Molecular genetic studies of HLA-DRB1 alleles in patients with unexplained recurrent abortion in the Japanese population

BACKGROUND: Recently, evidence that HLA antigens are markers for recurrent spontaneous abortion has gained increased attention. Although the association between HLA class II antigens and patients with unexplained recurrent abortion was elucidated by a large population study in a Caucasian population, such analyses have been conducted in only a small Japanese population. The aim of the present study was to determine whether HLA-DR antigens are associated with patient populations with unexplained recurrent abortion in the Japanese population. METHODS: HLA-DRB1 genotypes were determined using a PCR-restriction fragment length polymorphism (PCR-RFLP) method in 93 patients with unexplained recurrent abortion (79 primary recurrent aborters and 14 secondary recurrent aborters) and in 115 normal fertile women. The rate of possession of each HLA-DRB1 genotype was compared among the three populations. RESULTS: The rate of possession of the HLA-DRB1*1502 in patients with secondary recurrent abortion was significantly higher (P < 0.01 after correction for multiple comparisons) compared with the control, fertile women. The rate of possession of HLA-DRB1*1502 was also higher in patients with primary recurrent abortions than in controls, but the difference was not statistically significant after correction. CONCLUSIONS: These findings suggest that HLA-DRB1*1502 might be a risk allele for unexplained recurrent abortion in the Japanese population.     

Ovarian autoimmunity: greater frequency of autoantibodies in premature menopause and unexplained infertility than in the general population

The objective of this study was to: (1) assess the relative prevalence of ovarian, thyroid, nuclear, and cardiolipin antibodies associated with premature menopause and unexplained infertility and (2) compare ovarian and thyroid antibodies in premature menopause, unexplained infertility, and the general population. Autoantibodies were evaluated in women with premature menopause (n = 30), unexplained infertility with (n = 38) or without (n = 15) prior gonadotropin-induced ovulation, and normal cycling controls (n = 12) and in a population of women obtained from a blood bank (n = 53). Antibodies to ovary (OVAB), thyroid (THYAB; thyroid peroxidase and thyroglobulin), cardiolipin, and eight nuclear antigens were assessed by enzyme immunoassay. Organ-specific antibodies (ovary and thyroid) were present with significantly greater frequency than non-organ-specific antibodies (nuclear and cardiolipin) in premature menopause and unexplained infertility (60% (50/83) vs 16% (13/83) respectively; P < 0.0001). OVAB (53%, 44/83) were significantly more frequent than THYAB (30%, 25/83) in premature menopause and unexplained infertility (P = 0.0030). THYAB did not differ among all groups (P = 0.78). In premature menopause and treated or untreated unexplained infertility OVAB frequencies were 53, 61, and 33%, respectively, and were significantly more frequent than in the population (17%) (P = 0.0001). In unexplained infertility, individuals with no prior gonadotropin-induced ovulation had a lower frequency of OVAB than treated individuals (P = 0.07). The frequency distribution of optical density values for OVAB was significantly higher for premature menopause and unexplained infertility than for population or normal cycling women (P < 0.0001). Thus, only ovarian antibodies were significantly more frequent than other antibody markers of autoimmunity in premature menopause and unexplained infertility.     

不孕及反复自然流产患者血清抗精子抗体分析

目的：探讨不孕及反复自然流产与抗精子抗体（AsAb）的关系。方法：用金标法检测有反复自然流产史患者245例（流产组）、原发或继发不孕患者164例（不孕组）及正常妇女40例（对照组）血清中的AsAb。结果：不孕组AsAb总阳性率52.44%,流产组总阳性率48.57%,与对照组比较差异均有统计学意义（P〈0.05）。结论：AsAb与不孕及反复自然流产有着密切关系。     

The skewed TCR-BV repertoire displayed at the maternal-fetal interface of women with unexplained pregnancy loss

