{"paper_id":"b2ec4b1d-295f-49ff-b4af-4b3d6715425d","body_text":"The prevalence of infertility is around 9% worldwide ( 1 ),\nwhile it is 10-15% in the Middle East (ME) for many reasons, including a high incidence of postpartum infections,\niatrogenic tubal and pelvic infertility and women delaying\nchildbearing ( 2 ,  3 ). The number of women treated with\n in vitro  fertilization (IVF) in the ME has increased from\n8305 cycles in 2005 to 11876 cycles in 2008 ( 4 ). The live\nbirth rate per cycle is the ultimate success, and therefore\nit has been used in multiple studies ( 5 - 7 ). The outcome\nas livebirth per fresh IVF cycle is more evocative for patients coming for counseling, than the outcome as a positive pregnancy test per cycle. However, the best way is to\ncounsel patients about the cumulative chances of success\nafter a defined number of IVF cycles ( 8 ). Some centers\nwho have adopted the single embryo transfer policy have\nreported cumulative live birth rates (CLBRs) as a fresh embryo transfer cycle followed by cryo-warmed cycles, all resulting from one episode of ovarian stimulation ( 8 - 12 ). On\nthe other hand, others have included only fresh cycles for\nCLBR assessment ( 6 ,  13 - 15 ). Although it has been previously reported that the live birth rates decrease after the 4th\ncycle ( 13 ,  16 ), there is no medical reason behind limiting\nthe number of cycles. Many patients are likely to discontinue their infertility treatments because of the psychological\nburden of the process and the cost of repetitive failed IVF\ncycles ( 17 ). On the other hand, the decision of the couple\nto proceed with further fresh cycles is bounded by cultural\nfactors where the continuation of marriage is dependent on\nhaving children and many couples are reluctant to seek egg\nor sperm donation cycles for ethical and religious reasons.\nTo the best of our knowledge, CLBR after IVF/intra-cytoplasmic sperm injection (ICSI) cycles has never been reported\nat a national level in Lebanon, nor in the ME. It is important to\ndetermine these rates and how they change with repeated cycles, according to maternal age and type of infertility. It is essential to define an IVF cycle for these patients as the initiation\nof ovarian stimulation with subsequent fresh embryo transfer.\nWe aim to determine whether the CLBR increases over\nmultiple successive IVF cycles, providing patients with a\nbetter estimation of their chances of a live birth.\n\nThe Ethical approval for this study was obtained from the Institutional Review Board at the AUBMC (BIO – 2017- 0331).\nThis retrospective cohort study was performed on all patients scheduled to have fresh IVF/ICSI cycles at the AUBMC between January 2016 and December 2016. One IVF\ncycle is defined as a fresh embryo transfer attempt resulting\nfrom one episode of ovarian stimulation. All embryo transfers involving the transfer of one or more embryos were\nincluded in the study to reproduce the daily practice of assisted reproductive technologies in our region.\nCycles that were excluded are those which were cancelled before the oocyte retrieval or before the embryo\ntransfer, patients who had their IVF cycles after December 2016 and cycles with frozen embryos/frozen oocytes.\nCancellation rate was 5%.\nBaseline characteristics included different age categories (≤35, 36-39 and ≥40 years) and different types of\ninfertility (male factor, unexplained infertility, ovulatory\ndisorders, endometriosis, low ovarian reserve, tubal infertility and combined factors). Data collected included\nlevels of anti-müllerian hormone and/or day 3 follicle\nstimulating hormone (FSH) and estradiol.\nPatients underwent controlled ovarian stimulation and\noocyte retrieval after 10-12 days of stimulation. All cycles\nincluded were ICSI cycles. Fresh embryo transfer took\nplace two, three or five days after the oocyte retrieval. All\ncycles with pre-implantation genetic testing (PGT) or frozen embryo transfer were excluded.