Conventional IVF performs similarly

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<p>Vol.:(0123456789)1 3</p><p>https://doi.org/10.1007/s10815-022-02700-z</p><p>ASSISTED REPRODUCTION TECHNOLOGIES</p><p>Conventional IVF performs similarly in women</p><p>with and without endometriosis</p><p>Paola Viganò1  · Marco Reschini1  · Marta Ciaffaglione1 · Veronica Cucè1 · Maíra Casalechi2  · Laura Benaglia1  ·</p><p>Paolo Vercellini3,4  · Edgardo Somigliana1,3</p><p>Received: 5 October 2022 / Accepted: 17 December 2022</p><p>© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023</p><p>Abstract</p><p>Purpose A reduced oocyte competence has been claimed as one of the factors underlying infertility in women with endo-</p><p>metriosis. This idea has justified the hypothesis that intracytoplasmic sperm injection (ICSI), rather than conventional IVF</p><p>(c-IVF), may overcome oocyte impairment and ensure better assisted reproduction technology (ART) outcomes; however,</p><p>data from the literature are controversial. Thus, the aim of this study was to compare ART success rates following (c-IVF)</p><p>between women with and without endometriosis in the presence of normozoospermic partners.</p><p>Methods This is a retrospective, matched case–control study of 314 patients who underwent c-IVF cycles between January</p><p>2014 and December 2020. Women with endometriosis were matched in a 1:1 ratio with patients undergoing ART for other</p><p>indications, considering age (± 6 months), number of oocytes retrieved (± 1), and study period. The main outcome meas-</p><p>ures included total fertilization failure, fertilization rate, embryo quality, cumulative clinical pregnancy, and live birth rates.</p><p>Results The fertilization rate and the proportion of women with total fertilization failure did not differ between women with</p><p>and without endometriosis. Similarly, all other embryological variables did not also differ, except for the number of top-</p><p>quality cleavage stage embryos which was higher in the endometriosis group. Cumulative clinical pregnancy and live birth</p><p>rates were similar between women with and without endometriosis.</p><p>Conclusion A diagnosis of endometriosis does not negatively affect the performance of c-IVF; thus, c-IVF can be efficiently</p><p>used in women affected, unless a male factor is also involved. This issue holds clinical relevance to help operators on their</p><p>insemination technique decision-making.</p><p>Keywords Endometriosis · Conventional IVF · In vitro fertilization · ICSI · Assisted reproductive technologies</p><p>Introduction</p><p>Ten percent of reproductive-aged women worldwide are</p><p>affected by endometriosis, and, among infertile women,</p><p>25–50% suffer from this disease [1]. In line with this, this</p><p>disorder is being considered one of the major indications</p><p>for assisted reproduction technology (ART) procedures [2].</p><p>The relation between endometriosis and infertility has been</p><p>explained by several mechanisms including the disruption of</p><p>pelvic anatomy [3], the association with adenomyosis, and</p><p>the presence of a local inflammatory environment poten-</p><p>tially able to affect sperm-zona pellucida (ZP) interaction</p><p>[4], hamper gamete fertilization [5, 6], damage the ovarian</p><p>tissue [7], and inhibit the physiological fertilized egg migra-</p><p>tion through the fallopian tubes [8].</p><p>Women with endometriosis may face challenges even</p><p>during ART cycles. For instance, an increased risk of unex-</p><p>pected poor ovarian response [9] and a lower number of</p><p>oocytes retrieved have been demonstrated in these patients</p><p>compared to women without the disease [1]. Accordingly,</p><p>cycle cancelation rate has been reported to be increased</p><p>[10] and markers of ovarian reserve to be decreased [11],</p><p>* Paola Viganò</p><p>paola.vigano@policlinico.mi.it</p><p>1 Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale</p><p>Maggiore Policlinico, Via F. Sforza 28, 20122 Milan, Italy</p><p>2 Division of Human Reproduction, Hospital das Clínicas,</p><p>Universidade Federal de Minas Gerais, Belo Horizonte,</p><p>Brazil</p><p>3 Department of Clinical Sciences and Community Health,</p><p>Università Degli Studi Di Milano, Milan, Italy</p><p>4 Gynecology Unit, Fondazione IRCCS Ca’ Granda Ospedale</p><p>Maggiore Policlinico, Milan, Italy</p><p>/ Published online: 13 January 2023</p><p>Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>http://crossmark.crossref.org/dialog/?doi=10.1007/s10815-022-02700-z&domain=pdf</p><p>http://orcid.org/0000-0003-3674-5912</p><p>http://orcid.org/0000-0002-9868-3043</p><p>http://orcid.org/0000-0003-0015-3157</p><p>http://orcid.org/0000-0002-7404-9830</p><p>http://orcid.org/0000-0003-4195-0996</p><p>http://orcid.org/0000-0002-0223-0032</p><p>1 