PROBLEM: The study was undertaken to investigate T-cell receptor (TCR) variable beta (BV)-chain usage at maternal-fetal interface and explore the relationship between the skewed TCR-BV usage and unexplained pregnancy losses. METHOD OF STUDY: A total of 57 patients with unexplained pregnancy loss including 39 cases with unexplained spontaneous abortion and 18 cases with unexplained recurrent spontaneous abortion (RSA) were chosen in Renji Hospital, Shanghai Second Medical University matched with 41 women with normal pregnancies in first trimester between September 2002 and November 2003. A high-resolution spectratyping analysis of complementarity-determining region 3 (CDR3) was used to detect and compare the degree and pattern of TCR-BV repertoire usage at the maternal-fetal interface between patients with pregnancy loss and normal controls. RESULTS: There were two comparisons of TCR usage performed between patients and controls, which included the degree (mean value of every TCR-BVn expression) and the pattern (skewed TCR-BVn frequency). The skewed TCR-BVn is defined as an absolute BVn usage of > 5% calculated from the formula or a double increased BVn usage compared with the mean value of normal BVn. According to the degree of TCR-BV usage, BV2 (P = 0.046), BV10 (P = 0.016), and BV11 (P = 0.030) in spontaneous abortion group and BV19 (P = 0.038) in RSA group showed higher usage, while BV5.2 (P = 0.006 and P = 0.046) in both abortion groups showed significantly lower usage when compared with normal controls. About the pattern of skewed TCR-BV distribution, we found that TCR-BV2, -3, -6, and -7 were the four most common BV families in deciduas of patients with both types of abortion and normal controls. Women with spontaneous abortion demonstrated higher frequency of BV10 (P = 0.035) and lower frequencies of BV4 (P = 0.002) and BV5.2 (P = 0.003) in comparison with controls. In RSA, higher frequencies of BV15 (P = 0.018), BV19 (P = 0.049), and BV20 (P = 0.018), in the mean time, lower frequencies of BV4 (P = 0.026) and BV7 (P = 0.018) distributions were verified. CONCLUSIONS: Our results suggested that a significant skewed TCR-BV repertoire occurred at the maternal-fetal interface with patients undergoing abortion. The specific skewed usages of TCR-BV might be associated with the susceptibility to unexplained pregnancy loss.     

Review of unexplained infertility and obstetric outcome: a 10 year review.

BACKGROUND: Increased maternal and fetal risks have been reported in pregnancies following unexplained infertility. Our aims were to examine the obstetric and perinatal outcome of singleton pregnancies in couples with unexplained infertility and explore the impact of fertility treatment. METHODS: Women with unexplained infertility were identified from the Aberdeen Fertility Clinic Database. Their unit numbers were matched against the Aberdeen Maternity and Neonatal Databank (AMND) in order to extract obstetric records of those women with subsequent pregnancy outcomes. The general obstetric population served as a control group. RESULTS: Women with unexplained infertility were older [30.8 versus 27.9 years, 95% confidence interval (CI) for difference = +2.4 to +3.4] and more likely to be primiparous (59 versus 40%, 95% CI = +1.3 to +1.9). After adjusting for age and parity they had a higher incidence of pre-eclampsia, abruptio placentae, preterm labour, emergency Caesarean section and induction of labour in comparison with the general population (P < 0.05). Perinatal outcome did not differ between women with unexplained infertility and those of the general population. The multiple pregnancy rate was 5.4% higher following fertility treatment than in women who conceived spontaneously (95% CI = +2.8 to +9.7). CONCLUSIONS: Women with unexplained infertility are at higher risk of obstetric complications which persist even after adjusting for age, parity and fertility treatment. The reasons are however unclear and merit further study.     

