Immunotherapy for Recurrent Pregnancy Loss: Analysis of Results From Clinical Trials

PROBLEM: Up to 80% of unexplained recurrent spontaneous abortions (RS A) are thought to have an immunologic mechanism. Yet clinical trials using immunotherapy to treat women experiencing RSA have low treatment effects. The present study was undertaken to explain the low treatment effects. METHODS: Results of clinical trials using allogeneic leukocyte immunization and intravenous (IV) immunoglobulin (Ig) are compared. The mechanisms of pregnancy loss are reviewed in light of data on frequency of karyotype abnormalities in trophoblast of failing pregnancies. RESULTS: Results of two independent analyses using allogeneic leukocyte immunization as immunotherapy for all women with RSA revealed live birth ratios of 1.16 (P = 0.03) and 1.21 (P = 0.02). When the analysis was limited to primary aborters, the live birth ratio increased to 1.46 (P = 0.006). Live birth ratio after immunotherapy for all RSA using IVIg was 1.88 (P = 0.04). Because of low treatment effects, confounders to treatment success of maternal age and number of previous abortions were studied. Chromosomal abnormalities have been identified in 55% of concepti from RSA. The frequency of chromosomal abnormalities remained constant for up to six pregnancy losses. Women with a history of primary compared to secondary RSA had a higher frequency of karyotypically abnormal concepti (χ² = 4.54, P < 0.05). Risk factors for RSA also include number of previous losses. CONCLUSION: Chromosomal abnormalities are a significant confounder when evaluating efficacy of immunotherapy for treatment of RSA. Some women with RSA have a high risk of recurrent chromosomal problems.     

Maternal Anti-Placental Cell-Mediated Reactivity and Spontaneous Abortions

PROBLEM: Does Th1/Th2 balance determine pregnancy outcome, and if so, what determines Th1/Th2 balance in pregnancy? METHOD: Review and synthesis of existing data. RESULTS: A bias toward Th1 is strongly correlated with pregnancy failure in mice and humans. Pregnancy usually shifts the balance toward Th2 and placental factors/progesterone and progesterone-stimulated CD8⁺ T cell production of suppressor factor; TGFβ2 and IL4/ 10 may be responsible. The bias toward a Th1 response may result from intracellular parasitic infection and other as yet undefined factors. CONCLUSION: The Th1/Th2 balance thesis appears to be valid.     

9号染色体臂间倒位对生育影响的研究

作者对本室检查的2344例外周血染色体作归类研究.经卡方检验,生育有关组与生育无关组inv(9)检出率存在显著性差异(P<0.05).提示inv(9)有生育遗传效应.     

Allo-immunization elicits CCR5 antibodies,SDF-1 chemokines,and CD8-suppressor factors that inhibit transmission of R5 and X4 HIV-1 in women

Studies in humans suggest that allo-immunization induces CC-chemokines, CD8-suppressor factors (SF) and anti-HIV immunity. Here we report that allo-immunization with unmatched leucocytes from partners of women with recurrent spontaneous abortion elicits specific antibodies to the CCR5 receptor. Such antibodies inhibit replication of M-tropic HIV-1 (R5) and MIP-1beta-mediated chemotaxis. These CCR5 antibodies were also found in the sera of multiparous women that were naturally immunized by semi-allogeneic fetal antigens. The specificity of these antibodies was demonstrated by adsorption with CCR5 transfected HEK-293 cells, a baculovirus CCR5 preparation and a peptide of the 2nd extra-cellular loop of CCR5. Allo-immunization also stimulated increased concentrations of the CXC chemokine, SDF-1alpha and CD8-SF that inhibit T-tropic HIV-1 (X4) replication. We suggest that allo- immunization may elicit (a) CC chemokines, CCR5 antibodies and CD8-SF that inhibit M-tropic HIV-1 infection and (b) the CXC chemokine SDF-1alpha and CD8-SF that inhibit T-tropic HIV-1 infection.     

Preventive effect of monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associate antigen-1 on murine spontaneous fetal resorption

PROBLEM: Are cell adhesion molecules involved in the murine model of immunologically‐mediated spontaneous abortion?
METHOD OF STUDY: Pregnant CBA/J female mice mated with DBA/2 male mice were injected with monoclonal antibodies (MAbs) to intercellular adhesion molecule‐1 (ICAM‐1) and leukocyte function‐associate antigen‐1 (LFA‐1). On day 13 of gestation, viable and resorbed embryos were counted. Natural killer (NK) cell activity in the spleen, mixed lymphocyte reactions (MLR), mixed lymphocyte‐placenta reactions (MLPR), and levels of interferon (IFN)‐Γ were assayed.
RESULTS: Significant suppression of fetal resorption was observed by the injection of MAb to ICAM‐1 and LFA‐1. NK cell activity and the MLR anti‐(CBA/J×DBA/2)F1 were reduced in the antibody‐treated CBA/J spleen. Moreover, the level of IFN‐Γ was significantly lower in the MLPR supernatants from the antibody‐treated group than those of the control group.
CONCLUSIONS: One mechanism in the murine model of spontaneous abortion may be through the interaction of cell adhesion molecules, which may modulate NK cell activities and cytokine production.     

