Endometriosis, Ovarian Reserve and Live Birth Rate Following In Vitro Fertilization/Intracytoplasmic Sperm Injection

► endometriosis ► ovarian reserve ► assisted reproduction ► IVF ► ICSI

Purpose To evaluate whether women with endometriosis have different ovarian reserves and reproductive outcomes when compared with women without this diagnosis undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ ICSI), and to compare the reproductive outcomes between women with and without the diagnosis considering the ovarian reserve assessed by antral follicle count (AFC).

This retrospective cohort study ev aluated all women who underwent IVF/ ICSI in a university hospital in Brazil between January 2011 and December 2012. All patients were followed up until a negative pregnancy test or until the end of the pregnancy. The primary outcomes assessed were number of retrieved oocytes and live birth. Women were divided into two groups a ccording to the diagnosis of endometri- osis, and each group was divided again into a group that had AFC /C20 6 (poor ovarian reserve) and another that had AFC /C21 7 (normal ovarian reserve). Continuous variables with normal distribution were compared using unpaired t-test, and those without normal distribution, using Mann-Whitney tes t. Binary data were compared using either Fisher’s exact test or Chi-square ( /C31 2)t e s t .T h es i g n ificance level was set as p < 0.05.

787 women underwent IVF/ICSI (241 of which had endometriosis). Although the mean age has been similar between women with and without the diagnosis of endometriosis (33.8 /C6 4 versus 33.7 /C6 4 . 4y e a r s ,r e s p e c t i v e l y ) ,p o o ro v a r i a nr e s e r v e s were much more common in women with endometriosis (39.8 versus 22.7%). The chance of achieving live birth was similar between women with the diagnosis of endometriosis and those without it (19.1 versus 22.5%), and also when considering only women with a poor ovarian reserve (9.4 versus 8.9%) and only those with a normal ovarian reserve (25.5 versus 26.5%). received January 5, 2016 accepted March 30, 2016 published online May 19, 2016 DOI http://dx.doi.org/ 10.1055/s-0036-1584126. ISSN 0100-7203. Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil Original Article THIEME 218

Subfertility is the inability of achieving a pregnancy after one year of regular, unprotected intercourse. 1 Approximately 15% of women in reproductive age are considered subfer- tile. 2–4 Assisted Reproduction Technologies (ARTs), particu- larly in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), are frequently used to help subfertile couples to conceive. Endometriosis is one of the most cited causes of subfer- tility, being much more common in subfertile (25 –40%) than in fertile woman (0.5 –5.0%). 5 This disease is de fined by the presence of endometrial tissue outside the uterine cavity, and the mechanisms through which endometriosis impairs fertility are still unclear. 6 Pelvic adhesions and distortion of pelvic anatomy are associated with subfertility, and are frequently observed in moderate and severe cases of endo- metriosis. 7 However, the mechanism underlying minimal or mild endometriosis related to subfertility is unclear, and may be related to impairment of oocyte development, embryo- genesis and implantation. 8–10 The ideal fertility treatment for women with endometriosis is not well established yet, but ART treatments are responsible for the highest success rates.11,12 The relationship between the presence and severity of endometriosis and the reproductive outcomes in women undergoing ART are controversial.13–15 The first meta-analysis evaluating this issue found that endometriosis reduces the chances of achieving pregnancy in IVF/ICSI cycles, and that patients with moderate to severe endometriosis (III/IV) have even worse results. 14 The second review observed that only severe endometriosis impairs implantation and clinical preg- nancy rates when compared with women without the dis- ease. 15 However, the latest and largest published review found moderate quality evidence suggesting that endometriosis does not affect the chance of achieving clinical pregnancy and live birth when considering only the fresh transfer cycle. 13 Fur- thermore, the same review suggests that patients with endo- metriosis have a reduced ovarian reserve, once fewer oocytes are retrieved from women in this group. Since a poor ovarian reserve is associated with poor reproductive outcomes, 16,17 it is possible that the differences in the ovarian reserve, and not endometriosis itself, might be the cause of the heterogeneity observed in the studies published so far. 13

