More is better: oocyte number and cumulative live birth rate

There is no question that the success of in vitro fertilization (IVF) improved dramatically with the introduction of gonadotropins to stimulate the production of multiple oocytes. In the pioneering days of IVF, the retrieval of more than a single oocyte markedly increased the chance of having an embryo available for transfer and the chance of a resulting live birth. Since then, the enduring question has been "is more better?" Would high doses of gonadotropins lead to more oocytes and more live births? Or is there a limited number of quality oocytes that can be produced in a single cycle? In the last decade, there has been much effort devoted to determining whether there is an optimal oocyte number or gonadotropin dose that would maximize the chances for successful IVF outcomes. To investigate the possibility that the quest for more oocytes might be detrimental, several studies, including one in the current issue of Fertility and Sterility by Fanton et al. (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar), used data reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART CORS). This large database allows studies of hundreds of thousands of IVF cycles from a diverse US population. Two of the earliest studies were published in Fertility and Sterility in 2014 and 2015. In their 2014 study, Steward et al. (2Steward R.G. Lan L. Shah A.A. Yeh J.S. Price T.M. Goldfarb J.M. et al.Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.Fertil Steril. 2014; 101: 967-973Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) analyzed data from 256,381 fresh nondonor IVF cycles reported to the SART CORS from 2008 to 2010 and sought to identify the optimal number of retrieved oocytes that would maximize live birth rates while minimizing the rate of ovarian hyperstimulation syndrome (OHSS). During the study period, the overall rate of OHSS was 1.2%. In this study, the live birth rate increased up to 15 oocytes, and then plateaued. With the retrieval of more than 15 oocytes; however, the rate of OHSS increased considerably. The incidence of OHSS was 1.67% for cycles with the retrieval of 16–20 oocytes and 6.34% for cycles in which >25 oocytes were retrieved. The investigators recommended less aggressive stimulation protocols, arguing that the retrieval of >15 oocytes significantly increased the risk of OHSS without improving the live birth rate (2Steward R.G. Lan L. Shah A.A. Yeh J.S. Price T.M. Goldfarb J.M. et al.Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.Fertil Steril. 2014; 101: 967-973Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar). In 2015, a study by Baker et al. (3Baker V.L. Brown M.B. Luke B. Smith G.W. Ireland J.J. Gonadotropin dose is negatively correlated with the live birth rate: analysis of more than 650,000 assisted reproductive technology cycles.Fertil Steril. 2015; 104: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) examined the correlation between total gonadotropin dose and live birth rates using data from 658,519 fresh autologous IVF cycles that were reported to SART CORS from 2004 to 2012. Consistent with findings by Steward et al. (2Steward R.G. Lan L. Shah A.A. Yeh J.S. Price T.M. Goldfarb J.M. et al.Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.Fertil Steril. 2014; 101: 967-973Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar), live birth rates increased with increasing number of oocytes retrieved. Live birth rates, however, were negatively correlated with gonadotropin doses. Based on animal data, the investigators speculated that high gonadotropin doses could be detrimental for the oocytes, leading to poor quality embryos. They also noted reports of deleterious effects on the endometrium with the use of high doses of gonadotropins (3Baker V.L. Brown M.B. Luke B. Smith G.W. Ireland J.J. Gonadotropin dose is negatively correlated with the live birth rate: analysis of more than 650,000 assisted reproductive technology cycles.Fertil Steril. 2015; 104: 1145-1152Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Outside the United States, other databases are available. All fertility clinics in the United Kingdom are required to submit data to the Human Fertilization and Embryology Authority (4Bahadur G. Homburg R. Jayaprakasan K. Raperport C.J. Huirne J.A.F. Acharya S. et al.Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.BMJ Open. 2023; 13e064711Crossref Scopus (3) Google Scholar). A recent study, published by Bahadur et al. in 2023 (4Bahadur G. Homburg R. Jayaprakasan K. Raperport C.J. Huirne J.A.F. Acharya S. et al.Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.BMJ Open. 2023; 13e064711Crossref Scopus (3) Google Scholar), sought to evaluate the relationship between oocyte numbers and live birth rate by analyzing nondonor IVF cycles performed in the United Kingdom from 2015 to 2018. There were 172,341 fresh oocyte retrieval cycles during the study period. The highest live birth rate was found in cycles with the retrieval of 16–25 oocytes. With the retrieval of more oocytes, there was a significant decline in the live birth rate. The investigators hypothesized that oocytes may be compromised when large numbers are retrieved (4Bahadur G. Homburg R. Jayaprakasan K. Raperport C.J. Huirne J.A.F. Acharya S. et al.Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.BMJ Open. 2023; 13e064711Crossref Scopus (3) Google Scholar). These studies include a large number of cycles from a heterogeneous population but are limited by the constraints of their databases. In the study by Bahadur et al. (4Bahadur G. Homburg R. Jayaprakasan K. Raperport C.J. Huirne J.A.F. Acharya S. et al.Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.BMJ Open. 2023; 13e064711Crossref Scopus (3) Google Scholar) using the Human Fertilization and Embryology Authority database, live birth rate was reported per cycle with fresh and frozen cycles analyzed together. Before 2014, SART CORS did not link retrieval cycles to subsequent frozen embryo transfer (FET) cycles. Consequently, early studies, which used data from SART CORS, only included fresh embryo transfers. Subsequent pregnancies resulting from cryopreserved embryos could not be considered. Steward et al. (2Steward R.G. Lan L. Shah A.A. Yeh J.S. Price T.M. Goldfarb J.M. et al.Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.Fertil Steril. 2014; 101: 967-973Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar) found that retrieval of more oocytes led to more cryopreserved embryos. It is possible that an increased cumulative live birth rate, resulting from all the subsequent FETs from oocyte retrieval, would compensate for a potential decrease in live birth rate in the initial fresh cycle. In this issue of Fertility and Sterility, using more recent data from SART CORS, Fanton et al. (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar) examine cumulative live birth rates and revisit the perennial question of whether retrieval of more oocytes leads to better IVF outcomes (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar). The study included 402,411 autologous oocyte retrieval cycles and their linked FETs between 2014 and 2019. Cumulative live birth rate was found to increase with the retrieval of a higher number of oocytes. Consistent with previous findings by Steward et al. (2Steward R.G. Lan L. Shah A.A. Yeh J.S. Price T.M. Goldfarb J.M. et al.Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles.Fertil Steril. 2014; 101: 967-973Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar), the rate of OHSS was also positively correlated with the number of oocytes. The overall incidence of OHSS (moderate and severe) was 0.87% with the retrieval of 16–20 oocytes and 4.2% for cycles in which more than 40 oocytes were retrieved (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar). The investigators concluded that "future studies should investigate the optimal way in which to balance the risks of OHSS against the benefits of increased cumulative live birth rate (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar)." The data contained in the study by Fanton et al. (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar), however, suggest that OHSS may be less of a concern now. During their study, the percentage of cycles complicated by OHSS decreased from 1.2% in 2014 to 0.34% in 2019, despite an increase in the average number of oocytes retrieved, from 12.8 to 13.5. The decline in OHSS may be attributed to other changes in IVF practice that were observed during the study period, such as a decrease in fresh embryo transfers. From 2014 to 2019, the percentage of primary transfers that were FETs more than doubled—from 21% to 58%. Part of the increase in "freeze all" cycles may be attributed to the increased use of preimplantation genetic testing (PGT). The percentage of cycles in which PGT was performed increased more than three-fold, from 16% to 50% during the study period. It is likely that the incidence of OHSS will continue to decline as fewer IVF cycles result in fresh embryo transfers and other strategies, such as gonadotropin-releasing hormone agonist triggers, are employed. It is worthwhile to revisit the question of "is more better?" with data that reflects the current practice of IVF. Earlier observations, considering only fresh embryo transfers per cycle, may have underestimated the oocyte's potential. It is notable that in the 2023 study by Fanton et al. (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar), live birth rate with fresh transfers was lower than with frozen primary transfers, even when PGT was not performed, which supports the idea that the use of gonadotropins may have negative effects on the endometrium and not on the oocytes. When considering only fresh embryo transfers, the live birth rate was highest with retrieval of 11–30 oocytes and decreased slightly when more oocytes were retrieved. From their data, it seems that for fresh embryo transfers, more oocytes are not better. This, however, does not hold true when frozen transfers are considered. When frozen primary transfers were also included, there was a plateau, but no decline, in the live birth rate with the retrieval of additional oocytes. In the current practice of IVF, only few oocyte retrievals are associated with fresh embryo transfers. In addition to freezing embryos to permit PGT, patients are choosing to bank embryos for the future. For some patients, the goal of oocyte retrieval will not be immediate pregnancy, but to stockpile enough embryos to build their entire family. The study by Fanton et al. (1Fanton M. Cho J.H. Baker V.L. Loewke K. A higher number of oocytes retrieved is associated with an increase in 2PNs, blastocysts, and cumulative live birth rates.Fertil Steril. 2023; 119: 762-769Abstract Full Text Full Text PDF Scopus (6) Google Scholar) demonstrates that higher numbers of retrieved oocytes are associated with higher cumulative live birth rates. Their study suggests that for the current practice of IVF, "more is better" and provides reassurance that retrieving more oocytes is not at the expense of oocyte quality. A higher number of oocytes retrieved is associated with an increase in fertilized oocytes, blastocysts, and cumulative live birth ratesFertility and SterilityVol. 119Issue 5PreviewTo investigate the association between the number of oocytes retrieved and the numbers of fertilized oocytes and blastocysts and cumulative and primary transfer live birth rates (LBRs). Full-Text PDF Open Access