3</p><p>especially if women previously underwent a surgical inter-</p><p>vention to the ovaries. Endometriosis has been also sug-</p><p>gested to negatively affect oocyte quality in terms of relevant</p><p>clinical and biological outcomes [12]. Nevertheless, based</p><p>on the recent meta-analyses, a lower success rate follow-</p><p>ing ART procedures was not consistently demonstrated in</p><p>women with endometriosis and endometriomas [10, 13],</p><p>supporting the idea that ART may somehow overcome the</p><p>detrimental effects associated with the disease.</p><p>Therefore, a better understanding of the factors causing</p><p>infertility in women affected by endometriosis and of the</p><p>ART-based interventions that could improve the outcomes</p><p>represents a priority in reproductive medicine. In this con-</p><p>text, the concept that endometriosis itself is responsible for</p><p>a reduced oocyte competence [4, 12, 14] and for molecular</p><p>alterations in granulosa cells has justified the hypothesis that</p><p>intracytoplasmic sperm injection (ICSI), rather than con-</p><p>ventional IVF (c-IVF), may overcome oocyte impairment</p><p>and, therefore, lead to better ART outcomes. Data from the</p><p>literature are controversial on this point. Comparing sibling</p><p>oocytes, Komsky-Elbaz et al. have indicated that ICSI leads</p><p>to a higher fertilization rate and a greater mean number of</p><p>embryos compared to c-IVF in couples with stages III–IV</p><p>endometriosis [15]. Conversely, Tan et al. suggested that</p><p>the peculiar frailty of oocytes in case of endometriosis may</p><p>favor microinjection-related traumas, arguing against the</p><p>systematic use of ICSI [16]. According to Scarafia and cow-</p><p>orkers, ICSI and c-IVF outcomes were comparable in case</p><p>of women with endometriomas [17]. Importantly, knowl-</p><p>edge on this important topic has been hindered by the fact</p><p>that previous studies have retrospectively compared results</p><p>between ICSI and c-IVF. This implied the inclusion of male</p><p>infertility or other reasons to perform ICSI as an important</p><p>confounding factor. Moreover, studies on sibling oocytes do</p><p>not allow to investigate the real impact on pregnancy rate.</p><p>To overcome possible issues in the study design, the aim</p><p>of this study was to compare ART success rates following</p><p>c-IVF between women with and without endometriosis</p><p>in the presence of normozoospermic partners. This study</p><p>design should overcome the limitations of previous inves-</p><p>tigations. This specific issue holds clinical relevance since</p><p>the clarification of the c-IVF efficacy in endometriosis will</p><p>be extremely useful to clinicians and embryologists on their</p><p>insemination technique decision-making.</p><p>Methods</p><p>Ethical approval</p><p>This retrospective matched case–control study was approved</p><p>by the local Institutional Review Board (344–2021). All</p><p>women referring to the unit signed an informed consent for</p><p>their data to be used for scientific purposes.</p><p>Study design and participants</p><p>Clinical data from women who underwent ART proce-</p><p>dures at the Infertility Unit of the Fondazione Ca’ Granda,</p><p>Ospedale Maggiore Policlinico Milano, in Italy, between</p><p>January 2014 and December 2020 were recovered by</p><p>a review of medical records. Couples had to fulfill the</p><p>following inclusion criteria: female age between 18 and</p><p>42 years old at the day of oocyte retrieval. Exclusion</p><p>criteria included charts with inconsistent or incomplete</p><p>data, cases undergoing pre-implantation genetic testing</p><p>(PGT) for genetic disorders (PGT for aneuploidies was</p><p>conversely not done in our Center), and cases with ICSI</p><p>indications (presence of male factor infertility or previous</p><p>c-IVF cycles</p><p>with total fertilization failure). The follow-</p><p>ing semen parameters defined cases: sperm concentra-</p><p>tion < 15 × 106/mL; total motility < 40% and progressive</p><p>motility < 32%; concentration of round cells > 1 × 106/mL</p><p>[18], or a progressive motility < 65% after capacitation.