Role of microparticles in recurrent miscarriages and other adverse pregnancies: a review

The multiple functions attributed to microparticles (MPs) include blood coagulation, inflammation, tumorigenesis, angiogenesis, immunomodulatory functions and intercellular cross talk. These have drawn considerable interest during the last few years. The prothrombotic nature of MPs has linked them with almost all groups of thrombotic disorders including recurrent miscarriage (RM) and other abnormal pregnancy outcomes. Two authors (SS and RP) conducted a search independently on the computerized databases MEDLINE and EMBASE using relevant key words. Contradictory reports were observed on the association of MPs with RM. While most of the reports showed increased prevalence of MPs, both platelet and endothelial cell derived, in RM, some did not show any association. Almost all the reports showed a strong association of MPs with preeclampsia (PE), while the association with other adverse pregnancy conditions was not very conclusive. It may be concluded that MPs by themselves may result in adverse conditions or that they may be additive factors to an already existing prothrombotic state due to acquired or genetic thrombophilia or some unknown thrombophilic condition, besides the pre-existing hypercoagulable status of pregnancy.     

Chromosome inversions and a novel chromosome insertion associated with recurrent miscarriages in South India

The aim of the present study was to investigate the contribution of chromosomal abnormalities and the frequency of a particular type of aberration in couples of South Indian origin with recurrent miscarriages. A total of 160 couples with recurrent miscarriages were analyzed using Giemsa-Trypsin-Giemsa (GTG) banding and Fluorescence in situ hybridization (FISH) wherever necessary. Chromosomal abnormalities were detected in 18 individuals representing 11.25% of the samples analyzed. Present study describes majority of the cases with chromosome inversions found to be common among the referred couples. Among the abnormal karyotypes, we report for the first time an unique case of chromosome insertion in a woman with the karyotype 46,XX,ins(12;6)(q24.2;q23q25) associated with recurrent miscarriages. The overall incidence of abnormalities and the predominance of chromosome inversions indicates to physicians that routine chromosome analysis of infertile couples of South Indian origin should be essentially considered before the planning of Intra Cytoplasmic Sperm Injection (ICSI), and also the priorities for cytogenetic screening in individual cases should be established.     

Thyroid autoimmunity in patients with recurrent spontaneous miscarriages.

Recurrent spontaneous miscarriage (RSM) is a multifactorial problem. Auto- and alloimmune parameters have been implicated. Antithyroid antibodies (ATA) were tested in a group of women with RSM. The presence of antipaternal antibodies (APCA) was evaluated as an index of alloimmune contribution. Thirty euthyroid women with RSM (three or more consecutive miscarriages) aged 25-37 years were compared with 15 matched controls. Thyroid peroxidase (TPO) and thyroglobulin antibodies were tested with a chemiluminescence immunoassay and APCA were tested with a cross-match reaction. Results were compared using the chi-squared test. There was a higher frequency of ATA in women with RSM compared to controls (37% versus 13%, p < 0.05). Twenty of the women (67%) with RSM were tested negative for APCA, indicating an alloimmune contribution to their infertility. In this subgroup of women, the frequency of ATA continued to be higher than controls (40% versus 13%, p < 0.05). In conclusion, women with RSM, independent of APCA status, have a higher frequency of ATA. This may represent an additional marker for impaired regulation of the maternal immune system.     

Prevalence of chronic endometritis in recurrent miscarriages

Chronic endometritis was identified immunohistochemically in 9.3% of patients with recurrent miscarriages (in 12.9% of patients with miscarriages of unknown etiology). Chronic endometritis is not negligible in patients with recurrent miscarriages.     

Study of the birthweight of parents experiencing unexplained recurrent miscarriages.