Women diagnosed with endometriosis are more likely to have a poor ovarian reserve; however, their chance of conceiving by IVF/ICSI is similar to the one observed in patients without endometriosis and with a comparable ovarian reserve. Resumo Objetivo Avaliar se mulheres com endometriose possuem diferenças quanto a reserva ovariana (RO) e a resultados de reprodução assistida quando comparadas a mulheres sem este diagnóstico submetidas IVF/ICSI ( in vitro fertilization/intracytoplas- mic sperm injection ), e comparar resultados reprodutivos entre mulheres com e sem o diagnóstico, considerando a RO obtida pe la contagem de folículos antrais (CFA). Métodos Este estudo de coorte retrospectivo avaliou todas as mulheres submetidas à FIV/ICSI em uma universidade do Brasil nos anos de 2011 e 2012. Todas as pacientes foram seguidas até um teste negativo de gravidez ou até o final da gestação. Os desfechos primários analisados foram o número do oócitos captados e nascidos vivos. As mulheres foram divididas em 2 grupos de acordo com o diagnóstico de endome- triose e subdivididas de acordo com a CFA /C20 6( b a i x aR O )e /C21 7 (RO normal). As variáveis contínuas com distribuição normal foram comparadas pelo teste t não pareado e sem distribuição normal pelo t este de Mann-Whitney. Os dados binários f o r a mc o m p a r a d o sp o ra m b o so st e s t e sQ u i - q u a d r a d o(/C31 2)ee x a t od eF i s h e r .On í v e ld e significância foi de finido como p < 0,05. Resultados 787 mulheres foram submetidas a IVF/ICSI (241 com endometriose). Embora a média de idade tenha sido simila r entre as mulheres com e sem o diagnóstico de endometriose (33,8 /C6 4 versus 33,7 /C6 4.4 anos, respectivamente), a baixa RO é muito mais comum em mulheres com endometriose (39,8 versus 22,7%). A chance de obter um nascido vivo foi similar entre as mulheres com e sem endometriose (19,1 versus 22,5%), e também quando consideradas apenas as mulheres com baixa RO (9,4 versus 8,9%), e apenas com RO normal (25,5 versus 26,5%). Conclusões Mulheres diagnosticadas com endome triose são mais susceptíveis a ter baixa RO; no entanto, suas chances de conceber por IVF/ICSI são similares às observadas em pacientes sem endometriose e com uma RO comparável. Palavras-chave ► endometriose ► reserva ovariana ► reprodução assistida ► fertilização in virto ► ICSI Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Endometriosis, Ovarian Reserve and Live Birth Rate Following IVF\ICSI Coelho Neto et al. 219 Thus, the objective of this study was to evaluate whether women with endometriosis have different ovarian reserves and reproductive outcomes when compared with women without this diagnosis undergoing IVF/ICSI. We also com- pared the reproductive outcomes between women with and without the diagnosis of endometriosis considering the ovarian reserve assessed by antral follicle count (AFC) evalu- ated before the beginning of the controlled ovarian stimula- tion (COS) for FIV/ICSI.