</p><p>Patients were grouped as follows: (1) patients with endo-</p><p>metriosis (n = 157) who were diagnosed by ultrasound</p><p>and had this diagnosis documented on, at least, two dif-</p><p>ferent occasions and, at least, on two menstrual cycles</p><p>apart or who had been submitted previously to surgery</p><p>(ASRM stage III–IV) and had proper histologic documen-</p><p>tation and (2) control patients (n = 157) who underwent</p><p>ART due to unexplained infertility (n = 109), tubal factor</p><p>(n = 17), ovulatory disorders (n = 15), and reduced ovar-</p><p>ian reserve (n = 16). Control group was matched on a 1:1</p><p>ratio by age (± 6 months), numbers of oocytes collected</p><p>(± 1), and study period (the next woman fulfilling the</p><p>criteria for selecting and matching). We first identified</p><p>cases (women with endometriosis) with complete docu-</p><p>mentation and then matched controls. Women without a</p><p>history of surgery for endometriosis but who were diag-</p><p>nosed with soft markers of the disease such as reduced</p><p>or absent sliding sign [19, 20] were excluded from both</p><p>cases and controls.</p><p>Controlled ovarian hyperstimulation</p><p>Controlled ovarian hyperstimulation and collection of folli-</p><p>cular aspirates were performed according to the institutional</p><p>protocol, reported elsewhere [21–23]. Protocol of ovarian</p><p>hyperstimulation and initial dose of FSH, as well as dose</p><p>adjustments during treatment, was chosen on a case-by-case</p><p>basis, according to patients’ characteristics. Patients at risk</p><p>of ovarian hyperstimulation syndrome (OHSS) (presence of</p><p>25 follicles with a diameter ≥ 12 mm on the day of trigger-</p><p>ing) had the prescription of hCG replaced by GnRH agonist</p><p>600 Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>1 3</p><p>0.2 ml if they were receiving the protocol with GnRH antag-</p><p>onists. Serum progesterone was assessed on the day of hCG</p><p>administration, and oocyte pick up was performed 36 h after</p><p>the triggering of ovulation. Women with elevated progester-</p><p>one and those at risk of OHSS did not undergo fresh embryo</p><p>transfer. No adjuvant treatments — such as acetylsalicylic</p><p>acid, cortisone, and low-weight-molecular heparin — were</p><p>prescribed, except for folic acid that was conversely system-</p><p>atically given.</p><p>In fresh cycles, vaginal progesterone was given for</p><p>2 weeks after the oocyte retrieval. In frozen cycles, women</p><p>could be treated with either natural cycle or hormone</p><p>replacement therapy (HRT) [22]. Those cases with regular</p><p>menstrual cycles were generally scheduled for the transfer</p><p>using the natural cycle scheme. These women did not receive</p><p>any therapeutic support. Women receiving HRT continued</p><p>the therapy for the whole first trimester of pregnancy.</p><p>In vitro fertilization</p><p>Based on the policy of our unit, the decision between c-IVF</p><p>and ICSI was taken by the embryologists on the day of</p><p>oocyte retrieval considering previous cycle outcome (cases</p><p>with previous total fertilization failure were allocated to</p><p>ICSI) and the results of the semen analysis at the time of the</p><p>procedure. A history of previous pathological semen was not</p><p>an indication to ICSI.</p><p>Cumulus–oocyte complexes (COCs) retrieved were</p><p>incubated in G-IVF™ Plus, a human serum albumin</p><p>(hSA)-supplemented fertilization media culture (Vitrolife,</p><p>Gothenburg, Sweden) under Ovoil™ culture oil (Vitrolife,</p><p>Gothenburg, Sweden). Semen was prepared by gradient</p><p>protocol followed by a swim-up technique, in accordance</p><p>with the standard protocol of the service [21]. Up to four</p><p>COCs were inseminated with about 25,000 spermatozoa/</p><p>mL. Sixteen-eighteen hours after insemination, the</p><p>remaining cumulus cells were removed, and fertilization</p><p>was checked as previously described [24]. Zygotes were</p><p>cultured in G-1™ Plus, a hSA-supplemented cleavage</p><p>media culture (Vitrolife, Gothenburg, Sweden) under</p><p>Ovoil™ culture oil until day 3 of development. Following</p><p>the protocol of  our institution, embryos were selected</p><p>for fresh transfer at the cleavage stage (day 3). In some</p><p>cases, when several top-/good-quality day 3 embryos were</p><p>available, they were transferred at blastocyst stage at day</p><p>5. All the supernumerary embryos were relocated to G-2™</p><p>Plus, a hSA-supplemented  blastulation media culture</p><p>(Vitrolife, Gothenburg, Sweden) until blastocyst stage.</p><p>The surplus expanded blastocysts obtained were frozen.</p><p>Patients at risk of OHSS or who had serum progesterone</p><p>levels > 1.5 ng/mL on the day of trigger were submitted to a</p><p>freeze-all protocol, and no fresh embryos were transferred.