OBJECTIVE: To examine birthweight and preterm birth rates in couples with unexplained recurrent miscarriages. DESIGN: A case control study. Birth data of couples with recurrent miscarriages were obtained from midwife records. Time and sex-matched births from the same records served as controls. SETTING: A Regional Hospital in Denmark. SUBJECTS: 79 singleborn women with recurrent miscarriages and 60 of their male partners comprised the main study groups. Two control groups comprised 474 female and 360 male singleborn infants who survived day 7 postpartum. MAIN OUTCOME MEASURES: Mean birthweight in the two main study groups and in subgroups with histories of 3, 4 and greater than or equal to 5 miscarriages. RESULTS: The mean birthweight of the women with recurrent miscarriages was 3265 g (SE 70) and in female controls 3414 g (SE 23) (P less than 0.025). The 17 women with five or more miscarriages had a mean birthweight of 2991 g (SD 140) (P less than 0.001 compared with controls). Of the women in the study group 10.8% were born preterm compared with 2.9% of the controls (P = 0.01). The mean birthweight of the male partners in the study group, 3470 g (SE 68), did not differ significantly from that of 3504 g (SE 31) in the male controls (P less than 0.5). CONCLUSIONS: Women suffering unexplained recurrent miscarriages have on average had a significantly lower than normal birthweight themselves, whereas this was not observed in their male partners. This points towards the existence of a birthweight-reducing trait associated with recurrent miscarriages, the trait being manifest only in the woman.     

The endocrinological basis of recurrent miscarriages

PURPOSE OF REVIEW: This review discusses the endocrinological aspects of recurrent miscarriage based on the literature from January 2004 to January 2005, elaborating on the advances in the field and their impact on diagnosis and management. RECENT FINDINGS: Endometrial luteal phase defect is associated with recurrent miscarriage. Fifty years have passed since the diagnostic criteria for dating the endometrial biopsy was established by Noyes et al. This has been the gold standard and last year its accuracy and clinical utility were critically analysed. A Cochrane review has shown a small but statistically significant difference in the live birth rate in the subgroup of women in which progestogen was used to prevent recurrent miscarriage. Endocannabinoids and fatty acid amide hydrolase have been found to have a potential role in signalling for implantation and maintenance of pregnancy. SUMMARY: Abnormal secretory endometrial changes may adversely affect the early pregnancy outcome. Other dating techniques using biochemical and molecular markers of endometrial function may prove useful in predicting outcome. Use of progestogens with or without estrogens for prevention of recurrent miscarriage needs to be investigated further in larger randomized controlled trials. The role of endocannabinoids and agents modulating their receptors are potentially very exciting areas to be explored further.     

Thyroid autoimmunity in patients with recurrent spontaneous miscarriages

Recurrent spontaneous miscarriage (RSM) is a multifactorial problem. Auto- and alloimmune parameters have been implicated. Antithyroid antibodies (ATA) were tested in a group of women with RSM. The presence of antipatemal antibodies (APCA) was evaluated as an index of alloimmune contribution.

Thirty euthyroid women with RSM (three or more consecutive miscarriages) aged 25–37 years were compared with 15 matched controls. Thyroid peroxidase (TPO) and thyroglobulin antibodies were tested with a chemiluminescence immunoassay and APCA were tested with a cross-match reaction. Results were compared using the chi-squared test.

There was a higher frequency of ATA in women with RSM compared to controls (37% versus 13%, p < 0.05). Twenty of the women (67%) with RSM were tested negative for APCA, indicating an alloimmune contribution to their infertility. In this subgroup of women, the frequency of ATA continued to be higher than controls (40% versus 13%, p < 0.05).

In conclusion, women with RSM, independent of APCA status, have a higher frequency of ATA. This may represent an additional marker for impaired regulation of the maternal immune system.     

Role of CYP17 and CYP19 polymorphisms in idiopathic recurrent miscarriages among South Indian women

