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.     

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     

Antibodies to Chlamydia trachomatis in sera of women with recurrent spontaneous abortions.

OBJECTIVE: The relationship between high-titer immunoglobulin G antibodies to Chlamydia trachomatis and recurrent spontaneous abortions was evaluated. STUDY DESIGN: Sera from the female partners of 258 couples with unexplained infertility, no history of chlamydial infection, and negative cervical cultures were diluted 1:128 and tested for immunoglobulin G antibodies to Chlamydia trachomatis. A subset of patients was also tested for antibodies to cytomegalovirus, cardiolipin, nuclear antigens, lactoferrin, and spermatozoa. RESULTS: Seven (41%) of 17 women with three abortions and 6 (60%) of 10 women with four abortions had chlamydial antibodies as opposed to 20 (13.5%) of 148 with no abortions, 6 (12.8%) of 47 with one abortion, and 4 (12.1%) of 33 with two abortions (p < 0.01). The incidence of > or = 3 spontaneous abortions was 31.8% among women with high-titer chlamydial antibodies and 7.5% among women who had seronegative results (p < 0.001). There was no relation between any of the other antibodies and > or = 3 abortions or antibodies to Chlamydia trachomatis. CONCLUSION: High-titer immunoglobulin G antibody to Chlamydia trachomatis was associated with recurrent spontaneous abortions. The mechanism may involve reactivation of a latent chlamydial infection, endometrial damage from a past chlamydial infection, or an immune response to an epitope shared by a chlamydial and a fetal antigen.     

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 correlation of the uterine and ovarian blood flows with parity of nonpregnant women having a history of recurrent spontaneous abortions

The objective of the present investigation was to study the expression of the proliferation marker Ki-67 in cervical intraepithelial lesions in women with AIDS. We studied 18 low-grade cervical intraepithelial lesions (Lo-CIN) and 8 high-grade cervical intraepithelial lesions (Hi-CIN ) in AIDS patients and 18 Lo-CIN and 14 Hi-CIN in patients from the general population. Positive Ki-67 nuclei were counted. A significantly higher number of Ki-67-positive cells (p < 0.001) was found in Lo-CIN of AIDS patients (mean 29.18 +/- 10.44) as compared with Lo-CIN of general-population women (mean 17.08 +/- 7.40), whereas no significant difference in positive Ki-67 nuclei was observed in the Hi-CIN of AIDS patients and of patients from the general population (p > 0.05). We conclude that the proliferative potential of cervical cells in Lo-CIN - as studied by the expression of the proliferation marker Ki-67 - is higher in AIDS patients than in the general population.     

Prospective study of anticardiolipin antibodies in immunized and untreated women with recurrent spontaneous abortions.

OBJECTIVE: To investigate whether active leukocyte immunization increases levels of anticardiolipin antibodies in women with recurrent spontaneous abortions. To assess the impact of anticardiolipin antibodies on pregnancy outcome in these women. DESIGN: Patients who had received various treatments in an ongoing randomized trial were studied prospectively. SETTING: A department of clinical immunology investigating women with recurrent spontaneous abortions from all over Denmark. PATIENTS: Eighty-nine patients with unexplained recurrent spontaneous abortions whose pregnancies had been completed during the course of the trial. INTERVENTIONS: After randomization, 44 patients were actively immunized with husband's or third party leukocytes, and 27 patients received placebo. Eighteen patients received anticoagulation therapy in pregnancy. MAIN OUTCOME MEASURES: Changes in levels of immunoglobulin (Ig)M class and IgG class anticardiolipin antibodies after active immunization. Frequency of new miscarriages in patients who were positive or negative for anticardiolipin antibodies. RESULTS: Neither IgM nor IgG anticardiolipin antibodies changed significantly after active immunization (P greater than 0.2). The interim results of the immunization trial showed a success rate of 68% in the treated group versus 56% in the placebo group (not significantly different). Relative risk of miscarriage in anticardiolipin antibody-positive patients compared with anticardiolipin antibody-negative patients was 1.3 (95% confidence interval 0.7 to 2.2; P = 0.4) in the combined study groups. CONCLUSIONS: Patients eligible for active immunization did not exhibit significant changes in anticardiolipin antibody levels subsequent to the treatment. The treatment did not seem to provide any overall benefit with respect to pregnancy outcome. Prospectively, the risk of miscarriage in patients positive for anticardiolipin antibodies was not significantly increased.     

