibrinolytic system genes are associated with RSA in Sinhalese women. These likely impair implantation.     

Clinical study on circulating antisperm antibodies in women with recurrent abortion

Couples with a history of recurrent spontaneous abortions (RSA) were analyzed for circulating antisperm antibodies (Ab) with an enzyme-linked immunosorbent assay (ELISA), a Franklin-Dukes (F-D) and a sperm immobilization test(SIT). The three tests were positive in 31.5%, 25.9% and 18.5% for wives and 24.1%, 11.1% and 7.4% for husbands in RSA couples. There was a statistical significance (P less than 0.01) as compared with the control group. The ELISA method was found to be most sensitive, and the positive rate of antisperm antibodies in wives was higher than that in husbands. The Ab titer of RSA group varied within 1:8 approximately 1:512, with 60% above 1:32. The pregnant weeks (P greater than 0.05) did not seem to affect the antisperm Ab titer, nor did the aborting frequency. Our study suggests that antisperm Ab is one of the important causes of RSA in women.     

甲状腺自身抗体与复发性流产关系的初步探讨

目的 研究抗甲状腺球蛋白抗体和抗甲状腺过氧化物酶抗体与复发性流产（RSA）之间的关系。方法 2004-08—2005—10选取山东省立医院妇产科门诊100例有复发性流产史非妊娠妇女为研究组，其中原发性RSA62例（原发性RSA组），继发性RSA38例（继发性RSA组），100例有正常妊娠史非孕健康妇女为对照组，化学发光免疫法测两组血清中的抗甲状腺抗体。结果 研究组血清中抗甲状腺球蛋白抗体和抗甲状腺过氧化物酶抗体的阳性率分别为：24％和28％，明显高于对照组的4％和6％（P〈0、05）。原发性与继发性RSA患者血清中抗体阳性率差异无显著性（P〉0、05）。结论 在复发性流产患者中，甲状腺自身抗体的阳性率增高，需进一步研究治疗后对妊娠结局的影响。     

Intrauterine development and MNSs blood groups in repeated spontaneous abortion.

OBJECTIVES: To determine whether the maternal MNSs genotype has an effect on the birth weight and gestation duration of the live offspring of women with repeated primary spontaneous abortion (RSA). METHODS: The study sample consisted of 239 healthy white women who had been delivered of a live infant, and 137 women with a history of primary RSA-54 of whom had recently been delivered of a live infant and 83 who had had a spontaneous abortion. Maternal MNSs phenotypes were determined by standard serological methods, and the results were analyzed for relationships between these phenotypes and the mothers' reproductive status and the infants' birth weight and gestational age. Analysis of variance, the chi(2)-test of independence, and the Mantel-Haenszel test for linear association were performed for data analysis. RESULTS: Infants born to mothers with the Ss genotype showed significantly lower birth weight and gestational duration compared with the infants of mothers with other genotypes. Additionally, the MNSs haplotype was found to be associated with birth weight. CONCLUSIONS: Previous studies have shown that the MNSs system influences the gestational age of aborted fetuses in cases of RSA. The present study supports the hypothesis that this genetic factor influences intrauterine growth and development in women experiencing RSA.     

HLA-C C1C2 heterozygosity may protect women bearing the killer immunoglobulin-like receptor AA genotype from spontaneous abortion

Spontaneous abortion is the most common complication of human pregnancy. Natural killer (NK) cells expressing killer immunoglobulin-like receptors (KIRs), which may recognize HLA-C (i.e. its C1 or C2 groups) on trophoblast cells, constitute a large leukocyte population in the endometrium. This study investigated whether genetic polymorphisms in the KIR and HLA-C genes are risk factors for spontaneous abortion. One hundred and twenty-five couples with at least two spontaneous abortions, including eighty-five couples with idiopathic recurrent abortion (RSA; three or more abortions), and 117 control couples (with two or more healthy-born children) were tested. The frequencies of the individual KIR genes in the patients were similar to those in the controls. In the group of KIR AA women with HLA-C C2C2 partners, the HLA-C C1C2 heterozygotes were present in the controls but not in the patients (p=0.015 for all patients and p=0.0048 for RSA, but both comparisons lost significance after Bonferroni correction), whereas both homozygotes, C1C1 and C2C2, were absent in the control women but present among the aborting ones. Therefore, our results suggest that among KIR AA women who have HLA-C C2C2 partners, HLA-C heterozygous females show a trend towards an increased chance of successful pregnancy.     