Association Between Major Histocompatibility Antigen and Reproductive Performance

ABSTRACT: Many studies have both supported and refuted an association between HLA antigens and reproductive performance. To clarify these discrepant results, HLA antigens from 59 couples experiencing recurrent spontaneous abortions and 79 couples with unexplained infertility were compared with 51 fertile couples. Patients with recurrent spontaneous abortions were classified as either primary (no children) or secondary (abortions after having children or stillbirths) aborters, and patients with unexplained infertility were classified as primary (never pregnant) or secondary (previously pregnant) infertiles. The amount of antigenic disparity, homozygosity, and the probability of producing a heterozygotic offspring were analyzed for each group. Significantly more disparities at combined HLA loci and at DR loci were observed when childbearing controls were compared with primary aborters. Significant disparity between controls and secondary aborters was at the DQ locus. Total homozygosity as well as homozygosity at DR and DQ loci were significantly increased among primary aborters, but not secondary aborters, and at the B locus among secondary, but not primary infertile couples. Significant association in probability of heterozygote production was seen at the DQ locus in patients with primary infertility. These results indicate that controversy involving association of HLA and reproductive performance can be explained by properly classifying recurrent spontaneous aborters and unexplained infertiles.     

Possible susceptibility of the HLA-DPB1*0402 and HLA-DPB1*04 alleles to unexplained recurrent abortion: analysis by means of polymerase chain reaction-restricted fragment length polymorphism method

PROBLEM: To clarify whether HLA-DP antigens are associated with patient population of unexplained recurrent abortion. METHOD OF STUDY: The frequency of HLA-DPB1 alleles in patients with unexplained recurrent abortion, and the compatibility of HLA-DPB1 alleles between patient couples, were studied using a polymerase chain reaction (PCR)-restricted fragment length polymorphism (RFLP) method. Thirty patients who had a history of unexplained primary recurrent abortion, and their husbands, were typed for HLA-DPB1 genotype. Two hundred and ninety-nine base pair fragments from the second exon of HLA-DPB1 genes were selectively amplified using the PCR-primers. After amplification, the DNAs were digested with restriction endonucleases, and subjected to electrophoresis in a 12% polyacrilamide gel to determine HLA-DPB1 genotype. RESULTS: The frequency of HLA-DPB1*0402 and DPB1*04 alleles in the patient group (n = 30) was significantly increased, as compared to that in the normal fertile women (n = 30). The frequency of HLA-DPB1*04 allele in the patient group was significantly increased, as compared to that in the general population (n = 112). No significant compatibility of HLA-DPB1 alleles could be observed between patient couples and normal fertile couples. CONCLUSION: These findings suggest a possible new class II association with patient population of unexplained recurrent abortion.     

Prevention of Unexplained Recurrent Spontaneous Abortion Using Intravenous Immunoglobulin: A Prospective,Randomized, Double-Blinded,Placebo-Controlled Trial

PROBLEM: The efficacy of intravenous immunoglobulin (IVIG) for treatment of unexplained recurrent spontaneous abortion was assessed in a prospective, randomized, double-blinded, and placebo-controlled study. METHOD OF STUDY: The study took place in a provincial recurrent pregnancy loss clinic, located in a tertiary/quaternary care academic center. The study subjects were women with a history of two or more documented consecutive spontaneous pregnancy losses under 20 weeks of gestation, excluding any associated with aneuploidy by karyotype analysis, and with no evidence of genetic, endocrine, infectious, anatomic, or autoimmune factors associated with a history of recurrent spontaneous abortion. The subjects were randomized to receive either intravenous immunoglobulin (Gamimune N) as treatment or normal saline as placebo. Randomization was stratified for primary, secondary, and unclassified unexplained recurrent spontaneous abortion. Success was defined as an ongoing pregnancy beyond 20 weeks of gestation. RESULTS: Sixty-two subjects enrolled in the trial. There were 37 index pregnancies and 6 cross-over pregnancies. There was no clinically significant difference between the treatment arm and the placebo arm in terms of subsequent pregnancy success. There seemed to be a higher success rate with the stratified analysis of couples with secondary unexplained recurrent spontaneous abortion, but the trial did not have sufficient power to confirm this. CONCLUSIONS: Based on this trial and three similar trials in the literature, a multicentered trial is needed to determine conclusively whether IVIG is effective in the treatment of unexplained recurrent spontaneous abortion.     

