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In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study
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GYOBFE-2977; No. of Pages 7 Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
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Original article
In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study Re´sultats en FIV apre`s ablation des endome´triomes par e´nergie plasma : e´tude cas te´moin re´trospective I. Motte a,b, H. Roman a,b,c,*, B. Clavier a,b, F. Jumeau d, I. Chanavaz-Lacheray a,b, M. Letailleur a,b, B. Darwish a,b, N. Rives b,c,d a
Department of gynecology and obstetrics, Rouen university hospital, 76031 Rouen, France Expert Center in the Diagnostic and Multidisciplinar Management of Endometriosis ‘‘Rouendometriose’’, 76031 Rouen, France c Research Group 4308 ‘‘Spermatogenesis and Gamete Quality’’, IHU Rouen Normandy, IFRMP23, reproductive biology laboratory, Rouen university hospital, 76031 Rouen, France d Department of reproductive biology, Rouen university hospital, 76031 Rouen, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2016 Accepted 5 August 2016 Available online xxx
Objective. – Ovarian endometrioma ablation using plasma energy appears to be a valuable alternative to cystectomy, because it could spare underlying ovarian parenchyma resulting in high spontaneous and overall pregnancy rates. After initial postoperative decrease, anti-mullerian hormone (AMH) level progressively increases several months after ablation. The aim of our study was to assess the outcomes of in vitro fertilization (IVF) in women managed for ovarian endometriomas by ablation using plasma energy, when compared to those in women free of endometriosis. Methods. – Retrospective preliminary case-control study, enrolling women undergoing IVF or IntraCytoplasmic Sperm Injection (ICSI), from July 2009 to December 2014. Cases were infertile women with previous ovarian endometrioma ablation using plasma energy and were matched by age, AMH level and assisted reproductive technique with controls presumed free of endometriosis. IVF/ICSI response (type of protocol, dose of gonadotrophin, number of oocytes, fertilization rate) and outcomes were compared between the two groups. Results. – In all, 37 cases were compared to 74 controls. Age (30.9 4.4 years vs. 31.7 4.2 years), AMH level (2.8 2 ng/mL vs. 2.8 1.7 ng/mL) and ART procedures (ICSI in 24.3% vs. 27%) were comparable between the two groups. Of the 37 cases, previous surgical procedures on right and left ovaries were performed in 27% and 21.6% of patients respectively, 81% of patients were nullipara. AFSr score was 73 41, while deep endometriosis infiltrated the rectum and the sigmoid colon in respectively 40.5% and 27% of patients. Despite a lower number of oocytes retrieved, cases presented better implantation rate, pregnancy and delivery rates per cycle, oocyte retrieval, transfer, and embryo, as well as superior cumulative birth rate per transfer. Conclusion. – Ovarian endometrioma ablation using plasma energy is followed by good IVF/ICSI outcomes, suggesting that surgical procedure spares underlying ovarian parenchyma. These results consolidate those of previous studies reporting high spontaneous conception rate. Hence, ovarian endometrioma ablation using plasma energy appears to be a valuable alternative to cystectomy in patients presenting with endometriosis and pregnancy intention. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Antimullerian hormone AMH ICSI IVF Ovarian endometriomas Plasma energy Fertility
* Corresponding author at: Department of gynecology and obstetrics, Rouen university hospital–Charles-Nicolle, 1, rue de Germont, 76031 Rouen, France. E-mail address: [email protected] (H. Roman). http://dx.doi.org/10.1016/j.gyobfe.2016.08.008 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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R E´ S U M E´
Mots cle´s: AMH ICSI IVF Endome´triomes E´nergie plasma Fertilite´
Objectif. – La chirurgie des endome´triomes ovarien par e´nergie plasma semble eˆtre une alternative inte´ressante a` la kystectomie. Elle permettrait d’e´pargner le parenchyme ovarien sous-jacent et d’obtenir des taux de grossesse spontane´s e´leve´s. Apre`s une diminution postope´ratoire initiale, l’hormone antimu¨lle´rienne (AMH) augmente progressivement jusqu’a` plusieurs mois apre`s l’ablation. Le but de notre e´tude e´tait d’e´tudier les re´sultats en fe´condation in vitro (FIV) chez les femmes traite´es pour endome´triomes ovariens par ablation a` l’aide de l’e´nergie plasma, compare´ a` des te´moins sans endome´triose. Me´thodes. – Il s’agit d’une e´tude cas-te´moins re´trospective incluant des femmes prises en charge en FIV ou injection intra-cytoplasmique de spermatozoı¨des (ICSI), a` partir de juillet 2009 jusqu’a` de´cembre 2014. Les femmes infertiles ayant eu une ablation d’endome´triome ovarien par e´nergie plasma ont e´te´ apparie´es par aˆge, taux d’AMH et technique de FIV avec des femmes sans endome´triose. La re´ponse en FIV/ICSI (type de protocole, dose de gonadotrophine, nombre d’ovocytes, taux de fe´condation) et les re´sultats ont e´te´ compare´s entre les deux groupes. Re´sultats. – Au total, 37 cas ont e´te´ compare´s a` 74 te´moins. L’aˆge (30,9 4,4 ans vs 31,7 4,2 ans), le taux d’AMH (2,8 2 ng/mL vs 2,8 1,7 ng/mL) et le type de proce´dure (ICSI 24,3 % contre 27 %) e´tait comparable entre les deux groupes. Quatre-vingt-un pour cent des patients e´taient nullipare. Le score AFSR e´tait de 73 41, tandis que l’endome´triose profonde infiltrait le rectum et le coˆlon sigmoı¨de chez respectivement 40,5 % et 27 % des patients. En de´pit d’un nombre infe´rieur d’ovocytes ponctionne´s, les cas pre´sentaient un meilleur taux d’implantation, taux de grossesse et taux d’accouchement par cycle, ovocytes re´cupe´re´s, transferts et embryons. Conclusion. – L’ablation des endome´triomes par e´nergie plasma permet d’obtenir de bons re´sultats en FIV/ ICSI, sugge´rant que cette proce´dure chirurgicale e´pargnerait le parenchyme ovarien sous-jacent. Ces re´sultats consolident ceux des e´tudes pre´ce´dentes ayant re´ve´le´ un taux de grossesse spontane´e e´leve´. Par conse´quent, l’ablation des endome´triomes ovariens avec l’e´nergie plasma semble eˆtre une alternative inte´ressante a` la kystectomie chez les patients pre´sentant des endome´triomes et ayant un de´sir de grossesse. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction The relationship between the management of ovarian endometriomas and infertility feeds one of the most exciting debates in the field of endometriosis. Recent guidelines concluded that performing cystectomy of endometriomas in infertile women referred for assisted reproductive technology (ART) does not improve pregnancy rates [1,2]. Although pre-in vitro fertilization (IVF) management of ovarian endometriomas is not contraindicated in women with endometriosis-associated pain or inaccessible follicles, surgeons must be aware of the risk of postoperative ovarian reserve impairment with negative impact on ART results [2]. Thus, surgery is the current management worldwide for ovarian endometriomas in infertile patients seeking both pregnancy and health improvement. Notwithstanding, surgery by cystectomy is a valuable treatment for infertility in many cases of severe endometriosis [3]. Surgery may considerably raise the rates of spontaneous pregnancy for patients with stage 4 endometriosis, as long as great care is taken by the surgeon to preserve ovarian tissue [4,5]. For this reason, the decision to refer an infertile patient to either surgical or ART department can be challenging. Although the choice of primary ART is obvious in patients with irreversible tubal destruction or spermatic abnormalities, the strategy is debatable in infertile patients with pelvic pain or symptomatic deep infiltrating endometriosis. However, fear of ovarian failure after endometrioma cystectomy is the major factor ultimately impacting the decision. In our practice, fear of ovarian failure after cystectomy determined introduction in 2009 of an ablative technique employing plasma energy. Our surgical procedure was inspired by that employed by Jacques Donnez for more than 20 years, in which CO2 laser is used to ablate endometriomas inner wall [6]. Since 2009, we have continuously evaluated the benefits and
the limits of our procedure through a step-by-step clinical research protocol. In 2009, we started by assessing the histological effects of ablation using plasma energy on ovarian parenchyma suggesting that our technique is an ovarian tissue sparing procedure [7]. Then, we assessed the ultrasound features of ovaries managed by ablation using plasma energy for endometriomas, which revealed increased ovarian volumes and antral follicle count when compared to ovarian cystectomy [8,9]. The third step focused on the biological parameters related to ovarian ablation, and assessed postoperative variations of anti-mullerian hormone (AMH) [10]. The fourth step assessed recurrences and pregnancy rate following endometrioma ablation, which retrieved encouraging results in terms of overall and spontaneous pregnancy rate [4,11]. The aim of our study was to assess the outcomes of IVF or intracytoplasmic sperm injection (ICSI) in women managed for ovarian endometriomas by ablation, when compared to the outcomes recorded in women without endometriosis having undergone IVF or ICSI for various other medical reasons.