\nLive birth and CLBRs per cycle were the main outcome\nmeasures, stratified by maternal age and type of infertility in up to six IVF cycles. Live birth was defined as a\nnewborn delivered after 24 weeks of gestation. Once a\nwoman succeeded in achieving her first live born baby\nfrom IVF, she does not contribute further to the cumulative rates calculation. All women without a live birth in a\nprevious cycle were eligible for a subsequent cycle. The\nCLBR at one cycle expressed the likelihood of a live birth\nat that cycle and from all preceding cycles.\nFor all patients included, descriptive statistics of demographics and treatment characteristics were analyzed. A\nsummary of the statistics was prepared as percentages for\ncategorical variables and is compared using the chi-square\ntest. The mean ± standard deviation (SD) was used for\ncontinuous variables and was compared using Student's t\ntest or one-way analysis of variance (ANOVA).\nThe primary outcome of this study was the CLBR. Patients were not re-enrolled after having a first live birth in\na previous IVF cycles.\nThe live birth rate per fresh IVF treatment was calculated\nat different number of cycles, through dividing the number\nof women in each cycle who had their first live birth by the\ntotal number of IVF cycles. Conservative CLBR was also\ncalculated by dividing the total number of women who had\ntheir first live birth up to the corresponding cycle by the\ntotal number of women who ever attempted IVF ( 18 ). The\nbinomial distribution was used to calculate the 95% confidence intervals. A log-rank test compared the live birth rate\nand CLBR within each cycle and across all cycles.\nStatistical analysis and computations were performed\nusing Statistical Package for Social Sciences (SPSS IBM\nversion 24 software, AUBMC, Lebanon), and a value of\nP<0.05 was considered to be statistically significant.\n\nIn this cohort study a total of 706 women underwent fresh\nIVF cycles at the AUBMC from January 2016 to December\n2016. After exclusions, 547 women with 736 fresh ovarian stimulation cycles were included in the analysis ( Fig .1 ),\nwith a yield of 10.4 ± 7.8 oocytes retrieved per cycle.\nFlow chart of eligible cycles.\nAUBMC; American University of Beirut Medical Center.\nTables 1 and 2 summarize the baseline characteristics of\nthe cohort. Sixty-five percent of the patients undergoing\nIVF cycles were younger than 35 years of age. The mean\nduration of infertility was 4.2 years with male infertility\nbeing the most frequent diagnosis (42.5%).\nCharacteristics of the 736 fresh IVF Cycles at the American\nUniversity of Beirut Medical Center in 2016\nSpring (March to May), Summer (June to August), Fall (September to November), Winter (December to February). IVF; In vitro fertilization, COS; Controlled ovarian stimulation, hCG; Human chorionic gonadotropin, and GnRHa; Gonadotropin releasing hormone agonist.\nCharacteristics of the 736 fresh IVF Cycles at the American University of Beirut Medical Center in 2016\nData are presented as mean ± SD.\nIVF; In vitro fertilization, BMI; Body mass index, FSH; Follicle-stimulating hormone, AMH;\nAnti-mullerian hormone, and PN; Pronuclear.\nCycles were stimulated with various protocols, with\nthe antagonist protocol being the most commonly used\n(85.7%). Final oocyte maturation was mainly triggered\nby human chorionic gonadotropin (hCG) (78% of cycles),\nwhile the remaining cycles were triggered by gonadotropin releasing hormone agonist (GnRH) agonist. Transvaginal oocyte collection was performed 35-36 hours after the trigger. The luteal phase was supported by vaginal\n(micronized progesterone suppositories), intra-muscular\nand/or oral progesterone (Dydrogesterone).\nThe average number of embryos transferred per patient\nwas 2.7, and 81% of the embryo transfers were performed\non day 2 or day 3 with a fresh cleavage-stage embryo. This\nresulted in 216 live births (29.3%), where 61.6% were singletons and 38.4% were multiple gestations (Table S1, See\nSupplementary Online Information at  www.ijfs.ir ).\nThe overall CLBR for all treatment cycles and all age\ngroups is shown in  Figure S1  (See Supplementary Online Information at  www.ijfs.ir ). The conservative CLBRs\nacross all cycles up to cycle number 6 were calculated\n( Table 3 ). Overall, the live birth rate resulting from the\nfirst fresh IVF cycle is 33.0% (95% CI: 27.8-38.2). This\nvalue remained above 20% up to the sixth cycle. The conservative CLBR showed an increase with each successive\nfresh cycle to reach 56.9% (95% CI: 51.3-62.4) after 3\ncycles and 67.9% (95% CI: 62.5-73.0) after 6 cycles.