Immunotherapy and recurrent abortion: a randomized clinical trial. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial. Short-term therapy for recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study. Immunotherapy for recurrent spontaneous abortions in a Chinese population. Induction of MLR-Bf and protection of fetal loss: a current double blind randomized trial of paternal lymphocyte immunization for women with recurrent spontaneous abortion. Controlled trial of treatment of recurrent spontaneous abortion by immunisation with paternal cells. Intravenous immunoglobulin for treatment of recurrent pregnancy loss. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Prevention of recurrent spontaneous abortion by intravenous immunoglobulin: a double-blind placebo-controlled study. Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial. Placebo-controlled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v. immunoglobulin. Prevention of unexplained recurrent spontaneous abortion using intravenous immunoglobulin: a prospective, randomized, double-blinded, placebo-controlled trial. Treatment of recurrent aborters by immunization with paternal cells--controlled trial.
We conducted a randomized trial comparing expectant management versus immunotherapy with paternal leukocytes to improve obstetric outcome in women with unexplained recurrent abortion. Eligible for the study were women with unexplained recurrent abortion (three or more miscarriages and no live birth), negative findings of immunological screening and no inhibition of the mixed lymphocyte culture. These women were seen for the first time between October 1988 and March 1991 in a network of obstetric departments in Northern Italy. Subjects positive for HLA DR3 or with a partner positive for hepatitis virus B antigen were not eligible. A total of 44 women entered the study. Patients were randomly allocated to immunotherapy (22 women) or expectant management (22 women). Women allocated to immunotherapy were given 200 x 10(6) purified paternal lymphocytes before pregnancy. Median follow-up was 24 months (range 10-39) in the immunotherapy group and 25 months (range 11-38) in the expectant management group. Out of the 22 women randomized to immunotherapy, 16 became pregnant and the corresponding value was 14 in the expectant management group. Spontaneous abortion occurred in six out of the 16 pregnancies observed in the treated women. Among the 14 pregnancies observed in the expectant management group, two aborted and one late fetal death occurred. The cumulative proportions of women who became pregnant over 4 years were 37 and 45% in the immunotherapy and expectant management groups respectively; this difference was not significant. No adverse effect was observed in treated women. 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.
                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.
                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.
                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. It is still unclear whether i.v. immunoglobulins (Ig) can facilitate the reproductive prognosis of women who have suffered recurrent pregnancy loss. We report the results of a multicentre placebo-controlled study on the effect of Ig administration on pregnancy outcome in 46 women who had suffered at least three recurrent miscarriages. All were screened to exclude chromosomal or Müllerian abnormalities, the presence of antinuclear antibodies, lupus anticoagulant (LA) or elevated titres of anticardiolipin antibodies which may have revealed an underlying autoimmune problem. To avoid a selection bias towards ongoing pregnancies, i.v. Ig or placebo were administered between weeks 5 and 7 of gestation for 2 consecutive days as soon as each woman knew she was pregnant and before embryonic heart activity could be detected. A further infusion was administered at week 8 when ultrasonography confirmed an ongoing embryonic development. In all, 68% of the women who received Ig went to term versus 79% of those who received a placebo (not significant), with no significant differences in the pregnancy course or the perinatal outcome. These results suggest either that women with recurrent miscarriages who have no recognized cause of pregnancy loss have a good reproductive prognosis without any treatment or that the emotional care associated with the administration of a placebo can indirectly facilitate the progression of pregnancy. The efficacy of immunotherapy for the treatment of recurrent spontaneous abortions was tested in patients selected from the same ethnically homogeneous population of Chinese in Taiwan in whom the immunogenetics of gestational trophoblastic tumors and of recurrent spontaneous abortion had been studied. The patients, who included both primary and secondary aborters, were randomly assigned to three groups: those who were immunized with their own lymphocytes (controls) (49); those who were immunized with their husbands' lymphocytes (39); and those who were immunized with third party lymphocytes (11). The data were analyzed individually for the primary and secondary aborters and collectively for both groups combined. The number of babies born, the number of current pregnancies, and the number of recurrent abortions were not statistically