Length of ovarian stimulation does not impact live birth rate in fresh donor oocyte cycles: a SART CORS study.

Purpose To evaluate the effect of controlled ovarian hyperstimulation length and total gonadotropin (GN) dose on recipient live birth rate (LBR) in fresh donor oocyte cycles.

Data was obtained from SART CORS on all fresh donor oocyte GnRH antagonist cycles (n = 1049) between 2014 and 2015 which resulted in a single embryo transferred. Donor and recipient demographic information and cycle characteristics were extracted. Binomial regression was used to estimate LBR with respect to days of stimulation (DOS) and total GN dose. Multivariate analysis was performed to evaluate these relationships after controlling for confounders.

Overall LBR in fresh donor oocyte cycles was 57%. Average stimulation length was 14.3 ± 4.9 days, and total GN dose was 2464 ± 1062 IU. On univariate analysis, neither days of stimulation (p = 0.5) nor total GN dose (p = 0.57) was independently correlated with LBR. However, in prolonged stimulations (> 15 days) with high total GN dose (> 3000 IU), as both the cycle length and total GN dose increased, LBR significantly decreased from 63.81 to 48.15% (p = 0.02) and from 67.61 to 48.15% (p = 0.01), respectively. Multivariate analysis showed no significant effect of either DOS or total GN dose on LBR.

LBR is significantly decreased in fresh donor oocyte cycles when cycles are prolonged with high total GN dose. However, after controlling for confounders neither DOS nor total GN dose significantly affects LBR.

In vitro fertilization, Live birth rate, Controlled ovarian hyperstimulation, Gonadotropin dose, Prolonged ovarian stimulation, Donor

In vitro fertilization (IVF) with oocyte donation is a popular option for patients unable to conceive with autologous oocytes. In 2016, there were 8973 donor oocyte transfer cycles in the USA with 62.9% using fresh donor oocytes and the remainder using frozen donor oocytes [1]. Despite increasing popularity in frozen donor oocyte cycles and improvements in both freeze and thaw techniques, studies show mixed results in live birth rates (LBR) in fresh versus frozen donor oocyte cycles, and fresh continues to be the primary method employed in this population [2]. Additionally, a recent SART study showed improved perinatal outcomes in fresh versus frozen donor oocyte cycles [3]. Given the limited availability and financial burden of donor oocytes, it is critical to optimize potentially modifiable factors in both the donor and recipient cycles in order to improve LBRs. Oocyte donation involves management and treatment of two patients, the donor and the recipient. Consequently, LBR after oocyte donation is dependent upon a variety of factors such as donor age, oocyte quality, ovarian response to controlled ovarian hyperstimulation (COH), and the recipient’s endometrial receptivity [4–7]. When optimizing fresh donor oocyte cycles, both the COH of the donor and the endometrial preparation of the recipient should be carefully considered. Two potentially modifiable factors related to the COH are cumulative gonadotropin (GN) dose and length of ovarian stimulation. Data from fresh autologous IVF-embryo transfer (IVF-ET) cycles demonstrates that longer COH and higher total GN dose are associated with decreased LBR [9–13]. However, it is unclear how these parameters affect LBR in fresh donor oocyte cycles as the donors are typically young with normal ovarian reserve, and without an infertility diagnosis. In addition, in fresh donor oocyte IVF-ET cycles, any potential negative influence of the COH on the endometrium may not influence LBR as seen in autologous fresh IVF-ET cycles. Cycle variables, including DOS and GN dose, have been poorly studied in oocyte donation cycles. Only one study with donor oocytes demonstrated a similar trend to that of autologous data, showing decreasing LBR with increasing GN dose [8]. There is limited and inconsistent data from single center studies examining donor reproductive and cycle characteristics predictive of pregnancy success [7]. The objective of this study is to evaluate the effect of days of stimulation and total GN dose on live birth rate on fresh donor oocyte IVF-ET cycles through the national Society for Assisted Reproductive Technology Clinic Outcome System (SART CORS) database.