\nConservative CLBR stratified for the different age groups\nare presented in  Figure S2  (See Supplementary Online Information at  www.ijfs.ir ) and in Table 4. The live birth rates\nfluctuated with an overall decrease with progressive cycles\nand in patients younger than 35 years were 37.4%, 34.2%,\n30.6%, 34.5%, and 33.3% at cycles 1 through 5, respectively. Following 6 cycles, CLBRs reached 69.9% (95%\nCI: 63.8-75.6) in patients younger than 35 years and 83.7%\n(95% CI: 69.3-93.2) in patients between 36 and 39 years\nold. The CLBR decreased after the age of 40, as a plateau\nin success rates was reached after the 4 th  cycle with 21.9%\n(95% CI: 9.3-40.0). The log-rank test revealed significantly\ndifferent age-specific rates (P<0.05).\nLive birth rates within initiated treatment cycle and conservative cumulative live birth rates across all cycles\nCI; Confidence interval\nCLBRs across all age groups\nCLBRs; Cumulative live birth rate and CI; Confidence interval.\nConservative CLBR categorized by the different types\nof infertility are presented in  Figure S3  (See Supplementary Online Information at  www.ijfs.ir ). With the exception of women with low ovarian reserves, couples with\ndifferent types of infertility have a similar live birth rate\nat the first cycle when compared to all other cycles. The\nCLBR after 6 cycles for couples with low ovarian reserves\nis the lowest with 29.4% (95% CI: 10.3-56.0).\n\nThis 1-year cohort showed significant CLBRs based\non fresh IVF cycles, even in women older than 40 years\nof age. These numbers can help physicians counsel patients about the chances of successful live births in terms\nof age and type of infertility with repeated cycles. Because of the health system differences between the ME\nand Western countries (financial constraints, lack of insurance coverage, ethical and religious reasons), we assessed the CLBRs in fresh IVF cycles only. We chose 6\ncycles, because of the significant reduction in success in\nCLBRs after 4 to 6 cycles noted in the literature ( 6 ,  13 ).\nMoreover, the number of patients receiving more than 6\ncycles is low. In this study, the CLBRs following 1 to 6\nsuccessive IVF cycles in a referral tertiary center in the\nME was calculated. The conservative estimates of the\nCLBR increased by more than 50% from cycle number\n1 (33.0%, 95% CI: 27.8-38.2) to cycle number 6 (67.9%,\n95% CI: 62.5-73.0) across all cycles, whilst it increased\nby 53.5% in patients who were ≤35 years old, by 36% in\npatients between 36 and 39 years of age and by only 10%\nin patients ≥40.\nIt is believed that the success rate within a cycle decreases with an increase in the number of cycles ( 5 ), however, the cumulative rates in our cohort increased up to\nthe sixth cycle. The cumulative rates also increased up\nto the fourth cycle in women aged ≥40 years old (21.9%,\n95% CI: 9.3-40.00). Occasional live births were achieved\nin patients older than 40 with a probability of 3.1% per\nstarted cycle in our cohort compared to 0.46% in a singlecenter Japanese cohort study ( 19 ). These findings are in\nline with a study published by Smith et al. ( 20 ) who categorized women older than 40 years of age into 2 groups\nand showed that women aged 40 to 42 still have acceptable chances up to the ninth cycle, while women older\nthan 42 show an increase up to the fifth cycle only. The\nsame authors also showed that patients with a low yield\nof oocytes retrieved in previous cycles still benefit from\ncontinuing successive cycles if they are younger than 40\nyears. On the contrary, we showed that when including\nall reproductive ages in the study, patients with low ovarian reserve and low number of oocytes retrieved have the\nlowest cumulative rates, plateauing after the second cycle with a 29.41% chance of success. Moreover, our rates\nwere similar to those reported in previous studies, as the\nCLBRs decreased in older ages ( 21 ).