Human chorionic gonadotrophin-beta gene sequences in women with disorders of HCG production

Women with recurrent abortion, primary unexplained infertility, and gestational trophoblastic neoplasia (GTN) manifest disordered human chorionic gonadotrophin (HCG) secretion. Mutations in the HCG beta/luteinizing hormone (LH) beta gene complex could cause aberrant HCG production in these disorders. The purpose of this study was to determine whether HCG beta gene deletions occur in women with recurrent abortion or primary unexplained infertility, and whether HCG beta gene duplications are present in women with GTN. DNA was extracted from 10 patients with unexplained recurrent abortion, 10 patients with unexplained primary infertility, 12 patients with GTN, three partners of women with GTN, and 30 controls. Southern blots were constructed and hybridized with DNA probes for HCG beta-5 and the LH beta gene. No gene deletions were identified in patients with recurrent abortion or primary unexplained infertility. Likewise, no gene duplications were identified in women with GTN. A previously described Mbol restriction fragment length polymorphism (RFLP) was identified in both patients and controls. A new Pstl RFLP was also characterized, but was present in patients and controls. Deletion/duplication mutations in the HCG beta/LH beta gene complex do not appear to be common causes of aberrant HCG production in humans with these disorders.      

自身抗体与不孕及自发性流产关系的探讨

目的检测抗心磷脂抗体(ACA)和抗精子抗体(AsAb)两种自身抗体在不孕及自发性流产患者中存在的情况,并观察应用阿司匹林治疗ACA阳性反复流产患者的临床效果。方法应用酶联免疫吸附(ELISA)法检测150例原发或继发不孕患者(不孕组)、198例自发性流产或有胚胎停育史患者(流产组)及40例正常对照组血清中的ACA及AsAb抗体。对其中53例ACA阳性反复流产患者在孕前一个月或孕早期采用低剂量阿司匹林治疗。结果不孕组及流产组ACA总阳性率分别为48.00%和50.51%,与对照组(7.50%)相比有非常显著性差异(P<0.001);不孕组及流产组AsAb阳性率分别为31.33%和25.25%,与对照组(10.00%)比较亦有显著性差异(P<0.05)。53例经治疗患者活产婴儿48例,妊娠成功率为90.57%。结论ACA和AsAb等自身抗体是导致不孕及自发性流产的免疫学因素之一,应用低剂量阿司匹林治疗ACA阳性反复流产患者是保证其妊娠成功的有效方法。     

Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility

PROBLEM: Preconception high peripheral natural killer (NK) cell activity in women with recurrent spontaneous abortion can predict subsequent miscarriages. We have examined prospectively, for the first time, the pregnancy rate in patients with unexplained infertility by measuring the peripheral NK activity. METHOD OF STUDY: We tested the peripheral NK activity of 94 infertile women who despite treatment were unable to conceive for 6 or more months (mean; 2.4 years). Peripheral NK activity was measured by a chromium-51 release cytotoxicity assay. Women were followed for 2 years and assessed. RESULTS: In 77 patients who were followed for 2 years, 28 had conceived but 49 did not. The peripheral NK activity of the group that became pregnant (mean +/- S.D.; 34.5 +/- 13.8%) was significantly lower than that of non-conception group (42.3 +/- 13.3%, P = 0.017). CONCLUSIONS: Our finding suggests that elevated peripheral NK activity in patients with unexplained infertility is a risk factor for attaining pregnancy success.     

抗子宫内膜抗体和抗精子抗体在临床中的价值探讨

目的探讨抗精子抗体和抗子宫内膜抗体在临床上检测原发性不孕和复发性自然流产的价值。方法回顾性分析2018年1月至2018年12月在复旦大学附属妇产科医院诊治的原发性不孕患者及复发性自然流产患者病史,以同期进行常规检查的孕妇作为对照,对比研究对象抗子宫内膜抗体、抗精子抗体的水平,分析抗子宫内膜抗体、抗精子抗体在原发性不孕和复发性自然流产中可能的相关性。结果收集到原发性不孕患者170例及复发性自然流产患者238例病史资料,以同期进行常规检查的孕妇208例作为对照组。原发性不孕患者抗精子抗体检测阳性例数显著高于对照组,但抗子宫内膜抗体并无显著改变;复发性自然流产患者抗子宫内膜抗体检测阳性率显著高于对照组,但抗精子抗体并无明显不同;早孕期流产患者抗精子抗体检测阳性率显著高于对照组;发生复发性自然流产在4次以上的病人,其体内抗子宫内膜抗体和抗精子抗体的水平均显著高于对照组。结论抗子宫内膜抗体和抗精子抗体检测在复发性自然流产和原发性不孕患者中具有相关的临床价值,应加强备孕人群的筛查工作,及早干预。     

