- Email: [email protected]
Coasting vs. cryopreservation of all embryos for prevention of ovarian hyperstimulation syndrome in in vitro fertilization
Coasting vs. cryopreservation of all embryos for prevention of ovarian hyperstimulation syndrome in in vitro fertilization In the patient at risk for ovarian hyperstimulation syndrome, coasting will result in fewer eggs retrieved and embryos produced when compared with cryopreservation of all embryos. However, both strategies are associated with a similar incidence of ovarian hyperstimulation syndrome, with achievement of comparable cumulative pregnancy rates. (Fertil Steril 2008;90:1259–62. 2008 by American Society for Reproductive Medicine.)
Ovarian hyperstimulation syndrome (OHSS) is a potentially fatal iatrogenic complication of IVF (1). In many cases, the earliest sign of impending OHSS is an exuberant E2 response to gonadotropin stimulation (2). To avert OHSS, the physician has but a few tools available. One common technique is to coast the patient. In coasting, gonadotropin stimulation is withdrawn, and E2 levels are allowed to decline before hCG is administered. Another technique, cryopreservation of all embryos, aims to reduce the risk of OHSS by postponing embryo transfer and cryopreserving all embryos at the two-pronuclear stage (2PN) (3). Although current literature appears to indicate that either coasting or cryopreservation is a reasonable approach to take, it is not clear whether one of these two strategies results in superior outcomes. To better understand whether one of these two strategies results in improved outcomes, including cumulative pregnancy rates, we performed a retrospective analysis of all high-responder cycles that were managed with either strategy. This study was approved by the Institutional Review Board of Brigham and Women’s/Partners’ Healthcare. A total of 3,394 IVF cycles performed between January 1, 2001 and March 15, 2003 at Brigham and Women’s Hospital was reviewed. Of these, 658 (19.4%) cycles were identified in which the patient, on any day in her cycle, reached an E2 of R3,000 pg/mL. Of these high responders, 57 cycles were identified in which gonadotropin was withdrawn for R1 days before hCG was given (coasting group). An additional 76 cycles were identified in which the patient had cryopreservation of all to reduce the likelihood of OHSS (cryopreservation group). Patients on their third or more IVF cycle were excluded (coasting group, n ¼ 2; cryopresReceived March 29, 2006; revised and accepted July 26, 2007. E.S.G. is a consultant for Medacorp, Boston, MA. Presented in part at the 59th Annual Meeting of the American Society of Reproductive Medicine, San Antonio, Texas, October 11–15, 2003. Reprint requests: Heather G. Huddleston, M.D., University of California, San Francisco, Department of Obstetrics and Gynecology, 2356 Sutter Street, 7th Floor, Box 0916, San Francisco, California 94115 (FAX: 415-353-7744; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.07.1383
ervation group, n ¼ 5). In addition, patients who were coasted but then also had all embryos frozen were excluded (n ¼ 12). The final data set included 43 coasting cycles and 59 cryopreservation cycles. The interval for assessing subsequent cryopreserved embryo transfers was January 1, 2001–January 1, 2005. All patients underwent controlled ovarian hyperstimulation with gonadotropins, with frequent monitoring of E2 levels and follicle counts per standard protocols. At no time was gonadotropin stimulation withheld for patients in the cryopreservation group, although the dose may have been lowered. In the cryopreservation group, hCG was administered when two follicles reached mean diameters of 18 mm. In the coasting group, the follicle criteria could have been met before the administration of hCG, which was not administered until E2 levels fell to <4,000 pg/mL. The decision regarding whether to recommend the patient for coasting or cryopreservation was made by the physician reviewing the case and was driven by individual physician preference. Patients in the cryopreservation group had freezing of their embryos at the 2PN stage. Coasting patients may or may not have had surplus embryos frozen