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The challenge of meta-analysis and the need to register clinical trials
FERTILITY AND STERILITY威 VOL. 74, NO. 2, AUGUST 2000
LETTERS TO THE EDITOR The Challenge of Meta-Analysis and the Need to Register Clinical Trials To the Editor: I read with interest the recent meta-analysis of Agrawal et al. (1) because I believe a properly conducted metaanalysis can contribute to evidence-based decision making. I was surprised, however, to see included in the meta-analysis a study of mine (ref. 31), which from the title alone (FSH alone or in combination with hMG) apparently did not meet the inclusion or exclusion criteria listed by the authors. The authors state that two identified studies were excluded because they compared FSH⫹hMG vs. hMG. Our own study was a comparison of FSH with and without hMG; there was no comparison of FSH vs. hMG; therefore, it does not belong in this meta-analysis.
Copyright ©2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
42 consecutive candidates were randomized. Thus, it is surprising that randomization led to arms containing 25 (hMG) and 17 (FSH) patients with no dropouts. Randomization also led to 20 of the 25 hMG patients having tubal disease, whereas only 3 of 17 FSH patients were in this category; 1 of 25 hMG couples had male factor whereas for FSH 6 of 17 did. Because the study examined IVF (i.e., no ICSI) the FSH group would be at a disadvantage for fertilization potential and therefore pregnancy potential. This biased allocation of subjects makes the data inappropriate for meta-analysis. Despite this bias, the FSH group’s pregnancy outcome compares favorably with that of hMG, further bringing into question any conclusions based on these (biased) PR results. It is noteworthy that in the meta-analysis (1) it is stressed that studies in which the treatment groups were not homogeneous were excluded.
On further reading a number of other discrepancies arise that seriously undermine the integrity of the present study. Thus, articles by O’Shaughnessy et al. (ref. 21) and Check et al. (ref. 24) are remarkably similar: same co-authors, same time frame of study 1992–1993, same number of patients, and same pregnancy rates (PR) per transfer. I suspect that one study has been counted twice.
For the short protocols the only publication is Daya et al. (ref. 22) so de facto no meta-analysis has occurred. Therefore, it is misleading to present this data (short protocol) as having been meta-analyzed.
The study from Soderstrom-Anttila et al. (ref. 36) was conducted in volunteer oocyte donors. Assisted reproduction technology (ART) pregnancy is a complex interplay of ovarian output (oocyte-embryo number and quality) and endometrial preparation. In regular ART cycles both these effects of stimulation on the endometrium are no longer relevant. The inclusion of this one donor egg study with the 10 nondonor egg studies leads to a heterogeneous rather homogeneous group of studies.
Juan Balasch, M.D. Institut Clinic of Gynecology, Obstetrics and Neonatology Faculty of Medicine-University of Barcelona Barcelona, Spain February 22, 2000
The exclusion of the study by Tanbo et al. (ref. 20) because patients had all polycystic ovaries (PCO) is puzzling because PCO is not mentioned in the study exclusion criteria. With no doubt, patients having PCO were included in other studies analyzed in the meta-analysis because anovulation is an indication for IVF. The results from the study by Fries et al. (ref. 19) were excluded because the authors were apparently unable to obtain pertinent data for evaluation. It is of interest that the study by Fries et al. was included in the meta-analysis by Daya et al. (2) published in the Journal and PR are provided. With the work of Gordon et al. (refs. 38 and 39) the comparability of the treatment arms is questionable because randomization led to unequal and perhaps noncomparable study arms (39 and 29 patients). In the study by Yang et al. (ref. 34), the abstract states that 420
There are serious irredeemable problems with the present study that we think deserves to be reconsidered.
References 1. Agrawal R, Holmes J, Jacobs HS. Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil Steril 2000;73:338 – 43. 2. Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA. Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil Steril 1995;64:347–54.