Hysteroscopic metroplasty improves gestational outcome in women with recurrent spontaneous abortion

STUDY OBJECTIVE: To compare the reproductive outcome in women with recurrent spontaneous abortion (RSA) associated with septate uterus after hysteroscopic metroplasty compared with patients who did not undergo surgery. DESIGN: Longitudinal evaluation (Canadian Task Force classification II-2). SETTING: University of Rome, Tor Vergata-affiliated endoscopic unit. PATIENTS: Forty-eight consecutive women with septate uterus and RSA were enrolled in the study. INTERVENTIONS: Hysteroscopic metroplasty. MEASUREMENTS AND MAIN RESULTS: Reproductive outcome in terms of term pregnancy was significantly improved after hysteroscopic metroplasty compared with controls (76% vs. 20%). No differences were found in the prevalence of preterm delivery between groups (4% vs. 5%). CONCLUSION: Our data suggest that hysteroscopic septum incision can improve pregnancy outcome in patients with RSA associated with septate uterus.     

Clinical implications of congenital uterine anomalies: a meta-analysis of comparative studies

The clinical implications of congenital uterine anomalies (CUA), and the benefits of hysteroscopic resection of a uterine septum, were evaluated. Studies comparing reproductive and obstetric outcome of patients with and without CUA and of patients who had and had not undergone hysteroscopic resection of a uterine septum, were evaluated. Meta-analysis of studies indicated that the pregnancy rate was decreased in women with CUA (RR 0.85, 95% CI 0.73 to 1.00; marginally significant finding, P = 0.05). The spontaneous abortion rate was increased in women with CUA (RR 1.68, 95% CI 1.31 to 2.15). Preterm delivery rates (RR 2.21, 95% CI 1.59 to 3.08), malpresentation at delivery (RR 4.75, 95% CI 3.29 to 6.84), low birth weight (RR 1.93, 95% CI 1.50 to 2.49) and perinatal mortality rates (RR 2.43, 95% CI 1.34 to 4.42) were significantly higher in women with CUA. Hysteroscopic removal of a septum was associated with a reduced probability of spontaneous abortion (RR 0.37, 95% CI 0.25 to 0.55) compared with untreated women. Presence of CUA might be associated with a detrimental effect on the probability of pregnancy achievement, spontaneous abortion and obstetric outcome. Hysteroscopic removal of a septum may reduce the probability of a spontaneous abortion.     

Mixed lymphocyte reaction blocking factors (MLR-Bf) as potential biomarker for indication and efficacy of paternal lymphocyte immunization in recurrent spontaneous abortion

Objectives

The majority of cases of unexplained recurrent spontaneous abortion (RSA) remains unclear and is found to be associated with alloimmune antibodies termed as mixed lymphocyte reaction blocking factor (MLR-Bf). The decreased production of MLR-Bf may play major role in the immunologic failure of pregnancy and can lead to abortion. The present study was aimed at evaluating MLR-Bf as potential biomarker of indication and the efficacy of immunotherapy with paternal lymphocytes (LIT) in women with RSA.

Materials and methods

A total of 97 women with history of unexplained RSA were recruited for this prospective study. These women showed negative for MLR-Bf and registered for lymphocyte immunotherapy with husband cells. Women with autoimmune pathology or anti-phospholipid syndrome were excluded. All individuals gave their consent to participate in the study.

Results

We have analyzed MLR proliferative response and MLR-Bf in nonpregnant women with history of RSA before and after LIT. Following LIT, the initially low MLR proliferative response was restored at 76.6 % of women, and MLR-Bf activity in blood serum could be detected in 74 % of women. The rate of successful pregnancy was shown to be significantly higher in women positive for MLR-Bf (50/72) as compared with the MLR-Bf negative women (7/25; χ ² = 0.0003).

Conclusion

The data obtained demonstrate that LIT with the paternal lymphocytes in MLR-Bf negative women is accompanied by increased proliferative cell response to the paternal alloantigens and by enhanced production of soluble suppressor activity factors (MLR-Bf) that is associated with improved pregnancy outcome in women with history of RSA.     