Factors related to subsequent reproductive outcome in couples with repeated pregnancy loss

Specific factors in a couple's history may influence the recurrence risk following repeated pregnancy loss (RPL). Couples with RPL were contacted several years following evaluation and information concerning subsequent pregnancies was obtained. Linear regression analysis was utilized to determine which factors in the history were significant predictors of pregnancy outcome following evaluation. A family history of RPL or a “genetic defect” was a highly significant predictor of subsequent unsuccessful pregnancies. Surgical, but not medical, treatment for RPL was a significant predictor of eventual successful outcome. The number of abortions prior to evaluation for RPL, presence of a liveborn child, maternal age at evaluation, and intercurrent infertility all failed to be significant predictors of pregnancy outcome after evaluation.     

A prospective study of the incidence, time of appearance and significance of anti-paternal lymphocytotoxic antibodies in human pregnancy

The incidence and natural history of serum anti-paternal cytotoxic antibody (APCA) in normal pregnancy and spontaneous abortion was investigated prospectively in 306 women (64 primigravidae and 242 multigravidae), in order to establish whether serum APCA is a useful screening test in the diagnosis, treatment and prognosis for patients with recurrent pregnancy loss. Pre-pregnancy, serial pregnancy and post delivery serum samples were tested against partner's lymphocytes, using a microdroplet lymphocytotoxicity assay. The incidence of serum APCA in the 256 pregnancies successfully completed was 32%, compared with 10% amongst the 50 pregnancies ending in spontaneous abortion. The lower incidence of positive APCA tests in unsuccessful pregnancies was explained by our finding that positive APCA tests are related to the gestational age of the pregnancy and are rarely demonstrable before 28 weeks gestation. Since APCA usually disappears between pregnancies, its usefulness as a diagnostic test for immunotherapy against recurrent abortion should be questioned.     

Tricho-rhino-phalangeal syndrome type III

We present the first case of direct and inverted reciprocal chromosome insertions between human chromosomes 7 and 14, ascertained because of repeated spontaneous abortions. Prometaphase GTG banding analysis showed the karyotype to be 46, XX, inv ins (7;14)(7pter→7q11.23::14q32.2→14q22::7q21.2→7qter), dir ins(14;7)(14pter→14q22::7q11.23→7q21.2::14q32.2→14qter). Origins of the insertion have been confirmed by chromosome painting with libraries specific for chromosomes 7 and 14 using fluorescence in situ hybridization. © 1994 Wiley-Liss, Inc.     

HLA-G polymorphisms in couples with recurrent spontaneous abortions

The etiology of a fraction of recurrent spontaneous abortions (RSA) may involve immunological mechanisms. Aberrant profiles of Th1 and Th2 cytokines have been observed which are not present in uncomplicated pregnancies. Studies of classical HLA class I and II antigens in relation to RSA have not been conclusive. Furthermore, these antigens are not expressed in the placenta with the exception of HLA-C. However, HLA-G is expressed on especially invasive cytotrophoblasts and exists in both membrane and soluble forms. HLA-G may be involved in materno-fetal tolerance. Therefore, 61 RSA couples (with three or more spontaneous abortions) and 47 fertile control couples were HLA-G genotyped by direct DNA sequencing and analyzed for specific polymorphisms. No statistically significant differences were observed in the distribution of HLA-G alleles between controls and RSA couples, however, 15% of the RSA women carried the HLA-G*0106 allele compared to 2% of the control women. The 14 bp deletion polymorphism in exon 8 was investigated separately. There were a greater number of heterozygotes for the 14 bp polymorphism in the group of fertile control women than expected, according to Hardy-Weinberg equilibrium. Furthermore, the HLA-G alleles without the 14 bp sequence were prominent in the RSA males in contrast to the RSA women in whom alleles including the 14 bp sequence were frequently observed, especially as homozygotes. These results are discussed in relation to two hypotheses concerning HLA-G and RSA. A hypothesis of HLA-G histo-incompatibility between fetus/placenta and the mother was not supported by the data. Another hypothesis concerned certain HLA-G alleles associated with an altered expression profile of HLA-G isoforms or reduced expression of certain HLA-G isoforms.     

低分子肝素联合阿司匹林对复发性自然流产患者血凝状态的影响

目的:探讨低分子肝素(LMWH)联合阿司匹林对复发性自然流产(RM)患者血凝状态的影响.方法:将98例血栓前状态(PTS)复发性自然流产患者随机分为两组,每组49例.对照组行口服阿司匹林肠溶片;研究组在对照组治疗的基础上行LMWH腹壁皮下注射,对比治疗前后两组患者凝血状态改善情况及母婴结局.结果:治疗后两组患者的凝血四项中PT、TT、APTT值较治疗前显著升高,研究组的提高水平显著优于对照组,差异有统计学意义;FIB、D-二聚体(D-Dimer)水平较治疗前显著降低,研究组的改善水平与对照组相比,差异有统计学意义;两组治疗后PLT水平与治疗前比较降低,差异有显著性意义,组间比较无显著性差异.结论:LMWH联合阿司匹林能显著改善RM患者的凝血状态,恢复凝血和抗凝平衡,缓解患者血栓前状态,提高妊娠活婴产率,降低流产率.