Endometriosis related infertility Files/D3/Charles Chapron.pdf · 18/09/2014 3 Endometriosisis -...
Transcript of Endometriosis related infertility Files/D3/Charles Chapron.pdf · 18/09/2014 3 Endometriosisis -...
18/09/2014
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Endometriosisrelated infertility:
A global approach in 2014 ?
Université Paris Descartes,
Sorbonne Paris Cité
Faculté de Médecine, AP-HP,
GHU Ouest, CHU Cochin, Paris, France
Professor Charles Chapron, M.D
Head of Department,
GynecologySurgical unit:
C Chapron, B Borghese, P Santulli, H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, A Bititi, P Marzouk, L Marcellin
Medical unit: A Gompel, G Plu-Bureau, L Maitrot
Reproductive Endocrinology unit:D de Ziegler, P Santulli, V Gayet, I Streuli, FX Aubriot
Intestinal surgeryB Dousset, M Leconte
RadiologyAE Millischer
Laboratory: GeneticD Vaiman, F Mondon, S Barbaux
Laboratory: ImunulogyB Weill, F Batteux, C Nicco, C Chéreau
Laboratory: Reproductive biologyJP Wolf, V Lange, K Pocate,JM Kuntzman, C Chalas
Statistical unitF Goffinet, PY Ancel
D. de Ziegler, Professor and Head, Reproductive Endocrinology and Infertility unit,A. Gompel, Professor and Head, Medical Gynecological unit,
C. Chapron, Professor and Chair, Dpt Gynecology Obstetrics II and Reproductive Medicine
Endometriosis and infertility: PathogenesisPelvic cavity:
Inflammation-related process interfereswith sperm-oocyte intercations:
Reduced chances of IN VIVO fertilization
Uterus: Alterations of eutopic endometrium:
- Activation CYP-19- Resistance to P4 (PR-D)
Ovaries: Decreased ovarian response to COH:
- More FSH / hMG needeed- Less oocytes obtained
Receptivity
de Ziegler, Borghese and Chapron The Lancet (2010)
Endometriosis related infertility
- Specifications and pathogenesis
- What are the therapeutic options ?
- How to choose between the therapeutic options?
- Proposition for a strategy
Endometriosis - related infertilityManagement options
Endometriosisrelated infertility
Expectant
Ovarian suppression
Surgery
Controlled ovarian
hyperstimulation
Intracervicaland intrauterine
insemination
Assisted Reproductive Technologies:
FIV, ICSI Association of medical and surgical Ttt
(per and/or post op)
Endometriosis related infertilityManagement options
- Medical treatment
- Surgery
- Assisted Reproductive Technologies
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Endometriosis related infertilityManagement options
- Medical treatment
- Surgery
- Assisted Reproductive Technologies
Hughes et al., Cochrane Database (2007)
Endometriosis related infertilityOvarian Suppression versus Placebo
All options are contraceptive
Endometriosis related infertilityManagement options
- Medical treatment
- Surgery
- Assisted Reproductive Technologies
Vercellini et al., Human Reprod 2009;24:254-69.