2. Methods We performed a retrospective case-control study enrolling women aged between 18 and 43 years, having undergone IVF or ICSI in the Department of Gynecology and Obstetrics, Rouen University Hospital, France, from July 2009 to December 2014. Cases were infertile patients managed for ovarian endometriomas by ablation using plasma energy before one or more IVF or ICSI procedures carried out in our facility. Controls were patients managed for infertility due to any aetiology, except endometriosis, by IVF or ICSI in our department from November 2009 to November 2014. Controls were matched to cases based on age, AMH level and ART procedure (IVF or ICSI). For each case, we enrolled two controls with similar age ( 1 year) and AMH level
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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close to that of the case (up to 0.5 ng/mL) recruited from the database of the ART department. In the current study, cases were prospectively enrolled in the CIRENDO database (the North-West Inter Regional Female Cohort for Patients with Endometriosis), a prospective cohort financed by the G4 Group (The University Hospitals of Rouen, Lille, Amiens and Caen, France), and coordinated by the corresponding author of the present study (H.R.). Information was obtained from surgical and histological records and from self-questionnaires completed before surgery. Data recording, patient contact and follow-up were carried out by a clinical research technician. Women were included in the CIRENDO database only when endometriosis was confirmed by both surgical exploration and biopsy. Postoperative follow-up was based on data from the afore-mentioned questionnaires completed at 1, 3 and 5 years. Prospective data recording and analysis were approved by the French authorities CNIL (Commission nationale de l’informatique et des liberte´s : the French data protection commission) and CCTIRS (Comite´ consultatif pour le traitement de l’information en matie`re de recherche dans le domaine de la sante´: the advisory committee on information technology in healthcare research). In our daily practice during the study period, all women presenting with ovarian endometriomas benefited from laparoscopic treatment of one or more ovarian cysts exclusively treated by ablation using plasma energy (no patient underwent cystectomy). Endometrioma ablation was performed with the PlasmaJet1 system (Plasma Surgical, Inc., Roswell, GA, USA) and has been previously described [7]. Other localizations of the disease were treated by either excision or ablation using plasma energy, with the goal of complete surgical treatment of the disease. Where deep endometriosis nodules infiltrated the digestive tract, patients also underwent appropriate colorectal surgery by shaving, disc excision or colorectal resection, depending on patient characteristics and informed choice. Endometriomas smaller than 30 mm were only treated when the main goal of surgery was the management of associated deep endometriosis or lysis of adhesions thought to be involved in patient infertility. Post-operatively, the surgeon advised patients on their capacity to conceive and recommended attempting spontaneous conception or planning ART. IVF or ICSI was planned either immediately postoperatively or after up to 9 months of unsuccessful spontaneous conception [4,12]. Briefly, the factors taken into account to counsel expectative or immediate ART were fallopian tube status at the end of surgery, ovarian reserve before surgery correlated with procedures carried out on ovaries and spermatic parameters. Depending on their domiciliation or preference, patients underwent IVF or ICSI in our department or elsewhere. Only patients undergoing at least one IVF or ICSI procedure in our ART center at Rouen University Hospital were included in the study. When the patients were referred to colleagues in the ART department of our facility, they were able to benefit from further IVF procedures or not, depending on ovarian reserve and expected responsiveness to controlled hyperstimulation. Patients were stimulated either by a long gonadotropin releasing hormone agonist (GnRHa), or an antagonist protocol. Once pituitary desensitization had been achieved and no ovarian cyst was revealed by pelvic ultrasound examination, ovarian stimulation was begun using doses of recombinant follicle stimulating hormone (FSH) ranging between 75 and 450 IU/day depending on body mass index (BMI), patient age, size and number of follicles and 17 Estradiol (E2) level. Transvaginal oocyte retrieval was scheduled 35–36 hours after human chorionic gonadotropin (hCG) injection. Embryo transfer was performed 2 to 3 days later. On Day 2, individually cultured embryos were evaluated on the basis of the number of blastomeres, blastomere size, fragmentation rate and presence of multinucleated blastomeres. Embryos with four regular blastomeres and less than 20% fragmentation were
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defined as top-quality embryos. The luteal phase was supported by vaginal administration of micronized progesterone (400 mg/day) from the day of ovarian puncture to the day of pregnancy test. Pregnancies were diagnosed by an increasing concentration of serum beta-hCG, which was tested 14 days after embryo transfer. Clinical pregnancy was confirmed by the presence of a gestational sac after vaginal ultrasound examination at 8-week gestation. The present case-control study was approved by the Institutional Ethics Committee for Non Interventional Research. Statistical analysis was performed using Stata 9.0 software (Stat Corporation, Lakeway Drive, TX, USA). Cases and controls were compared using either the Kruskal Wallis test (continuous variable) or the Fisher exact test (qualitative variables). The logistic regression model was used to estimate the probability of pregnancy depending on independent predictive factors. P < 0.05 was considered statistically significant. 3. Results From July 2009 to December 2014, 272 women underwent ablation using plasma energy of one or more ovarian endometriomas (Fig. 1). Following surgery and according to surgeon’s advice, some patients had no immediate pregnancy intention and continued contraceptive pill intake, other patients attempted spontaneous conception, while other patients sought ART management in various facilities either in France or abroad. During postoperative follow-up, 46 patients were referred to the ART department of Rouen University Hospital for IVF or ICSI, either immediately postoperatively or after 6 to 9 months of unsuccessful spontaneous conception. In nine of them, the surgeon’s suggestion for IVF was challenged on the basis of low ovarian reserve; however, prior to surgery, eight of the nine had preoperative AMH inferior to 1 ng/mL and one of the nine had preoperative AMH at 1.8 ng/mL. Nevertheless, three of the nine patients ultimately spontaneously conceived (33%), while another patient became pregnant following oocyte donation. Subsequently, 37 of the 46 patients referred for ART actually underwent ART procedure and were enrolled in the study. Of these 37 patients, 28 underwent IVF and 9 had ICSI. They were matched with 74 controls following the above mentioned inclusion criteria (Table 1). The clinical history of the 37 patients treated by endometrioma ablation and enrolled in the study is presented in Table 2. Previous surgical procedures on the right ovary (cystectomy or oophorectomy) were performed in 27% of patients, and on the left ovary in 21.6% of patients. Overall, 81% of patients were nullipara and 83% had preoperative pregnancy intention. Infertility was documented preoperatively in 62.2% of patients. Preoperative pelvic and digestive complaints are listed in Table 2. Overall values of standardized gastrointestinal questionnaires suggested that the majority of patients experienced constipation and impaired gastrointestinal quality of life. Intraoperative findings describing the severity and localizations of endometriosis are listed in Table 3. Deep endometriosis infiltrating the rectum and the sigmoid colon was recorded in 40.5 and 27% of patients respectively. The rate of ovarian endometriomas was as high as 81% in each ovary. At the end of surgery, 54% of patients were directly referred to the ART department for IVF or ICSI, 2.7% for simple stimulation, while 43.2% of them were advised to attempt postoperative spontaneous conception for 6 to 9 months before seeking ART care. Characteristics of women with and without successful IVF/ICSI procedures were compared and are presented in Table 4. Nine patients were not able to benefit from ART because of low ovarian reserve and were not included in the study. Four of the nine had a documented history of infertility and all nine were nulligravida. Four women had previously been managed by one (two patients) or more than one cystectomy (two patients). When
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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Fig. 1. Study flow-chart.
compared to the 37 cases, these nine women were older (37.2 3.4 years, P < 0.001) and had lower preoperative AMH level (0.64 0.55 ng/mL, P = 0.008). Endometrioma ablation was bilateral in five of the nine patients (P = 0.46). No differences were revealed concerning preoperative symptoms, associated localizations or cyst diameter. Postoperatively, three patients achieved spontaneous pregnancy (33%) and one following oocyte donation (11%). The main characteristics of the 74 controls who underwent ART management in our department are reported in Table 1. The main reason for infertility was fallopian tube obstruction (46%, Fig. 2). ART procedures used in each group and the response to ovarian stimulation are compared in Table 5 revealing that the number of oocytes retrieved was significantly higher in the control group. There was a higher number of ART procedures recorded in controls, specifically in the subgroup of patients requiring ICSI, which explains the higher rate of ICSI in controls. Table 6 presents the results of ART management which were systematically better in the group of patients managed for endometriomas using plasma energy. When the comparison only concerned the first attempt at Table 1 Main baseline characteristics of cases and controls.
Age (years)a Body mass index (kg/m2)a Obstetrical history Nulligesta Nullipara Smoking Day 3 FSH level (UI/L)a AMH level (ng/mL)a Partner’s progressive sperm mobility (million/mL)a ICSI IVF
Cases n = 37 (%)
Controls n = 74 (%)
P
30.9 4.4 23.3 4.4
31.7 4.2 23.3 4.4
0.31 0.95
21 (56.8) 30 (81.1) 7 (18.9) 7.7 2.2 2.8 2 1.6 1.4
41 (55.4) 56 (75.8) 23 (31.1) 7.3 2.2 2.8 1.7 1.8 2
1 0.63 0.26 0.45 0.93 0.50
9 (24.3) 28 (75.7)
20 (27) 54 (73)
0.75 0.75
AMH: anti-Mullerian hormone; FSH: follicle stimulating hormone; ICSI: IntraCytoplasmic Sperm Injection; IVF: in vitro fertilization a Data are expressed as mean standard deviation. A P-value < 0.05 was considered significant.
pregnancy by a couple, the differences between outcomes were also statistically significant. When spontaneous and ART induced pregnancies were taken together, the overall pregnancy rate was 56.8% in the case group. In the whole population of 46 patients referred for ART, the spontaneous and ART induced pregnancy rates were 52.2%. 4. Discussion Our study reports the first series of infertile women managed by IVF or ICSI after ovarian endometrioma surgery by ablation using Table 2 Clinical history of case patients and main symptoms related to endometriosis. Cases n = 37 (%) History of gynecological surgery Justification for previous surgeries Pelvic pain Infertility Ovarian cysts Endometriosis Cystectomy Right ovary Left ovary Right oophorectomy Adhesiolysis Unilateral salpingectomy Obstetrical history Nulligesta Nullipara Dysmenorrhea Primary dysmenorrhea Biberoglou & Behrman dysmenorrhea scorea Cyclic symptoms associated with dysmenorrhea Defecation pain Constipation Diarrhea Having had sexual intercourse Deep dyspareunia Biberoglou & Behrman deep dyspareunia scorea a
17 (45.9) 12 (32.4) 3 (8.1) 1 (2.7) 1 (2.7) 9 8 1 4 3
(24.3) (21.6) (2.7) (10.8) (8.1)
21 (56.8) 30 (81.1) 37 (100) 18 (48.6) 1.9 0.7 22 (59.5) 14 (37.8) 13 (35.1) 37 (100) 32 (86.5) 1.8 0.9
Data are expressed as mean standard deviation.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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GYOBFE-2977; No. of Pages 7 I. Motte et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx Table 3 Intraoperative findings.