Recent reports suggest the relevance of gene polymorphisms in predicting reproductive outcome. The present study was aimed at investigating the relationship between the 5' UTR polymorphism of CYP17, a tetranucleotide repeat and a trinucleotide deletion polymorphism in CYP19. A case-control-based study approach was used, which included 143 cases and 88 controls from the South Indian population. A PCR-sequencing based genotyping was used to ascertain the status of the individual. The A1, A2 allele frequencies of CYP17 among the cases were 72 and 28% while among the controls were 68 and 32% respectively (OR 1.21, 95% CI: 0.63-2.32). The 7/7 repeat of CYP19 was the predominant one with a distribution frequency of 55% in the cases and 58% in the controls. The deletion was observed in 39% of the cases and 36% of the controls (OR 1.14, 95% CI: 0.62-2.10). Minor genotypes when taken together represented at a higher frequency in cases than those in controls (13 against 2%, P-value: 0.006). No statistically significant association exists between the CYP17 and CYP19 trinucleotide deletion polymorphisms and the risk of idiopathic recurrent miscarriages among women from South India. However, larger repeat numbers of the tetra nucleotide (except the common 7/11 genotype) showed significant association at 95% level.     

Anti-annexin as a marker in patients with recurrent miscarriages

ObjectiveTo investigate the possible role of anti-annexin A5 antibodies in inducing recurrent miscarriage.DesignCross-sectional study.SettingBenha University Hospital.Participants and interventionsPregnant women during the first trimester of pregnancy with a history of three or more consecutive pregnancy losses were compared to Multigravidae women during the first trimester of pregnancy with no history of pregnancy losses for group II. Women were screened for anti-annexin A5 antibodies.ResultsThere were no statistically significant correlations between anti-annexin A5 antibodies in both groups (P>0.05).ConclusionThe present study did not confirm that anti-annexin A5 antibodies have significance in predicting RM when measured in healthy women.     

The association of HLA-G and immune markers in recurrent miscarriages

Objective: To determine role of human leukocyte antigen (HLA)-G, CD8, CD16, CD56, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α for recurrent miscarriages in feto–maternal interface.

Method: Chorion and decidua samples were obtained from 11 women with unwanted pregnancies (healthy pregnancy, HP) and 10 women with missed abortion diagnosis after at least two pregnancy losses (recurrent miscarriage, RM). In addition, endometrial tissues were obtained from 10 non-pregnant women (NonP). The expressions of markers were evaluated using the Western blot analysis. The values obtained between different groups were compared.

Results: The highest protein expression of CD56 was found in the HP compared to NonP and RM. Meanwhile, the lowest protein expression of CD16 was observed in the NonP compared to HP and RM. The HLA-G expression exhibited the highest level in HP; however, there was no statistically significant difference between groups. CD8 and IFNγ expressions were lowest in the NonP group; however, TNF-α was highest in the RM group.

Conclusions: The CD56 expression of uterine NK cells may be an indicator of a HP. However, not statistically significant, the increased expression of CD16, CD8, and also significantly increased expression of TNF may be associated with the predominant cytotoxic activity in the maternal immune system in patients with RM. Although there was no change in the expression of HLA-G, this finding may mean that the maternal immune system is unresponsive to HLA-G-mediated immunosuppressive signals originating from the fetus in these cases.     

White blood cell immunization and anticardiolipin antibody levels in women with recurrent miscarriages.

To determine whether WBC immunization stimulates production of anticardiolipin antibodies, anticardiolipin antibodies were measured before and 6 weeks after WBC immunization. Twenty-four non-pregnant women, who had had recurrent miscarriages for which a definitive cause could not be determined, were immunized with their partner's WBC. No significant differences in levels of anticardiolipin antibodies were detected between paired samples of sera obtained before and 6 weeks after WBC immunization. White cell immunization in nonpregnant women did not stimulate production of anticardiolipin antibodies.     

A study of pregnancy loss in 352 women with recurrent miscarriages

Aim The aim of the study was to investigate the type of pregnancy loss (PL) in women with recurrent miscarriages.Materials and methods The study population included 411 women with a history of recurrent pregnancy loss (RPL) attending the Recurrent Miscarriage Clinic of the 2nd Department of Obstetrics and Gynecology, University of Athens (tertiary referral center). Subjects were divided in groups according to their underlying pathology and in some of them appropriate treatment was applied.Results The study of the 323 pregnancies achieved after referral, revealed that the PL after ultrasonographic detection of fetal heart (FH) is overall increased, is more common in women with anatomical uterine anomalies and unexplained RPL, and treatment reduces its rate in women with anatomical uterine anomalies and an inadequate luteal phase. The PL before the detection of FH is reduced after treatment in women with thrombotic tendency and an inadequate luteal phase.     