\nWhen the cause of infertility was taken into account, the\ndifferences noted in CLBRs were insignificant among patients with male factor, unexplained, tubal and combined\ninfertility. In addition, couples with a male factor had the\nhighest CLBRs as it is also outlined in the biggest US\nstudy by Luke et al. ( 22 ). Furthermore, it is worth mentioning that in patients with anovulation the CLBRs reach\nplateaus after the third cycles at 65.5%. These results may\nbe explained by the distorted steroidogenesis of the theca\ncells and metabolic imbalance found in patients with polycystic ovary syndrome (PCOS). The quality of the oocytes has previously been showed to be poorer in patients\nsuffering from PCOS and the finest dosage of ovarian\nhormonal stimulation in patients undergoing IVF is still\ndebatable ( 23 ). Thus, multiple new therapies are implemented in order to improve pregnancy outcomes in this\nsubcategory of patients. Among them, myo-inositol has\na pivotal role in cellular signaling, as it has been shown\nto improve glucose uptake and FSH signaling affecting\npositively the oocyte quality ( 24 ). Nonetheless, data is not\nstrong enough to support this improvement in pregnancy\noutcomes and additional clinical trials are needed in this\nregard ( 24 - 26 ).\nOnly patients with low ovarian reserve had their CLBR\nplateauing after the second cycle with only 29.4%, which\nis significantly different from the rest of our study cases\nmentioned here. With an improvement in cumulative rates\nof only 7% after 2 cycles and subsequent stabilizing after\n6 consecutive cycles, it may be concluded that assisted\nreproductive technologies in patients with low ovarian\nreserves may be futile and especially after 3 cycles. Nevertheless, the number of events in this particular group\nwas too small to draw definite conclusions. These findings contradict previous reports that showed no substantial differences in the CLBRs among women with various\ncauses of infertility ( 27 - 30 ).\nThese results show that for patients willing to continue\ntheir treatment, the CLBRs after 6 cycles would be 69.9%\n(95% CI: 63.8-75.6) at the age of 35 years or younger,\nwhich is close to the live birth rate of 75% in a woman\ntrying to conceive naturally. However, the CLBR at the\nage of 40 years for our subjects is 31.2% (95% CI: 16.1-\n50.0), which is slightly lower than the 44% of natural conception ( 31 ,  32 ). Considering the age-related reduction in\nsuccess rates in IVF treatments, our results are reassuring\nthat a CLBR up to 83.7% in women aged 36 to 39 years\n(95% CI: 69.3-93.2) is achievable, encouraging women\nyounger than 40 years to repeat their IVF treatment cycles\nwhen the cost is not a barrier to the treatment. Our findings are in line with a previous report showing that patients older than 40 years are less likely to conceive with\nrepeated cycles compared to the younger ones ( 27 ), thus\npatients older than 40 years of age should be adequately\ncounseled that IVF at this point does not improve the agerelated decrease in fertility.\nIn a retrospective study on 4810 transfers, the possible\nbeneficial effects of transvaginal ultrasound-guided ET was\nassessed and it was shown that the number of pregnancies\nper ET significantly increased when performed under transvaginal ultrasound compared to trans-abdominal (38% vs.\n30%, P<0.001). Transvaginal ultrasound may simplify difficult transfers via a better monitoring of the trans-cervical\narea improving the overall technique ( 33 ).\nThe multiple pregnancy rate was 38.4 %, with 83.1%\ntwins, and 15.7% triplets, reflecting the continuing practice of transferring more than 2 embryos in the ME. The\nmean number of embryos transferred in this study was 2.7\n(± 0.9). These rates are high when compared to averages\nreported in the American and European registries, with\nonly 25.1% risk of multiple births ( 29 ). The percentage\nof multiples is slightly lower than the ones observed in\nArgentina (43.1%), Brazil (55.9%) and Taiwan (40.5%)\n( 34 ). This indicates the utmost priority for establishing\nnew policies and regulations regarding the number of\nembryos transferred per cycle to lower the increased risk\nof perinatal and maternal morbidity and mortality associated with multiple pregnancies ( 35 ). With improvements\nin cryopreservation methods, consecutive fresh and frozen single-embryo transfer cycles should be encouraged,\nthus taking into account frozen cycles when estimating\nCLBRs.