Table 4 Characteristics of cases stratified by the results of ART management. Cases n = 37 (%)
Operative time (minutes)a Operative route Laparoscopy Laparoscopy followed by open route AFSr scorea Douglas pouch complete obliteration Associated localizations Diaphragm Appendix Sigmoid colon Rectum Vagina Adenomyosis Management of ovarian endometriomas Right Left Adhesiolysis Right adnexa Left adnexa Deep posterior endometriosis nodules Left USL Right USL Rectovaginal septum Left USL, right USL and rectovaginal septum Surgical procedures on digestive tract Rectal shaving (when more than 1 rectal nodule) Rectal disc excision Colorectal resection Sigmoid colon disc excision Sigmoid colon resection Cecum resection Appendectomy Transitory stoma Surgical procedures on urinary tract Resection of the bladder Treatment of peritoneal implants Complete Incomplete (widespread implants) Surgeon advice concerning further pregnancy intention Spontaneous conception if postoperative normal fertility assessment Ovulation induction Intrauterine insemination Systematic IVF Oocyte donation
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144 92 35 (94.6) 2 (5.4) 73 41 16 (43.2) 7 (18.9) 8 (21.6) 10 (27) 15 (40.5) 10 (27) 22 (59.4) 30 (81.1) 30 (81.1) 26 (70.3) 32 (86.5) 6 (16.2) 5 (13.5) 10 (27) 10 (27) 19 (51.4) 10 (27) 1 (2.7) 6 (16.2) 2 (5.4) 7 (18.9) 1 (2.7) 6 (16.2) 3 (8.1) 1 (2.7) 1 (2.7) 0 32 (86.5) 16 (43.2) 1 (2.7) 0 20 (54.1) 0
AFS: American Fertility Score; IVF: in vitro fertilization; USL: uterosacral ligament. a Data are expressed as mean standard deviation.
plasma energy. The pregnancy rate recorded in our population is encouraging, as it is higher than that observed in controls free of endometriosis presenting comparable baseline age, ovarian reserve and undergoing similar ART procedures. Furthermore, our results are either comparable or better than those previously reported in series of patients with endometriomas undergoing either primary IVF [13] or endometrioma cystectomy followed by IVF [14]. The major weakness of our study is related to its small sample size. Even though our department is a tertiary referral centre and routinely managed patients with ovarian endometriomas by ablation using plasma energy during the study period, only 13% of these patients were ultimately referred to the ART unit of our facility. The main explanation is due to the fact that the majority of our patients with endometriosis are domiciled outside of our local area (Seine-Maritime, Normandy) and logically patients decide to undergo ART in a center closer to home. Conversely, our study presents several strengths. This was a comparative study, with a control group representative of the general population of women referred for IVF. The second strength is related to the high homogeneity of surgical procedures performed on ovarian endometriomas, which are routinely performed by several surgeons in the same department. Thus,
Age (years)a Age group (years) < 25 25–29 30–38 38 Smoking Endometrioma size 30 mm 30–49 mm 40–49 mm 50–59 mm 60 mm Endometrioma cyst Unilateral Bilateral Preoperative AMH level (ng/mL)a AMH group 2 ng/mL 2–4 ng/mL 4 ng/mL Operative time (min)a AMH level before ART (ng/mL)
Pregnant n = 19 (%)
Not pregnant n = 18 (%)
P
29.9 3.4
31.9 5.1
0.17 0.32
3 (16) 12 (63) 4 (21) 0 (0) 5 (26)
2 8 5 3 2
(11) (44) (28) (17) (11)
6 4 4 2 3
3 4 2 4 5
(17) (22) (11) (22) (28)
(32) (21) (21) (10) (16)
0.40 0.64
0.51 6 (32) 13 (68) 3.6 1.9
8 (44) 10 (56) 1.9 1.2
2 (18) 5 (46) 4 (36) 139 96 2.7 1.6
6 (55) 4 (36) 1 (9) 149 90 2.5 1.4
0.02 0.17
0.76 0.60
AMH: anti-Mullerian hormone; ART: assisted reproductive technology; VAS: Visual Analogue Scale. a Data are expressed as mean standard deviation. A P-value < 0.05 was considered significant.
our results accurately assess the impact of endometrioma ablation using plasma energy as previously described in our abovementioned reports [4]. The third strength is related to the high prevalence of severe endometriosis in cases, as the majority of patients presented with stage 4 endometriosis or colorectal nodules, in which the likelihood of spontaneous pregnancy was reasonably low. Last but not least, our study logically continues our previous clinical research focusing on conservative surgery using plasma energy in endometriosis, and our results accord with previous data suggesting good preservation of ovarian parenchyma after ablation using plasma energy. The study we report today is related to the fourth step of our clinical research, and is the basis for the fifth step represented by a further randomized trial comparing clinical outcomes related to ablation and cystectomy. In a comparative study, statistically better results in cases may merely be due to unusually poor results in controls. The results observed in our controls were close to those recorded in the French national database in 2012, in which pregnancy rate per oocyte retrieval averaged 20% [15]. As our study inclusion criteria may result in lower ovarian reserve in controls than in the general population of women undergoing IVF or ICSI in France, we believe that the outcomes recorded in our control group are valid.
Fig. 2. Etiology of controls’ infertility.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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Table 5 Parameters of controlled ovarian hyperstimulation and characteristics of ART cycles.
Procedure employed Number of ICSI cycles Number of IVF cycles Stimulation protocol Antagonist protocol Long protocol Number of cycles per patienta Abandon rate Total dose of gonadotrophin used (IU)a 17 b estradiol level (pg/mL)a Endometrial thickness (mm)a Number of follicles > 15 mm Number of oocytes retrieved Number of mature oocytes Fertilization ratea Cleavage ratea Transfer rate Embryo quality Type 1 Type 2 Type 3 Type 4 Number of transferred embryosa
Cases a = 37 (%)
Controls n = 74 (%)
P
63 13 (20.6) 50 (79.4) 63 15 (23.8) 48 (76.2) 1.7 0.9 18 (28.6) 2,375 870 1,916 952 11.5 2.7 5.9 3.4 7.2 4.3 6.9 4.2 0.54 0.28 0.97 0.1 43 (95.6) 68 9 (33.8) 36 (52.9) 23 (13.2) 0 1.5 0.6
177 66 (37.3) 111 (62.7) 177 34 (19.2) 143 (80.8) 2.4 1.3 52 (29.4) 2,300 912 1,838 897 11.5 2.9 6.4 3.7 9.1 5.5 8 5.2 0.45 0.29 0.93 0.18 114 (91.2) 199 33 (16.6) 81 (40.7) 85 (42.7) 0 1.6 0.8
0.02
0.47
0.005 1 0.58 0.57 0.98 0.38 0.03 0.13 0.17 0.17 0.51 0.21
0.40
FSH: follicle stimulating hormone; ICSI: IntraCytoplasmic Injection; IVF: in vitro fertilization; n: number of patients. Embryo quality is defined by: type 1: cells are of equal size; no fragmentation seen; type 2: cells are of equal size and fragmentation less than 20%; type 3: cells are of unequal size and/or fragmentation 21 to 50%; type 4: cells are of unequal size and/or fragmentation more than 51%. a Data are expressed as mean SD. A P-value < 0.05 was considered significant. Table 6 ART outcomes.
Implantation rate Pregnancy rate Per transfer Per embryo Per cycle Per oocyte retrieval Delivery rate Per transfer Per embryo Per cycle Per oocyte retrieval Child rate per couple Cumulative rate of birth per transfer Multiple pregnancy rate Rate of miscarriage Ectopic pregnancy rate Biochemical pregnancy rate
Cases n = 37 (%)
Controls n = 74 (%)
P
26 (38.2)
37 (18.6)
0.002
22 22 22 22
(51.2) (32.4) (34.9) (43.1)
35 35 35 35
(30.7) (17.6) (19.8) (23.3)
0.025 0.016 0.02 0.011
19 19 19 19 18 20 5 2 0 1
(44.2) (27.9) (30.2) (37.3) (48.6) (46.5) (26.3) (9.1) (0) (4.5)
27 27 27 27 28 30 4 4 2 2
(23.7) (13.6) (15.3) (18) (37.8) (26.3) (14.8) (11.4) (5.7) (5.7)
0.018 0.009 0.015 0.007 0.311 0.021 0.46 1 0.52 1
A P-value < 0.05 was considered significant.