Treatment outcome in women suffering from recurrent miscarriages and antiphospholipid syndrome

OBJECTIVE: To evaluate the outcomes of treatment in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. MATERIALS AND METHODS: 148 observed women suffering from recurrent abortion with presence of lupus anticoagulant antibodies (LA) and/or high moderate concentration of anticardiolipin antibodies (ACA) have been divided randomly into followed three treated groups: I--56 patients treated by low-dose of acetylsalicylic acid (LDA, 75 mg daily); II--39 patients treated by low molecular weight heparin (applied in dose of 20 g daily); III--53 patients treated by LDA and low molecular weight heparin simultaneously. RESULTS: It has been affirmed that coincidental application of low-dose of acetylsalicylic acid and low molecular weight heparin statistically more often increase the percentage of successful pregnancy in comparison with application of low molecular weight heparin or acetylsalicylic acid alone. In the group where only low-dose of acetylsalicylic acid was applied the success of pregnancy equaled 89.3%, in the group where only low molecular weight heparin was applied the successful pregnancy equaled 81.1% and in the group with acetylsalicylic acid and low molecular weight heparin being applied together the successful pregnancy equaled 92.5%. In has simultaneously been affirmed that the percentage of pregnancy loss is statistically higher in the women suffering from isolated occurrence of lupus anticoagulant antibodies (21.2%) in comparison with the women suffering from occurrence of anticardiolipin antibodies (6.7%) and anticardiolipin antibodies with lupus anticoagulant antibodies simultaneously. CONCLUSION: 1. Simultaneous application of low-doses of acetylsalicylic acid and low molecular weight heparin seems to be the best solution in patients suffering from recurrent spontaneous abortion and antiphospholipid syndrome. 2. The occurrence of anticardiolipin antibodies in the serum of blood in patients suffering from antiphospholipid syndrome is a better foretelling factor for the future pregnancy outcome than the occurrence of lupus anticoagulant antibodies.     

Preimplantation genetic diagnosis for aneuploidy screening in patients with unexplained recurrent miscarriages

OBJECTIVE: To determine the aneuploidy rate in embryos of women with idiopathic recurrent miscarriages and to evaluate whether preimplantation genetic diagnosis for aneuploidy screening could be a feasible approach to improve the possibility of successful pregnancy in these couples. DESIGN: Prospective cohort study. SETTING: Tertiary university referral center. PATIENT(S): Women (n = 49) with recurrent idiopathic miscarriages. INTERVENTION(S): In vitro fertilization with preimplantation genetic diagnosis for aneuploidy screening. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (PR) and aneuploidy rate. RESULT(S): The aneuploidy rate was, respectively, 43.85% and 66.95% in the younger and older group. The ongoing PR per cycle was 25.71% in the younger and 2.94% in the older patients. CONCLUSION(S): There is no therapeutic evidence to prescribe IVF with or without preimplantation genetic diagnosis for aneuploidy screening for this heterogeneous group of patients.     

Inherited thrombophilia in women with recurrent miscarriages and pregnancy loss in anamnesis--own experience

Single nucleotide polymorphisms of the genes coding for coagulation factors are the cause of congenital thrombophilia which might lead to recurrent miscarriages and fetal loss in advanced pregnancy. The most frequent reasons of thrombophilia are the following: factor V Leiden (1691G>A), mutation 20210G>A of prothrombin gene, and 677C>T of 5, 10-methylenetetrahydrofoliate reductase gene. The following article briefly summarizes the administration of antithrombotic prophylaxis (low-molecular weight heparin, acetylsalicylic acid) which seems to be an effective course of action to prevent complications in next pregnancies. What is more, adverse events after long-term usage of low-molecular weight heparin and acetylsalicylic acid in prophylactic doses have not been observed. Due to lack of complete randomized investigation about the inclusion of antithrombotic prophylaxis in this group of pregnant women, common scheme of administration and optimal dosage is yet to be established.