Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial

We thank Yamamoto and Suzuki for their comments on our recent paper that revealed a high dose of intravenous immunoglobulin (IVIG) in early pregnancy was effective for women with ≥4 recurrent pregnancy losses (RPLs) of unexplained aetiology.1Yamada H Deguchi M Saito S Takeshita T et al.Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: a double-blind, randomized, placebo-controlled trial.eClin Med. 2022; 50: 1-12https://doi.org/10.1016/j.eclinm.2022.101527Summary Full Text Full Text PDF Scopus (12) Google Scholar As they pointed out, this double-blind randomised controlled trial is referred to as a phase III study in the clinical study protocol according to agreement with the Japan Pharmaceuticals and Medical Devices Agency, given the current lack of promising treatments for unexplained RPL.2NIH U.S. National Library of Medicine ClinicalTrials.govA study of the Efficacy and Safety of GB-0998 in Patients With Unexplained Recurrent Miscarriage.https://clinicaltrials.gov/ct2/show/NCT02184741Google Scholar However, the editor and reviewers of the journal indicated that this trial should be essentially called a pivotal Phase II study but not a Phase III study, considering the sample size and the number of inclusion/exclusion criteria. A phase II efficacy study establishes how well the treatment might work in a select group of patients rather than a phase III/IV effectiveness study (to estimate how well the treatment might work in an unselected, real-world population). Second, the clinical study protocol describes that the primary outcome is ongoing pregnancy rate at 22 weeks of gestation in women who received the study drug excluding those who miscarried due to fetal chromosome abnormality (modified intention-to-treat [modified-ITT] population). However, this trial found that the ratio of miscarriage with abnormal chromosome karyotype in the IVIG group (3/50, 6·0%) was significantly lower than that in the placebo group (10/49, 20·4%, p=0·03). This is potentially a part of IVIG treatment effect, and the IVIG might have a preventative role in averting miscarriage with abnormal chromosome karyotype increasing the ratio of live birth. Similarly, in 2015 Greco et al. discovered that transferred embryos with abnormal chromosome karyotype have the ability to develop into healthy euploid newborns, one year after the start of this trial.3Greco E Minasi MG Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts.N Engl J Med. 2015; 373: 2089-2090Crossref PubMed Scopus (369) Google Scholar In addition, the ratio of miscarriage with unknown chromosome karyotype in the IVIG group (4/19, 21·1%) was higher than that in the placebo group (1/31, 3.2%, p=0·0622), but these miscarriages with unknown karyotype had been counted as miscarriages with normal chromosome karyotype for the statistical analyses in the modified-ITT population. These problems confound interpretations of results in the modified-ITT population. For that reason, the editor and reviewers of the journal directed that the ITT population, but not the modified-ITT should be set up to anticipate a treatment effect and, consequently, we mainly described and discussed results in all women who received the study drug (ITT population). HY, MD, SS, and TT contributed the contents of this reply and gave approval of the version to be published. None. Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy lossesIn the recent article of eClinicalMedicine,1 the authors demonstrate that high-dose intravenous immunoglobulin may be effective in recurrent pregnancy losses (RPL). This achievement in an area where double-blind randomised controlled trials are difficult to conduct is to be applauded. On the other hand, we would like to point out two areas in the article that may cause misunderstanding and reduce the value of it. Full-Text PDF Open Access