Alloimmune neonatal neutropenia is a potential side effect of immunization with leukocytes in women with recurrent spontaneous abortions.

Alloimmunization of a mother against granulocytes causing alloimmune neonatal neutropenia (ANN) in her newborn was found likely to be attributed to previous intradermal injections of paternal lymphocytes. Immunotherapy with leukocytes which was performed for recurrent spontaneous abortions hence provides the possibility of granulocyte alloimmunization and increases the risk of the occurrence of ANN.     

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.     

Previous reproductive history in mothers presenting with spontaneous abortions.

Information on the previous reproductive history of 3467 mothers presenting with a spontaneous abortion is compared with that of a control series presenting with a livebirth. In 1384 abortions the chromosome constitution of the fetal products was determined. The mothers who had delivered a chromosomally normal abortion more often had a history of previous repeated abortions, while those of chromosomally abnormal abortions tended to have fewer repeated abortions but an excess of previous viable children with Down's syndrome. Data are also presented on 23 mothers with two spontaneous abortions of known karyotype; these, together with similar data obtained elsewhere, made it possible to estimate an overall rate of recurrence of chromosome defects in conceptions of the same parents, and the probability that affected fetuses will survive to a viable stage in pregnancy. The clinical and genetic implications of the findings are briefly discussed.     

Hormonal treatment of recurrent spontaneous abortions

A retrospective study with 79 pregnant women was conducted. All of them were diagnosed as spontaneous abortion. The patients were separated in two group and the women have been treated in two schemes--51%--Utrogestan and 49%--Utrogestan and Profasi. The medication was applied only into the first trimester of the pregnancy. The duration of the therapy was 15.0 +/- 12.34 days. The mean gestational age in this study was 7.6 +/- 3.0 gestational weeks. Women with a first pregnancy and spontaneous abortion were excluded from the study. The number of this hormonal treated pregnancy was 2.84 +/- 1.13. 10.2% of the followed women had 3 and more than 3 miscarriages. The followed group of women was historically and clinically heterogenic. For that reason we think that many other factors could play a role in the optimum outcome of this pregnancy. The criteria for positive result we accepted the vital embryo/fetus on the time of dehospitalization. From these pregnancy only 3 terminated with miscarriage--3.79%. The rest of 96.2% went at home with intact pregnancy. The authors try to find a theoretical support for use of micronized progesterone Utrogestan--there could be some changes in the cellular and humoral immunity at repeated abortions, related to the change of the cytokine production. It could be find an ability to realize a readjustment of the endocrine system of the mother and to control the immune reaction in the fetoplacental unit.     

Pregnancy outcome following recurrent spontaneous abortions

OBJECTIVE: The purpose of the present study was to examine the association between spontaneous consecutive recurrent abortions and pregnancy complications such as hypertensive disorders, abruptio placenta, intrauterine growth restriction and cesarean section (CS) in the subsequent pregnancy. METHODS: A population-based study comparing all singleton pregnancies in women with and without two or more consecutive recurrent abortions was conducted. Deliveries occurred during the years 1988-2002. Stratified analysis, using a multiple logistic regression model was performed to control for confounders. RESULTS: During the study period 154,294 singleton deliveries occurred, with 4.9% in patients with history of recurrent consecutive abortions. Using a multivariate analysis, with backward elimination, the following complications were significantly associated with recurrent abortions-advanced maternal age, cervical incompetence, previous CS, diabetes mellitus, hypertensive disorders, placenta previa and abruptio placenta, mal-presentations and PROM. A higher rate of CS was found among patients with previous spontaneous consecutive recurrent abortions (15.9% versus 10.9%; OR = 1.6; 95% CI, 1.5-1.7; P < 0.001). Another multivariate analysis was performed, with CS as the outcome variable, controlling for confounders such as placenta previa, abruptio placenta, diabetes mellitus, hypertensive disorders, previous CS, mal-presentations, fertility treatments and PROM. A history of recurrent abortion was found as an independent risk factor for CS (OR = 1.2; 95% CI, 1.1-1.3; P < 0.001). About 58 cases of inherited thrombophilia were found between the years 2000-2002. These cases were significantly more common in the recurrent abortion as compared to the comparison group (1.2% versus 0.1%; OR = 11.1; 95% CI, 6.5-18.9; P < 0.001). CONCLUSION: A significant association exists between consecutive recurrent abortions and pregnancy complications such as placental abruption, hypertensive disorders and CS. This association persists after controlling for variables considered to coexist with recurrent abortions. Careful surveillance is required in pregnancies following recurrent abortions, for early detection of possible complications.     