Consequently, the significantly better results revealed in our cases were not artificially due to bad results in controls, but probably represent new and valid findings concerning the benefits of endometrioma ablation using plasma energy. The question remains as to whether the good results recorded in the group of women with endometriosis could be due to a bias in the selection of cases with overall rather favorable predictive factors for fertility. In our opinion, the answer is negative, because the majority of our patients presented with severe pelvic endometriosis and strong arguments for infertility. Indeed, 24.3% and 21.6% had previously had one or more cystectomy on each ovary, 18.9% had experienced ectopic pregnancies, 81% were nullipara, 84% presented with deep endometriosis nodules, which infiltrated the rectum in 40.5% and the sigmoid colon in 27%, complete obliteration of Douglas pouch was found in 43% and overall AFSr score was 73 41. Furthermore, in our daily practice,
only the most severe patients are directly referred for postoperative IVF. Among women enrolled in this series, surgeons advised attempting spontaneous conception for up to 9 months in 43.2%, and postoperative IVF appeared to be unavoidable in only 54% of patients (Table 3). In a recent article presenting a series of patients managed for ovarian endometriosis with and without associated colorectal endometriosis, only 34.7% of patients were directly referred for postoperative IVF [4], while 64.7% of conceptions recorded in the series were spontaneous. It is in our opinion that surgical management of endometriosis is a good option in infertile women with severe endometriosis and pregnancy intention, as cumulative pregnancy rate appears to be at least as good as that recorded after primary IVF management [3]. Our results must be compared to those reported following primary IVF in women presenting with ovarian endometriomas, as well as to those recorded in patients previously managed by cystectomy. It has already been shown that unoperated endometriomas do not affect responsiveness to hyperstimulation [16]. However, in a recent review of the literature, Yang et al. [17] pooled the results of numerous studies previously published and reported that unoperated endometriomas are related to a lower number of oocytes retrieved and embryos formed, while implantation, pregnancy and live birth rates are not affected. Our results presented in Tables 5 and 6 are roughly comparable to those reported in patients with unoperated endometriomas [18]: mean number of oocytes retrieved 7.2 vs. 7.1, pregnancy rate per embryo 32.4% vs. 39%, delivery rate per embryo 27.9% vs. 29%. These results suggest that endometrioma ablation using plasma energy did not impair the IVF or ICSI outcomes that would have been recorded if endometriomas had not been operated. As regards the comparison with previously reported IVF or ICSI results in patients whose endometriomas were managed by cystectomy, our results are encouraging. A review of studies in the literature since 2000, reported implantation rates after cystectomy that varied up to 32.1% [19] and pregnancy rates up to 47% [20], even though in the majority of studies pregnancy rates were inferior to 40% [21,22]. Our results are comparable, if not better, than those observed after cystectomy [14], suggesting that ablation of ovarian endometriomas in patients undergoing postoperative IVF is a valuable alternative to cystectomy. One may inquire whether or not surgery was necessary in patients enrolled in our series, as it was proposed before IVF. It should be underlined that IVF and ICSI were performed before surgery in respectively 16.2% and 8.1% of our cases, but progressive aggravation of pelvic and digestive complaints prompted surgery thereafter. Detailed listing of baseline complaints provides accurate data on the severity of preoperative symptoms justifying surgery. To date, no pathophysiological theory can definitely explain these encouraging results after ovarian endometriosis ablation using plasma energy. In the human ovary, AMH expression is negligible in primordial follicles, low in granulosa cells of primary follicles but highest in granulosa cells of secondary, pre-antral and small antral follicles 4 mm in diameter [23]. In larger antral follicles, AMH expression gradually disappears [24]. It is possible that ablation using plasma energy not only spares underlying ovarian tissue and decreases inflammatory phenomena, but also promotes the development of primordial, primary and secondary follicles. This may explain why AMH level could progressively increase after surgery [10], providing better reproductive outcomes when compared to those of patients free of endometriosis with comparable baseline AMH level. Roustan et al. [25] recently observed that IVF outcomes and live birth rate were significantly impaired in women with diminished ovarian reserve (AMH level < 2 ng/mL) caused by a previous cystectomy for endometrioma compared to women with idiopathic etiology. Although the majority of our patients had
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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AMH level > 2 ng/mL, it is noteworthy to emphasize that our results were different to those of Roustan et al. [25]. This difference may be directly due to better preservation of ovarian reserve related to ablation using plasma energy when compared to cystectomy [9]. An ablative approach in ovarian endometriomas is well recorded in the literature. As far back as 1990, endometrioma ablation using CO2 laser was employed with good postoperative pregnancy rate [6], which was comparable to that observed after cystectomy [26]. More recently, it has been shown that similar effects might be obtained by ethanol instillation into the cyst (ethanol sclerotherapy) using the transvaginal route. When compared to cystectomy, ethanol sclerotherapy before stimulation in recurrent endometriomas allowed better preservation of ovarian reserve and ovarian response to stimulation, as well as higher clinical and cumulative pregnancy rate [27]. These data support the hypothesis that endometrioma ablation is a valuable alternative to cystectomy, which may spare ovarian tissue located underneath the nodule. In our opinion, isolated management of endometriomas in patients with associated deep endometriosis may be considered in specific circumstances such as large cysts that complicate oocyte retrieval in patients with asymptomatic deep localizations or in patients with large deep lesions for whom surgery could lead to postoperative complications delaying IVF. Our study only represents an intermediate step in our clinical research focusing on the best management of patients with endometriosis and pregnancy intention. In a recent paper, we discussed why primary surgery followed by IVF or not is a valuable treatment in patients with deep colorectal endometriosis and pregnancy intention [3]. Even though recent guidelines state that no data support the fact that performing surgery before IVF improves IVF outcomes [2], delaying surgery may increase the risk of various complications and functional troubles as well as that of more aggressive further surgery [3]. In addition, surgery may be required before IVF in patients with various pelvic pains and poor quality of life [2]. Our study provides encouraging information concerning these latter patients, as it suggests that performing complete endometriosis surgery and ovarian endometrioma ablation using plasma energy offer good postoperative fertility outcomes.
[2] [3] [4]
[5]
[6] [7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
Funding [19]
No financial support was received for this study. The NorthWest Inter Regional Female Cohort for Patients with Endometriosis (CIRENDO) is financed by the G4 Group (The University Hospitals of Rouen, Lille, Amiens and Caen).
[20]
[21]
Disclosure of interest Horace Roman reports personal fees for participating in a symposium and a master class presenting his experience in the use of PlasmaJet. The other authors have not supplied their declaration of competing interest.
[22]
[23]
[24]
Acknowledgements [25]
We thank Miss Amelie Breant, for her valuable management of the CIRENDO database. The authors are grateful to Nikki Sabourin-Gibbs, Rouen University Hospital, for her help in editing the manuscript. References [1] Benschop L, Farquhar C, van der Poel N, Heineman MJ. Interventions for women with endometrioma prior to assisted reproductive technology.
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Cochrane Database Syst Rev 2010;10(11):CD008571. http://dx.doi.org/ 10.1002/14651858.CD008571.pub2. Dunselman GAJ, Vermeulen N, Becker C, et al. ESHRE guideline: 1014 management of women with endometriosis. Hum Reprod 2014;29(1015):400–12. Roman H. Colorectal endometriosis and pregnancy wish: why doing primary surgery. Front Biosci 2015;7:83–93. Roman H, Quibel S, Auber M, et al. Recurrences and fertility after endometrioma ablation in women with and without colorectal endome – 1061 triosis: a prospective cohort study. Hum Reprod 2015;30:558–68. Cohen J, Thomin A, Mathieu d’Argent E, Laas E, Canlorbe G, Zilberman S, et al. Fertility before and after surgery for deep infiltrating endometriosis with and without bowel involvement: a literature review. Minerva Gynecol 2014;66: 575–87. Donnez J, Nisolle M, Gillet N, Smets M, Bassil S, Casanas-Roux F. Large ovarian endometriomas. Hum Reprod 1996;11:641–6. Roman H, Pura I, Tarta O, Mokdad C, Auber M, Bourdel N, et al. Vaporization of ovarian endometrioma using plasma energy: histological findings of a pilot study. Fertil Steril 2011;95:1853–6. Auber M, Bourdel N, Mokdad C, Martin C, Diguet A, Marpeau L, et al. Ultrasound ovarian assessments after endometrioma ablation using plasma energy. Fertil Steril 2011;95:2621–4. Roman H, Auber M, Mokdad C, Martin C, Diguet A, Marpeau L, et al. Ovarian endometrioma ablation using plasma energy versus cystectomy: a step toward better preservation of the ovarian parenchyma in women wishing to conceive. Fertil Steril 2011;96:1396–400. Roman H, Bubenheim M, Auber M, Marpeau L, Puscasiu L. Antimullerian hormone level and endometrioma ablation using plasma energy. JSLS 2014;18. http://dx.doi.org/10.4293/JSLS. 2014.00002 [e.2014.00002]. Roman H, Auber M, Bourdel N, Martin C, Marpeau L, Puscasiu L. Postoperative recurrences and fertility after endometrioma ablation using plasma energy: retrospective assessment of a 3-year experience. J Minim Invasive Gynecol 2013;20:573–82. Bourdel N, Dejou-Bouillet L, Roman H, Jaffeux P, Aublet-Cuvelier B, Mage G, et al. Endometriosis and postoperative infertility. A prospective study (Auvergne cohort of endometriosis). Gynecol Obstet Fertil 2012;40:337–43. Ballester M, Mathieu d’Argent E, Morcel K, Belaisch-Allart J, Nisolle M, Daraı E. Cumulative pregnancy rate after ICSI-IVF in patients with colorectal endometriosis: results of a multicentre study. Hum Reprod 2012;27:1043–9. Berlanda N, Vercellini P, Somigliana E, Frattaruolo MP, Buggio L, Gattei U. Role of surgery in endometriosis-associated subfertility. Semin Reprod Med 2013;31:133–43. Agence de la biome´decine. E´valuation des re´sultats des centres d’assistance me´dicale a` la procre´ation pratiquant la fe´condation in vitro en France; 2012 [Accessed 25 July 2015]http://www.agence-biomedecine.fr/IMG/pdf/ nationalresumefiv2012.pdf. Benaglia L, Pasin R, Somigliana E, Vercellini P, Ragni G, Fedele L. Unoperated ovarian endometriomas and responsiveness to hyperstimulation. Hum Reprod 2011;26:1356–61. Yang C, Geng Y, Li Y, Chen C, Gao Y. Impact of ovarian endometrioma on ovarian responsiveness and IVF: a systematic review and meta-analysis. Reprod Biomed Online 2015;31:9–19. Benaglia L, Bermejo A, Somigliana E, Faulisi S, Ragni G, Fedele L, et al. In vitro fertilization outcome in women with unoperated bilateral endometriomas. Fertil Steril 2013;99:1714–9. Bianchi PHM, Pereira RMA, Zanatta A, Alegretti JR, Motta ELA, Serafini PC. Extensive excision of deep infiltrative endometriosis before in vitro fertilization significantly improves pregnancy rates. J Minim Invasive Gynecol 2009;16:174–80. Wong BC, Gillman NC, Oehninger S, Gibbons WE, Stadtmauer LA. Results of in vitro fertilization in patients with endometriomas: is surgical removal beneficial? Am J Obstet Gynecol 2004;191:597–606 [discussion 606–7]. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, Arici A, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81:1194–7. Bongioanni F, Revelli A, Gennarelli G, Guidetti D, Delle Piane LD, Holte J. Ovarian endometriomas and IVF: a retrospective case-control study. Reprod Biol Endocrinol 2011;9:81. http://dx.doi.org/10.1186/1477-7827-9-81. Suzuki N, Yoshioka N, Takae S, Sugishita Y, Tamura M, Hashimoto S, et al. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod 2015;30:608–15. Weenen C, Laven JS, Von Bergh AR, Cranfield M, Groome NP, Visser JA, et al. Anti-Mullerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 2004;10:77–83. Roustan A, Perrin J, Debals-Gonthier M, Paulmyer-Lacroix O, Agostini A, Courbie`re B. Surgical diminished ovarian reserve after endometrioma cystectomy versus idiopathic DOR: comparison of in vitro fertilization outcome. Hum Reprod 2015;30:840–7. Caramona F, Martinez-Zamora MA, Rabanal A, Martinez-Roman S, Balasch J. Ovarian cystectomy versus laser vaporization in the treatment of ovarian endometriomas: a randomized clinical trial with a five-year follow-up. Fertil Steril 2011;96:251–4. Yazbeck C, Madelenat P, Ayel JP, Jacquesson L, Bontoux LM, Solal P, et al. Ethanol sclerotherapy: a treatment option for ovarian endometriomas before ovarian stimulation. Reprod Biomed Online 2009;19:121–5.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
GYOBFE-2977; No. of Pages 7 Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
Available online at
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Original article
In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study Re´sultats en FIV apre`s ablation des endome´triomes par e´nergie plasma : e´tude cas te´moin re´trospective I. Motte a,b, H. Roman a,b,c,*, B. Clavier a,b, F. Jumeau d, I. Chanavaz-Lacheray a,b, M. Letailleur a,b, B. Darwish a,b, N. Rives b,c,d a
Department of gynecology and obstetrics, Rouen university hospital, 76031 Rouen, France Expert Center in the Diagnostic and Multidisciplinar Management of Endometriosis ‘‘Rouendometriose’’, 76031 Rouen, France c Research Group 4308 ‘‘Spermatogenesis and Gamete Quality’’, IHU Rouen Normandy, IFRMP23, reproductive biology laboratory, Rouen university hospital, 76031 Rouen, France d Department of reproductive biology, Rouen university hospital, 76031 Rouen, France b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2016 Accepted 5 August 2016 Available online xxx
Objective. – Ovarian endometrioma ablation using plasma energy appears to be a valuable alternative to cystectomy, because it could spare underlying ovarian parenchyma resulting in high spontaneous and overall pregnancy rates. After initial postoperative decrease, anti-mullerian hormone (AMH) level progressively increases several months after ablation. The aim of our study was to assess the outcomes of in vitro fertilization (IVF) in women managed for ovarian endometriomas by ablation using plasma energy, when compared to those in women free of endometriosis. Methods. – Retrospective preliminary case-control study, enrolling women undergoing IVF or IntraCytoplasmic Sperm Injection (ICSI), from July 2009 to December 2014. Cases were infertile women with previous ovarian endometrioma ablation using plasma energy and were matched by age, AMH level and assisted reproductive technique with controls presumed free of endometriosis. IVF/ICSI response (type of protocol, dose of gonadotrophin, number of oocytes, fertilization rate) and outcomes were compared between the two groups. Results. – In all, 37 cases were compared to 74 controls. Age (30.9 4.4 years vs. 31.7 4.2 years), AMH level (2.8 2 ng/mL vs. 2.8 1.7 ng/mL) and ART procedures (ICSI in 24.3% vs. 27%) were comparable between the two groups. Of the 37 cases, previous surgical procedures on right and left ovaries were performed in 27% and 21.6% of patients respectively, 81% of patients were nullipara. AFSr score was 73 41, while deep endometriosis infiltrated the rectum and the sigmoid colon in respectively 40.5% and 27% of patients. Despite a lower number of oocytes retrieved, cases presented better implantation rate, pregnancy and delivery rates per cycle, oocyte retrieval, transfer, and embryo, as well as superior cumulative birth rate per transfer. Conclusion. – Ovarian endometrioma ablation using plasma energy is followed by good IVF/ICSI outcomes, suggesting that surgical procedure spares underlying ovarian parenchyma. These results consolidate those of previous studies reporting high spontaneous conception rate. Hence, ovarian endometrioma ablation using plasma energy appears to be a valuable alternative to cystectomy in patients presenting with endometriosis and pregnancy intention. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Antimullerian hormone AMH ICSI IVF Ovarian endometriomas Plasma energy Fertility
* Corresponding author at: Department of gynecology and obstetrics, Rouen university hospital–Charles-Nicolle, 1, rue de Germont, 76031 Rouen, France. E-mail address: [email protected] (H. Roman). http://dx.doi.org/10.1016/j.gyobfe.2016.08.008 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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2
R E´ S U M E´
Mots cle´s: AMH ICSI IVF Endome´triomes E´nergie plasma Fertilite´
Objectif. – La chirurgie des endome´triomes ovarien par e´nergie plasma semble eˆtre une alternative inte´ressante a` la kystectomie. Elle permettrait d’e´pargner le parenchyme ovarien sous-jacent et d’obtenir des taux de grossesse spontane´s e´leve´s. Apre`s une diminution postope´ratoire initiale, l’hormone antimu¨lle´rienne (AMH) augmente progressivement jusqu’a` plusieurs mois apre`s l’ablation. Le but de notre e´tude e´tait d’e´tudier les re´sultats en fe´condation in vitro (FIV) chez les femmes traite´es pour endome´triomes ovariens par ablation a` l’aide de l’e´nergie plasma, compare´ a` des te´moins sans endome´triose. Me´thodes. – Il s’agit d’une e´tude cas-te´moins re´trospective incluant des femmes prises en charge en FIV ou injection intra-cytoplasmique de spermatozoı¨des (ICSI), a` partir de juillet 2009 jusqu’a` de´cembre 2014. Les femmes infertiles ayant eu une ablation d’endome´triome ovarien par e´nergie plasma ont e´te´ apparie´es par aˆge, taux d’AMH et technique de FIV avec des femmes sans endome´triose. La re´ponse en FIV/ICSI (type de protocole, dose de gonadotrophine, nombre d’ovocytes, taux de fe´condation) et les re´sultats ont e´te´ compare´s entre les deux groupes. Re´sultats. – Au total, 37 cas ont e´te´ compare´s a` 74 te´moins. L’aˆge (30,9 4,4 ans vs 31,7 4,2 ans), le taux d’AMH (2,8 2 ng/mL vs 2,8 1,7 ng/mL) et le type de proce´dure (ICSI 24,3 % contre 27 %) e´tait comparable entre les deux groupes. Quatre-vingt-un pour cent des patients e´taient nullipare. Le score AFSR e´tait de 73 41, tandis que l’endome´triose profonde infiltrait le rectum et le coˆlon sigmoı¨de chez respectivement 40,5 % et 27 % des patients. En de´pit d’un nombre infe´rieur d’ovocytes ponctionne´s, les cas pre´sentaient un meilleur taux d’implantation, taux de grossesse et taux d’accouchement par cycle, ovocytes re´cupe´re´s, transferts et embryons. Conclusion. – L’ablation des endome´triomes par e´nergie plasma permet d’obtenir de bons re´sultats en FIV/ ICSI, sugge´rant que cette proce´dure chirurgicale e´pargnerait le parenchyme ovarien sous-jacent. Ces re´sultats consolident ceux des e´tudes pre´ce´dentes ayant re´ve´le´ un taux de grossesse spontane´e e´leve´. Par conse´quent, l’ablation des endome´triomes ovariens avec l’e´nergie plasma semble eˆtre une alternative inte´ressante a` la kystectomie chez les patients pre´sentant des endome´triomes et ayant un de´sir de grossesse. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction The relationship between the management of ovarian endometriomas and infertility feeds one of the most exciting debates in the field of endometriosis. Recent guidelines concluded that performing cystectomy of endometriomas in infertile women referred for assisted reproductive technology (ART) does not improve pregnancy rates [1,2]. Although pre-in vitro fertilization (IVF) management of ovarian endometriomas is not contraindicated in women with endometriosis-associated pain or inaccessible follicles, surgeons must be aware of the risk of postoperative ovarian reserve impairment with negative impact on ART results [2]. Thus, surgery is the current management worldwide for ovarian endometriomas in infertile patients seeking both pregnancy and health improvement. Notwithstanding, surgery by cystectomy is a valuable treatment for infertility in many cases of severe endometriosis [3]. Surgery may considerably raise the rates of spontaneous pregnancy for patients with stage 4 endometriosis, as long as great care is taken by the surgeon to preserve ovarian tissue [4,5]. For this reason, the decision to refer an infertile patient to either surgical or ART department can be challenging. Although the choice of primary ART is obvious in patients with irreversible tubal destruction or spermatic abnormalities, the strategy is debatable in infertile patients with pelvic pain or symptomatic deep infiltrating endometriosis. However, fear of ovarian failure after endometrioma cystectomy is the major factor ultimately impacting the decision. In our practice, fear of ovarian failure after cystectomy determined introduction in 2009 of an ablative technique employing plasma energy. Our surgical procedure was inspired by that employed by Jacques Donnez for more than 20 years, in which CO2 laser is used to ablate endometriomas inner wall [6]. Since 2009, we have continuously evaluated the benefits and
the limits of our procedure through a step-by-step clinical research protocol. In 2009, we started by assessing the histological effects of ablation using plasma energy on ovarian parenchyma suggesting that our technique is an ovarian tissue sparing procedure [7]. Then, we assessed the ultrasound features of ovaries managed by ablation using plasma energy for endometriomas, which revealed increased ovarian volumes and antral follicle count when compared to ovarian cystectomy [8,9]. The third step focused on the biological parameters related to ovarian ablation, and assessed postoperative variations of anti-mullerian hormone (AMH) [10]. The fourth step assessed recurrences and pregnancy rate following endometrioma ablation, which retrieved encouraging results in terms of overall and spontaneous pregnancy rate [4,11]. The aim of our study was to assess the outcomes of IVF or intracytoplasmic sperm injection (ICSI) in women managed for ovarian endometriomas by ablation, when compared to the outcomes recorded in women without endometriosis having undergone IVF or ICSI for various other medical reasons.
