July 28, 1999
Richard Horton
Editor-in-Chief, The Lancet
42 Bedford Square
London WC1B 3SLUnited Kingdom
Dear Sir:
I am writing this letter in regards to the article authored by Carol Ober et al entitled
“ Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial”. Authors of the journal are Carole Ober, Theodore Karrison, Randall R. Odem, Randall B Bames, D Ware Branch, Mary D. Stephenson, Beverly Baron, Mary Ann Walker, James R. Scott, James R. Schreiber.
I will fax you the cover page of a NIH grant for this study which lists me as a co-principal investigator. The title of this grant was “Therapies for Recurrent Miscarriage: A randomized Study”. The grant was projected as a 5-year trial including 524 couples of recurrent pregnancy losses of unknown etiology. As co-principal investigator, I should have been forwarded a copy of this article for my critique. This did not occur and today, the Associated Press – London contacted my office and faxed a copy of the article and the accompanying press release.
I have serious concerns regarding this manuscript.
1. Laboratory tests for the trial were done at my institute and obviously no input was made regarding the interpretation and analysis of the serological studies. I was not informed about this article until today. Study conclusion is rather resolute although the trial failed to recruit an adequate number of study patients.
2. The study failed to induce immune responses. Only 26% of women who received lymphocyte immunization developed HLA antibody response per authors. There is no laboratory data presented to explain this lack of response We feel that either the lymphocyte immunization was prepared and/or given correctly to elicit this low response.
3. The press release for a small size double blind trials gives broad exposure to public broadcasting and scientifically, it only adds further to the controversies regarding lymphocyte immunization, which has been practiced for the last 20 years. There are a vast amount of studies done through out the world and enough scientific evidence to support lymphocyte immunization.
4. It is quite interesting to see the pregnancy losses in control group are pre-embryonic contrary to treatment group being mainly embryonic and fetal. This may suggest that lymphocyte immunization promotes the fetal survival, however, the lymphocyte immunization was sub-optimal. When manuscripts written are so negatively biased, valuable information can be easily neglected.
5. Authors stated that 21 of 59 abortuses received genetic study. Seven of them had abnormal genetic studies and 4 additional fetuses have fetal abnormalities. All (total 11) abnormal fetuses are from treatment group. Authors did not reflect this data for outcome analysis although there is no evidence that lymphocyte immunization can prevent pregnancy losses which is genetically driven. If the manuscript is not biased, this concern should be included and additional analysis should be made.
When genetically abnormal pregnancies were excluded:
7. Authors reported that higher proportion of treatment group had had a previous live birth (P=0.054). From previous meta-analysis, lymphocyte immunization has been reported to be more effective in women with primary abortions. This has not been discussed or considered in this study.
8. The author stated that if her data is added to previous meta-analysis done in 1995, the effect of immunotherapy did not reach significance. Before this opinion is published, the data should be sent to Dr. David Clark who also participated in meta analysis for fair review.
If you have any questions, please feel free to contact me at any time.
Sincerely,
Treatment group : 26 miscarried vs. 31 delivered
Control group: 22 miscarried vs. 41 delivered
By Mantel Haenszel, P=0.234, Odd ratio 1.56 (0.70
Treatment group: 25 miscarried vs. 31 delivered
Control group 18 miscarried vs. 41 delivered
By mantel Haenszel analysis
P=0.119, Odd ratio 1.84 (0.80
ALAN E. BEER, M.D.
Director, Reproductive Medicine
Professor, Department of Microbiology and Immunology
Professor, Department of Gynecology and Obstetrics