Study design and population The Albert Einstein College of Medicine/Montefiore Medical Center Institutional Review Board and SART Research Committee approved this population based historical cohort study. We analyzed all fresh donor-recipient GnRH antagonist IVF-ET cycles from the SART database from 2014 to 2015. We extracted demographic information from donors and recipients as well as cycle characteristics. Inclusion criteria were all donor oocyte GN cycles using GnRH antagonist-based protocols, where a fresh single embryo transfer was performed. Exclusion criteria were cycles without data recorded for GN dose and/or days of stimulation. In addition, we excluded cycles with GN doses less than 650 IUs to avoid false representation of the total GN dose, as well as cycles with gonadotropin stimulation less than 2 days and greater than 40 days to maintain clinical relevance. Finally, we excluded cycles with frozen oocytes as well as pre-implantation genetic testing cycles. Days of stimulation was defined as the length of time between cycle start and retrieval minus 2 days to account for the time between ovulation induction to retrieval. Patient demographic information included donor age and type (anonymous or directed). Recipient demographic information included age, gravidity, parity, body mass index (BMI), etiology of infertility, and ovarian reserve testing. In addition to DOS and GN dose, cycle characteristics included number of oocytes retrieved, number of embryos cryopreserved, use of conventional IVF or intracytoplasmic sperm injection (ICSI) for insemination, day of transfer (days 2 through 6), and pregnancy outcomes. Data was collected and verified by SART and reported to the Centers for Disease Control and Prevention in compliance with the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493). The data in the SART CORS are validated annually with some clinics having on-site visits for chart review based on an algorithm for clinic selection. During each visit, data reported by the clinic were compared with information recorded in patients’ charts. Ten out of 11 data fields selected for validation were found to have discrepancy rates of ≤ 5% [1]. Outcome measures The primary outcome measure was recipient live birth rate (LBR). LBR is defined as live births (≥ 24 weeks gestation) per embryo transfer. Secondary outcomes included number of oocytes retrieved and number of embryos cryopreserved in fresh IVF donor cycles. Statistical analysis We summarized the data using means, standard deviations, and frequencies, as appropriate. We assessed associations between patient (donor and recipient) and cycle characteristics via Chi-square tests. We used Cochran-Armitage trend tests to evaluate linear trends in response across GN dose and days of stimulation categories. Binomial regression models estimated the relative risk of live birth with respect to days of stimulation and total GN dose singularly and after adjustment for a priori confounders including donor age, donor type (anonymous vs directed), recipient parity, recipient BMI, and recipient diagnosis. We added both days of stimulation and total GN dose to the final multivariate model to understand how these closely linked variables affect LBR jointly. Additionally, we estimated Spearman correlation coefficients between DOS, GN dose, number of oocytes retrieved, and number of embryos cryopreserved. We considered two-sided p values less than 0.05 statistically significant. We conducted all analyses using SAS version 9.4 (SAS Institute Inc., Cary NC USA).