ConsiderSx + 6-18 Mo
in vivoCumulative PR
50%
Time (months)6 18
Endometriosis - related infertility
≥ 12 months
< 12 months
Pregnancy: 0.79 (95% CI: 0.46–1.35)
Vercellini et al., RBMO (2010)
Endometriosis - related infertility :Postoperative delayed initiation of attempted conception
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Endometriosisis - related infertility
Marcoux et al.,NEJM (1997)
Deep infiltrating endometriosis (DIE) N # IUP % IUP
Coronado et al., 1990 33 13 39.4 Nehzat et al., 1994 8 1 12.5 Bailey et al., 1994 49 24 48.9 Jerby et al., 1999 7 3 42.8 Chapron et al., 1999 30 15 50.0 Possover et al., 2000 15 8 53.3 Redwine and Wright, 2001 23 7 30.4 Kavallaris et al., 2003 38 18 47.4 Fedele et al., 2004 50 17 34.0 Thomassin et al., 2004 15 4 26.7 Chopin et al., 2005 78 42 53.8 Daraï et al., 2005 22 10 45.5 Fleisch et al., 2005 17 4 23.5 Keckstein et al., 2005 95 47 49.5 Mohr et al., 2005 58 23 39.6 Lyons et al., 2006 3 3 100.0 Vercellini et al., 2006 44 15 34.1 Ferrero et al., 2009 46 22 47.8 Meuleman et al., 2009 33 16 48.5 Stepniewska et al., 2009 30 12 40.0 Total 694 304 43.8
43.8%
Laparoscopic excision of endometrioma (OMA) N # IUP % IUP
Daniell et al., 1991 32 12 37.5 Marrs et al., 1991 23 7 30.4 Bateman et al., 1994 21 9 42.8 Crosignani et al., 1996 22 6 27.3 Montanino et al., 1996 11 5 45.5 Donnez et al., 1996 814 414 50.8 Sutton et al., 1997 66 30 45.5 Beretta et al., 1998 9 6 66.7 Milingos et al., 1998 32 17 53.1 Busacca et al., 1999 67 39 58.2 Jones and Sutton, 2002 39 15 38.5 Alborzi et al., 2004 32 19 59.4 Fedele et al., 2006 90 29 32.2 Vercellini et al., 2006 237 128 54.0 Total 1495 736 49.2
49.2%
De Ziegler, Borghese and Chapron Lancet (2010)
OMA
DIE
Stages I and II
Meuleman et al., Ann Surg (2013)
Deep endometriosis related infertility :Laparoscopic surgery in women
with moderate to severe endometriosisPatientsoperated
Wishing to conceive
Pregnant
127 94 (74%) 48 (51%)
76 54 (71%) 27 (50%)
44%
58%
1 Y
ear
2 Y
ears
3 Y
ears
73%
Meuleman et al., Ann Surg (2013)
Deep endometriosis related infertility :Laparoscopic surgery in women
with moderate to severe endometriosis
Only 41% conceived spontaneously
Bowel resection p
Yes No
Recurrence 2/76 (3 %) 6/127 (5%) < 0.05
Intestinal DIE: Surgical techniques
Spontaneousconception
IVFtreatment
Expectation of pregnancy
Time after surgery (days)
Stepniewska et al., Hum Reprod (2009)Bowel resection Residuel bowelendometriosis
Bowelresection
Residuel bowelendometriosis
Conception No Conception
1 year
No bowelendometriosis
2 years
4 years
Pre opAMH levels≥ 3.1ng/ml
Raffi et al., JCEM (2012)
Laparoscopic excision of OMAs
Muzii et al., Fertil Steril (2002)
Oma cyst wall: no follicule
Oma cyst wall: Scanty primordial follicule
Oma cyst wall: Two primordial follicule
Ovarian cysts Recognizable ovariantissue adjacent to OC wall
N n %
OMAs 26 14 54
Serous 7 0 0
Dermoid 6 1 17
Mucinous 3 0 0
Total 42 15 36
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Deep endometriosis: Complications
....................................................................................
