Letters to the Editor |
Couples with infertility belong to a very vulnerable group, they should not be exploited
Centre for Reproductive Medicine and Biology, Department of Obstetrics and Gynaecology, Research Institute GROW, Academisch Ziekenhuis Maastricht and Maastricht University, Maastricht, The Netherlands
1 Correspondence address. E-mail: ana{at}sgyn.azm.nl
The recent mini-review on the treatment of repeated implantation failure (RIF) by Margalioth et al. (2006)
has caught our attention. It is timely, concise and to the point. Margalioth et al. mention possible etiologies and suggest methods for treatment of RIF after IVF. There is no doubt in our mind that some of these methods will have been followed by a successful pregnancy in an isolated case, or even in a small number of cases. These cases should lead to generating a clinical research question. This, in turn, should be answered in carefully designed prospective clinical trials. In order to derive conclusions about the application of the suggested treatment options in daily practice, large-scale investigations in well-defined representative groups are mandatory. That is where statistics and methodology come into the picture. Regarding RIF, in many circumstances there is no or insufficient evidence. We should recognize and accept that. The discrepancy between the content of the above-mentioned RIF review and the recommendations by the authors gives us reasons for concern. Not only do they state (referring to patients with three failed IVF cycles and reasonably good embryos) ‘because we do not have the ability to do PGS at our unit, we transfer in these cases as many embryos as possible’, implying that preimplantation genetic screening (PGS) is of proven value in the treatment of RIF and that transferring many embryos is a valid option, but also they recommend a cornucopia of other treatments, none of which has been proven to be of potential benefit in patients with RIF.
The review states that heparin increases the pregnancy rate (PR) in RIF patients. The reference, however, is to a non-systematic narrative review by Fiedler and Wurfel (2004) in an almost inaccessible journal which, at careful reading, states exactly the opposite: ‘there is no defined autoantibody syndrome in RIF even if it may be assumed that it exists. Conclusive evidence for a benefit of heparin (and aspirin) in this situation is lacking as well’. Margalioth et al. (2006) continue to suggest that administration of ‘leucocyte ultrafiltrate’ significantly improves IVF results in RIF patients. They refer to an ‘interim’ analysis report of a case series by Wurfel et al. (2001) in which, in one arm of the study, 8 of 20 patients conceived, whereas in the same period of time in the same clinic an overall PR of 21.2% was obtained. The paper was published in German in the Zentralblatt für Gynäkologie. Today, five years later, neither a follow-up nor a final publication of these remarkable findings has reached the scientific literature, neither in German, nor in any other language. The review continues ‘vaginal administration of micronized estradiol to maximize estrogenic effect (Tourgeman et al., 2001) or antifibrotic (sic!, A.N. and J.E.) treatment with pentoxifylline and high-dose vitamin E (Lédée-Bataille et al., 2002) has been shown to increase PR in cases with a thin endometrium’. Neither of the studies did however. Tourgeman et al. (2001) reported an uncontrolled case series of 10 oocyte recipients with a thin endometrium, of whom 7 conceived after micronized estradiol, Lédée-Bataille et al. (2002), also in an uncontrolled case series, administered pentoxifylline and vitamine E to oocyte recipient patients and obtained 5 pregnancies, 3 of which occurred spontaneously (in oocyte recipient patients!) and 2 after embryo transfer.
It would take too much space to detail all objections to the other conclusions of this review, but also the following recommendations lack scientific evidence in RIF patients: ‘after three failures, repeated hysteroscopy (...) is highly recommended’, ‘a change in the stimulation protocol has a place’, ‘assisted hatching, PGS and co-culture are probably beneficial’, ‘long-term use of danazol or GnRH agonists probably has a place in repeated failures with endometriosis’, ‘the use of IVIG (i.e. intravenous immunoglobulin, A.N. and J.E.) is very controversial but may be justified after many failures in specific cases’ and ‘steroids might have a place in patients with any sign of autoimmunity’. The authors themselves acknowledge that none of these treatments is based on hard data from randomized controlled trials, but they then continue to state that ‘everyone agrees that taking a different approach achieves a pregnancy in many cases that failed repeatedly’. We beg to disagree. Couples with infertility belong to a very vulnerable group. They will do almost anything to achieve a pregnancy. They deserve our dedicated care and evidence-based treatment. In case such an evidence-base is lacking, the patients should be counselled accordingly and, if the occasion arises, they might be invited to participate in a carefully designed clinical trial. They should not be exploited.
References
Fiedler K, Wurfel W. Effectivity of heparin in assisted reproduction. Eur J Med Res (2004) 9:207–214.[Web of Science][Medline]
Lédée-Bataille N, Olivennes F, Lefaix J-L, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod (2002) 17:1249–1253.
Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T. Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod (2006) 21:3036–3043.
Tourgeman DE, Slater CC, Stanczyk FZ, Paulson RJ. Endocrine and clinical effects of micronized estradiol administered vaginally or orally. Fertil Steril (2001) 75:200–202.[CrossRef][Web of Science][Medline]
Wurfel W, Fiedler K, Krusmann G, Smolka B, Von Hertwig I. Improving treatment outcome by LeukoNorm Cytochemia in patients with multiple, failed IVF or ICSI treatment cycles [article in German]. Zentralbl Gynäkol (2001) 123:361–365.[CrossRef][Medline]
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