on day 3 or 5 after retrieval, depending on embryo quality. Patients who pursued a cryopreserved embryo transfer cycle used exogenous hormone preparations with leuprolide acetate and oral, transdermal, or vaginally administered E2. All cycles in which a transfer was planned had luteal P supplementation starting the day after oocyte retrieval, or starting 4 days before transfer in cryopreserved embryo transfer cycles. Patient characteristics, cycle parameters, and outcomes were compared. Pregnancy rates (delivered per cycle start) were based on the first transfer only (fresh for the coasting group and frozen for the cryopreservation group). Cumulative pregnancy rates (per cycle start) considered all subsequent pregnancies resulting from embryos that were frozen during the index cycle. Transfers that did not exclusively make use of embryos from the index cycle were excluded from analysis. Pregnancies resulting in either chemical pregnancies or spontaneous abortions were considered as one group. Patients with OHSS symptoms were
Fertility and Sterility Vol. 90, No. 4, October 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
1259
admitted to the hospital for hemoconcentration (hematocrit of >44%), significant discomfort caused by moderate to large ascites, and/or pleural effusion requiring treatment. Statistical analysis was performed with InStat (version 3.06; GraphPad Software Co, San Diego, CA). All continuous variables were examined for normality with the KolmogorovSmirnov test. Mann Whitney U test and t-test were used where appropriate. The Fisher’s exact test was used to analyze categorical data. A P value of significance was set to .05. Patients in the coasting (n ¼ 43) and cryopreservation (n ¼ 59) groups were similar with respect to age and day 3 FSH. Although this study was restricted to patients undergoing either a first or second cycle, significantly more cryopreservation patients, compared with coasting patients, were on their first attempt (mean IVF attempt number, 1.2 vs. 1.4, respectively, P¼.04). The majority of patients underwent a protocol involving luteal down-regulation with recombinant FSH only. A comparable amount of gonadotropin was used by each group, resulting in similar peak E2 levels and numbers of follicles at hCG administration. Coasting patients had gonadotropin administration withheld for a mean (SD) of 2.3 1.1 days; a majority of these patients (86%) were coasted for %3 days. Coasting patients achieved significantly higher peak E2 levels during their cycle (5,203 1,422.9 pg/mL vs. 4,713 718.0 pg/mL; P¼.03). As might be expected given the goal of coasting, the E2 at time of hCG was lower in the coasting group compared with in the cryopreservation group (3,314.1 920.2 pg/mL vs. 4,694 717.5 pg/mL; P<.0001). Although each group had an equivalent number of follicles measured, coasting patients had fewer oocytes (17.9 6.1 vs. 30.4 12.5; P<.0001) and mature oocytes retrieved (14.8 5.6 vs. 24.3 10.6; P<.0001). Moreover, the oocyte to follicle ratio was lower for coasting patients, compared with cryopreservation patients (0.8 0.3 vs. 1.2 0.4; P<.0001), as was the E2 to follicle ratio (154.7 83.7 vs. 205.0 73.5; P¼.0002). There were two cycle cancellations in the coasting group, both as a result of significant E2 drops that were thought by the reviewing physician to portend poor outcome. There were no cycle cancellations in the cryopreservation group. The number of 2PN embryos produced was lower for coasting compared with cryopreservation patients (9.5 5.7 compared with 17.6 9.0; P<.0001). The mean number of embryos frozen at the 2PN stage in the cryopreservation group was 17.6 ( 9.0) per patient. Four of the cryopreservation patients had not undergone at least one transfer of thawed embryos as of January 2005. The reasons for nontransfer were the following: [1] failed survival of all embryos (n ¼ 1), [2] inability to achieve adequate uterine preparation (n ¼ 1), [3] natural conception (n ¼ 1), or [4] personal reasons (n ¼ 1). After first transfer, for cryopreservation patients, the mean number of frozen 2PN embryos remaining was 7.74 (8.44) per patient. Patients in the coasting group had a mean of 1260
Huddleston et al.