Complicat ion Observed incidence(%)
Neurogenic bladder dysfunction 4–10
Rectovaginal fistula formation 2–10
Blood transfusion 2–6
Inadvertent rectal perforation 1–3
Anastomotic leakage 1–2
Pelvic abscess 1–2
Temporary diverting loop ileostomy/colostomy
0.5–1.5
Intraoperative ureteral lesion 0.5–1
Post-operative ureteral fistula formation 0.5–1
Post-anastomotic rectal stenosis 0.5–1
Post-anastomotic ureteral stenosis 0.5–1
Vercellini et al., Hum Reprod (2009)
Surgery for endometriosis (n = 790 patients)
No (n = 471; 60%) Yes (n = 309; 40%)
SUP 109 (23.1%) 22 (7.1%)
OMA 152 (32.3%) 45 (14.6%)
DIE 210 (44.6%) 242 (78.3%) 4.5 (3.2 - 6.2)
- DIE isolated 144 (68.6%) 138 (57.0%)
- DIE associated OMA 66 (31.4%) 104 (43.0%)
Endometriotic lesions Previous surgery for Osis OR 95% CI
Worst DIE lesion Previous surgery for Osis OR 95% CI
No (n = 471; 60%) Yes (n = 309; 40%)
USL 71 (34.0%) 32 (13.3)
Vagina 21 (10.0%) 16 (6.7%)
Bladder 18 (8.6%) 17 (7.0%)
Intestine 77 (36.8%) 159 (66.0%) 3.2 (2.1 - 4.8)
Ureter 22 (10.5%) 17 (7.0%) (Sibude and Chapron, Obstet Gynecol (in press)
Coef = 0.62, 95% CI 0.47-0.77, p<0.0001
Nu
mb
er
of
DIE
le
sio
ns
Determinants for existence of DIE: Results with multiple logistic regression analysis
AOR (95% CI) p
Previous surgery (yes vs no) 2.7 (1.7-4.3) <0.001
Previous surgery for endometriosis (n = 790 patients)
(Sibiude and Chapron, Obstet Gynecol (in press)
Endometriosis:Surgical management
Disease Surgery
Progression
Recurrence
Unnecessary
Inappropriate
?
Endometriosis:and pain
SUP
OMAs
DIE
DIE
The Lancet (2010)
Vercellini et al., Am J Obstet Gynecol (2006)Vercellini et al., Hum Reprod Update (2009)
Reduce rate of:
- Recurrence DM OR : 0.15 ; CI 0.06 - 0.06
- Recurrence DP OR : 0.08 ; CI 0.01 - 0.51
- Recurrence NCPP OR : 0.10 ; CI 0.02 - 0.5656
Hart (2005)
Sutton (1994)
Surgery
Endometriosis related infertilityManagement options
- Medical treatment
- Surgery
- Assisted Reproductive Technologies
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Canada 2004
Australia 2009
France2001-2005
USA2009
IVF ICSI IVF + ICSI IVF + ICSI IVF + ICSI
Primary diagnosis Pregnancies(% per retrieval)
Pregnancies(% per retrieval)
Pregnancies (% per initiated cycle)
Pregnancies(% per initiated cycle)
Live births(% per aspiration)
Male factor 31.0% 37.7% 24.9% 20.1% 37.6%
Tubal factor 33.5% 29.4% 23.5% 21.0% 32.2%
Idiopathic 36.4% 34.7% 23.7% 21.6% 33.7%
Endometriosis 37.8% 41.4% 25.7% 23.7% 35.3%
Ovulatory disorder 35.6% 36.3% 23.2% 22.6% 40.4%
Other 37.6% 27.9% 18.5%% 27.7%
Gunby J et al. Fertil Steril (2008)Yueping A et al. Assisted Reproductive technology in Australia and New Zeland (2009)
FIVNAT (2001-2005)USA, 2009 aspirations: National Center for Chronic Disease Prevention and Health Promotion Division of Reproductive Health
Endometriosis: ART outcome
Harb et al., BJOG (2013)
Singleton pregnancies resulting from IVF/ICSI: Obstetric and perinatal outcomes
Outcome OR 95% CI
Ante-partum haemorrhage 2.49 (2.30 - 2.69)
Congenital anomalies 1.67 (1.33 - 2.09)
Hypertensive disorders of pregnancy 1.49 (1.39 - 1.59)
Preterm rupture of membrane 1.16 (1.07 - 1.26)
Caesaren section 1.56 (1.51 - 1.60)
Low birth weight 1.65 (1.56 - 1.75)
Perinatal mortality 1.87 (1.48 - 2.37)
Preterm delivery 1.54 (1.47 - 1.62)
Gestational diabetes 1.48 (1.33 - 1.66)
Induction of labor 1.18 (1.10 - 1.28)
Small for gestational age 1.39 (1.27 - 1.53)
Pandey et al., Hum Reprod (2012)
ART: Reasons for and predictors of discontinuation
Gameiro et al., HR Update (2012)
Infertiles patients with Omas:
Garcia-Velasco et al., Fertil Steril (2004)
Unoperated Bilateral OMAs: ART outcome
Benaglia et al., Fertil Steril, (2013)
Characteristics Case n = 39 Control n = 78 p
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OMAs and oocytes quality: IVF cycles
Filippi et al., Fertil Steril, (2014)
Surgery versus ARTSurgery ART
Fertility results
Limits Specific complicationsUnnecessary surgeriesOvarian reserve damage
Specific complicationsPost ponction infections No efficient for pain
Advantages Pelvic pain treatmentAvoid risk of ovariancancer
OMA surgery not necessary
Endometriosis related infertility
- Specifications and pathogenesis
- What are the therapeutic options ?