2. Methods We performed a retrospective case-control study enrolling women aged between 18 and 43 years, having undergone IVF or ICSI in the Department of Gynecology and Obstetrics, Rouen University Hospital, France, from July 2009 to December 2014. Cases were infertile patients managed for ovarian endometriomas by ablation using plasma energy before one or more IVF or ICSI procedures carried out in our facility. Controls were patients managed for infertility due to any aetiology, except endometriosis, by IVF or ICSI in our department from November 2009 to November 2014. Controls were matched to cases based on age, AMH level and ART procedure (IVF or ICSI). For each case, we enrolled two controls with similar age ( 1 year) and AMH level
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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close to that of the case (up to 0.5 ng/mL) recruited from the database of the ART department. In the current study, cases were prospectively enrolled in the CIRENDO database (the North-West Inter Regional Female Cohort for Patients with Endometriosis), a prospective cohort financed by the G4 Group (The University Hospitals of Rouen, Lille, Amiens and Caen, France), and coordinated by the corresponding author of the present study (H.R.). Information was obtained from surgical and histological records and from self-questionnaires completed before surgery. Data recording, patient contact and follow-up were carried out by a clinical research technician. Women were included in the CIRENDO database only when endometriosis was confirmed by both surgical exploration and biopsy. Postoperative follow-up was based on data from the afore-mentioned questionnaires completed at 1, 3 and 5 years. Prospective data recording and analysis were approved by the French authorities CNIL (Commission nationale de l’informatique et des liberte´s : the French data protection commission) and CCTIRS (Comite´ consultatif pour le traitement de l’information en matie`re de recherche dans le domaine de la sante´: the advisory committee on information technology in healthcare research). In our daily practice during the study period, all women presenting with ovarian endometriomas benefited from laparoscopic treatment of one or more ovarian cysts exclusively treated by ablation using plasma energy (no patient underwent cystectomy). Endometrioma ablation was performed with the PlasmaJet1 system (Plasma Surgical, Inc., Roswell, GA, USA) and has been previously described [7]. Other localizations of the disease were treated by either excision or ablation using plasma energy, with the goal of complete surgical treatment of the disease. Where deep endometriosis nodules infiltrated the digestive tract, patients also underwent appropriate colorectal surgery by shaving, disc excision or colorectal resection, depending on patient characteristics and informed choice. Endometriomas smaller than 30 mm were only treated when the main goal of surgery was the management of associated deep endometriosis or lysis of adhesions thought to be involved in patient infertility. Post-operatively, the surgeon advised patients on their capacity to conceive and recommended attempting spontaneous conception or planning ART. IVF or ICSI was planned either immediately postoperatively or after up to 9 months of unsuccessful spontaneous conception [4,12]. Briefly, the factors taken into account to counsel expectative or immediate ART were fallopian tube status at the end of surgery, ovarian reserve before surgery correlated with procedures carried out on ovaries and spermatic parameters. Depending on their domiciliation or preference, patients underwent IVF or ICSI in our department or elsewhere. Only patients undergoing at least one IVF or ICSI procedure in our ART center at Rouen University Hospital were included in the study. When the patients were referred to colleagues in the ART department of our facility, they were able to benefit from further IVF procedures or not, depending on ovarian reserve and expected responsiveness to controlled hyperstimulation. Patients were stimulated either by a long gonadotropin releasing hormone agonist (GnRHa), or an antagonist protocol. Once pituitary desensitization had been achieved and no ovarian cyst was revealed by pelvic ultrasound examination, ovarian stimulation was begun using doses of recombinant follicle stimulating hormone (FSH) ranging between 75 and 450 IU/day depending on body mass index (BMI), patient age, size and number of follicles and 17 Estradiol (E2) level. Transvaginal oocyte retrieval was scheduled 35–36 hours after human chorionic gonadotropin (hCG) injection. Embryo transfer was performed 2 to 3 days later. On Day 2, individually cultured embryos were evaluated on the basis of the number of blastomeres, blastomere size, fragmentation rate and presence of multinucleated blastomeres. Embryos with four regular blastomeres and less than 20% fragmentation were
3
defined as top-quality embryos. The luteal phase was supported by vaginal administration of micronized progesterone (400 mg/day) from the day of ovarian puncture to the day of pregnancy test. Pregnancies were diagnosed by an increasing concentration of serum beta-hCG, which was tested 14 days after embryo transfer. Clinical pregnancy was confirmed by the presence of a gestational sac after vaginal ultrasound examination at 8-week gestation. The present case-control study was approved by the Institutional Ethics Committee for Non Interventional Research. Statistical analysis was performed using Stata 9.0 software (Stat Corporation, Lakeway Drive, TX, USA). Cases and controls were compared using either the Kruskal Wallis test (continuous variable) or the Fisher exact test (qualitative variables). The logistic regression model was used to estimate the probability of pregnancy depending on independent predictive factors. P < 0.05 was considered statistically significant. 3. Results From July 2009 to December 2014, 272 women underwent ablation using plasma energy of one or more ovarian endometriomas (Fig. 1). Following surgery and according to surgeon’s advice, some patients had no immediate pregnancy intention and continued contraceptive pill intake, other patients attempted spontaneous conception, while other patients sought ART management in various facilities either in France or abroad. During postoperative follow-up, 46 patients were referred to the ART department of Rouen University Hospital for IVF or ICSI, either immediately postoperatively or after 6 to 9 months of unsuccessful spontaneous conception. In nine of them, the surgeon’s suggestion for IVF was challenged on the basis of low ovarian reserve; however, prior to surgery, eight of the nine had preoperative AMH inferior to 1 ng/mL and one of the nine had preoperative AMH at 1.8 ng/mL. Nevertheless, three of the nine patients ultimately spontaneously conceived (33%), while another patient became pregnant following oocyte donation. Subsequently, 37 of the 46 patients referred for ART actually underwent ART procedure and were enrolled in the study. Of these 37 patients, 28 underwent IVF and 9 had ICSI. They were matched with 74 controls following the above mentioned inclusion criteria (Table 1). The clinical history of the 37 patients treated by endometrioma ablation and enrolled in the study is presented in Table 2. Previous surgical procedures on the right ovary (cystectomy or oophorectomy) were performed in 27% of patients, and on the left ovary in 21.6% of patients. Overall, 81% of patients were nullipara and 83% had preoperative pregnancy intention. Infertility was documented preoperatively in 62.2% of patients. Preoperative pelvic and digestive complaints are listed in Table 2. Overall values of standardized gastrointestinal questionnaires suggested that the majority of patients experienced constipation and impaired gastrointestinal quality of life. Intraoperative findings describing the severity and localizations of endometriosis are listed in Table 3. Deep endometriosis infiltrating the rectum and the sigmoid colon was recorded in 40.5 and 27% of patients respectively. The rate of ovarian endometriomas was as high as 81% in each ovary. At the end of surgery, 54% of patients were directly referred to the ART department for IVF or ICSI, 2.7% for simple stimulation, while 43.2% of them were advised to attempt postoperative spontaneous conception for 6 to 9 months before seeking ART care. Characteristics of women with and without successful IVF/ICSI procedures were compared and are presented in Table 4. Nine patients were not able to benefit from ART because of low ovarian reserve and were not included in the study. Four of the nine had a documented history of infertility and all nine were nulligravida. Four women had previously been managed by one (two patients) or more than one cystectomy (two patients). When
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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Fig. 1. Study flow-chart.
compared to the 37 cases, these nine women were older (37.2 3.4 years, P < 0.001) and had lower preoperative AMH level (0.64 0.55 ng/mL, P = 0.008). Endometrioma ablation was bilateral in five of the nine patients (P = 0.46). No differences were revealed concerning preoperative symptoms, associated localizations or cyst diameter. Postoperatively, three patients achieved spontaneous pregnancy (33%) and one following oocyte donation (11%). The main characteristics of the 74 controls who underwent ART management in our department are reported in Table 1. The main reason for infertility was fallopian tube obstruction (46%, Fig. 2). ART procedures used in each group and the response to ovarian stimulation are compared in Table 5 revealing that the number of oocytes retrieved was significantly higher in the control group. There was a higher number of ART procedures recorded in controls, specifically in the subgroup of patients requiring ICSI, which explains the higher rate of ICSI in controls. Table 6 presents the results of ART management which were systematically better in the group of patients managed for endometriomas using plasma energy. When the comparison only concerned the first attempt at Table 1 Main baseline characteristics of cases and controls.