Correspondence
2.4 (3.63) surplus embryos frozen on either day 3 or 5 after their fresh transfer. When only the first embryo transfer was considered (fresh for coasting patients and frozen for cryopreservation patients), the implantation rate for the cryopreservation group was 0.17, compared with 0.29 for the coasting group (P¼.027). However, the number of embryos transferred was higher in the cryopreservation group (3.98 1.47 vs. 3.29 1.64; P¼.04). As a result, pregnancy rates (delivered per cycle start) were identical (37.3% vs. 37.3%). After the first transfer, 31 patients (52.5%) in the cryopreservation group and 17 (39.5%) in the coasting group had frozen embryos remaining (2PN stage for cryopreservation group, D3 or D5 for the coasting group). In addition, the cryopreservation group had significantly more mean residual embryos cryopreserved than did the coasting group (7.74 8.44 vs. 2.37 3.63; P¼.03). Nevertheless, cumulative pregnancy rates were not statistically significant (52.5% vs. 44.2%). A power analysis indicated that a total of 390 patients would be necessary in each group for a 10% difference in pregnancy rates to be found significant. However, the nonsignificant trend toward a higher cumulative pregnancy rate per cycle start in the cryopreservation group should be noted: cryopreservation cycles were 30% more likely to result in pregnancy compared with coasting cycles (odds ratio, 1.3; 95% confidence interval, 0.6, 2.8). Finally, we evaluated the risk of OHSS that necessitated hospital admission. The incidence of OHSS was similar between groups (9.3% [4/43] vs. 6.8 % [4/59]), as were mean days of hospitalization (5.25 vs. 5.0). The data are summarized in Table 1. Coasting and cryopreservation of all embryos are two very different strategies for managing the patient at risk for OHSS. Coasting is thought to prevent OHSS by leading to atretic changes in a subset of follicles. Our finding of an egg to follicle ratio of 0.8 in coasting patients (compared with 1.2 for cryopreservation patients) may illustrate this follicular atresia. In contrast, cryopreservation of all embryos prevents OHSS by simply eliminating the rise of hCG that is associated with a successful implantation. There is a now-growing body of literature that describes coasting through retrospective series (4–8), as well as one small prospective randomized study involving 30 patients (9). A qualitative systemic review concluded that coasting results in acceptable pregnancy rates but does not completely avoid the risk of OHSS (10). A Cochrane review found insufficient prospective evidence to indicate whether coasting affects either the incidence of OHSS or pregnancy rates (11). Similarly, cryopreservation of all embryos has been the subject of several retrospective series, which have indicated a reduction in OHSS risk and acceptable pregnancy rates (12–14). A Cochrane review concluded, on the basis of two studies, that there was insufficient prospective evidence to conclude that cryopreservation prevented OHSS, compared with albumin administration or no cryopreservation (15). Vol. 90, No. 4, October 2008
TABLE 1 Characteristics of patients and cycles, as well as cycle outcomes. Parameter Age (y) Attempt no. Day 3 FSH Down-regulation protocol (%) Stimulation with recombinant FSH only (%) Polycystic ovary syndrome (%) Intracytoplasmic sperm injection (%) No. of 75-IU ampules of gonadotropins E2 on day of hCG (pg/mL) Peak E2 (pg/mL) No. of follicles at hCG No. of eggs retrieved No. of mature eggs E2-follicle ratio (pg/mL) Egg-follicle ratio No. of 2PN embryos Cancellations per start (%) No. of embryos transferreda Implantation ratea (%) Delivered pregnancies per starta (%) Multiple gestationa (%) Pregnancy loss per starta,b (%) Cumulative delivered pregnancies per start (%) Hospital admission for OHSS per start (%) No. of days hospitalizedc
Coasting group (n [ 43 cycles)
Cryopreservation group (n [ 59 cycles)
P value
33.9 4.1 1.2 0.4 6.7 1.6 90.7 86.1
34.1 4.3 1.4 0.5 6.8 1.9 93.2 86.4
NS .05 NS NS NS
16.3 39.5 33.9 13.3
22.0 37.3 34.8 15.7
NS NS NS
3,314.1 920.2 5,203.0 1,422.9 23.9 6.2 17.9 6.1 14.8 5.6 154.7 83.7 0.80 0.3 9.5 5.7 4.8 3.29 1.47 26.5 37.3 36.4 18.6 44.2
4,694.0 717.5 4,713 718 25.0 7.2 30.4 12.5 24.3 10.6 205.0 73.5 1.2 0.4 17.6 9.0 0 3.98 1.64 14.5 37.3 18.8 11.9 52.3
.0001 .03 NS < .0001 < .0001 .0002 .0001 .0001 NS .04 .0009 NS NS NS NS
9.4
6.8
NS
5.0 2.2
5.0 2.9
NS
Note: Values are mean (SD) unless otherwise stated. NS ¼ not significant. a Considers first transfer only. b Chemical pregnancies and spontaneous abortion. c Included 4 patients from each group. Huddleston. Coasting vs. cryopreservation of all embryos. Fertil Steril 2008.