- How to choose between the therapeutic options?
- Proposition for a strategy
Endometriosis: n = 870 patients
Pelvic pain Infertility
Asymptomatic
202 23.2%
SUP 21 10.4%OMA 36 17.8%DIE 145 71.8%
* Oma + 76 52.4%* Oma - 69 47.6%
453 52.1%
SUP 52 11.5%OMA 105 23.2%DIE 296 65.3%
110 12.6%
SUP 25 22.7%OMA 59 53.6%DIE 26 23.6%
Chapron and Santulli, (2013)
105 120%
SUP 49 46.7%OMA 29 27.6%DIE 27 25.7%
* Oma + 9 33.3%* Oma - 18 66.7%
p < 0.001
≠
OMAs and Pelvic Pain: Relationship
Hum Reprod (2012)
OMA
DIE
OMAs and Pelvic Pain: Relationship
Hum Reprod(2012)
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OMA: Factors associated with DIE in the multiple logistic regression analysis
Lafay – Pillet and Chapron Hum Reprod (2014)
Parameters Ad OR 95% CI AUC
0.84
Duration of pain > 24 months 3.8 1.9 - 7.7
VAS DP > 5 or GI symptoms > 5 6.0 2.9 - 12.1
Severe dysmenorrhea 3.8 1.9 - 7.6
Infertility (primary or secondary) 2.5 1.2 - 4.9
Number of DIE score points contributedby each factor and clinical prediction rule.
Lafay – Pillet and Chapron Hum Reprod (2014)
OMA:
Total Score PointsSum
Predicted risk(95% CI)
< 13: Low risk 10% (7 - 15)
≥ 35: High risk 88% (83 - 92)
OMA: Performance of clinical scoringsystem to predict associated DIE
Lafay – Pillet and Chapron Hum Reprod (2014)
Training sample
Validation sample
Deep endometriosis:Frequency of associatedovarian endometriomas
(n = 636 patients)
Main lesion Associated OMAs
N n %
Bladder 51 8 15.7
USL 279 49 17.6
Vagina 93 19 20.4
Ureter 29 13 44.8
Intestine 184 86 46.7
Total 636 175 27.5
Chapron et al., Fertil Steril (2010)
Deeply infiltrating endometriosis (n = 500 patients).Results according to the presence of OMA
OMA - OMA + p - value
Mean number of DIE lesions 1.64 ± 1.0 2.51 ± 1.72 < 0.0001
rAFS scores
Implants 6.7 ± 4.9 28.1 ± 10.1 < 0.0001
Adhesions 16.5 ± 23.7 36.2 ± 28.7 < 0.0001
Total 23.6 ± 25.7 65.6 ± 33.1 < 0.0001
Chapron et al., Fertil Steril (2009)
Adenomyosis and intestinal DIEAssociated OMA
Intestinal DIE Ad Ose post + Ad Ose post - p OR (95% CI)
N % N %
OMAs + 37 53.6 9 30.0 0.025 2.7 (1.1 - 6.7)
OMAs - 32 46.4 21 70.0
Chapron, (in preparation)
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Painful OMAsModern management
OMAs DIEVAS
≥ 7« Severe » OMAs
IntestineUreter
USLVaginaBladder
« Isolated » OMAs
Preoperative work-up imaging:Referral center
Chapron – Santulli et al., Hum Reprod (2012)
< 7
Painful ovarian endometrioma
Painful ovarian endometrioma Painful ovarian endometrioma
DIE: Excisional surgeryDeep infiltrating endometriosis (DIE) N # IUP % IUP