significantly different between the control and the immunized groups, and a similar small number of congenital abnormalities (4-9%) occurred in both the control and immunized groups. The increase in the blocking effect for the mixed lymphocyte reaction was not related to the success of the postimmunization pregnancies. Thus, this study does not show any significant improvement in the rate of livebirths in women immunized with their husbands' lymphocytes or with third party lymphocytes compared to that in a placebo-controlled group of women. The present study was conducted to evaluate the efficacy of paternal lymphocyte (PL) immunotherapy and its relation with the development of mixed lymphocyte reaction blocking antibodies (MLR-Bf) and the success of pregnancy outcome in women with recurrent spontaneous abortion (RSA). A total of 124 women with unknown causes of abortions was registered for immunotherapy under double blind randomized trial by using the list of computer-generated numbers. Each 5 x 10(6) autologous lymphocyte (AL), third party lymphocyte (TPL) and PL was dissolved separately in 1 ml of sterile normal saline (NS). Each 1 ml of cell suspension and neat NS was injected in women with RSA through intramuscular (250 microl), intradermal (250 microl), subcutaneous (250 microl) and intravenous (250 microl) routes. All women participants with RSA received six identical immunizations at the regular interval of 4 weeks, and were then screened for the development of MLR-Bf after the completion of immunization course, and also at the first, second and third trimesters (12th, 24th and 36th weeks) of pregnancy. However, nonimmunized MLR-Bf positive women with RSA did not receive any kind of therapy (NT) and were used as one of the control group in the present study. We have observed that PL-immunized women with RSA showed a significantly increased level of MLR-Bf (>30) and pregnancy success (84%) as compared to those women with RSA who received either AL (33%), TPL (31%), NS (25%) or those who did not receive any kind of treatment (NT, 44%; P<0.001). Our results indicated the importance of immunotherapy with PL in women with RSA and also showed that MLR-Bf can be considered as one of the important factors for pregnancy improvement. In a paired sequential double-blind trial of immunological treatment of recurrent spontaneous abortion successful outcome of the next pregnancy was significantly more common in women injected with purified lymphocytes prepared from their husbands' blood than in those injected with their own lymphocytes. 17 of 22 women given paternal cells had successful pregnancies, compared with 10 of 27 given their own cells. Efficacy of immunotherapy for treatment of recurrent spontaneous abortion (SA) has been controversial. The low treatment effect of white blood cell immunization lead to investigations of alternative treatments including intravenous (i.v.) immunoglobulin (Ig). To evaluate the efficacy of IVIg for treatment of recurrent SA, a prospective, randomized, double blinded, placebo-controlled trial was performed.
                Ninety-five women experiencing two or more consecutive spontaneous abortions, with no known cause were randomized and received either IVIg 500 mg/kg/month or placebo (albumin).
                Of 95 women participating in the study, 47 received IVIg and 48 received placebo. Medication was discontinued in 34 women who failed to conceive within four cycles. The remaining 61 women achieved pregnancy. Pregnancy outcomes included 29 deliveries and 32 recurrent SA. Among women delivering live births 18 (62%) received IVIg and 11 (38%) received placebo. By contrast, 21 (66%) women experiencing recurrent SAs received placebo and 11 (34%) received IVIg. Among 61 women who conceived, 29 received IVIg and 32 received placebo. Of the 29 women who conceived and received IVIg, 18 (62%) delivered live births and 11 (38%) experienced recurrent SA. Of 32 women who conceived and received placebo 11 (34%) delivered live births and 21 (66%) had recurrent SA. The difference in live birth rates between women receiving IVIg and placebo was significant (P = 0.04, odds ratio 3.1).
                IVIg is effective in enhancing the percentage of live births among women experiencing unexplained recurrent SA. Previous trials of intravenous immunoglobulin (IvIg) treatment of women with recurrent miscarriage (RM) have provided diverging results. This may be due to different inclusion criteria and suboptimal treatment protocols in some trials.
                According to a computer-generated list, 58 women with at least four unexplained miscarriages were randomly assigned to receive infusions of high doses of IvIg or placebo starting as soon as the pregnancy test was positive.
                In the intention-to-treat analysis, a 45% live birth rate was found in both allocation groups. In patients with secondary RM, 50% in the treatment group and 23% in the placebo group had successful pregnancies (P = not significant). When data from the present and a previous placebo-controlled trial of the same treatment were combined, 15/26 (58%) of the patients with secondary RM in the treatment group versus 6/26 (24%) in the placebo group had successful outcomes (P < 0.02). Only 7% of the karyotyped abortuses were abnormal.