Hysteroscopic findings in 344 women with recurrent spontaneous abortion

STUDY OBJECTIVE: To evaluate the prevalence of different anatomic factors in women with recurrent spontaneous abortion (RSA). DESIGN: Retrospective analysis over 9 years (Canadian Task Force classification II-2). SETTING: University hospital-affiliated endoscopic unit. PATIENTS: Three hundred forty-four consecutive patients with RSA and 922 controls referred for abnormal uterine bleeding. INTERVENTION: Diagnostic hysteroscopy. MEASUREMENTS AND MAIN RESULTS: Major and minor uterine mullerian abnormalities (septate, unicornuate uteri) were found significantly more often in women with RSA than in controls (32% vs 6%, p <0.001). The frequency of acquired uterine anomalies (submucous myomas, polyps) was significantly higher in controls (32% vs 9%, p <0.001). No significant differences were observed between groups in frequency of adhesions (4% vs 2%). CONCLUSION: Major mullerian uterine abnormalities are associated with RSA, and minor uterine anomalies may be correlated with an increased risk of recurrent miscarriage.     

脂肪乳替代免疫球蛋白在自然杀伤细胞升高导致复发性流产孕妇中的疗效观察

目的:探讨脂肪乳替代免疫球蛋白在自然杀伤(NK)细胞升高致复发性流产(RSA)孕妇中的临床应用。方法:回顾性分析在我中心接受治疗的283例排除其他因素确诊是NK细胞升高导致的RSA孕妇,所有患者均按常规进行保胎治疗,在孕4周末确诊为NK细胞升高后按照患者意愿选择添加免疫球蛋白(IVIG)治疗(IVIG组,n=92),或添加脂肪乳治疗(脂肪乳组,n=103),另有88例不同意使用IVIG或脂肪乳治疗者作为对照组,比较各组孕4周末和孕12周的外周血NK细胞比例及临床妊娠率差异。结果:静脉滴注IVIG或脂肪乳后(孕12周),患者静脉外周血NK细胞比例(分别为15.38±3.85%、16.10±4.05%)较对照组(21.30±4.62%)降低,而临床妊娠率(分别为81.52%、78.64%)较对照组(45.45%)高,差异均有统计学意义(P0.05),而2个添加治疗组间妊娠成功率无统计学差异(P0.05)。结论:IVIG和脂肪乳均可降低RSA患者静脉外周血NK细胞比例,提高临床妊娠率,且两者疗效相当。     

Occurrence of placental abruption in relatives

Objective  The aim of this study was to assess the recurrence of placental abruption by severity, comparing the risk in a woman with that of recurrence in her sister and in the partner of her brother.
Design  Prospective observational study.
Setting  General population.
Population  Population-based study based on records of pregnancies from the Medical Birth Registry of Norway; 377 902 sisters with 767 395 pregnancies, 168 142 families incorporating 2–10 sisters, and 346 385 brothers with 717 604 pregnancies in their partners were identified.
Methods  Placental abruption with preterm birth, birthweight below 2500 g or perinatal death was defined as severe, other cases as mild. Because of the nested family data structure, multilevel multivariate regression was used.
Main outcome measures  Placental abruption (severe and mild).
Results  Adjusted odds ratios of recurrence of mild and severe abruption were 6.5 (1.7%) and 11.5 (3.8%), respectively, compared with risks of 0.2 and 0.3% in the total population. After a severe abruption, odds ratios in her sisters were 1.7–2.1, whereas mild abruption produced no increased recurrence in sisters. The estimated heritability between sisters of severe abruption was 16%. No excess rate of abruption was observed between sisters and brothers' partners, between brothers' partners, or from brothers' partners to sisters. The odds ratios for a third abruption after a second abruption and a second severe abruption were 38.7 (19%) and 50.1 (24%), respectively.
Conclusions  The recurrence risk of placental abruption in the same woman was higher after severe than mild abruption. Severe abruption was associated with a two-fold risk in sisters. Pregnancies following a second abruption should be considered very high risk.     