This retrospective cohort study included all women who under- went IVF/ICSI at the fertility clinic of the university hospital of the Ribeirão Preto Medical School, Universidade de São Paulo, Brazil, between January 2011 and December 2012. All data were obtained from medical records by one author. The study protocol was approved by the Institutional Review Board, which waived the requirement for additional informed consent due to the retrospective nature of the study. Women were considered eligible if they had undergone IVF/ICSI between January 2011 and December 2012 at our fertility clinic. If women had undergone more than one cycle of COS during this period, only the data from the first cycle with planned embryo transfer were included. All women were followed up until a negative pregnancy test or the end of a pregnancy. In or der to divide the women into groups, we assessed the diagnosis of endometriosis made by laparoscopy and/or ultrasound and the baseline AFC, performed before the beginning of the treatment by transvaginal ultrasound using a Voluson E8 Expert (GE Healthcare Austria GmbH & Co OG, Zipf, Austria) operated by one of four well-trained sonolo- gists. Ultrasound is considered the first-line imaging method for women with suspected pelvic endometriosis: although it fails to identify super ficial endometriosis, the method has an excellent diagnostic accuracy for endometrioma and deep infiltrating endometriosis. 18–23 The unit of analysis of all parameters was the number of women. The primary endpoints of this study were the number of retrieved oocytes and the rates of live birth. The following parameters were assessed: clinical pregnancy, presence of surplus frozen embryos, occurrence of embryo transfer and oocyte retrieval, cancellation of the cycle due to poor response, number of oocytes retrieved, baseline AFC, body mass index (BMI), age, and the protocol used for COS. In cases in which women did not undergo oocyte retrieval and embryo transfer, we considered that the number of both oocytes retrieved and embryos transferred was zero; by doing that, all women were included in the analysis. Further- more, for 5.7% of women, AFC data was missing; so, for subgrouping purposes, we considered that those patients had an AFC /C21 7, and grouped them within the largest sub- group. All variables were obtained from the medical records. Statistical Analysis First, women were divided into two groups: those that had and those that did not have the diagnosis of endometriosis. For a second analysis, women were further stratified into two subgroups: AFC /C20 6a n dA F C /C21 7. This latter analysis was performed to separate women with expected poor ovarian response according to the AFC cutoff values suggested in the Bologna criteria. 24 The study size was determined by the primary outcome number of oocytes retrieved. Considering a difference of one oocyte retrieved as being clinically rele- vant,25 a standard deviation (SD) of 4.5 oocytes retrieved at our service, 26 a proportion of women with endometriosis to be close to 30%, 13 significance level ¼ p < 0.05, we would need 760 women to have a power of 80% to detect this difference. A mean of 40 women are submitted to treatment cycle per month in our clinic. Considering that part of these women repeat the treatment in a short period of time, we calculated that we would need to retrieve data from 24 months in order to examine the estimated sample size. With that sample size, the power to detect an absolute 5% decrease in live birth rates was 40%, and of detecting a decrease of 10% in live birth rates was 90%. The normality of distribution of continuous variables was analyzed using the Kolmogorov-Smirnov test. Continuous variables with normal distribution were summarized as mean /C6 SD and compared between the two groups using unpaired t-test. Continuous variables without normal distri- bution were summarized as median (interquartile range) and comparisons were made between the two groups using Mann-Whitney test. Binary data were presented as ratio and proportion and compared between the two groups using either Fisher ’s exact test or Chi-square ( /C31 2) test. The level of significance was de fined as p < 0.05. We also calculated the relative risk (RR), the mean difference (MD) and their 95% confidence interval (CI) for the studied outcomes. All statis- tical analysis were performed using SPSS (version 18.0, SPSS Inc., Chicago, IL, USA).