Coronado et al., 1990 33 13 39.4 Nehzat et al., 1994 8 1 12.5 Bailey et al., 1994 49 24 48.9 Jerby et al., 1999 7 3 42.8 Chapron et al., 1999 30 15 50.0 Possover et al., 2000 15 8 53.3 Redwine and Wright, 2001 23 7 30.4 Kavallaris et al., 2003 38 18 47.4 Fedele et al., 2004 50 17 34.0 Thomassin et al., 2004 15 4 26.7 Chopin et al., 2005 78 42 53.8 Daraï et al., 2005 22 10 45.5 Fleisch et al., 2005 17 4 23.5 Keckstein et al., 2005 95 47 49.5 Mohr et al., 2005 58 23 39.6 Lyons et al., 2006 3 3 100.0 Vercellini et al., 2006 44 15 34.1 Ferrero et al., 2009 46 22 47.8 Meuleman et al., 2009 33 16 48.5 Stepniewska et al., 2009 30 12 40.0 Total 694 304 43.8
The Lancet (2010)
43.8%
Intestinal DIE and infertility: ICSI - IVF
Ballester et al., Hum Reprod (2012)
CMR after ICSI - IVF
Mathieu d’Argent et al., Fertil Steril (2011)
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Intestinal DIE and infertility: ICSI - IVF
Ballester et al., Hum Reprod (2012)
Adenomyosis
Age
AMH
Endometriosis: AMH levels according to the type of Osis lesions and prior OMA surgery
Streuli, de Ziegler and Chapron, Hum Reprod (2012)
Endometriosis: AMH levels according to the presence of OMAs and prior OMA surgery
Streuli, de Ziegler and Chapron, Hum Reprod (2012)
Endometriosis: Logistic regression analysisof factors preidcting AMH levels < 1 ng/ml
Streuli, de Ziegler and Chapron, Hum Reprod (2012)
Fertilitypreservation:
Oocyte vitrification
Rienzi et al., Hum Reprod (2012)
Effect of patients and cycle characteristics on delivery obtained with vitrified oocytes.
(logistic regression)
*
* *Endometriosis related infertility
- Specifications and pathogenesis
- What are the therapeutic options ?
- How to choose between the therapeutic options?
- Proposition for a strategy
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Take home messages
Pelvic pain
Infertility
Take home messages
Strategy
- Multidisciplinary management
Endometriosis
and
Patients
- Global approach
Surgery
Medical Ttt
ART
SUP OMAs DIE
Adenomyosis
Pelvic pain
Infertility
1
1
de Ziegler, Borghese and ChapronThe Lancet (2010)
In principleNO surgery
Ovarian suppression(3 months)
IVF / ICSI
« EmergencyART »
Infertilitywork-up
Ovarian reserveTime available for In Vivo
Ovarian endometriomais the « KEY lesion »
Risk factor for DIE severity
Ovariandamage
Risk factor for associated
Adosis to DIE
Take home message
Deep infiltrating endometriosis
Painful OMA
Ovarian endometrioma:Modern management
Infertility Pelvic painA
Referral center
VAS < 7: Isolated Omas
VAS ≥ 7: Omas associated
with severe DIE
Classical center
CB
?
New concept:« Emergency ART »
Surgery
SurgeryART withoutsurgery
Previous ART ?- Medical Ttt ?
- Fertilitypreservation ?
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Take home messages
Best indication for surgery
in cases of endometriosis
related infertility is
pelvic pain
Take home messages
Necessity to reconsider the strategy:
Surgery ART? ? ?
Take home messages
Surgery:
* Avoid unnecessary procedures
* Precise the best moment
* New concept: Once onlyin « the endometriosis life »