</p><p>Assessment of embryo scores was conducted based on</p><p>the Istanbul consensus [24]. Briefly, cleaved embryos were</p><p>assessed accordingly to the number of cells and rated based on</p><p>(i) fragmentation; good < 10% of fragmentation, fair 10–25%</p><p>of fragmentation, and poor > 25% of fragmentation; (ii) cell</p><p>size; good for stage-specific cell size, fair for stage-specific cell</p><p>size for the majority of cells, poor for cell size not stage-spe-</p><p>cific; and (iii) multinucleation; good for no multinucleation;</p><p>fair for no evidence of multinucleation; and poor for multi-</p><p>nucleated. Based on this, a “top-quality” embryo at 68 ± 1 h</p><p>post-insemination was an 8-cell non-multinucleated symmetric</p><p>embryo with < 10% of fragmentation. Blastocysts were given</p><p>a rating based on (i) the degree of expansion and hatching</p><p>status (from 1 as early to 4 as hatched blastocyst); (ii) the inner</p><p>cell mass scored as follows: good, prominent, easily discern-</p><p>ible, with many cells that are compacted and tightly adhered</p><p>together; fair, easily discernible, with many cells that are</p><p>loosely grouped together; and poor, difficult to discern, with</p><p>few cells; and (iii) the trophectoderm scored as good, many</p><p>cells forming a cohesive epithelium; fair, few cells forming a</p><p>loose epithelium; and poor, very few cells [24]. Accordingly,</p><p>a “top-quality” blastocyst was defined as those expanded or</p><p>hatched with both an inner cell mass and multicellular trophec-</p><p>toderm scored good or with only one of the two parameters</p><p>scored fair and the other one scored good [25].</p><p>Statistics</p><p>Outcome data were analyzed using SPSS Statistics (soft-</p><p>ware version 26.0; IBM Corp, USA). A Shapiro–Wilk test</p><p>was used to verify the normal distribution. The statisti-</p><p>cally significant differences between the two groups were</p><p>evaluated using different tests according to the characteris-</p><p>tics of the examined variables. Unpaired Student’s t test or</p><p>Mann–Whitney test was used for continuous variables. A</p><p>chi-squared test or Fisher’s exact test was used for categori-</p><p>cal variables. Values of P < 0.05 were regarded as statisti-</p><p>cally significant.</p><p>The calculated sample size consisted of at least 300</p><p>women, 150 with endometriosis and 150 without the disease.</p><p>This number was estimated based on the following statistical</p><p>assumptions: (i) type I and type II errors equal to 0.05 and</p><p>0.20, respectively; (ii) an expected rate of women with total</p><p>fertilization failure in the unexposed group (controls) of 4%;</p><p>and (iii) a difference deemed to be of clinical relevance of</p><p>9% based on previous observations [15].</p><p>Results</p><p>A total of 314 women undergoing ART were included in</p><p>the study; 157 women were affected by moderate–severe</p><p>endometriosis; and 157 were not affected. Matching was also</p><p>601Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>1 3</p><p>possible, and we did not have to exclude affected women</p><p>because of the lack of a control to match. Specific subgroup</p><p>diagnoses of endometriosis are shown in Table 1, as well as</p><p>baseline characteristics of the two study groups. The endo-</p><p>metriosis group had a lower body mass index (BMI), higher</p><p>AMH levels and a shorter duration of infertility and was</p><p>treated more frequently with the GnRH agonist (Table Sup-</p><p>plementary 1). The other variables evaluated did not</p><p>vary</p><p>significantly between the two groups. Specific characteristics</p><p>of the seminal fluid of the male partner at the time of the</p><p>procedure were also similar (Table 2). The median [inter-</p><p>quartile range] number of oocytes was almost  identical,</p><p>being 6 [3-11] in the endometriosis group vs. 6 [4-11] in the</p><p>control group (p=0.90), as expected (groups were matched</p><p>for this variable).</p><p>The main outcomes in the two groups are illustrated in</p><p>Table 3. Total fertilization failure rate, fertilization rate,</p><p>the number of cleavage stage embryos, the number of</p><p>Table 1 Baseline characteristics</p><p>of the two study groups</p><p>Data are reported as median [interquartile range] or number (percentage)</p><p>Characteristics Endometriosis Controls p</p><p>n = 157 n = 157</p><p>Age (years) 35 [32–37] 35 [32–37] 0.89</p><p>BMI (Kg/m2) 20.8 [19.5–22.7] 21.6 [19.5–24.6] 0.05</p><p>FSH (IU/ml) 6.7 [5.6–8.6] 6.8 [5.8–8.0] 0.68</p><p>AMH (ng/ml) 2.6 [1.6–3.6] 2.0 [1.1–3.2] 0.001</p><p>AFC 12 [7–16] 11 [8–16] 0.72</p><p>Duration of infertility (years) 2.0 [1.5–3.5] 3.0 [3.0–5.0] < 