During the study period, 787 women underwent IVF/ICSI in our clinic; data were analyzed from all 787 cycles. All women were followed until a negative pregnancy test or the end of the pregnancy, with reproductive outcomes analyzed in all cases. In the analysis of the 787 women included, 241 (30.6%) were diagnosed with endometriosis. The diagnosis of endo- metriosis was performed by ultrasound in only 30 partic - ipants (12.4%); by laparoscopy in 182 of them (75.5%); and by both laparoscopy and ultrasound in 29 subjects (12.0%). Considering the 546 women without the diagnosis of endo- metriosis, 151 (26.7%) underwent laparoscopy with negative findings for endometriosis, and 395 women presented no clinical or ultrasonographic suspicion of endometriosis, and, therefore, did not undergo laparoscopy. In the subgroup with a poor ovarian reserve (AFC /C20 6), 220 women were included, and of these, 96 (43.6%) had endometriosis. Among these women, the diagnosis of endometriosis was performed by ultrasound in only 12 (12.5%) of them; by laparoscopy in 70 (72.9%) of them; and by both laparoscopy and ultrasound in 14 women (14.6%). In the subgroup without a poor ovarian reserve (AFC /C21 7), 567 women were included, and of these, Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Endometriosis, Ovarian Reserve and Live Birth Rate Following IVF\ICSI Coelho Neto et al.220 145 (25.6%) had endometriosis. Among these patients, the diagnosis of endometriosis was performed by ultrasound in only 18 (12.4%) of them; by laparoscopy in 112 (77.2%) of them; and by both laparoscopy and ultrasound in 15 women (10.3%). Regarding the type of COS, 68.1% (536 women) used gonadotropin-releasing hormone (GnRH) antagonist pro- tocol with standard exogenous gonadotropins (150 – 300IU/day); 21.1% (166 women) used GnRH agonist pro- tocol with standard exogenous gonadotropins; and 10.8% (85 women) used clomiphene citrate with low-dose exog- enous gonadotropins ( < 150 UI/day). For final follicular maturation, 93.9% (739 women) used urinary or recombi- nant human chorionic gonadotropin (hCG) for triggering, while 6.1% (48 women) used GnRH agonist. Oocytes were r e t r i e v e d3 4t o3 6h o u r sa f t e rt h et r i g g e r i n g .T h ed i s t r i - bution of COS protocols between the groups is described in ►Tables 1 , 2 and 3. When considering all women, no signi ficant difference was observed between the two groups regarding age, and BMI was slightly lower in the endometriosis group. Param- eters of ovarian reserve and response to the treatment were worse among women with endometriosis: they had lower AFC, fewer oocytes retrieved, more cycles cancelled due to poor response, fewer women underwent oocyte retrieval/ embryo transfer, and fewer had surplus frozen embryos. Notwithstanding, there was no evidence of difference on live birth rates and clinical pregnancy ( ►Table 1 ). We also performed a subgroup analysis, stratifying women into two subgroups: those with a poor ovarian reserve (AFC /C20 6) and those without a poor ovarian reserve (AFC/C21 7). The proportion of women with AFC /C20 6 was signi ficantly higher in participants with endometriosis: 39.8 versus 22.7% (►Table 1 ). Among women with a poor ovarian reserve, we observed that those with endometriosis were signi ficantly younger, with no difference on BMI. Unlike the previous analysis, there was no difference in the parameters related to the response of the treatment between women with and without endometriosis: number of oocytes retrieved, number of cycles cancelled due to poor response, proportion of women undergoing oocyte retrieval and embryo transfer, proportion of women with surplus frozen embryos, live birth, and clinical pregnancy. Notwithstanding, AFC was lower in the endome- triosis group ( ►Table 2 ). In the subgroup of women without a poor ovarian reserve (AFC /C21 7), we did not observe any difference in age, but women with endometriosis had a lower BMI. Women with endometriosis presented lower AFC and less oocytes retrieved, while no difference was observed in the number of cycles cancelled due to poor response, the propor- tion of women undergoing oocyte retrieval and embryo transfer, the proportion of women with surplus frozen embryos, live birth rates, and clinical pregnancy. Table 1 Evaluated parameters of all women undergoing IVF/ICSI d u r i n gt h es t u d yp e r i o dd i v i d e db a s e do nt h ed i a g n o s i so f