Within our center, both coasting and cryopreservation of all embryos are used in the management of the high responder, allowing us to evaluate subsequent patient outcomes in a single practice. In this study, we found both strategies to be equally effective in preventing hospitalization for OHSS (6.8% in the cryopreservation group vs. 9.3% in the coasting group), although neither strategy eliminated the risk. We found significant differences in several intermediate outcomes. Cryopreservation patients had more total and mature eggs retrieved and produced nearly twice as many embryos as did coasting patients. Nevertheless, we found that pregnancy rates, when considering the first transfer only, were comparable. This finding is striking, given that the frozen embryo cycles were associated with Fertility and Sterility
a decreased implantation rate when compared with fresh cycles. However, as per the policy at our center, the number of embryos transferred in the frozen cycles was also higher, leading to equivalency in overall pregnancy rates. Because a larger number of embryos was available to patients in the cryopreservation group, we were interested in determining whether this would translate into a higher cumulative pregnancy rate for the cryopreservation group. Only one study of which we are aware calculated a cumulative pregnancy rate for patients undergoing either of these strategies. Tummon et al. (11) found a cumulative pregnancy rate of 77% in a series of 30 patients who were undergoing cryopreservation of all embryos. To our knowledge, this parameter has not been previously assessed in coasting cycles. In the
1261
current study, we find a trend toward a higher cumulative pregnancy rate in the cryopreservation group (52.3% vs. 44.2%); indeed, cryopreservation cycles were 30% more likely to result in pregnancy, compared with coasting cycles (odds ratio, 1.3; 95% confidence interval, 0.6, 2.8). Although this difference was not statistically significant, the sample size for the current study was small, and the observed difference may have clinical significance. In conclusion, it appears that the very high responder can be appropriately managed with either strategy. The decision regarding which technique to use may best be made by allowing both patient and physician to consider the relative merits of each strategy as it applies in the individual case. As shown here, cryopreservation of all embryos offers the advantage of the production of more embryos. Coasting avoids the inconvenience, and possibly the added expense, of postponing an eagerly awaited fresh transfer. Heather G. Huddleston, M.D. Catherine Racowsky, Ph.D. Katharine V. Jackson, B.S. Janis H. Fox, M.D. Elizabeth S. Ginsburg, M.D. Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts REFERENCES 1. Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 2003;9:275–89. 2. Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 1983;40:31–6. 3. Queenan JT Jr. Embryo freezing to prevent ovarian hyperstimulation syndrome. Mol Cell Endocrinol 2000;169:79–83.
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Correspondence
4. Dhont M, Van der Straeten F, De Sutter P. Prevention of severe ovarian hyperstimulation by coasting. Fertil Steril 1998;70:847–50. 5. Waldenstrom U, Kahn J, Marsk L, Nilsson S. High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by ‘‘prolonged coasting’’ of very hyperstimulated patients: a multicentre study. Hum Reprod 1999;14:294–7. 6. Tortoriello DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K, Santoro N. ‘‘Coasting’’ does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 1998;69:454–60. 7. Grochowski D, Wolczynski S, Kuczynski W, Domitrz J, Szamatowicz J, Szamatowicz M. Correctly timed coasting reduces the risk of ovarian hyperstimulation syndrome and gives good cycle outcome in an in vitro fertilization program. Gynecol Endocrinol 2001;15:234–8. 8. Benadiva CA, Davis O, Kligman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997;67:724–7. 9. Egbase PE, Sharhan MA, Grudzinskas JG. Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized study. Hum Reprod 1999;14:1421–5. 10. Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update 2002;8:291–6. 11. D’Angelo A, Amso N. ‘‘Coasting’’ (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;3:CD002811. 12. Tummon IS, Contag SA, Thornhill AR, Session DR, Dumesic DA, Damario MA. Cumulative first live birth after elective cryopreservation of all embryos due to ovarian hyperresponsiveness. Fertil Steril 2004;81:309–14. 13. Wada I, Matson PL, Troup SA, Hughes S, Buck P, Lieberman BA. Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome. Hum Reprod 1992;7:962–6. 14. Queenan JT Jr, Veeck LL, Toner JP, Oehninger S, Muasher SJ. Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers. Hum Reprod 1997;12:1573–6. 15. D’Angelo A, Amso N. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;2: CD002806.
