Meta-analysis of recombinant FSH and urinary-derived gonadotrophins for IVF or ICSI

Madelon van Wely1 and Fulco van der Veen

Center for Reproductive Medicine, Obstetrics and Gynaecology, H4-205, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

1 To whom correspondence should be addressed. e-mail: m.vanwely{at}amc.uva.nl

Dear Sir,

We read with interest the meta-analysis by Al Inany et al. (2003Go), that compared recombinant (r)FSH and urinary-derived gonadotrophins for IVF or ICSI. This is an interesting topic and outcomes may especially be of interest for those patients that have to pay for the infertility treatment themselves. Several Cochrane systematic reviews have now been performed searching for the best available evidence in this area. Urinary FSH has been compared with hMG (Daya, 1996Go), (r)FSH was compared with urinary FSH (Daya and Gunby, 2000Go) and recently hMG was compared with (r)FSH (Van Wely et al., 2003Go).

We appreciate the effort of the authors to firstly combine all comparisons with (r)FSH and to subsequently perform secondary analyses for the urinary derived gonadotrophins, i.e. hMG, purified urinary-derived FSH and highly purified urinary-derived FSH.

The drawback of this meta-analysis is that the authors do not give information on ultimate treatment success, i.e. live birth or ongoing pregnancy. For a useful comparison of the different gonadotrophins one has to take miscarriages into account. An effect of FSH devoid of LH on early miscarriages has been observed previously (Westergaard et al., 2000Go).

Also the Cochrane Menstrual Disorders and Subfertility Group has as policy now, that they expect the primary outcome to be live birth or, at the very least, ongoing pregnancy in papers comparing treatment success. Interim markers, such as biochemical or clinical pregnancy, can only be secondary outcomes since they are not of ultimate concern.

Live birth is not always given in the articles included in the meta-analysis, however in most articles ongoing pregnancy of live birth was registered. All four papers that were included in the comparison rFSH versus hMG for IVF or ICSI reported ongoing pregnancies or live birth (Van Wely et al., 2003Go).

We furthermore would like to draw the attention of the authors to an error in the clinical pregnancy rate that was extracted from the paper of The European and Israeli Study Group on highly purified hMG versus rFSH (2002Go). In this paper two populations were analysed, the intention-to-treat (ITT) population comprising 727 patients (373 in the hMG and 354 in the rFSH group) and the per-protocol population comprising 693 patients (357 in the hMG and 336 in the rFSH group). Naturally for meta-analyses one should use the ITT data. Strangely the authors report the ongoing pregnancy rates that were reached in the per protocol population (85 in the hMG and 71 in the rFSH group) and refer to these pregnancies as clinical pregnancies. Actually 98 clinical pregnancies were found in the hMG group and 78 in the rFSH group. Had the authors used the right data for their analysis comparing rFSH with hMG the odds ratio would not have been an inconclusive 0.81 (95% CI: 0.63 to 1.05) but would have lead to a borderline significant outcome in favour of hMG [OR: 0.78 (95% CI: 0.61–1.00)].

References

Al-Inany, H., Aboulghar, M., Mansour, R. and Serour, G. (2003) Meta-analysis of recombinant versus urinary-derived FSH: an update. Hum. Reprod., 18, 305–313.[Abstract/Free Full Text]

Daya, S. (1996) Follicle-stimulating hormone and human menopausal gonadotropin for ovarian stimulation in assisted reproduction cycles (Cochrane Review). The Cochrane Library, Oxford, Update Software.

Daya, S. and Gunby, J. (2000) Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction cycles (Cochrane Review). The Cochrane Library, Oxford, Update Software.

The European and Israeli Study Group on highly purified hMG versus rFSH (2002) Efficacy and safety of highly purified menotropin versus recombinant follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection cycles: a randomized, comparative trial. Fertil. Steril., 78, 520–528.[CrossRef][ISI][Medline]

van Wely, M., Westergaard, L.G., Bossuyt, P.M. and Van der Veen, F (2003) Human menopausal gonadotropin versus recombinant follicle stimulation hormone for ovarian stimulation in assisted reproductive cycles (Cochrane Review). The Cochrane Library, Issue 1, Oxford, Update Software.

Westergaard, L.G., Laursen, S.B. and Yding Andersen, C. (2000) Increased risk of early pregnancy loss by profound suppression of luteinizing hormone during ovarian stimulation in normogonadotrophic women undergoing assisted reproduction. Hum. Reprod., 15, 1003–1008.[Abstract/Free Full Text]