endometriosis Parameter Endometriosis Control Mean SD N Mean SD N p/C3 Age 34.4 4.3 241 34.5 4.5 546 0.7 BMI 24.2 4.0 225 25.1 4.2 525 0.01 Median IQR N Median IQR N p/C3/C3 AFC 8.0 4 –13 233 12.0 7 –20 509 < 0.001 Number of oocytes retrieved 4.0 2 –8 241 6.0 3 –10 546 < 0.001 %n N %n N p/C3/C3/C3 Proportion of women with AFC /C20 6 39.8% 96 241 22.7% 124 546 < 0.001 Cycle cancelled - poor response 6.2% 15 241 2.7% 15 546 0.03 Underwent OR 92.5% 223 241 97.1% 530 546 0.007 Underwent ET 77.2% 186 241 83.2% 454 546 0.06 Women with surplus embryos 32.0% 77 241 42.1% 230 546 0.007 Clinical pregnancy 22.4% 54 241 27.5% 150 546 0.2 Live birth 19.1% 46 241 22.5% 123 546 0.3 COS FSH þ Ant 63.1% 152 241 72.7% 397 546 0.01 FSH þ Ago 22.8% 55 241 19.4% 106 546 CC þ FSH þ Ant 14.1% 34 241 7.9% 43 546 Abbreviations: AFC, antral follicle count; Ago, agonist protocol; Ant, antagonist protocol; BMI, body mass index; CC, clomiphene citrate; COS, controlled ovarian stimulation; ET, embryo trans fer; FSH, follicle-stimulating hormone; IQR, interquartile range; n, number of events; N, number of woman analyzed; OR, oocyte retrieval; SD, standard deviation. Notes: /C3 p values calculated by unpairedt-test; /C3/C3 p values calculated by Mann-Whitney test;/C3/C3/C3 p values calculated by Fisher exact test or Chi-square (/C312) test. Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Endometriosis, Ovarian Reserve and Live Birth Rate Following IVF\ICSI Coelho Neto et al. 221 Table 3 Evaluated parameters of women undergoing IVF/ICSI during the study period without a poor ovarian reserve (AFC /C21 7) divided based on the diagnosis of endometriosis Parameter Endometriosis Control Mean SD N Mean SD N p/C3 Age 33.8 4.0 145 33.7 4.4 422 0.7 BMI 24.2 3.8 135 25.4 4.2 406 0.01 Median IQR N Median IQR N p/C3/C3 AFC 12.0 9.0 –17.5 137 15.0 10.0 –22.0 385 < 0.001 Number of oocytes retrieved 6.0 3.0 –10.0 145 7.0 4.75 –11.0 422 0.02 %n N %n N p/C3/C3/C3 Cycle cancelled - poor response 2.8% 4 145 1.4% 6 422 0.3 Underwent OR 95.9% 139 145 98.3% 415 422 0.1 Underwent ET 84.8% 123 145 88.2% 372 422 0.3 Women with surplus embryos 43.4% 63 145 50.2% 212 422 0.2 Clinical pregnancy 29.7% 43 145 31.5% 133 422 0.8 Live birth 25.5% 37 145 26.5% 112 422 0.9 COS FSH þ Ant 70.3% 102 145 73.7% 311 422 0.6 FSH þ Ago 26.2% 38 145 22.0% 93 422 CC þ FSH þ Ant 3.4% 5 145 4.3% 18 422 Abbreviations: AFC, antral follicle count; Ago, agonist protocol; Ant, antagonist protocol; BMI, body mass index; CC, clomiphene citrate; COS, controlled ovarian stimulation; ET, embryo transfer; FSH, follicle-stimu lating hormone; IQR, interquartile range; n, number of events; N, number of woman analyzed; OR, oocyte retrieval; SD, standard deviation. Notes: /C3 p values calculated by unpairedt-test; /C3/C3 P values calculated by Mann-Whitney test;/C3/C3/C3 P values calculated by Fisher exact test or Chi-square (/C312) test. Table 2 Evaluated parameters of women undergoing IVF/ICSI during the study period with a poor ovarian reserve (AFC /C20 6) divided based on the diagnosis of endometriosis Parameter Endometriosis Control Mean SD N Mean SD N p/C3 Age 35.2 4.5 96 37.3 3.6 124 < 0.001 BMI 24.2 4.4 90 24.4 4.2 119 0.8 Median IQR N Median IQR N p/C3/C3 AFC 3.5 3.0 –5 . 09 65 . 0 3 . 3 –6.0 124 < 0.001 Number of oocytes retrieved 2.00 0.3 –4 . 89 63 . 0 1 . 0 –5.0 124 0.2 %n N %n N p/C3/C3/C3 Cycle cancelled - poor response 11.5% 11 96 7.3% 9 124 0.4 Underwent OR 87.5% 84 96 92.7% 115 124 0.3 Underwent ET 65.6% 63 96 66.1% 82 124 1.0 Women with surplus embryos 14.6% 14 96 14.5% 18 124 1.0 Clinical pregnancy 11.5% 11 96 13.7% 17 124 0.7 Live birth 9.4% 9 96 8.9% 11 124 1.0 COS FSH þ Ant 52.1% 50 96 69.4% 86 124 0.03 FSH þ Ago 17.7% 17 96 10.5% 13 124 CC þ FSH þ Ant 30.2% 29 96 20.2% 25 124 Abbreviations: AFC, antral follicle count; Ago, agonist protocol; Ant, antagonist protocol; BMI, body mass index; CC, clomiphene citrate; COS, controlled ovarian stimulation; ET, embryo transfer; FSH, follicle-stimu lating hormone; IQR, interquartile range; n, number of events; N, number of woman analyzed; OR, oocyte retrieval; SD, standard deviation. Notes: /C3 p values calculated by unpairedt-test; /C3/C3 p values calculated by Mann-Whitney test;/C3/C3/C3 p values calculated by Fisher exact test or Chi-square (/C312) test. Rev Bras Ginecol Obstet Vol. 38 No. 5/2016 Endometriosis, Ovarian Reserve and Live Birth Rate Following IVF\ICSI Coelho Neto et al.222