Vol. 90, No. 4, October 2008
Ovarian hyperstimulation syndrome (OHSS) is a potentially fatal iatrogenic complication of IVF (1). In many cases, the earliest sign of impending OHSS is an exuberant E2 response to gonadotropin stimulation (2). To avert OHSS, the physician has but a few tools available. One common technique is to coast the patient. In coasting, gonadotropin stimulation is withdrawn, and E2 levels are allowed to decline before hCG is administered. Another technique, cryopreservation of all embryos, aims to reduce the risk of OHSS by postponing embryo transfer and cryopreserving all embryos at the two-pronuclear stage (2PN) (3). Although current literature appears to indicate that either coasting or cryopreservation is a reasonable approach to take, it is not clear whether one of these two strategies results in superior outcomes. To better understand whether one of these two strategies results in improved outcomes, including cumulative pregnancy rates, we performed a retrospective analysis of all high-responder cycles that were managed with either strategy. This study was approved by the Institutional Review Board of Brigham and Women’s/Partners’ Healthcare. A total of 3,394 IVF cycles performed between January 1, 2001 and March 15, 2003 at Brigham and Women’s Hospital was reviewed. Of these, 658 (19.4%) cycles were identified in which the patient, on any day in her cycle, reached an E2 of R3,000 pg/mL. Of these high responders, 57 cycles were identified in which gonadotropin was withdrawn for R1 days before hCG was given (coasting group). An additional 76 cycles were identified in which the patient had cryopreservation of all to reduce the likelihood of OHSS (cryopreservation group). Patients on their third or more IVF cycle were excluded (coasting group, n ¼ 2; cryopresReceived March 29, 2006; revised and accepted July 26, 2007. E.S.G. is a consultant for Medacorp, Boston, MA. Presented in part at the 59th Annual Meeting of the American Society of Reproductive Medicine, San Antonio, Texas, October 11–15, 2003. Reprint requests: Heather G. Huddleston, M.D., University of California, San Francisco, Department of Obstetrics and Gynecology, 2356 Sutter Street, 7th Floor, Box 0916, San Francisco, California 94115 (FAX: 415-353-7744; E-mail: [email protected]).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.07.1383
ervation group, n ¼ 5). In addition, patients who were coasted but then also had all embryos frozen were excluded (n ¼ 12). The final data set included 43 coasting cycles and 59 cryopreservation cycles. The interval for assessing subsequent cryopreserved embryo transfers was January 1, 2001–January 1, 2005. All patients underwent controlled ovarian hyperstimulation with gonadotropins, with frequent monitoring of E2 levels and follicle counts per standard protocols. At no time was gonadotropin stimulation withheld for patients in the cryopreservation group, although the dose may have been lowered. In the cryopreservation group, hCG was administered when two follicles reached mean diameters of 18 mm. In the coasting group, the follicle criteria could have been met before the administration of hCG, which was not administered until E2 levels fell to <4,000 pg/mL. The decision regarding whether to recommend the patient for coasting or cryopreservation was made by the physician reviewing the case and was driven by individual physician preference. Patients in the cryopreservation group had freezing of their embryos at the 2PN stage. Coasting patients may or may not have had surplus embryos frozen on day 3 or 5 after retrieval, depending on embryo quality. Patients who pursued a cryopreserved embryo transfer cycle used exogenous hormone preparations with leuprolide acetate and oral, transdermal, or vaginally administered E2. All cycles in which a transfer was planned had luteal P supplementation starting the day