We analyzed 1049 fresh donor COH IVF-ET cycles from the SART 2014–2015 registry in which an embryo was transferred to the recipient. In addition to the recipient pregnancy outcomes, the donor demographics and cycle characteristics represented a good prognosis population (Tables 1 and 2). The average donor age was 26.1 ± 3.4 years, recipient age was 41.5 ± 5.5 years, and 93% of patients utilized an anonymous donor. The majority of donor oocyte embryo transfers were blastocyst transfers. The average stimulation length was 14.3 ± 4.9 days, and total GN dose was 2464 ± 1062 IU with an average of 172.3 IU per day. Days of stimulation and total GN dose are positively correlated (r = 0.15, p = < 0.0001). On average, 22.8 ± 10.5 oocytes were retrieved, and 6.1 ± 4.6 embryos were cryopreserved per cycle. The LBR in this cohort was 57%. Table 1. | Factor | Mean (SD) | |---|---| | Recipient age (years) | 41.5 (5.5) | | Donor type | | | Anonymous | 93% (976) | | Directed | 7% (73) | | Donor age (years) | 26.1 (3.4) | | BMI (recipient) (kg/m2) | 25.5 (5.8) | | Nulliparous (recipient) | 31.5% (330) | | Diagnosis+ | | | Male infertility | 12.9% (135) | | Endometriosis | 3.9% (41) | | PCOS | 2.9% (30) | | Diminished ovarian reserve | 75.2% (789) | | Tubal | 4.9% (51) | | Uterine | 6.2% (65) | | Unexplained | 6.0% (63) | | Other | 17.9% (188) | *All data summarized as mean (SD) unless otherwise specified as % (n) ++Patient may have more than 1 infertility diagnosis Table 2. | Factor | Mean (SD) | |---|---| | Total GN dose | 2464 (1062) | | Intracytoplasmic sperm injection | 70.6% (741) | | Days of stimulation | 14.3 (4.9) | | 4–8 | 7.3% (77) | | 9 | 6.7% (70) | | 10 | 9.1% (95) | | 11 | 8.2% (86) | | 12 | 9.5% (100) | | > 12 | 59.2% (621) | | Number oocytes retrieved | 22.8 (10.5) | | Embryos cryopreserved | 6.1 (4.6) | | Blastocyst transfer | 96.7% (1018) | | Clinical pregnancy rate | 67% (703) | | Miscarriage rate** | 9.3% (98) | | Live birth rate | 57% (598) | *All data summarized as mean (SD) unless otherwise specified as % (n) **Miscarriage defined as clinical pregnancy loss before 20 weeks estimated gestational age In the univariate analysis (Table 3), neither DOS (p = 0.5) nor total GN dose (p = 0.57) was separately correlated with live birth rate. However, in stimulations that were prolonged with a high total GN dose, there was a decrease in LBR (Table 4). In cycles with > 15 days of stimulation and GN doses > 3000 IU, as both the cycle length and total GN dose increased, LBR significantly decreased from 63.81 to 48.15% (p = 0.02) and from 67.61 to 48.15% (p = 0.01), respectively (Table 5). Table 3. | Total GN dose (IU) | Live birth rate (%) (n) | Days of stimulation | Live birth rate (%) (n) | |---|---|---|---| | ≤ 2000 | 59.04%222 | ≤ 12 | 58.18%249 | | 2001–3000 | 55.14%236 | 13–15 | 56.23%158 | | > 3000 | 57.14%140 | > 15 | 56.18%191 | | p Value (trend) | 0.55 | p Value (trend) | 0.57 | Table 4. | Days of stimulation | |||| |---|---|---|---|---| | GN dose (IU) | ≤ 12 days | 13–15 days | > 15 days | p Valueb | | ≤ 2000 | 55.25% | 61.11% | 63.81% | 0.14 | | 2001–3000 | 57.39% | 50.40% | 56.69% | 0.82 | | > 3000 | 67.61% | 60.61% | 48.15% | 0.01 | | p Valuea | 0.10 | 0.81 | 0.02 | aHolding days of stimulation fixed, trend for GN dose with respect to live birth rate bHolding GN dose fixed, trend for days of stimulation with respect to live birth rate Table 5. | Factor | Group | Relative risk (95% CI) | p Value | |---|---|---|---| | Donor type | Anonymous Ref: Known | 1.115 (0.886,1.404) | 0.35 | | Donor age (years) | 1.002 (0.985,1.019) | 0.81 | | | Recipient parity | 1 | 1.212 (1.029,1.428) | 0.02 | | 2 | 1.098 (0.779,1.547) | 0.59 | | | >2 Reference: 0 | 1.23 (0.801,1.889) | 0.34 | | | Recipient gravidity | 1 | 0.795 (0.68,0.93) | 0.004 | | 2 | 0.835 (0.691,1.009) | 0.06 | | | >2 Reference: 0 | 0.776 (0.638,0.944) | 0.01 | | | Recipient BMI (kg/m2) | 30.0 Reference: 18.5–25.0 | 0.933 (0.789,1.104) | 0.42 | | | Recipient etiology | Diminished reserve | 0.862 (0.58,1.282) | 0.46 | | Endometriosis | 1.002 (0.763,1.316) | 0.99 | | | Male infertility | 1.148 (0.879,1.5) | 0.31 | | | Other | 0.879 (0.563,1.372) | 0.57 | | | Polycystic ovaries | 1.366 (0.899,2.075) | 0.14 | | | Tubal Ref: unexplained | 0.996 (0.783,1.265) | 0.97 | | | Days of stimulation | 12 days or fewer | 1.006 (0.879,1.153) | 0.93 | | > 15 days Reference: 13–15 days | 0.988 (0.858,1.138) | 0.87 | | | GN dose | ≤ 2000 | 1.094 (0.967,1.239) | 0.15 | | > 3000 Reference: 2001–3000 | 1.026 (0.886,1.187) | 0.73 | *Adjusting for donor age, donor type (anonymous vs directed), recipient gravidity, recipient parity, recipient BMI, recipient diagnosis In our multivariate analysis for LBR, we found that recipient parity was positively associated with LBR (p = 0.02), while recipient gravidity ≥ 1 was negatively associated with LBR (p = 0.01). Neither donor age, donor type, high recipient BMI, nor recipient infertility diagnosis was significantly associated with LBR. Interestingly, low recipient BMI < 18.5 kg/m2 was significantly negatively associated with LBR (p = 0.02). Finally, after adjusting for confounders, neither DOS nor total GN impacted LBR. Moreover, we found that high gonadotropin dose (> 3000 IU) was significantly correlated with fewer oocytes retrieved (r = − 0.11, p = 0.0004) and fewer embryos cryopreserved (r = − 0.16, p = <0.001). However, no significant correlation was seen between days of stimulation and either secondary outcome, number of oocytes retrieved, or number of embryos cryopreserved.

