Reply of the Authors

Abstract

We thank Dr. Scott and Colleagues for their interest in our article (1Christiansen O.B. Andersen A.M.N. Bosch E. Daya S. Delves P.J. et al.Evidence-based investigations and treatments of recurrent pregnancy loss.Fertil Steril. 2005; 83: 821-839Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). In response to their concerns, it should be noted that in the Cochrane review of immunotherapy in recurrent pregnancy loss (RPL) (2Scott J.R. Immunotherapy for recurrent miscarriage.Cochrane Database Sys Rev. 2003; (1):CD000112.Google Scholar), the data were pooled from trials with clinical heterogeneity in terms of dose (which varied from <100 × 106 to >1500 × 106 cells), routes of administration (which varied from exclusively intradermal to exclusively intravenous), and patient profile (which varied in the proportions of women with primary or secondary RPL). The dose and route of administration determine the immunomodulating effect of immunotherapy, and all three mentioned variables are strong prognostic indicators of outcome and should, as far as possible, be factored into any analyses of immunotherapy efficacy. A more reliable approach to meta-analysis is to use individual patient data rather than summary data from the published reports. Such analyses, performed as part of a worldwide collaborative study, demonstrated an overall benefit for immunotherapy (3The Recurrent Miscarriage Immunotherapy Trialist GroupWorldwide collaborative observational study and meta-analysis of allogeneic leukocyte immunotherapy for recurrent spontaneous abortion.Am J Reprod Immunol. 1994; 32: 55-72Crossref PubMed Scopus (244) Google Scholar), and a subgroup analysis performed in women with unexplained primary RPL and no evidence of antipaternal or autoimmune antibodies (4Days S. Gunby J. The Recurrent Miscarriage Immunotherapy Trialists GroupThe effectiveness of allogeneic leukocyte immunization in unexplained primary recurrent spontaneous abortion.Am J Reprod Immunol. 1994; 32: 294-302Crossref PubMed Scopus (99) Google Scholar) produced an overall odds ratio for live birth of 2.42 (95% confidence interval 1.31–4.47) in favor of immunotherapy. It is clear from this meta-analysis that the patient profile associated with a high chance of success with immunotherapy is one in which there is unexplained primary RPL, no pretreatment evidence of antipaternal antibody, and no autoimmune abnormality. The recurrent miscarriage (REMIS) trial (5Ober C. Karrison T. Odem R.R. Barnes R.B. Branch D.W. Stephenson M.D. et al.Mononuclear-cell immunization in prevention of recurrent miscarriages a randomized trial.Lancet. 1999; 354: 365-369Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar), which was terminated early after several interim analyses, resulted in a live birth rate after immunotherapy that was much lower than in all other studies (2Scott J.R. Immunotherapy for recurrent miscarriage.Cochrane Database Sys Rev. 2003; (1):CD000112.Google Scholar) and showed no benefit of the treatment. All previous trials of immunotherapy used fresh purified lymphoid cells from the male partner or donors. In contrast, in the REMIS study, the lymphoid cells after purification were stored overnight at 1°C–6°C and injected the next day. Cells stored in this manner have been shown to lose their immunomodulating effect (6Clark D.A. Chaouat G. Immunomodulation by CD200 as a basis for prevention of cytokine-dependent fetal loss syndrome.Am J Reprod Immunol. 2003; 49: 350-361Crossref Scopus (44) Google Scholar). Hence, the observation of a null effect is not surprising and leads one to conclude that the REMIS trial did not adequately test the efficacy of immunotherapy. We reiterate our position that, from the available evidence to date, immunotherapy in carefully selected women with RPL is efficacious. However, the ideal trial to evaluate the efficacy of immunotherapy is still awaited and requires stratification for important covariates and identification of the optimal dose and route of administration. We are keen to conduct such trials but have found that the conclusion of the Cochrane analysis is an obstacle to obtaining the necessary resources to undertake this important task. Weighing the evidence—metaquality and immunologic problems in in vitro fertilization cycles?Fertility and SterilityVol. 84Issue 3PreviewWe read with interest the article by Christiansen et al. (1) on the investigation and treatment of recurrent pregnancy loss. However, statements about the Cochrane review (2) and implications that lymphocyte immunization might be of value in certain patients warrant comment. Two independently performed meta-analyses from the same set of actual patient records originally showed a slight improvement in live birth rate with paternal lymphocyte immunization, and one of these formed the basis for the first Cochrane review (3, 4). Full-Text PDF