after oocyte retrieval, or starting 4 days before transfer in cryopreserved embryo transfer cycles. Patient characteristics, cycle parameters, and outcomes were compared. Pregnancy rates (delivered per cycle start) were based on the first transfer only (fresh for the coasting group and frozen for the cryopreservation group). Cumulative pregnancy rates (per cycle start) considered all subsequent pregnancies resulting from embryos that were frozen during the index cycle. Transfers that did not exclusively make use of embryos from the index cycle were excluded from analysis. Pregnancies resulting in either chemical pregnancies or spontaneous abortions were considered as one group. Patients with OHSS symptoms were
Fertility and Sterility Vol. 90, No. 4, October 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
1259
admitted to the hospital for hemoconcentration (hematocrit of >44%), significant discomfort caused by moderate to large ascites, and/or pleural effusion requiring treatment. Statistical analysis was performed with InStat (version 3.06; GraphPad Software Co, San Diego, CA). All continuous variables were examined for normality with the KolmogorovSmirnov test. Mann Whitney U test and t-test were used where appropriate. The Fisher’s exact test was used to analyze categorical data. A P value of significance was set to .05. Patients in the coasting (n ¼ 43) and cryopreservation (n ¼ 59) groups were similar with respect to age and day 3 FSH. Although this study was restricted to patients undergoing either a first or second cycle, significantly more cryopreservation patients, compared with coasting patients, were on their first attempt (mean IVF attempt number, 1.2 vs. 1.4, respectively, P¼.04). The majority of patients underwent a protocol involving luteal down-regulation with recombinant FSH only. A comparable amount of gonadotropin was used by each group, resulting in similar peak E2 levels and numbers of follicles at hCG administration. Coasting patients had gonadotropin administration withheld for a mean (SD) of 2.3 1.1 days; a majority of these patients (86%) were coasted for %3 days. Coasting patients achieved significantly higher peak E2 levels during their cycle (5,203 1,422.9 pg/mL vs. 4,713 718.0 pg/mL; P¼.03). As might be expected given the goal of coasting, the E2 at time of hCG was lower in the coasting group compared with in the cryopreservation group (3,314.1 920.2 pg/mL vs. 4,694 717.5 pg/mL; P<.0001). Although each group had an equivalent number of follicles measured, coasting patients had fewer oocytes (17.9 6.1 vs. 30.4 12.5; P<.0001) and mature oocytes retrieved (14.8 5.6 vs. 24.3 10.6; P<.0001). Moreover, the oocyte to follicle ratio was lower for coasting patients, compared with cryopreservation patients (0.8 0.3 vs. 1.2 0.4; P<.0001), as was the E2 to follicle ratio (154.7 83.7 vs. 205.0 73.5; P¼.0002). There were two cycle cancellations in the coasting group, both as a result of significant E2 drops that were thought by the reviewing physician to portend poor outcome. There were no cycle cancellations in the cryopreservation group. The number of 2PN embryos produced was lower for coasting compared with cryopreservation patients (9.5 5.7 compared with 17.6 9.0; P<.0001). The mean number of embryos frozen at the 2PN stage in the cryopreservation group was 17.6 ( 9.0) per patient. Four of the cryopreservation patients had not undergone at least one transfer of thawed embryos as of January 2005. The reasons for nontransfer were the following: [1] failed survival of all embryos (n ¼ 1), [2] inability to achieve adequate uterine preparation (n ¼ 1), [3] natural conception (n ¼ 1), or [4] personal reasons (n ¼ 1). After first transfer, for cryopreservation patients, the mean number of frozen 2PN embryos remaining was 7.74 (8.44) per patient. Patients in the coasting group had a mean of 1260
Huddleston et al.