胎盘NKT细胞在小鼠原因不明多发性流产中的作用研究

目的:通过检测原因不明多发性流产模型(CBA/J雌鼠×DBA/J雄鼠)小鼠胎盘中的NKT的细胞数量、成熟度和细胞因子的分泌格局,以探索NKT细胞失调在原因不明多发性流产中的可能作用.方法:分别建立正常妊娠模型(CBA/J雌鼠×BALB/C雄鼠)和原因不明多发性流产模型,用流式细胞仪检测滋养层细胞中NKT细胞和CD3~+T数量的变化,用ELISA方法检测Th1/Th2相关细胞因子,而胎盘淋巴细胞T-bet表达水平用荧光定量PCR法检测.结果:正常妊娠组与原因不明多发性流产组CD3~+T细胞数量无显著性变化(P＞0.05);正常妊娠过程中,胎盘淋巴细胞分泌IFN-γ的量逐渐下降,伴随有NKT细胞数量、成熟型比例逐渐下降,而原因不明多发性流产妊娠过程中则相反;多发性流产组与正常妊娠组相比,T-bet mRNA存在表达异常,并与NKT细胞成熟型比例、胎盘淋巴细胞分泌IFN-γ的量成正相关.结论:原因不明多发性流产的发生,可能与NKT细胞失调相关,妊娠早期与胎盘NKT细胞成熟型比例偏低,分泌IFN-γ不足有关,而妊娠中后期则与NKT细胞成熟型比例偏高,分泌IFN-γ过量有关,T-bet mRNA的表达异常是造成NKT细胞失调的因素之一.     

主动免疫治疗复发性自然流产的研究

目的探讨主动免疫在治疗复发性自然流产中的作用。方法选择年龄24～40岁、原因不明性复发性自然流产、封闭抗体阴性患者26例为试验组,选择同期在我科就诊、年龄相当、原因不明性复发性自然流产、封闭抗体阴性患者24例为对照组。对试验组进行淋巴细胞注射及常规保胎治疗,对照组使用常规保胎治疗。结果试验组妊娠成功率为73%,对照组为21%,P〈0.05,差异有显著性。结论主动免疫疗法在治疗原因不明性复发性自然流产中疗效确切,具有操作有效、无副作用等特点。     

Leukocyte activation in the decidua of chromosomally normal and abnormal fetuses from women with recurrent abortion

As part of our continuing programme to investigate immunological causes of unexplained recurrent pregnancy losses, we studied subpopulations of white blood cells and their activation status in decidua of women with a history of recurrent spontaneous abortion (RSA). We differentiated specifically between normal karyotyped male fetuses and abnormal karyotyped fetuses with trisomy 16 because trisomy 16 is not compatible with life and is thus a non-controversial cause of spontaneous miscarriage. Leukocytes were counted in paraffin-embedded decidua after immunohistological staining for CD45 (LCA), CD3, CD56, CD68, CD69 and CD25. Numbers of activated versus non-activated T lymphocytes, NK cells and macrophages were compared in decidua from women with: (i) unexplained RSA who had a normal male karyotype (n = 17) miscarriage; (ii) unexplained RSA who had a trisomy 16 (n = 21) miscarriage; and (iii) normal gestationally age-matched first trimester pregnancies following elective termination procedures (n = 20). Significantly more activated leukocytes were detected in the decidua of women with unexplained RSA who had a normal male karyotype compared to the other groups (P < 0.0001). In addition, numbers of cells comprising the major leukocyte subpopulation, CD56+ NK cells, appeared reduced in the decidua of women with unexplained RSA compared to decidua from women having elective terminations. Increased numbers of activated leukocytes in the decidua of women with a history of unexplained recurrent pregnancy loss who had a normal karyotyped pregnancy provide evidence that cellular immunity may be involved in unexplained recurrent pregnancy loss.     

