WORLDWIDE COLLABORATIVE OBSERVATIONAL STUDY AND METAANALYSIS ON ALLOGENIC LEUKOCYTE IMMUNOTHERAPY FOR RECURRENT SPONTANEOUS ABORTION

PROBLEM: Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no known cure. Therefore, effective t reatment is needed. Published results from controlled clinical trials of allogeneic leukocyte immunization of women suffering from RSA have given conflicting results. To address this controversy, the internatio nal raw data of all patients who had been entered into clinical trials that included a control group were collected and analyzed. The primar y question to be answered was whether alloimmune stimulation of the fe male partner improves the subsequent live birth rate. METHODS: Fifteen clinical centers were identified worldwide because they controlled ap propriate raw data. Consequently, nine randomized trials (seven double -blinded) were evaluated independently by two separate data analysis t eams to assure conclusions were robust. One team also compared randomi zed trials to the results of six nonrandomized cohort-controlled studi es to test for bias in nonrandomized trials. Factors predicting succes sful live births among couples with RSA were evaluated by logistic reg ression. RESULTS: Although the two independent analyses made use of di fferent definitions and utilized different statistical methods, the re sults of both were similar. The live birth ratios (ratio of live birth s in treatment and control groups) with 95% confidence intervals (CI) were 1.16 (CI, 1.01-1.34, P=0.031) and 1.21 (CI, 1.04-1.37, P=0.024), respectively. The absolute differences in live birth rates between tre atment and control groups were 8% and 10% in respective analyses. Resu lts in randomized and nonrandomized trials were surprisingly similar d espite significant differences in composition of control and treatment groups. Live birth rates were lower with older female partners, more than five abortions, with a positive ANA or with positive anticardioli pin antibodies. Live birth rates were higher if the female partner had prior to treatment serum antibodies to paternal leukocytes or convert ed from negative to positive with immunization. Approximately 0.5% of controls and 2.1% of treated patients experience side effects for a 1. 6% treatment related effect. There was no evidence of an increased ris k of adverse effects on the fetus. CONCLUSIONS: Two independent analys es of worldwide data on allogeneic leukocyte immunization for treatmen t of RSA suggest that alloimmunization may be an effective treatment. The treatment effect appears, however, to be small, and the data indic ate that immunotherapy helps only 8% to 10% of affected couples. A cur rent lack of diagnostic tests defining patients who most likely would benefit from immunotherapy, precludes the identification of a patient population that would benefit most from such treatment. The efficacy o f treatment in such a subgroup could be expected to increase and could be of sufficient magnitude to allow the determination of more effecti ve immunization protocols. This study does not exclude the possibility of a partial correction of a widely prevalent immunology defect by im munotherapy. The presence of such a defect would indicate a need for m ore effective therapy. The unexplained variation in pregnancy success rates of control groups among centers continues to present a statistic al problem, limiting the statistical evaluation of retroactively obtai ned data.