This study showed that although the mean age was similar between women with and without the diagnosis of endometri- osis, the proportion of participants with a poor ovarian reserve was significantly higher among young women diagnosed with endometriosis. Furthermore, women with endometriosis had fewer oocytes retrieved. Among women with a decreased functional ovarian reserve, those with endometriosis were signific a n t l yy o u n g e r .A l t h o u g ht h el i v eb i r t hr a t em i g h tb e considered slightly lower in women with endometriosis (19.1 versus 22.5%) without significant difference, it was very similar when considering only women with a low ovarian reserve (9.4 versus 8.9%) or a normal ovarian reserve (25.5 versus 26.5%). A recent review found moderate quality evidence suggest- ing that endometriosis does not affect the chance of achieving live birth and clinical pregnancy when considering the first embryo transfer, 13 which is in agreement with our results. Additionally, the same review observed that women with endometriosis have fewer oocytes retrieved, suggesting a reduced ovarian reserve, which is also in agreement with the findings of the present study. However, some of the studies published so far have observed signi ficantly worse

in women with endometriosis. 27–29 We believe that the difference among studies might be explained by the reduced ovarian reserve associated with endometriosis, as this reduction is related to poor assisted reproduction out- comes. 16 A recent and large observational study 16 examined data from more than 140,000 women with a single diagnosis of infertility; those with more than one cause were excluded from the analysis. Since this study considered that a reduced ovarian reserve was one of the causes of infertility, women with both endometriosis and a reduced ovarian reserve were not analyzed. This interesting study observed that couples with only endometriosis have live birth rates (43.0%) very similar to those observed in couples with only male factor (42.7%), with only ovulatory dysfunction (44.1%), and those with unexplained infertility (42%); however, all of these rates were much higher than those observed in couples in which the woman had a reduced ovarian reserve and no other cause of subfertility was detected (18.9%). 16 Since women with endometriosis are more likely to have a reduced ovarian reserve, there is a reasonable chance to observe worse repro- ductive outcomes in women with endometriosis by including all women without controlling for this confounding factor. Another very important observation is that among women with a decreased ovarian reserve, those with endometriosis are younger. Since age and ovarian reserve are the most important factors for the treatment ’ss u c c e s s , 16,30 when balancing risks and benefits, women with suspected endometriosis might be at an increased risk of facing a reduced ovarian reserve at an earlier age. The costs and psychological harms of an early fertility treatment should be weighed against the risk of a reduced o v a r i a nr e s e r v ea n d ,t h e r e f o r e ,w o r s er e p r o d u c t i v eo u t c o m e s for both natural conception and subsequent assisted reproduc - tive techniques, caused by the delay in treatment on behalf of a more precise diagnosis or intervention for endometriosis. Another interesting point is that women with endometriosis are more likely to have endometrioma, which interferes more with the AFC than with the number of oocytes retrieved and the chances of conceiving. 30,31 As this is a retrospective study, we had to rely on data from our medical records. Antral follicle count data was missing in 3% of the women with endometriosis and in 6% of the controls; therefore, for the subgroup analysis we as- sumed that all missing AFC were /C21 7. This source of bias could be overcome by a prospective study. Another issue is that not all women underwent a laparoscopy for the diagnosis of endometriosis. If on one hand it could be a source of bias because some participants lacked a precise diagnostic evaluation, on the other hand it improves gen- eralization, since not every woman undergoes laparoscopy previously to IVF/ICSI. The generalization of the findings described is limited because this is a retrospective observational study; however, it should encourage the development of new research evalu- ating reproductive outcomes in patients diagnosed with endometriosis taking into account their ovarian reserve. In conclusion, among women undergoing IVF/ICSI, those with endometriosis are more likely to have a poor ovarian reserve. However, women diagnosed with endometriosis have similar chances of conceiving when compared with other women with a similar ovarian reserve. Acknowledgments The authors are grateful to Universidade de São Paulo (USP), the Foundation for Support in Teaching, Research and Assistance (Faepa), and the Brazilian National Council for Research and Development (CNPq) for their financial support.

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