                IvIg may improve pregnancy outcome in patients with secondary RM. A new placebo-controlled trial focusing on this subgroup should be conducted to confirm the results. The aim of this study was to evaluate the therapeutic efficacy of intravenous immunoglobulin (IVIG) in the prevention of recurrent spontaneous abortion (RSA). In a double-blind, randomized, placebo-controlled study, 41 women with a history of unexplained recurrent spontaneous abortion were treated with IVIG or saline infusions during pregnancy. The birth of a child was considered a successful outcome. The overall success rate was 77% in the IVIG group compared with 79% in the placebo group. For women with primary RSA the success rates were 82 (IVIG) and 89% (placebo), and for women with secondary RSA the rates were 73 (IVIG) and 70% (placebo). We found no statistically significant difference in treatment results between IVIG and placebo. Couples with unexplained recurrent miscarriage may have an alloimmune abnormality that prevents the mother from developing immune responses essential for the survival of the genetically foreign conceptus. Immunisation with paternal mononuclear cells is used as a treatment for such alloimmune-mediated pregnancy losses. However, the published results on this treatment are conflicting. In this study (the Recurrent Miscarriage [REMIS] Study), we investigated whether paternal mononuclear cell immunisation improves the rate of successful pregnancies.
                Women who had had three or more spontaneous abortions of unknown cause were enrolled in a double-blind, multicentre, randomised clinical trial. 91 were assigned immunisation with paternal mononuclear cells (treatment) and 92 immunisation with sterile saline (control). The primary outcomes were the inability to achieve pregnancy within 12 months of randomisation, or a pregnancy which terminated before 28 weeks of gestation (failure); and pregnancy of 28 or more weeks of gestation (success). Two analyses were done: one included all women (intention to treat), and the other included only those who became pregnant.
                Two women in each group received no treatment, and eight (three treatment, five control) were censored after an interim analysis. In the analysis of all randomised women who completed the trial, the success rate was 31/86 (36%) in the treatment group and 41/85 (48%) in the control group (odds ratio 0.60 [95% CI 0.33-1.12], p=0.108). In the analysis of pregnant women only, the corresponding success rates were 31/68 (46%) and 41/63 (65%; odds ratio 0.45 [0.22-0.91], p=0.026). The results were unchanged after adjustment for maternal age, number of previous miscarriages, and whether or not the couple had had a previous viable pregnancy. Similar results were obtained in a subgroup analysis of 133 couples with no previous livebirth.
                Immunisation with paternal mononuclear cells does not improve pregnancy outcome in women with unexplained recurrent miscarriage. This therapy should not be offered as a treatment for pregnancy loss. The aim of this trial was to investigate whether infusions of i.v. immunoglobulins (Ig) to women with secondary recurrent spontaneous abortions and recurrent second trimester spontaneous abortions can increase the rate of successful pregnancy. In a prospective, double-blind, placebo-controlled trial, infusions of i.v. Ig (Nordimmun) or placebo were given during pregnancy to 34 women with a history of either unexplained recurrent spontaneous abortion subsequent to a birth or including at least one second trimester miscarriage. The success rate was 52.9% in the i.v. Ig group compared with 29.4% in the placebo group (not significantly different, therapeutic gain 23.5%, 95% confidence interval -8.6 to 55.7%). No changes in autoantibody concentrations or major lymphocyte subsets were induced by i.v. Ig treatment. In conclusion, an expected 55% therapeutic gain of i.v. Ig in recurrent spontaneous abortion could not be confirmed using the treatment regimen tested. However, to determine whether the trend of therapeutic gain of i.v. Ig in these women may be statistically significant, a larger trial is in progress. 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.
                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.
                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.
                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. A paired sequential trial was undertaken to establish whether paternal mononuclear cells improved the prognosis in couples with recurrent abortions. For this purpose, 10(7)-10(8) cells obtained from the blood of partners were injected intravenously, subcutaneously, and intra-dermally into women who had had three or more consecutive miscarriages with the same partner. Control women were given normal saline, injected in the same manner. The result of the sequential analysis showed that there was no significant beneficial effect of the cells compared to control. The overall success rate was 70% (32/46 couples). The success rate in patients given cells was 62% (13/21), while in those given saline it was 76% (19/25). While the overall success rate in this study compares with a number of other studies, we find an equally high success rate with non-immunized patients. We conclude that the value of immunization for the prevention of recurrent miscarriage has not been established.
Paternal cell immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no significant beneficial effect over placebo in improving the live birth rate.