Correspondence
2.4 (3.63) surplus embryos frozen on either day 3 or 5 after their fresh transfer. When only the first embryo transfer was considered (fresh for coasting patients and frozen for cryopreservation patients), the implantation rate for the cryopreservation group was 0.17, compared with 0.29 for the coasting group (P¼.027). However, the number of embryos transferred was higher in the cryopreservation group (3.98 1.47 vs. 3.29 1.64; P¼.04). As a result, pregnancy rates (delivered per cycle start) were identical (37.3% vs. 37.3%). After the first transfer, 31 patients (52.5%) in the cryopreservation group and 17 (39.5%) in the coasting group had frozen embryos remaining (2PN stage for cryopreservation group, D3 or D5 for the coasting group). In addition, the cryopreservation group had significantly more mean residual embryos cryopreserved than did the coasting group (7.74 8.44 vs. 2.37 3.63; P¼.03). Nevertheless, cumulative pregnancy rates were not statistically significant (52.5% vs. 44.2%). A power analysis indicated that a total of 390 patients would be necessary in each group for a 10% difference in pregnancy rates to be found significant. However, the nonsignificant trend toward a higher cumulative pregnancy rate per cycle start in the cryopreservation group should be noted: cryopreservation cycles were 30% more likely to result in pregnancy compared with coasting cycles (odds ratio, 1.3; 95% confidence interval, 0.6, 2.8). Finally, we evaluated the risk of OHSS that necessitated hospital admission. The incidence of OHSS was similar between groups (9.3% [4/43] vs. 6.8 % [4/59]), as were mean days of hospitalization (5.25 vs. 5.0). The data are summarized in Table 1. Coasting and cryopreservation of all embryos are two very different strategies for managing the patient at risk for OHSS. Coasting is thought to prevent OHSS by leading to atretic changes in a subset of follicles. Our finding of an egg to follicle ratio of 0.8 in coasting patients (compared with 1.2 for cryopreservation patients) may illustrate this follicular atresia. In contrast, cryopreservation of all embryos prevents OHSS by simply eliminating the rise of hCG that is associated with a successful implantation. There is a now-growing body of literature that describes coasting through retrospective series (4–8), as well as one small prospective randomized study involving 30 patients (9). A qualitative systemic review concluded that coasting results in acceptable pregnancy rates but does not completely avoid the risk of OHSS (10). A Cochrane review found insufficient prospective evidence to indicate whether coasting affects either the incidence of OHSS or pregnancy rates (11). Similarly, cryopreservation of all embryos has been the subject of several retrospective series, which have indicated a reduction in OHSS risk and acceptable pregnancy rates (12–14). A Cochrane review concluded, on the basis of two studies, that there was insufficient prospective evidence to conclude that cryopreservation prevented OHSS, compared with albumin administration or no cryopreservation (15). Vol. 90, No. 4, October 2008
TABLE 1 Characteristics of patients and cycles, as well as cycle outcomes. Parameter Age (y) Attempt no. Day 3 FSH Down-regulation protocol (%) Stimulation with recombinant FSH only (%) Polycystic ovary syndrome (%) Intracytoplasmic sperm injection (%) No. of 75-IU ampules of gonadotropins E2 on day of hCG (pg/mL) Peak E2 (pg/mL) No. of follicles at hCG No. of eggs retrieved No. of mature eggs E2-follicle ratio (pg/mL) Egg-follicle ratio No. of 2PN embryos Cancellations per start (%) No. of embryos transferreda Implantation ratea (%) Delivered pregnancies per starta (%) Multiple gestationa (%) Pregnancy loss per starta,b (%) Cumulative delivered pregnancies per start (%) Hospital admission for OHSS per start (%) No. of days hospitalizedc
Coasting group (n [ 43 cycles)
Cryopreservation group (n [ 59 cycles)
P value
33.9 4.1 1.2 0.4 6.7 1.6 90.7 86.1
34.1 4.3 1.4 0.5 6.8 1.9 93.2 86.4
NS .05 NS NS NS
16.3 39.5 33.9 13.3
22.0 37.3 34.8 15.7
NS NS NS
3,314.1 920.2 5,203.0 1,422.9 23.9 6.2 17.9 6.1 14.8 5.6 154.7 83.7 0.80 0.3 9.5 5.7 4.8 3.29 1.47 26.5 37.3 36.4 18.6 44.2
4,694.0 717.5 4,713 718 25.0 7.2 30.4 12.5 24.3 10.6 205.0 73.5 1.2 0.4 17.6 9.0 0 3.98 1.64 14.5 37.3 18.8 11.9 52.3
.0001 .03 NS < .0001 < .0001 .0002 .0001 .0001 NS .04 .0009 NS NS NS NS
9.4
6.8
NS
5.0 2.2
5.0 2.9
NS
Note: Values are mean (SD) unless otherwise stated. NS ¼ not significant. a Considers first transfer only. b Chemical pregnancies and spontaneous abortion. c Included 4 patients from each group. Huddleston. Coasting vs. cryopreservation of all embryos. Fertil Steril 2008.