0.05</p><p>Previous deliveries 6 (4%) 10 (6%) 0.44</p><p>Previous IVF cycles 0.15</p><p>0 137 (87%) 127 (81%)</p><p>1 18 (12%) 21 (13%)</p><p>2 2 (1%) 7 (5%)</p><p>≥ 3 0 (0%) 2 (1%)</p><p>Indication to IVF < 0.05</p><p>Unexplained - 109 (69%)</p><p>Tubal factor - 17 (11%)</p><p>Ovulatory disorder - 15 (10%)</p><p>Reduced ovarian reserve - 16 (10%)</p><p>Endometriosis 157 (100%) -</p><p>Endometriosis classification</p><p>Endometrioma 98 (62%) -</p><p>Unilateral 71 (45%) -</p><p>Bilateral 27 (17%) -</p><p>Deep endometriotic lesions 48 (31%) -</p><p>Previous surgery for endometriosis 73 (46%) -</p><p>Endometrioma excision 57 (36%) -</p><p>Deep endometriosis surgery 31 (20%) -</p><p>Table 2 Basal characteristics of</p><p>the male partners</p><p>Data are reported as median [interquartile range] or number (percentage)</p><p>Characteristics Endometriosis Controls p</p><p>n = 157 n = 157</p><p>Same characteristics</p><p>Volume (ml) 2.7 [2.0–3.5] 2.9 [2.0–4.0] 0.33</p><p>Basal concentration (number/ml) 66 × 106 [44–102] 58 × 106 [39–92] 0.08</p><p>Basal progressive motility (%) 47 [41–55] 48 [40–55] 0.98</p><p>Concentration after gradient (number/ml) 10 × 106 [4–25] 10 × 106 [5–24] 0.71</p><p>Progressive motility (%) after gradient 94 [91–96] 95 [92–97] 0.19</p><p>602 Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>1 3</p><p>blastocysts, and the number of blastocysts obtained did</p><p>not differ between the two groups. The clinical pregnancy</p><p>rate following fresh embryo transfer as well as the cumu-</p><p>lative pregnancy, implantation rates, and live birth rates</p><p>showed similar results between women with and without</p><p>endometriosis. The number of top-quality cleavage stage</p><p>embryos was higher in the endometriosis group compared</p><p>to the controls, the median [interquartile range] being 2</p><p>[1-4] and 1 [0–2], respectively (p < 0.05).</p><p>The odds ratio (OR) for total fertilization failure and</p><p>for live birth rate in patients with endometriosis was 0.66</p><p>(95%CI 0.18–2.38, p = 0.52) and 1.51 (95%IC 0.97–2.36,</p><p>p = 0.07), respectively. Considering the differences</p><p>obtained in the baseline characteristics (AMH, BMI dura-</p><p>tion of infertility, and protocol of stimulation), we have</p><p>controlled the variables in a multivariate regression model.</p><p>Results were the following: OR = 1.15; 95%CI, 0.174–7.79</p><p>(p = 0.89) for total fertilization failure and OR = 1.57;</p><p>95%IC, 0.83–2.95 (p = 0.16) for live birth rate.</p><p>Discussion</p><p>The results presented herein support the idea that infertility</p><p>mechanisms associated with endometriosis do not have a</p><p>detrimental impact on results of c-IVF.</p><p>Several alterations have been observed in patients</p><p>affected potentially impairing the processes of fertilization</p><p>and embryo development, which can be detected at differ-</p><p>ent levels. First, peritoneal fluid from patients with endo-</p><p>metriosis appears to be enriched in activated macrophages,</p><p>which, in turn, leads to a high concentration of macrophage-</p><p>related products, such as interleukin (IL)-1β, IL-6, IL-8,</p><p>tumor necrosis factor-a (TNF-α), and transforming growth</p><p>factor-β (TGF-β). These cytokines are thought to affect the</p><p>Table 3 Main outcomes</p><p>Data are reported as median [interquartile range] or number (percentage)</p><p>a Data are reported on number of patients with viable embryos available</p><p>Characteristics Endometriosis Controls p</p><p>n = 157 n = 157</p><p>Total number of retrieved oocytes 6 [3–11] 6 [4–11] 0.90</p><p>Number of patients with total fertilization failure 4 (3%) 6 (4%) 0.75</p><p>Fertilization rate (%) 77.7 [60.0–100.0] 75.0 [55.6–90.0] 0.24</p><p>Number of cleavage stage embryos 3 [2–6] 3 [2–6] 0.79</p><p>Number of top-quality embryos 2 [1–4] 1 [0–2] < 0.05</p><p>Number of patients without viable embryos available 7 (5%) 8 (6%) 1.00</p><p>Number of blastocysts 1 [0–2] 0 [0–2] 0.13</p><p>Number of top-quality blastocysts 0 [0–2] 0 [0–1] 0.11</p><p>Number of fresh transfers performed 0.42</p><p>At cleavage stage 96 (86%) 104 (90%)</p><p>At blastocyst stage 16 (14%) 12 (10%)</p><p>Pregnancy rate on fresh embryo transfer 42 (37%) 33 (28%) 0.21</p><p>Subsequent cryopreserved embryo transfers 67 (43%) 78 (50%) 0.26</p><p>Number of embryo transfers per patienta 0.13</p><p>0 1 (1%) 0 (0%)</p><p>1 103 (69%) 89 (60%)</p><p>2 23 (15%) 38 (25%)</p><p>≥ 3 23 (15%) 22 (15%)</p><p>Number of cumulative embryos transferred per patienta 0.15</p><p>0 1 (1%) 0 (0%)</p><p>1 97 (65%) 83 (56%)</p><p>2 28 (19%) 43 (29%)</p><p>≥ 3 24 (16%) 23 (15%)</p><p>Implantation