Fresh donor oocyte cycles are fundamentally different when compared with fresh autologous cycles, as donors are typically young without an infertility diagnosis and the effect of COH on the endometrium is not a factor in the recipients. Prior to this study, there was a paucity of data on the impact of donor cycle characteristics on LBR. In our data, fresh donor oocyte cycles tended to be long with a low daily gonadotropin dose. It was surprising to see that the average length of COH was 14.3 ± 4.9 days, which is longer than the typical stimulation seen in autologous IVF-ET cycles. This study supports the idea that COH length does not impact LBR after controlling for confounders. Therefore, the days it takes to achieve oocyte maturity are not critical to cycle outcomes. This holds true in ovulation induction studies, which have shown that using the stair-step method does not impact pregnancy outcomes despite prolonged follicular phase [14]. The “low and slow” approach used in fresh donor oocyte cycles was likely used as it allows for a larger number of retrieved eggs and a lower incidence of ovarian hyperstimulation syndrome in a population that is usually young with normal ovarian reserve [8, 9]. Donor age and donor type (anonymous vs directed) were not associated with LBR in our multivariate model. These results are in contrast to most existing literature which shows a decline in LBR with advancing donor age [5–7]. It is possible that those studies evaluated a larger age range than our study, where most donors were < 30 years old. One study found that donors age < 25 did not improve LBR over donors ages 25–30, which is consistent with our findings [15]. In addition, we found that recipients with a prior live birth (parity ≥ 1) had an improved LBR; however, those with prior pregnancies (gravidity ≥ 1) had a decreased LBR. This negative association with recipient gravidity ≥ 1 and LBR may represent pregnancy losses or voluntary terminations, and therefore this cohort of patients may represent those with an underlying pathology that increases the likelihood for miscarriage. While high BMI was not correlated with LBR, low birth weight was significantly associated with decreased LBR. The data on LBR outcomes in underweight patients undergoing IVF are conflicting, and further studies are necessarily to elucidate this connection, particularly in the donor population. Interestingly, there is no etiologic factor we found to be associated with LBR, either singularly, or when analyzed jointly in the adjusted model including both uterine factor and male factor. COH is utilized in order to increase the number of oocytes retrieved per cycle, thereby increasing the chances of obtaining a high-quality embryo and live birth. However, in the subset of patients requiring high doses of GN and prolonged stimulations, there was a significant decrease in LBR. There is literature elucidating a biological basis for the negative effect of GN stimulation on oocytes. GN stimulation has led to aneuploidy in luteinized granulosa cells of humans as well as in mouse oocytes matured in vitro [16, 17]. Multiple studies have demonstrated that superovulation alters epigenetic markers such as aberrant DNA methylation on expressed genes in humans [18–22]. Additionally, those requiring longer cycles with larger amounts of GN may represent a cohort of “poor responders” with a decreased sensitivity to GN. However, 93% were anonymous donors, who were selected for their favorable overall characteristics including a young age, absence of an infertility diagnosis, and normal ovarian reserve testing. Lastly, oocytes from longer cycles with larger amounts of GN might be post-mature, which could lead to decreased fertilization and live birth rate. In the multivariable model, neither total GN dose nor DOS was correlated with LBR, which could mean that these factors do not in themselves contribute to decreased LBR and any differences seen in the univariate model are more likely to be due to inherent patient characteristics that cannot be changed by altering stimulation parameter. Secondarily, we examined the association between total GN dose, DOS, number of oocytes retrieved, and number of embryos cryopreserved using Spearman’s correlation. We hypothesized that in the favorable donor oocyte patient, increasing GN dose would lead to a progressively greater response and thus increase number of oocytes retrieved and embryos cryopreserved. Surprisingly, the opposite was seen in that these patients had significantly fewer oocytes retrieved and embryos cryopreserved. This may again represent a direct negative effect of the GN stimulation on the oocytes or an inherent worse response by some donors, despite being screened as favorable candidates. Therefore, increasing total GN doses by either lengthening stimulation or increasing daily GN dose should not be done solely to maximize these outcomes. There are several strengths to our study design. The main strength is that this cohort is generalizable to many different clinical settings given we used a national registry data. It is also a large enough cohort to complete a multivariate model and isolate our study variables. There are limitations to this study. The study design is retrospective, thereby only evaluating an association between variables without assessing a causal relationship. Given we analyzed only fresh donor oocyte cycles, the sample size is smaller than seen in other registry studies; we split our study variable into only 3 groups as there were too few patients in the outlying groups when further subdivided. We had limited information on embryo quality and endometrial preparation protocols, variables which could affect LBR in fresh donor oocyte transfer cycles. Lastly, donor patient characteristics that could affect LBR were limited in order to maintain their anonymity such as donor parity and ovarian reserve testing. If available, these variables would have been added to the multivariate model. In conclusion, our findings showed that LBR is significantly decreased in fresh donor oocyte cycles when cycles are both prolonged with high total GN dose. However, after controlling for confounders, neither DOS nor total GN dose significantly impacts LBR. Acknowledgments SART wishes to thank all of its members for providing clinical information to the SART CORS database for use by patients and researchers. Without the efforts of our members, this research would not have been possible. Author’s contributions All authors contributed to the study conception and data collection. Data analysis was performed by Melissa Fazzari. The first draft of the manuscript was written by Alexa Cohen, Michelle Kappy, and Rachel Gerber, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Compliance with ethical standards Conflict of interest Erkan Buyuk, MD is a consultant for EMD-Serono. Other authors report no conflict of interest. Code availability SART-CORS database. Footnotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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