Age (years)a Body mass index (kg/m2)a Obstetrical history Nulligesta Nullipara Smoking Day 3 FSH level (UI/L)a AMH level (ng/mL)a Partner’s progressive sperm mobility (million/mL)a ICSI IVF
Cases n = 37 (%)
Controls n = 74 (%)
P
30.9 4.4 23.3 4.4
31.7 4.2 23.3 4.4
0.31 0.95
21 (56.8) 30 (81.1) 7 (18.9) 7.7 2.2 2.8 2 1.6 1.4
41 (55.4) 56 (75.8) 23 (31.1) 7.3 2.2 2.8 1.7 1.8 2
1 0.63 0.26 0.45 0.93 0.50
9 (24.3) 28 (75.7)
20 (27) 54 (73)
0.75 0.75
AMH: anti-Mullerian hormone; FSH: follicle stimulating hormone; ICSI: IntraCytoplasmic Sperm Injection; IVF: in vitro fertilization a Data are expressed as mean standard deviation. A P-value < 0.05 was considered significant.
pregnancy by a couple, the differences between outcomes were also statistically significant. When spontaneous and ART induced pregnancies were taken together, the overall pregnancy rate was 56.8% in the case group. In the whole population of 46 patients referred for ART, the spontaneous and ART induced pregnancy rates were 52.2%. 4. Discussion Our study reports the first series of infertile women managed by IVF or ICSI after ovarian endometrioma surgery by ablation using Table 2 Clinical history of case patients and main symptoms related to endometriosis. Cases n = 37 (%) History of gynecological surgery Justification for previous surgeries Pelvic pain Infertility Ovarian cysts Endometriosis Cystectomy Right ovary Left ovary Right oophorectomy Adhesiolysis Unilateral salpingectomy Obstetrical history Nulligesta Nullipara Dysmenorrhea Primary dysmenorrhea Biberoglou & Behrman dysmenorrhea scorea Cyclic symptoms associated with dysmenorrhea Defecation pain Constipation Diarrhea Having had sexual intercourse Deep dyspareunia Biberoglou & Behrman deep dyspareunia scorea a
17 (45.9) 12 (32.4) 3 (8.1) 1 (2.7) 1 (2.7) 9 8 1 4 3
(24.3) (21.6) (2.7) (10.8) (8.1)
21 (56.8) 30 (81.1) 37 (100) 18 (48.6) 1.9 0.7 22 (59.5) 14 (37.8) 13 (35.1) 37 (100) 32 (86.5) 1.8 0.9
Data are expressed as mean standard deviation.
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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GYOBFE-2977; No. of Pages 7 I. Motte et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx Table 3 Intraoperative findings.
Table 4 Characteristics of cases stratified by the results of ART management. Cases n = 37 (%)
Operative time (minutes)a Operative route Laparoscopy Laparoscopy followed by open route AFSr scorea Douglas pouch complete obliteration Associated localizations Diaphragm Appendix Sigmoid colon Rectum Vagina Adenomyosis Management of ovarian endometriomas Right Left Adhesiolysis Right adnexa Left adnexa Deep posterior endometriosis nodules Left USL Right USL Rectovaginal septum Left USL, right USL and rectovaginal septum Surgical procedures on digestive tract Rectal shaving (when more than 1 rectal nodule) Rectal disc excision Colorectal resection Sigmoid colon disc excision Sigmoid colon resection Cecum resection Appendectomy Transitory stoma Surgical procedures on urinary tract Resection of the bladder Treatment of peritoneal implants Complete Incomplete (widespread implants) Surgeon advice concerning further pregnancy intention Spontaneous conception if postoperative normal fertility assessment Ovulation induction Intrauterine insemination Systematic IVF Oocyte donation
5
144 92 35 (94.6) 2 (5.4) 73 41 16 (43.2) 7 (18.9) 8 (21.6) 10 (27) 15 (40.5) 10 (27) 22 (59.4) 30 (81.1) 30 (81.1) 26 (70.3) 32 (86.5) 6 (16.2) 5 (13.5) 10 (27) 10 (27) 19 (51.4) 10 (27) 1 (2.7) 6 (16.2) 2 (5.4) 7 (18.9) 1 (2.7) 6 (16.2) 3 (8.1) 1 (2.7) 1 (2.7) 0 32 (86.5) 16 (43.2) 1 (2.7) 0 20 (54.1) 0
AFS: American Fertility Score; IVF: in vitro fertilization; USL: uterosacral ligament. a Data are expressed as mean standard deviation.
plasma energy. The pregnancy rate recorded in our population is encouraging, as it is higher than that observed in controls free of endometriosis presenting comparable baseline age, ovarian reserve and undergoing similar ART procedures. Furthermore, our results are either comparable or better than those previously reported in series of patients with endometriomas undergoing either primary IVF [13] or endometrioma cystectomy followed by IVF [14]. The major weakness of our study is related to its small sample size. Even though our department is a tertiary referral centre and routinely managed patients with ovarian endometriomas by ablation using plasma energy during the study period, only 13% of these patients were ultimately referred to the ART unit of our facility. The main explanation is due to the fact that the majority of our patients with endometriosis are domiciled outside of our local area (Seine-Maritime, Normandy) and logically patients decide to undergo ART in a center closer to home. Conversely, our study presents several strengths. This was a comparative study, with a control group representative of the general population of women referred for IVF. The second strength is related to the high homogeneity of surgical procedures performed on ovarian endometriomas, which are routinely performed by several surgeons in the same department. Thus,
Age (years)a Age group (years) < 25 25–29 30–38 38 Smoking Endometrioma size 30 mm 30–49 mm 40–49 mm 50–59 mm 60 mm Endometrioma cyst Unilateral Bilateral Preoperative AMH level (ng/mL)a AMH group 2 ng/mL 2–4 ng/mL 4 ng/mL Operative time (min)a AMH level before ART (ng/mL)
Pregnant n = 19 (%)
Not pregnant n = 18 (%)
P
29.9 3.4
31.9 5.1
0.17 0.32
3 (16) 12 (63) 4 (21) 0 (0) 5 (26)
2 8 5 3 2
(11) (44) (28) (17) (11)
6 4 4 2 3
3 4 2 4 5
(17) (22) (11) (22) (28)
(32) (21) (21) (10) (16)
0.40 0.64
0.51 6 (32) 13 (68) 3.6 1.9
8 (44) 10 (56) 1.9 1.2
2 (18) 5 (46) 4 (36) 139 96 2.7 1.6
6 (55) 4 (36) 1 (9) 149 90 2.5 1.4
0.02 0.17
0.76 0.60
AMH: anti-Mullerian hormone; ART: assisted reproductive technology; VAS: Visual Analogue Scale. a Data are expressed as mean standard deviation. A P-value < 0.05 was considered significant.
our results accurately assess the impact of endometrioma ablation using plasma energy as previously described in our abovementioned reports [4]. The third strength is related to the high prevalence of severe endometriosis in cases, as the majority of patients presented with stage 4 endometriosis or colorectal nodules, in which the likelihood of spontaneous pregnancy was reasonably low. Last but not least, our study logically continues our previous clinical research focusing on conservative surgery using plasma energy in endometriosis, and our results accord with previous data suggesting good preservation of ovarian parenchyma after ablation using plasma energy. The study we report today is related to the fourth step of our clinical research, and is the basis for the fifth step represented by a further randomized trial comparing clinical outcomes related to ablation and cystectomy. In a comparative study, statistically better results in cases may merely be due to unusually poor results in controls. The results observed in our controls were close to those recorded in the French national database in 2012, in which pregnancy rate per oocyte retrieval averaged 20% [15]. As our study inclusion criteria may result in lower ovarian reserve in controls than in the general population of women undergoing IVF or ICSI in France, we believe that the outcomes recorded in our control group are valid.
Fig. 2. Etiology of controls’ infertility.
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Table 5 Parameters of controlled ovarian hyperstimulation and characteristics of ART cycles.