rate 87/239 (36%) 73/247 (30%) 0.13</p><p>Cumulative pregnancy rate per retrieval 86 (55%) 69 (44%) 0.07</p><p>Cumulative live births rate per retrieval 81 (52%) 65 (41%) 0.09</p><p>Number of patients without live birth with embryos</p><p>available to FET</p><p>6 (4%) 6 (4%) 1.00</p><p>603Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>1 3</p><p>sperm–COC interaction as well as sperm-ZP binding [26],</p><p>interfering with the fertilization process. Noteworthy, this</p><p>mechanism could play a detrimental role in vivo but not in</p><p>the IVF context, because in the latter situation, COCs are</p><p>not exposed to the peritoneal milieu, being directly aspi-</p><p>rated from the follicles. Second, and potentially more rel-</p><p>evant in the context of IVF, the intrafollicular environment</p><p>of women with endometriosis seems to be characterized by</p><p>a functional alteration of granulosa cells, mostly defined</p><p>by reduced levels of P450 aromatase expression and activ-</p><p>ity and a consequent abnormal estradiol production [7, 12,</p><p>27–30]. Also, GCs from patients affected have been shown</p><p>to produce an excessive amount of reactive oxygen species,</p><p>potentially activating endoplasmic reticulum stress and</p><p>damaging mitochondria. The overall consequence may be</p><p>an impaired COC maturation, follicle apoptosis, and meta-</p><p>bolic disturbance [31, 32]. Third, some reports supported</p><p>the idea that, in women with endometriosis, oocyte quality</p><p>is compromised. Specifically, an increased cortical granule</p><p>loss and ZP hardening have been observed in oocytes from</p><p>women with endometriosis. A limited ability of immature</p><p>oocytes from affected patients to undergo in vitro maturation</p><p>(IVM) has been also described [33]. Finally, oocytes from</p><p>women with endometriosis would contain less mitochondria,</p><p>being most of them abnormal [34], potentially reflecting a</p><p>decreased oocyte quality.</p><p>In this scenario, it has been hypothesized that ICSI, bet-</p><p>ter than c-IVF, could overcome some of these detrimental</p><p>effects of endometriosis on the reproductive process [15].</p><p>The rationale behind this hypothesis is that, to perform ICSI,</p><p>cumulus cells need to be stripped from the oocytes, decreas-</p><p>ing the amount of oxidative stress that the dysfunctional</p><p>cells would cause mainly during the fertilization process.</p><p>Also, the injection of the oocyte directly inside the ooplasm</p><p>would overcome any impairment of sperm binding to the</p><p>cumulus cells as well as any difficulties to penetrate the ZP.</p><p>In line with this hypothesis, a study has evaluated whether</p><p>ICSI would bring better results than c-IVF in sibling oocytes</p><p>from women with endometriosis. Interestingly, a better fer-</p><p>tilization rate and a lower rate of total fertilization failure</p><p>and of triploid fertilization were observed following ICSI</p><p>compared to c-IVF. However, some limitations of this study</p><p>should be considered: the</p><p>fertilization rate reported follow-</p><p>ing c-IVF was lower than the competency reference values</p><p>(55% vs ≥ 60%, respectively) and considerably lower than</p><p>the benchmark value (≥ 75%) [35]. Similarly, the total fer-</p><p>tilization failure rate reported by this study was higher than</p><p>competency reference values suggested by the Vienna Con-</p><p>sensus (13% vs. < 5%, respectively) [35]. These c-IVF rates</p><p>raise doubts on the correct performance of the technique. In</p><p>our study, the fertilization rate in the endometriosis group</p><p>after c-IVF was 78% and 75% in women with and with-</p><p>out endometriosis, respectively, in line with the benchmark</p><p>value suggested by the Vienna consensus [35]. The high</p><p>fertilization rate observed among women with endometriosis</p><p>in our study corroborates the validity of our conclusions.</p><p>Indeed, one could have argued that the inclusion among</p><p>controls of a large proportion of women with unexplained</p><p>infertility (69%) may have selected subjects with some unde-</p><p>tected problems in the fertilization per se, these problems</p><p>being the main cause of their infertility. In other words, one</p><p>could claim that also women in the control group could har-</p><p>bor some disturbances in the fertilization process. The obser-</p><p>vation of a fertilization rate above the benchmark in both</p><p>groups clearly argues against this possible criticism. To note,</p><p>even if not a primary aim, similar considerations could be</p><p>done for the live birth rate (52% among cases), a rate in line</p><p>with our standards [36]. Overall, given the similar outcomes</p><p>obtained when compared to infertile patients without the dis-</p><p>ease, the results from the present retrospective investigation</p><p>indicate that c-IVF can be efficiently performed in patients</p><p>with endometriosis in the presence of a normozoospermic</p><p>partner in terms of motility and concentration.