Situation non acceptable Echecs récidivants de FIV avec ou sans
Transcription
Situation non acceptable Echecs récidivants de FIV avec ou sans
Situation non acceptable Echecs récidivants de FIV avec ou sans anticorps anti-phospholipides Dans cette situation, il faut d’abord rechercher la cause des avortements. Les IgIV n’ont pas fait la preuve certaine de leur efficacité. Les études sont contradictoires. Effet des IgIV dans les avortements précoces récidivants Auteurs Type d’étude Posologie Résultats % de naissance : ↑ S du % de naissance : p = 0.012 Clark (2006) Méta-analyse 3 essais randomisés chez 172 femmes en échecs de FIV Stephen son (2000) Comparative versus placebo N = 51 échecs de FIV IgIV : % de naissance : 15% IgIV gpe versus 12% : NS 0.5 g/kg le jour du transfert d’embryon ou dans les 72h avant Balasch (1996) Ouverte N = 12 échecs d’implantation de l’embryon Ouverte N = 10 au moins 7 échecs de FIV les couples partagent au moins 3 HLA loci - test de cross-match négatif Ouverte N = 29 échecs de FIV IgIV : % d’implantation : 0 implantation 0.4 g/kg/j pdt 5 j de stimulation ovarienne 5 à 7 j avant transfert d’embryon IgIV : % de naissance : 7/10 succès dont 2 30 g x 2 : 1 dose avant la grossesses gémellaires ponction des ovules puis la 2ème dose dès l’existence d’un poul foetal Elram (2005) Coulam (1994) IgIV : 9/16 : grossesses 0.5 g /kg après implantation 1/13 : grossesse tous les 28 j jusquà S : p = 0.02 l’accouchement ou 28-32ème - femmes produisant > 3 sem embryons / cycle après stimulation : n = 16 - < 3 embryons / cycle : n = 13 Bibliographie Les référentiels de la Juste prescription du CEDIT (AP-HP), des Pharmaciens de CHU et des Hospices Civils de Lyon ont été les documents de base du travail bibliographique. La recherche bibliographique a été réalisée par interrogation systématique des banques de données Medline, Embase et Pascal. Elle a identifié préférentiellement les essais cliniques et les revues de synthèse publiés en langue française ou anglaise après janvier 1996. 1. Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006 Jan;23(1):1-13. 2. Elram T, Simon A, Israel S, Revel A, Shveiky D, Laufer N.Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod Biomed Online. 2005 Dec;11(6):745-9. 3. Coulam CB, Goodman C. Increased pregnancy rates after IVF/ET with intravenous immunoglobulin treatment in women with elevated circulating C56+ cells. Early Pregnancy. 2000 Apr;4(2):90-8. Afssaps – décembre 2010 1 4. Balasch J, Creus M, Fábregues F, Font J, Martorell J, Vanrell JA. Intravenous immunoglobulin preceding in vitro fertilizationembryo transfer for patients with repeated failure of embryo transfer. Fertil Steril. 1996 Mar;65(3):655-8. 5. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial..Fertil Steril. 2000 Dec;74(6):1108-13. Groupe de travail Dr ALADJIDI Nathalie, hémato-onco-pédiatre, Bordeaux Pr CHERIN Patrick, interniste, Paris Dr CHIFFOLEAU Anne, biologiste, Nantes Dr DEBRE Marianne, hémato-immuno-pédiatre, Paris Dr DONADIEU Jean, hémato-onco-immuno-pédiatre, Paris Pr FAIN Olivier, interniste Paris Pr GLOTZ Denis, néphrologue, Paris Pr KESSLER Michèle, néphrologue, Nancy Dr LARROCHE Claire, interniste, Paris Dr MADELAINE Isabelle, pharmacien, Paris Pr POLLACK Benoît, hématologue, Grenoble Dr ROTHSCHILD Chantal, hématologue, Paris Pr SIE Pierre, Hématologue, Toulouse Pr WAHL Denis, interniste et vasculaire, Nancy Groupe de lecture Pr DHOTE Robin, interniste, Paris Pr GODEAU Bertrand, interniste, Paris Pr GUILLEVIN Loïc, interniste, Paris Pr HACHULLA Eric, interniste, Lille Pr KESSLER Michèle, néphrologue , Nancy Pr LECOMPTE Thomas, hématologue, Nancy Pr LEVERGER Guy, hémato-immuno-pédiatre, Paris Pr MILPIED Noël, hématologue, Bordeaux Pr TRON François, hématologue, Rouen Pr VIALLARD Jean-François, interniste, Bordeaux Pr LE PARC Jean-Marie, rhumatologue, Paris Comité de qualification Pr CAULIN Charles, Président, thérapeutique, Paris Pr AULAGNER Gilles, pharmacien, représentant des HCL, Lyon Mme BONGRAND Marie-Claude, pharmacien, représentante des Pharmaciens de CHU, Marseille Dr DUMARCET Nathalie, Afssaps Dr CHASSANY Olivier, méthodologiste, Paris Mme FAUCHER-GRASSIN Joëlle, pharmacien, représentante des Pharmaciens de CHU Poitiers Pr LAVILLE Maurice, praticien hospitalier, représentant des HCL, Lyon Mme MONTAGNIER-PETRISSANS Catherine, pharmacien, représentante de la Juste prescription de l’AP-HP, Paris M. LIEVRE Michel, pharmacologue, Lyon Mme PIVOT, pharmacien, représentante des HCL Lyon Pr RICHÉ Christian, pharmacologue, Brest M. ROPERS Jacques, Afssaps Pr VICAUT Eric, médecin de santé publique, Paris Afssaps – décembre 2010 2 La Commission d’AMM du 24 Octobre 2008 présidée par le Pr Daniel VITTECOQ n’a pas émis d’objection à ce référentiel, qui a également été visé par la Commission de la transparence de la HAS, présidée par le Pr Gilles BOUVENOT. Résumés-abstracts Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006 Jan;23(1):1-13. PROBLEM: Intravenous Immunoglobulins (IVIG) are widely used off label in the treatment of early