Hormone and ultrasound parameters in ovarian stimulation cycles for direct intraperitoneal insemination.

To determine hormonal and ultrasound parameters associated with pregnancies, 115 women with unexplained infertility (n = 82), endometriosis (n = 22) or cervical factor (n = 11) were treated with direct intraperitoneal insemination (DIPI) after ovarian stimulation with clomiphene citrate and human menopausal gonadotrophins (HMG). Twenty women conceived and were compared with the remaining 95 non-pregnant women during one treatment cycle. Women with basal FSH levels less than or equal to 1.25 micrograms/l responded with higher oestradiol levels (P less than 0.0001), with the development of more follicles (P less than 0.05) and higher progesterone levels (P less than 0.05) than women with basal FSH levels greater than 1.25 micrograms/l, but the conception rates were similar. Women with miscarriages or biochemical pregnancies had a higher basal FSH value than both the women with term pregnancies and the non-pregnant women. Women with at least 3 preovulatory follicles greater than or equal to 15 mm had a higher pregnancy rate than those with fewer follicles, but a further increase was not observed above that number. The endometrium was thicker on the day of ovulation induction in cycles leading to a term pregnancy than in cycles without conception or with a biochemical pregnancy. No term pregnancy was observed when the endometrium was thinner than 8 mm. Women with a short luteal phase (less than 12 days) had a higher ratio of oestradiol/progesterone in the midluteal phase than women with a luteal phase of greater than or equal to 12 days and pregnant women.(ABSTRACT TRUNCATED AT 250 WORDS)     

In Vitro Suppression of Murine Blastocysts Growth by Sera From Women With Reproductive Disorders

ABSTRACT: Early mouse embryos at the two-cell stage were cultured in medium supplemented with sera from women with primary and secondary multiple spontaneous abortions and with long term unexplained infertility as compared to sera obtained from normal fertile women and pooled human male sera. On the basis of microscopic observation and uptake of ³H-thymidine we report a relationship between reproductive histories and the presence of a serum embryo inhibition factor in eight of ten sera samples from women with primary habitual abortions, six of ten sera from women with secondary habitual abortions, and ten of ten sera from women with unexplained infertility. This activity occurs independently of positive maternal antipaternal lymphocytotoxicity. Fractionation of serum samples by ammonium sulphate precipitation, resulted in removal of the embryo-inhibition factor with the IgG fraction in four of five primary habitual abortion cases and in two of five secondary habitual abortion patients, but not in the case of unexplained infertility. We propose that the appearance of such inhibition factor may be of relevance in the etiologies discussed in this paper and may possibly provide the basis for a new classification of idiopathic spontaneous habitual abortions, i.e. positive or negative for the embryo inhibition factor.     

Association of the A/G polymorphism at position 49 in exon 1 of CTLA-4 with the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population

PROBLEM: To investigate whether the A/G polymorphism at position 49 in exon 1 of cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which delivers a negative signal to T-cell activation, confers the susceptibility to unexplained recurrent spontaneous abortion in the Chinese population. METHOD OF STUDY: A total of 168 patients with unexplained recurrent spontaneous abortion (RSA), who were treated in the Renji Hospital affiliated to the Shanghai Second Medical University, were matched against 117 women with normal pregnancy history. Case-control study to compare the frequency of G/A alleles, AA/AG/GG genotypes and A + (AA + AG) /G+ (GG + AG) phenotypes of CTLA-4 between RSA patients and controls were performed. After amplification of CTLA-4 exon-1 region by polymerase chain reaction (PCR), restriction fragment-length polymorphism (RFLP) was used to detect the polymorphism at position 49 in exon-1 of CTLA-4 gene. Statistical significance was tested by SPSS software. RESULTS: There were dissimilar distributions of G/A alleles, AA/AG/GG genotypes and A+/G+ phenotypes of CTLA-4 between RSA patients and controls. The frequencies of G allele (P = 0.032) and GG genotype (P = 0.011) in RSA patients were significantly higher than those in controls, while the frequencies of AG genotype (P = 0.039) and A + (AA + AG) phenotype in RSA patients were decreased significantly (P = 0.011). CONCLUSIONS: Our findings suggest that A/G polymorphism in exon-1 of CTLA-4 is associated with the immunopathogenesis of RSA, and it confers susceptibility to RSA in Chinese population.     