</p><p>Regarding the control population chosen for this analysis,</p><p>it is well established that women with endometriosis tend to</p><p>have a lower ovarian reserve than women without the dis-</p><p>ease, which might be caused by the disorder itself or by iat-</p><p>rogenic damages when ovarian endometriomas are surgically</p><p>removed [37]. Therefore, in our study, the control group was</p><p>well-designed to match the case group according to women’s</p><p>age as well as the number of oocytes retrieved, thus normal-</p><p>izing the differences in ovarian reserve expected in women</p><p>with endometriosis. Accordingly, the median number of</p><p>oocytes retrieved (n = 6) in our study group was relatively</p><p>low. The control group also showed a low number, but this</p><p>was expected given that the number of oocytes retrieved was</p><p>a matching variable. Interestingly, the case group showed a</p><p>significantly lower BMI and infertility duration, in accord-</p><p>ance with data in the literature [38]. The difference in the</p><p>type of protocol of ovarian hyperstimulation (a higher pro-</p><p>portion of long protocols among women with endometriosis)</p><p>was expected since in the past it was suggested that this may</p><p>be of benefit for women with endometriosis [39]. However,</p><p>we did not deem this variable of relevance in the context of</p><p>the present study, and, to avoid selection biases, we did not</p><p>match also for this variable.</p><p>Our observation may be at first glance surprising as</p><p>it contrasts with the common view that endometriosis</p><p>may decrease fertilization, implantation, pregnancy, and</p><p>live birth rates in women undergoing ART [2, 40, 41].</p><p>In a recent study addressing the possible detrimental</p><p>effects of the disease on ovarian response and embryo</p><p>development in a cohort of women with a good ovarian</p><p>reserve, we have reported a higher rate of unexpected</p><p>poor response to ART treatment and fewer oocytes</p><p>retrieved in women affected. Fertilization rate and</p><p>604 Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>1 3</p><p>the rate of women who failed to develop good-quality</p><p>embryos were similar between women with and without</p><p>endometriosis. Despite the longer duration of stimula-</p><p>tion and the higher gonadotropin dosage used in women</p><p>with endometriosis, no difference was shown in the rate</p><p>of success of the procedure, the cumulative clinical and</p><p>live birth rates being very similar [9]. Our present find-</p><p>ings give support to these data. Importantly, the higher</p><p>rate of unexpected poor response to ART treatment and</p><p>fewer oocytes retrieved in women affected can justify</p><p>the small but significant higher levels of AMH in the</p><p>endometriosis group than in the control group that we</p><p>have herein observed. Since we have matched for number</p><p>of oocytes retrieved, a higher ovarian reserve in patients</p><p>with endometriosis may be needed to gain a similar num-</p><p>ber of oocytes than controls.</p><p>The present study includes a number of patients</p><p>(n = 157 in each group) adequate to reveal an increase</p><p>in total fertilization failure according to that reported</p><p>by Komsky-Elbaz et al. [15]. We were not able to con-</p><p>firm those findings. Moreover, all the patients affected</p><p>had a proper diagnosis of the disease according to the</p><p>criteria of the recent ESHRE guidelines [42]. Despite</p><p>these strengths, we are aware of some limitations of the</p><p>study. Firstly, this is a retrospective design, in which</p><p>reports might be subjected to misclassification bias.