\nThis is the first study in the ME to report CLBRs per cycle following fresh IVF treatment over a one-year period.\nWe classified our patients according to age and the type\nof infertility when to our knowledge other studies have\nfailed to do so. In addition, we included all patients presenting for their first cycle and undergoing fresh cycles,\nthus increasing the generalizability of our results. CLBRs\nwere calculated on the basis of conservative estimates reflecting that women who do not achieve a live birth at\ntheir first attempt, will have their chances increased after\nsuccessive attempts. In our study, we used live birth rates\nas a primary outcome while other studies reported pregnancy rates only ( 14 ,  15 ).\nBecause of the retrospective aspect of the study, confounders were not reliably controlled, and significant biases affected the outcome. Our study has several other\ndrawbacks. For instance, the cycles that were cancelled\nbefore oocyte retrieval were not recorded. This might\nhave led to a minor overestimation of the CLBRs, as patients with severely poor prognosis did not account for\nthe number of cycles and were excluded. However, only\n36 patients were deemed ineligible, concluding that our\nfindings are very close to the actual rates and the methodological bias had a relatively small influence on the final results. Patients who usually discontinue treatment are\npatients with very poor prognosis and are older than 40\nyears. In our cohort, only 16.3% of the cases were older\nthan 40 years and most women had a high oocyte yield\n(10.4 ± 7.8). Because of these two important factors, we\nexpect a very small difference between the rates that we\ncalculated and the actual rates. On the other hand, some\npatients had undergone previous IVF cycles in other centers, adding some bias to the results since different laboratories and techniques may have been used. Furthermore,\nthere was extensive heterogeneity in the different controlled ovarian stimulation protocols used limiting the\ngeneralizability of the results.\nOur observed results postulate the chances of obtaining a live birth after one or multiple consecutive cycles,\nbasing our decisions on some realistic expectations of\nCLBRs. In addition, it provides hope for older patients\nwhose CLBRs are not affected by their age up till the\nage of 40. This reveals the advancements in reproductive\ntechnologies with the growth of ICSI ( 35 ).\nIn a region that is highly influenced and controlled by\nreligious beliefs, different barriers exist for using assisted\nreproductive technologies, preventing the performance of\noocyte and sperm donation. Therefore, with these unanticipated findings, couples have no other options except to\nextend their treatment cycles beyond 4 cycles.\n\nThis study provides an approach for estimating the effectiveness of IVF over 6 successive cycles. We showed\nan increase in the CLBRs over multiple cycles reaching a\n67.9% chance of conception after 6 cycles, with variations\nby age and type of diagnosis. These findings are reassuring\nfor patients insisting to continue with their treatments given the meaningful cumulative chances of success. Thus,\nbarriers to continuation of treatment should be reduced\nwith improvement in couples’ counseling. Moreover, our\nresults show that IVF treatments approach the natural fertility rates in patients younger than the age of 40.\nHowever, the multiple pregnancy rate is still high in this\npart of the world due to the lack of regulations and policies. The practice is surrounded by an inequity in accessibility to this expensive form of health resource with fluctuation in the proportion of treatment cycles where few\npatients have the privilege of starting another IVF treatment in the case of a previous failed one.","source_license":"CC-BY-4.0","license_restricted":false}