Immunological analysis of women with repeated spontaneous abortions

The study deals with 9 women with recurrent abortions who do not possess the blocking factor which is present during normal pregnancy and which inhibits, nonspecifically, a cellular cytotoxicity reaction in vitro. Electrophoresis of the women's serum revealed an abnormal glycoprotein, migrating in the alpha-globulin zone, which gives a precipitate with an anti-gamma-globulin serum after mercaptoethanol treatment. These last two findings may indicate a possible abortion.     

NLRP7 variants in spontaneous abortions with multilocus imprinting disturbances from women with recurrent pregnancy loss

Journal of Assisted Reproduction and Genetics - Comparative analysis of multilocus imprinting disturbances (MLIDs) in miscarriages from women with sporadic (SPL) and recurrent pregnancy loss (RPL)...     

Chromosome abnormalities in 118 couples with recurrent spontaneous abortions

Cytogenetic studies were carried out on 118 couples with recurrent spontaneous abortions. Four major chromosomal abnormalities were found including two 13/14 Robertsonian translocations, one t(7;12) and one t(1;10) reciprocal translocation. The incidence of chromosomal abnormalities in this study was 3.39%, which is lower than the mean value of the published data. The clinical significance of balanced translocations in recurrent reproductive loss is discussed.     

The prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the families of couples with recurrent spontaneous abortions or gestational trophoblastic tumors.

This study extends our previous work on the genetics of recurrent spontaneous abortion and of gestational trophoblastic tumors in an ethnically homogeneous population of Chinese in Taiwan by comparing the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, second-, and third-degree relatives of the index couples to that of normally fertile couples from the same population. The rationale for this study was to provide another test for our hypothesis that genes linked to the major histocompatibility complex are responsible for the diseases in the index couples. If they are, these genes should segregate with a higher frequency in the relatives of the index couples than in the relatives of normally fertile couples and lead to a higher prevalence of these diseases in the extended families. Such a difference was found and adds support to our hypothesis that major histocompatibility complex-linked genes affect growth, development, and susceptibility to cancer.     

Chromosomal analysis in Japanese couples with repeated spontaneous abortions

Balanced chromosome rearrangements have been found at an increased frequency in couples with pregnancy wastage, especially recurrent spontaneous abortions, compared with the general population. In the present study, chromosomal analysis of peripheral blood cells, as one of the routine examinations of patients with repeated reproductive wastage, was performed on both partners of 639 Japanese couples. Among the 639 couples, 32 major chromosomal anomalies (5.0%) and 23 minor chromosomal variants (3.6%) were found. Both partners of one couple had an abnormal karyotype. The 32 major anomalies consisted of 19 reciprocal translocations, 9 Robertsonian translocations, one large inversion, two triple-X females, and one Turner mosaicism. The 23 minor variants included 15 cases of pericentric inversion of chromosome 9. The total number of pregnancies in the 54 couples with chromosomal anomalies was 181, but they resulted in only 18 normal liveborn neonates, indicating a 90.1% abortion rate. The present statistical study indicates that major chromosomal anomalies seem to be involved in repeated reproductive wastage.