</p><p>Moreover, confounders cannot be excluded in any asso-</p><p>ciation studies, and only randomized controlled trials</p><p>(RCTs) can provide a robust answer. However, given the</p><p>results emerging from our analysis, performance of an</p><p>RCT is ethically questionable, the condition of a clini-</p><p>cal equipoise being unfulfilled. Secondly, about 70% of</p><p>the control group consisted of patients with unexplained</p><p>infertility. One cannot exclude the presence of minimal</p><p>endometriosis in some of these cases. However, from</p><p>a clinical perspective, this possible limitation does not</p><p>hamper the main conclusion of the study (i.e., that ICSI</p><p>is not recommended) because most women with unex-</p><p>plained infertility does not currently undergo diagnostic</p><p>laparoscopy prior to proceed [43]. In addition, as alluded</p><p>above, the high fertilization rate observed in our study</p><p>(in line with modern benchmarks of quality) argues</p><p>against a relevant effect of this possible misdiagnoses,</p><p>regardless of the results observed in the control group.</p><p>Another limit of the study refers to the fact that we have</p><p>not considered sperm morphology as a specific criterion</p><p>to be used for the selection of the c-IVF strategy. It is to</p><p>consider that, since the impact of sperm morphology on</p><p>c-IVF success remains to be clarified [44], the parameter</p><p>is often not evaluated on the day of c-IVF, even in very</p><p>well-designed studies [45]. We, however, cannot exclude</p><p>that this may mask some issues related to the generaliz-</p><p>ability of the results.</p><p>In conclusion, this is the first study that has evaluated the</p><p>performance of c-IVF in patients affected by endometrio-</p><p>sis compared to a control group, controlling for the poten-</p><p>tial differences in ovarian reserve. Our results indicate that</p><p>c-IVF can be efficiently used to treat affected women, unless</p><p>a male factor is also involved.</p><p>Supplementary information The online version contains supplemen-</p><p>tary material available at https:// doi. org/ 10. 1007/ s10815- 022- 02700-z.</p><p>Funding This study was funded by the Italian Ministry of Health —</p><p>Current research IRCCS. M.C. acknowledges the support of Coorde-</p><p>nação de Aperfeiçoamento  de Pessoal do Nível Superior-Brasil</p><p>(CAPES) - Finance Code 001.</p><p>Data availability The database analysed during the current study is</p><p>available from the corresponding author on reasonable request.</p><p>Declarations</p><p>Conflict of interest E.S. declares honoraria and grants from Theramex,</p><p>Merck-Serono and Ferring. All the other authors have nothing to de-</p><p>clare.</p><p>References</p><p>1. Lee D, Kim SK, Lee JR, Jee BC. Management of endometriosis-</p><p>related infertility: considerations and treatment options. Clin Exp</p><p>Reprod Med. 2020;47(1):1–11. https:// doi. org/ 10. 5653/ cerm.</p><p>2019. 02971.</p><p>2. American Society of Reproductive Medicine. Endometriosis and</p><p>infertility:</p><p>a committee opinion. Fertil Steril. 2012;98(3):591–8.</p><p>https:// doi. org/ 10. 1016/j. fertn stert. 2012. 05. 031.</p><p>3. Taylor HS, Kotlyar AM, Flores VA. 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Intracytoplasmic sperm</p><p>injection versus conventional in-vitro fertilisation in couples</p><p>with infertility in whom the male partner has normal total sperm</p><p>count and motility: an open-label, randomised controlled trial.</p><p>The Lancet. 2021;397(10284):1554–63. https:// doi. org/ 10. 1016/</p><p>S0140- 6736(21) 00535-3.</p><p>Publisher's note Springer Nature remains neutral with regard to</p><p>jurisdictional claims in published maps and institutional affiliations.</p><p>Springer Nature or its licensor (e.g. a society or other partner) holds</p><p>exclusive rights to this article under a publishing agreement with the</p><p>author(s) or other rightsholder(s); author self-archiving of the accepted</p><p>manuscript version of this article is solely governed by the terms of</p><p>such publishing agreement and applicable law.</p><p>607Journal of Assisted Reproduction and Genetics (2023) 40:599–607</p><p>https://doi.org/10.1016/j.fertnstert.2006.12.046</p><p>https://doi.org/10.1016/j.fertnstert.2006.12.046</p><p>https://doi.org/10.1016/s0015-0282(02)03112-6</p><p>https://doi.org/10.1016/s0015-0282(02)03112-6</p><p>https://doi.org/10.1007/s10815-018-1143-3</p><p>https://doi.org/10.1093/hropen/hoac009</p><p>https://doi.org/10.1093/hropen/hoac009</p><p>https://doi.org/10.1093/hropen/hoz009</p><p>https://doi.org/10.1093/hropen/hoz009</p><p>https://doi.org/10.3390/jcm11195722</p><p>https://doi.org/10.1016/S0140-6736(21)00535-3</p><p>https://doi.org/10.1016/S0140-6736(21)00535-3</p><p>Conventional IVF performs similarly in women with and without endometriosis</p><p>Abstract</p><p>Purpose</p><p>Methods</p><p>Results</p><p>Conclusion</p><p>Introduction</p><p>Methods</p><p>Ethical approval</p><p>Study design and participants</p><p>Controlled ovarian hyperstimulation</p><p>In vitro fertilization</p><p>Statistics</p><p>Results</p><p>Discussion</p><p>References</p>