reproductive failure. As IVIG is expensive, and may have side-effects, evidence of efficacy is needed. Previous results have suggested that the pre-conception treatment of primary recurrent abortion patients might be effective, but the data set has been too small for adequate statistical power. More recently it has been suggested that IVIG may improve the success rate of in vitro fertilization and embryo transfer (IVF) in patients with prior IVF failures, but clinical trials have given conflicting results that need explanation. Systematic reviews generating inconclusive results have focused on methodological rigor to the exclusion of biological plausibility. METHODS: Review of current basic science of design, measurement, and evaluation of clinical trials and basic science mechanisms providing a rationale for treatment. Meta-analysis of published randomized controlled and cohort-controlled trials (updated with two unpublished data sets) evaluating IVIG treatment in IVF failure patients. Live birth rate was used as the most relevant endpoint. The ability of different sources of IVIG to suppress natural killer (NK) cell activity was determined using a standard (51)Cr-release assay in vitro. RESULTS AND CONCLUSIONS: Meta-analysis of three published randomized controlled trials (RCTs) of IVIG in IVF failure patients shows a significant increase in the live birth rate per woman (p = 0.012; Number Needed to Treat for 1 additional live birth, NNT = 6.0 women). Using live birth rate per embryo transferred, and adding data from two cohort-controlled trials to the meta-analysis further supports this conclusion (overall p = 0.000015, NNT = 3.7 women). Relevant variables appear to include properties and scheduling of the IVIG, and selection of patients with abnormal immune test results. Different IVIG preparations vary significantly in their ability to suppress NK activity in vitro. A rationale for use of IVIG is provided by a review of mechanisms of IVIG action and mechanisms underlying failure of chromosomally normal embryos. Elram T, Simon A, Israel S, Revel A, Shveiky D, Laufer N. Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod Biomed Online. 2005 Dec;11(6):745-9. This study sought to assess the efficacy of intravenous immunoglobulin (IVIg) in improving pregnancy rates and outcome, in a select group of patients with repeated IVF failure and human leukocyte antigen (HLA) similarity. Couples suffering from recurrent IVF failure, defined as at least seven attempts at embryo transfer with no successful implantations, who were found to share at least three HLA loci, and a negative cross-match test, were included in the study. The treatment consisted of two 30 g IVIg doses: one before oocyte retrieval, and a second as soon as a fetal pulse was identified on ultrasound. Ten couples comprised the study group. In total, these couples had undergone 98 IVF cycles with no successful pregnancies prior to initiation of the study. Following a total of 18 IVIg courses, seven women conceived, two women twice. Up to date, five women have delivered at least one live fetus, at 27 weeks or later. One woman is currently in the early third trimester of a twin pregnancy, and one woman had a late abortion at 19 weeks. The results suggest that couples with recurrent IVF failure and HLA similarity, may benefit from IVIg treatment. Coulam CB, Goodman C. Increased pregnancy rates after IVF/ET with intravenous immunoglobulin treatment in women with elevated circulating C56+ cells. Early Pregnancy. 2000 Apr;4(2):90-8. . Intravenous (IV) immunoglobulin (Ig) has been previously shown to increase pregnancy rates after previously failed in vitro fertilization (IVF) embryo (ET) attempts in women who are efficient embryo producers (fertilize at least 50% of oocytes retrieved and generate at least 3 embryos/cycle). Women experiencing implantation failure have a higher frequency of elevated percentage of circulating CD56+ (natural killer) cells (>12%) than fertile women (3-12%). To evaluate the effects of IVIg on pregnancy rates in women with elevated percentage of circulating CD56+ cells, 32 women who had previously failed IVF/ET (>12 embryos transferred without pregnancy) were studied. Pregnancy and live birth rates with and without IVIg were compared in the same woman. All 32 women had previously failed to conceive after at least 12 ET, were efficient embryo producers and had persistently elevated plasma concentrations of CD56+ cells. Each woman received IVIg 500mg/kg prior to ET. If serum hCG concentrations were positive for pregnancy, IVIg was continued at 500mg/kg/mo until 28 weeks gestation. Pregnancy rates with and without IVIg were 56% and 9% (P<0.0001). The rate of live birth was 38% Afssaps – décembre 2010 3 with IVIg and 0% without IVIg (P<0.0001). IVIg enhances pregnancy and live birth rates in women with elevated circulating CD56+ cells who have a history of implantation failure. Despite technologic advances leading to enhancement of fertilization rates after in vitro fertilization (IVF) (1, 2) implantation