Procedure employed Number of ICSI cycles Number of IVF cycles Stimulation protocol Antagonist protocol Long protocol Number of cycles per patienta Abandon rate Total dose of gonadotrophin used (IU)a 17 b estradiol level (pg/mL)a Endometrial thickness (mm)a Number of follicles > 15 mm Number of oocytes retrieved Number of mature oocytes Fertilization ratea Cleavage ratea Transfer rate Embryo quality Type 1 Type 2 Type 3 Type 4 Number of transferred embryosa
Cases a = 37 (%)
Controls n = 74 (%)
P
63 13 (20.6) 50 (79.4) 63 15 (23.8) 48 (76.2) 1.7 0.9 18 (28.6) 2,375 870 1,916 952 11.5 2.7 5.9 3.4 7.2 4.3 6.9 4.2 0.54 0.28 0.97 0.1 43 (95.6) 68 9 (33.8) 36 (52.9) 23 (13.2) 0 1.5 0.6
177 66 (37.3) 111 (62.7) 177 34 (19.2) 143 (80.8) 2.4 1.3 52 (29.4) 2,300 912 1,838 897 11.5 2.9 6.4 3.7 9.1 5.5 8 5.2 0.45 0.29 0.93 0.18 114 (91.2) 199 33 (16.6) 81 (40.7) 85 (42.7) 0 1.6 0.8
0.02
0.47
0.005 1 0.58 0.57 0.98 0.38 0.03 0.13 0.17 0.17 0.51 0.21
0.40
FSH: follicle stimulating hormone; ICSI: IntraCytoplasmic Injection; IVF: in vitro fertilization; n: number of patients. Embryo quality is defined by: type 1: cells are of equal size; no fragmentation seen; type 2: cells are of equal size and fragmentation less than 20%; type 3: cells are of unequal size and/or fragmentation 21 to 50%; type 4: cells are of unequal size and/or fragmentation more than 51%. a Data are expressed as mean SD. A P-value < 0.05 was considered significant. Table 6 ART outcomes.
Implantation rate Pregnancy rate Per transfer Per embryo Per cycle Per oocyte retrieval Delivery rate Per transfer Per embryo Per cycle Per oocyte retrieval Child rate per couple Cumulative rate of birth per transfer Multiple pregnancy rate Rate of miscarriage Ectopic pregnancy rate Biochemical pregnancy rate
Cases n = 37 (%)
Controls n = 74 (%)
P
26 (38.2)
37 (18.6)
0.002
22 22 22 22
(51.2) (32.4) (34.9) (43.1)
35 35 35 35
(30.7) (17.6) (19.8) (23.3)
0.025 0.016 0.02 0.011
19 19 19 19 18 20 5 2 0 1
(44.2) (27.9) (30.2) (37.3) (48.6) (46.5) (26.3) (9.1) (0) (4.5)
27 27 27 27 28 30 4 4 2 2
(23.7) (13.6) (15.3) (18) (37.8) (26.3) (14.8) (11.4) (5.7) (5.7)
0.018 0.009 0.015 0.007 0.311 0.021 0.46 1 0.52 1
A P-value < 0.05 was considered significant.
Consequently, the significantly better results revealed in our cases were not artificially due to bad results in controls, but probably represent new and valid findings concerning the benefits of endometrioma ablation using plasma energy. The question remains as to whether the good results recorded in the group of women with endometriosis could be due to a bias in the selection of cases with overall rather favorable predictive factors for fertility. In our opinion, the answer is negative, because the majority of our patients presented with severe pelvic endometriosis and strong arguments for infertility. Indeed, 24.3% and 21.6% had previously had one or more cystectomy on each ovary, 18.9% had experienced ectopic pregnancies, 81% were nullipara, 84% presented with deep endometriosis nodules, which infiltrated the rectum in 40.5% and the sigmoid colon in 27%, complete obliteration of Douglas pouch was found in 43% and overall AFSr score was 73 41. Furthermore, in our daily practice,
only the most severe patients are directly referred for postoperative IVF. Among women enrolled in this series, surgeons advised attempting spontaneous conception for up to 9 months in 43.2%, and postoperative IVF appeared to be unavoidable in only 54% of patients (Table 3). In a recent article presenting a series of patients managed for ovarian endometriosis with and without associated colorectal endometriosis, only 34.7% of patients were directly referred for postoperative IVF [4], while 64.7% of conceptions recorded in the series were spontaneous. It is in our opinion that surgical management of endometriosis is a good option in infertile women with severe endometriosis and pregnancy intention, as cumulative pregnancy rate appears to be at least as good as that recorded after primary IVF management [3]. Our results must be compared to those reported following primary IVF in women presenting with ovarian endometriomas, as well as to those recorded in patients previously managed by cystectomy. It has already been shown that unoperated endometriomas do not affect responsiveness to hyperstimulation [16]. However, in a recent review of the literature, Yang et al. [17] pooled the results of numerous studies previously published and reported that unoperated endometriomas are related to a lower number of oocytes retrieved and embryos formed, while implantation, pregnancy and live birth rates are not affected. Our results presented in Tables 5 and 6 are roughly comparable to those reported in patients with unoperated endometriomas [18]: mean number of oocytes retrieved 7.2 vs. 7.1, pregnancy rate per embryo 32.4% vs. 39%, delivery rate per embryo 27.9% vs. 29%. These results suggest that endometrioma ablation using plasma energy did not impair the IVF or ICSI outcomes that would have been recorded if endometriomas had not been operated. As regards the comparison with previously reported IVF or ICSI results in patients whose endometriomas were managed by cystectomy, our results are encouraging. A review of studies in the literature since 2000, reported implantation rates after cystectomy that varied up to 32.1% [19] and pregnancy rates up to 47% [20], even though in the majority of studies pregnancy rates were inferior to 40% [21,22]. Our results are comparable, if not better, than those observed after cystectomy [14], suggesting that ablation of ovarian endometriomas in patients undergoing postoperative IVF is a valuable alternative to cystectomy. One may inquire whether or not surgery was necessary in patients enrolled in our series, as it was proposed before IVF. It should be underlined that IVF and ICSI were performed before surgery in respectively 16.2% and 8.1% of our cases, but progressive aggravation of pelvic and digestive complaints prompted surgery thereafter. Detailed listing of baseline complaints provides accurate data on the severity of preoperative symptoms justifying surgery. To date, no pathophysiological theory can definitely explain these encouraging results after ovarian endometriosis ablation using plasma energy. In the human ovary, AMH expression is negligible in primordial follicles, low in granulosa cells of primary follicles but highest in granulosa cells of secondary, pre-antral and small antral follicles 4 mm in diameter [23]. In larger antral follicles, AMH expression gradually disappears [24]. It is possible that ablation using plasma energy not only spares underlying ovarian tissue and decreases inflammatory phenomena, but also promotes the development of primordial, primary and secondary follicles. This may explain why AMH level could progressively increase after surgery [10], providing better reproductive outcomes when compared to those of patients free of endometriosis with comparable baseline AMH level. Roustan et al. [25] recently observed that IVF outcomes and live birth rate were significantly impaired in women with diminished ovarian reserve (AMH level < 2 ng/mL) caused by a previous cystectomy for endometrioma compared to women with idiopathic etiology. Although the majority of our patients had
Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008
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AMH level > 2 ng/mL, it is noteworthy to emphasize that our results were different to those of Roustan et al. [25]. This difference may be directly due to better preservation of ovarian reserve related to ablation using plasma energy when compared to cystectomy [9]. An ablative approach in ovarian endometriomas is well recorded in the literature. As far back as 1990, endometrioma ablation using CO2 laser was employed with good postoperative pregnancy rate [6], which was comparable to that observed after cystectomy [26]. More recently, it has been shown that similar effects might be obtained by ethanol instillation into the cyst (ethanol sclerotherapy) using the transvaginal route. When compared to cystectomy, ethanol sclerotherapy before stimulation in recurrent endometriomas allowed better preservation of ovarian reserve and ovarian response to stimulation, as well as higher clinical and cumulative pregnancy rate [27]. These data support the hypothesis that endometrioma ablation is a valuable alternative to cystectomy, which may spare ovarian tissue located underneath the nodule. In our opinion, isolated management of endometriomas in patients with associated deep endometriosis may be considered in specific circumstances such as large cysts that complicate oocyte retrieval in patients with asymptomatic deep localizations or in patients with large deep lesions for whom surgery could lead to postoperative complications delaying IVF. Our study only represents an intermediate step in our clinical research focusing on the best management of patients with endometriosis and pregnancy intention. In a recent paper, we discussed why primary surgery followed by IVF or not is a valuable treatment in patients with deep colorectal endometriosis and pregnancy intention [3]. Even though recent guidelines state that no data support the fact that performing surgery before IVF improves IVF outcomes [2], delaying surgery may increase the risk of various complications and functional troubles as well as that of more aggressive further surgery [3]. In addition, surgery may be required before IVF in patients with various pelvic pains and poor quality of life [2]. Our study provides encouraging information concerning these latter patients, as it suggests that performing complete endometriosis surgery and ovarian endometrioma ablation using plasma energy offer good postoperative fertility outcomes.
[2] [3] [4]
[5]
[6] [7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
Funding [19]
No financial support was received for this study. The NorthWest Inter Regional Female Cohort for Patients with Endometriosis (CIRENDO) is financed by the G4 Group (The University Hospitals of Rouen, Lille, Amiens and Caen).
[20]
[21]
Disclosure of interest Horace Roman reports personal fees for participating in a symposium and a master class presenting his experience in the use of PlasmaJet. The other authors have not supplied their declaration of competing interest.
[22]
[23]
[24]
Acknowledgements [25]
We thank Miss Amelie Breant, for her valuable management of the CIRENDO database. The authors are grateful to Nikki Sabourin-Gibbs, Rouen University Hospital, for her help in editing the manuscript. References [1] Benschop L, Farquhar C, van der Poel N, Heineman MJ. Interventions for women with endometrioma prior to assisted reproductive technology.
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Please cite this article in press as: Motte I, et al. In vitro fertilization outcomes after ablation of endometriomas using plasma energy: A retrospective case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.08.008