Treatment of Recurrent Spontaneous Abortion by Immunization With Paternal Lymphocytes: Results of a Controlled Trial

PROBLEM: It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded. METHOD: A double-blind placebo controlled trial was instituted in women with unexplained recurrent spontaneous abortion, comparing immunization with 400 million paternal to 400 million maternal (autologous) lymphocytes. The groups were compared in a paired sequential trials chart, by logistic regression, and, in addition, a meta-analysis of this and other published trials was carried out. RESULTS: The live birth rate among pregnancies in paired couples with paternal lymphocyte immunization was 68% compared to 47% in the women who received their own cells. The results bordered on, but did not achieve, statistical significance. The women in each group were thoroughly investigated to exclude known causes of recurrent pregnancy loss and appeared to have been well matched in all variables. Women with lymphocytotoxic antibodies against paternal lymphocytes were excluded. Unlike our previous study there was not association between the time to conception and the chance of a successful outcome. Indeed, the time to conception was relatively short, 12 wk in all groups. The meta-analysis supported an overall modest favorable experience with paternal cells. CONCLUSION: The study is consistent with a general trend favoring paternal over maternal lymphocyte immunization but reinforces the need for larger multicenter controlled trials as well as more detailed biological study in humans to understand the nature of the maternal-fetal interface and its breakdown.     

Impact of Age on Reproductive Outcome in Women With Recurrent Spontaneous Abortions and Infertility of Immune Etiology

The objective of this paper is to determine whether age has any impact on conception rate, pregnancy outcome, or autoimmune status in women with recurrent spontaneous abortions (RSA) and infertility of immune etiology. One hundred twenty-four women with 3 or more RSA and 36 women with unexplained infertility were prospectively studied. Maternal anti-paternal lymphocyte antibodies and autoantibodies to phospholipids and nuclear antigens were tested. All achieved an adequate alloimmune recognition after lymphocyte immunization and followed for 1 year with optimal preconception autoimmune treatment. Conception rate and pregnancy outcome were prospectively studied. 1) 10.1% of women with RSA and 30.6% of women with infertility failed to achieve a pregnancy after 1 year of trial (P=0.0084); 2) in women with RSA, the number of previous fetal death after 28 weeks of gestation was significantly higher in women who failed to achieve a pregnancy within 1 year when compared to women who became pregnant (P=0.0296). Conception rate was not different with advancing age; 3) women with infertility demonstrated significantly higher incidence of anti-phosphatidylethanolamine antibody when compared to women with RSA (P=0.052); 4) in women with infertility, those who failed to achieve a pregnancy were significantly older (P=0.0012) and demonstrated a higher incidence of autoantibodies to phosphatidic acid than women with infertility who became pregnant (P=0.0339); 5) the subsequent spontaneous abortion rate while on optimal immune therapy was the same in the women with RSA (39.3%) and women with infertility (32%). Spontaneous abortion rate of women with RSA or infertility was not different among four age groups; 6) the presence of anti-cardiolipin antibody (P=0.0055) and higher gravidity (P=0.0354) correlated significantly with pregnancy failure in women with a history of infertility. The prevalence of auto-antibodies to phospholipids and nuclear components was not different among four age groups in women with RSA or infertility. Age does not affect pregnancy outcome or conception rate in women with RSA. In women with infertility of immune etiology, conception rate was significantly reduced over age 40 although pregnancy outcome was no different with advanced age.