复发性流产患者子宫动脉血流的超声多普勒变化

目的:探讨复发性流产(RSA)患者子宫动脉血流超声的血流参数及频谱波形的特征。方法:共纳入87例早孕妇女,其中有RSA史妇女41例,无流产史早孕妇女(对照组)46例,所有对象均行阴道超声多普勒测量子宫动脉血流参数,测量指标有:收缩期峰值流速/舒张末期流速(S/D)、搏动指数(PI)、阻力指数(RI)。随访妊娠结局,排除无流产史妇女中发生难免流产者。根据受试者工作曲线(ROC)比较各参数诊断价值,另将子宫动脉波形进行分类,同时比较RSA组和对照组波形的分布差异。结果:正常对照组排除难免流产7例后为39例。RSA组患者平均年龄29.7±3.4岁,正常对照组28.2±4.2岁。RSA组的子宫动脉S/D、PI、RI分别为6.98±1.67、1.46±0.12、0.84±0.04;正常对照组分别为5.30±1.05、1.31±0.15、0.81±0.12。RSA组的子宫动脉S/D与PI均高于对照组,差异有统计学意义,RI值组间差异无统计学意义(P0.05)。ROC曲线下面积三者均0.8,其中以PI最大;血流频谱波形A、0型的发生率较对照组高。结论:RSA患者的S/D、PI明显高于正常早孕妇女,高阻力血流波形发生率明显高于正常早孕妇女。     

Expression of CD28 and cytotoxic T lymphocyte antigen 4 at the maternal-fetal interface in women with unexplained pregnancy loss.

OBJECTIVE: To investigate the expression of CD28 and CTLA-4, two costimulatory molecules involved in T-cell activation at the maternal-fetal interface in women with unexplained pregnancy loss. METHODS: A total of 57 women, 39 with unexplained spontaneous abortion (SA) and 18 with unexplained recurrent spontaneous abortion (RSA), were enrolled in the study. A high-resolution spectratyping analysis of fluorescent bands was performed to detect CD28 and CTLA-4 expression in decidual tissues. RESULTS: The mean expression of CTLA-4 mRNA was significantly higher in women with SA than in controls (P<0.05). Moreover, the expression of CTLA-4 was higher in SA patients with genotype AA and phenotype A+ (AA+AG) than in controls (P<0.01). The expression of CTLA-4 was not significantly different in patients with RSA and in controls. The expression of CD28 was significantly decreased in patients with RSA (P<0.01) and SA (P<0.05) compared with controls. The mean ratios of CTLA-4/CD28 were significantly higher in patients with RSA (P<0.01) and SA (P<0.05) than in controls. CONCLUSIONS: This study suggests that an imbalance in CTLA-4/CD28 expression or suppressed T-cell activity at the maternal-fetal interface may confer susceptibility to unexplained pregnancy loss.     

Spontaneous abortion after amniocentesis in women with a history of spontaneous abortion

The incidence of spontaneous abortion after amniocentesis (19 to 28 weeks gestation) in women who have had previous spontaneous abortions is compared with the rate in women who have not had previous spontaneous abortions. The outcome of the pregnancy after amniocentesis and the previous history of spontaneous abortion is reported for 691 pregnancies. The rate of spontaneous abortion after amniocentesis was found to be significantly higher in women who had one or more previous spontaneous abortions, 12/238 (5 per cent), than in women who did not, 6/453 (1.3 per cent). In women who reported two or more previous spontaneous abortions, the rate was 7/81 (8.6 per cent). No statistically significant effect of maternal age or gravidity was detected. The incidence of spontaneous abortion after amniocentesis was greater in the three weeks following the procedure (three for each of the three weeks) than in the subsequent seven weeks (nine for seven weeks).     

不明原因重复性自然流产妇女配偶精子DNA完整性

目的:探讨精子DNA完整性与重复性自然流产(RSA)的关系。方法:85例不明原因RSA妇女配偶(RSA组)和50例已生育的成年健康男性(对照组)的精液,应用精子染色质扩散实验(SCD)检测精子DNA完整性。将RSA组根据1年后怀孕结果分为3个亚组:怀孕组(30例)、流产组(26例)、未孕组(29例)。结果:RSA妇女配偶DNA损伤精子的百分率(14.6±6.9)%与对照组的(12.9±3.8)%相比无统计学差异(P0.05)。DNA损伤精子百分率大于20%视为精子DNA完整性异常,则有17.6%的RSA患者配偶的精子DNA完整性异常,6%的正常生育男性精子DNA完整性异常,但差异无统计学意义(P0.05)。怀孕组、流产组、未孕组配偶的DNA损伤精子百分率分别为(12.4±5.3)%,(14.6±6.5)%和(16.8±8.1)%,未孕组与对照组比较,差异有统计学意义(P0.05),怀孕组、流产组与对照组比较,差异无统计学意义(P0.05)。结论:精子DNA完整性异常与RSA继发不育有关,有必要筛查RSA患者配偶的精子DNA完整性。