rates after embryo transfer (ET) have not increased significantly (3) over the last 20 years (4). Implantation rates after IVF/ET are influenced by the quality of the embryos and receptivity of the endometrium (3-9). Endometrial receptivity involves both hormonal (10-13) and immunologic (14-29) factors. Among the immunologic factors that play a crucial role in successful implantation are natural killer (NK) cells (14-18). NK cells present within the decidua that express CD56(but lack CD 16) have been associated with successful implantation (14-18). A deficiency of decidual CD56+ CD16- cells (18) and an increase in circulating CD56+ cells (25, 26) have been observed in women experiencing implantation failure. Women experiencing implantation failure after IVF and multiple ET have been successfully treated with intravenous (IV) immunoglobulin (Ig) (27). IVIg reduces activation of NK cells and NK killing activity both in vitro (29) and in vivo (30-31). This reduction in activation of NK cells is essential for normal implantation to occur (14). To further define the role of IVIg for treatment of implantation failure, pregnancy and live birth rates were compared before and after IVIg treatment in women undergoing IVF/ET who had elevated levels of circulating CD56+ cells. Coulam CB, Krysa LW, Bustillo M .Intravenous immunoglobulin for in-vitro fertilization failure. Hum Reprod. 1994 Dec;9(12):2265-9. The aim of this study was to determine the effectiveness of intravenous (i.v.) immunoglobulin (Ig) for treatment of individuals experiencing failure after in-vitro fertilization (IVF) and embryo transfer. A total of 29 women with unexplained infertility who failed to become pregnant after IVF/embryo transfer were divided into two groups based on performance in previous IVF cycles: 16 women had fertilization of > or = 50% of oocytes retrieved and/or produced > or = 3 embryos each cycle and 13 had fertilization of < 50% of oocytes retrieved and/or produced < 3 embryos each cycle. Each woman had received at least 12 transferred embryos (95th percentile for successful IVF patients) or had experienced two or more biochemical pregnancies without ultrasonic confirmation of implantation during previous IVF/embryo transfer attempts. All women received i.v. Ig 500 mg/kg prior to the next embryo transfer. Only one of the 13 (8%) women with suboptimal fertilization and embryo yield became pregnant in the treatment cycle. Of 16 women who had previously had fertilization of at least 50% of oocytes retrieved and produced at least three embryos, nine (56%) became pregnant in the treatment cycle. The difference in pregnancy rates between the two groups is significant (P = 0.02). Intravenous Ig is useful in the treatment of unexplained IVF failure in women who have oocyte fertilization rates > or = 50% and generate at least three embryos per cycle. Balasch J, Creus M, Fábregues F, Font J, Martorell J, Vanrell JA. Intravenous immunoglobulin preceding in vitro fertilization-embryo transfer for patients with repeated failure of embryo transfer. Fertil Steril. 1996 Mar;65(3):655-8. OBJECTIVE: To determine the effectiveness of immunotherapy with high-dose IV immunoglobulin preceding IVFET for patients with repeated failure of ET. DESIGN: Prospective, observational. SETTING: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting. PATIENTS: Twelve consecutive tubal infertility patients experiencing repeated unexplained IVF-ET failure including at least three ETs replacing three to four fresh embryos each. Two women shared three or more human leukocyte antigens (HLA) with the husband. INTERVENTION: During the subsequent new IVF-ET cycle, each patient received 400 mg/kg IV immunoglobulin daily for 5 days during ovarian stimulation, that is, 5 to 7 days before ET. MAIN OUTCOME MEASURES: Clinical pregnancies. RESULTS: No implantation occurred. There were no side effects. CONCLUSIONS: High-dose IV immunoglobulin is not a useful tool for IVF-ET failure. Stephenson MD, Fluker MRTreatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial..Fertil Steril. 2000 Dec;74(6):1108-13. OBJECTIVE: To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with repeated unexplained in vitro fertilization (IVF) failure. DESIGN: Prospective, randomized, double blind, placebocontrolled clinical trial. SETTING: A university-based and a free-standing IVF program. PATIENT(S): Fifty-one couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or replacement of cryopreserved embryos. INTERVENTION(S): Eligible women underwent a standard IVF stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks Afssaps – décembre 2010 4 later if a clinical pregnancy was confirmed by ultrasound. MAIN OUTCOME MEASURE(S): Live-birth rates. RESULT(S): Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group (P=0. 52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of 4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group (P=0.59). CONCLUSION(S): In this randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome. Afssaps – décembre 2010 5