PII S0015-0282(00)00660-9
To the Editor: The recent publication by Agrawal et al. (1) has raised several issues that deserve comment. First, is the lack of comprehensiveness of their search for trials comparing FSH and hMG for ovarian stimulation in IVF. I am in the midst of updating a systematic review on this subject published in the Cochrane Database of Systematic Reviews (2) and have identified many more randomized trials (from 1999 and earlier) than have Agrawal et al. (1). There are at least four more trials in the “short GnRH agonist protocol” group and seven additional trials in the “long GnRH agonist protocol” group. After the process of validating the data in these trials
LETTERS TO THE EDITOR The Challenge of Meta-Analysis and the Need to Register Clinical Trials To the Editor: I read with interest the recent meta-analysis of Agrawal et al. (1) because I believe a properly conducted metaanalysis can contribute to evidence-based decision making. I was surprised, however, to see included in the meta-analysis a study of mine (ref. 31), which from the title alone (FSH alone or in combination with hMG) apparently did not meet the inclusion or exclusion criteria listed by the authors. The authors state that two identified studies were excluded because they compared FSH⫹hMG vs. hMG. Our own study was a comparison of FSH with and without hMG; there was no comparison of FSH vs. hMG; therefore, it does not belong in this meta-analysis.
Copyright ©2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
42 consecutive candidates were randomized. Thus, it is surprising that randomization led to arms containing 25 (hMG) and 17 (FSH) patients with no dropouts. Randomization also led to 20 of the 25 hMG patients having tubal disease, whereas only 3 of 17 FSH patients were in this category; 1 of 25 hMG couples had male factor whereas for FSH 6 of 17 did. Because the study examined IVF (i.e., no ICSI) the FSH group would be at a disadvantage for fertilization potential and therefore pregnancy potential. This biased allocation of subjects makes the data inappropriate for meta-analysis. Despite this bias, the FSH group’s pregnancy outcome compares favorably with that of hMG, further bringing into question any conclusions based on these (biased) PR results. It is noteworthy that in the meta-analysis (1) it is stressed that studies in which the treatment groups were not homogeneous were excluded.
On further reading a number of other discrepancies arise that seriously undermine the integrity of the present study. Thus, articles by O’Shaughnessy et al. (ref. 21) and Check et al. (ref. 24) are remarkably similar: same co-authors, same time frame of study 1992–1993, same number of patients, and same pregnancy rates (PR) per transfer. I suspect that one study has been counted twice.
For the short protocols the only publication is Daya et al. (ref. 22) so de facto no meta-analysis has occurred. Therefore, it is misleading to present this data (short protocol) as having been meta-analyzed.
The study from Soderstrom-Anttila et al. (ref. 36) was conducted in volunteer oocyte donors. Assisted reproduction technology (ART) pregnancy is a complex interplay of ovarian output (oocyte-embryo number and quality) and endometrial preparation. In regular ART cycles both these effects of stimulation on the endometrium are no longer relevant. The inclusion of this one donor egg study with the 10 nondonor egg studies leads to a heterogeneous rather homogeneous group of studies.
Juan Balasch, M.D. Institut Clinic of Gynecology, Obstetrics and Neonatology Faculty of Medicine-University of Barcelona Barcelona, Spain February 22, 2000
The exclusion of the study by Tanbo et al. (ref. 20) because patients had all polycystic ovaries (PCO) is puzzling because PCO is not mentioned in the study exclusion criteria. With no doubt, patients having PCO were included in other studies analyzed in the meta-analysis because anovulation is an indication for IVF. The results from the study by Fries et al. (ref. 19) were excluded because the authors were apparently unable to obtain pertinent data for evaluation. It is of interest that the study by Fries et al. was included in the meta-analysis by Daya et al. (2) published in the Journal and PR are provided. With the work of Gordon et al. (refs. 38 and 39) the comparability of the treatment arms is questionable because randomization led to unequal and perhaps noncomparable study arms (39 and 29 patients). In the study by Yang et al. (ref. 34), the abstract states that 420
There are serious irredeemable problems with the present study that we think deserves to be reconsidered.
References 1. Agrawal R, Holmes J, Jacobs HS. Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis. Fertil Steril 2000;73:338 – 43. 2. Daya S, Gunby J, Hughes EG, Collins JA, Sagle MA. Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis. Fertil Steril 1995;64:347–54.
PII S0015-0282(00)00660-9
To the Editor: The recent publication by Agrawal et al. (1) has raised several issues that deserve comment. First, is the lack of comprehensiveness of their search for trials comparing FSH and hMG for ovarian stimulation in IVF. I am in the midst of updating a systematic review on this subject published in the Cochrane Database of Systematic Reviews (2) and have identified many more randomized trials (from 1999 and earlier) than have Agrawal et al. (1). There are at least four more trials in the “short GnRH agonist protocol” group and seven additional trials in the “long GnRH agonist protocol” group. After the process of validating the data in these trials