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.
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