Within our center, both coasting and cryopreservation of all embryos are used in the management of the high responder, allowing us to evaluate subsequent patient outcomes in a single practice. In this study, we found both strategies to be equally effective in preventing hospitalization for OHSS (6.8% in the cryopreservation group vs. 9.3% in the coasting group), although neither strategy eliminated the risk. We found significant differences in several intermediate outcomes. Cryopreservation patients had more total and mature eggs retrieved and produced nearly twice as many embryos as did coasting patients. Nevertheless, we found that pregnancy rates, when considering the first transfer only, were comparable. This finding is striking, given that the frozen embryo cycles were associated with Fertility and Sterility
a decreased implantation rate when compared with fresh cycles. However, as per the policy at our center, the number of embryos transferred in the frozen cycles was also higher, leading to equivalency in overall pregnancy rates. Because a larger number of embryos was available to patients in the cryopreservation group, we were interested in determining whether this would translate into a higher cumulative pregnancy rate for the cryopreservation group. Only one study of which we are aware calculated a cumulative pregnancy rate for patients undergoing either of these strategies. Tummon et al. (11) found a cumulative pregnancy rate of 77% in a series of 30 patients who were undergoing cryopreservation of all embryos. To our knowledge, this parameter has not been previously assessed in coasting cycles. In the
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current study, we find a trend toward a higher cumulative pregnancy rate in the cryopreservation group (52.3% vs. 44.2%); indeed, cryopreservation cycles were 30% more likely to result in pregnancy, compared with coasting cycles (odds ratio, 1.3; 95% confidence interval, 0.6, 2.8). Although this difference was not statistically significant, the sample size for the current study was small, and the observed difference may have clinical significance. In conclusion, it appears that the very high responder can be appropriately managed with either strategy. The decision regarding which technique to use may best be made by allowing both patient and physician to consider the relative merits of each strategy as it applies in the individual case. As shown here, cryopreservation of all embryos offers the advantage of the production of more embryos. Coasting avoids the inconvenience, and possibly the added expense, of postponing an eagerly awaited fresh transfer. Heather G. Huddleston, M.D. Catherine Racowsky, Ph.D. Katharine V. Jackson, B.S. Janis H. Fox, M.D. Elizabeth S. Ginsburg, M.D. Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts REFERENCES 1. Aboulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 2003;9:275–89. 2. Haning RV Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril 1983;40:31–6. 3. Queenan JT Jr. Embryo freezing to prevent ovarian hyperstimulation syndrome. Mol Cell Endocrinol 2000;169:79–83.
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4. Dhont M, Van der Straeten F, De Sutter P. Prevention of severe ovarian hyperstimulation by coasting. Fertil Steril 1998;70:847–50. 5. Waldenstrom U, Kahn J, Marsk L, Nilsson S. High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by ‘‘prolonged coasting’’ of very hyperstimulated patients: a multicentre study. Hum Reprod 1999;14:294–7. 6. Tortoriello DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K, Santoro N. ‘‘Coasting’’ does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 1998;69:454–60. 7. Grochowski D, Wolczynski S, Kuczynski W, Domitrz J, Szamatowicz J, Szamatowicz M. Correctly timed coasting reduces the risk of ovarian hyperstimulation syndrome and gives good cycle outcome in an in vitro fertilization program. Gynecol Endocrinol 2001;15:234–8. 8. Benadiva CA, Davis O, Kligman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997;67:724–7. 9. Egbase PE, Sharhan MA, Grudzinskas JG. Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized study. Hum Reprod 1999;14:1421–5. 10. Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update 2002;8:291–6. 11. D’Angelo A, Amso N. ‘‘Coasting’’ (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;3:CD002811. 12. Tummon IS, Contag SA, Thornhill AR, Session DR, Dumesic DA, Damario MA. Cumulative first live birth after elective cryopreservation of all embryos due to ovarian hyperresponsiveness. Fertil Steril 2004;81:309–14. 13. Wada I, Matson PL, Troup SA, Hughes S, Buck P, Lieberman BA. Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome. Hum Reprod 1992;7:962–6. 14. Queenan JT Jr, Veeck LL, Toner JP, Oehninger S, Muasher SJ. Cryopreservation of all prezygotes in patients at risk of severe hyperstimulation does not eliminate the syndrome, but the chances of pregnancy are excellent with subsequent frozen-thaw transfers. Hum Reprod 1997;12:1573–6. 15. D’Angelo A, Amso N. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;2: CD002806.
Vol. 90, No. 4, October 2008