Ovarian hyperstimulation syndrome: steps to maximize success and minimize effect for assisted reproductive outcome

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1 Ovarian hyperstimulation syndrome: steps to maximize success and minimize effect for assisted reproductive outcome Puja S. Gera, M.D., Laura L. Tatpati, M.D., Michael C. Allemand, M.D., Mark A. Wentworth, B.S., and Charles C. Coddington, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, Minnesota Objective: To investigate the strategies used to decrease the risk of ovarian hyperstimulation syndrome (OHSS) and their impact on pregnancy and live birth rates. Design: Retrospective cohort analysis. Setting: University hospital. Patient(s): One hundred eighty-eight patients undergoing fresh in vitro fertilization (IVF) cycles between 2000 and 2004, with peak serum estradiol levels >2500 pg/ml and presumed to be at risk for OHSS. Intervention(s): Coasting and elective embryo cryopreservation were evaluated for their effect on OHSS and live birth rates. Main Outcome Measure(s): Pregnancy, live birth rates, and OHSS incidence. Result(s): Out of 188 patients at risk for OHSS, 21 patients had their cycles coasted (group 1), and elective embryo cryopreservation was performed in 32 patients (group 2). In 135 patients with no other risk factors, ovulation was triggered with human chorionic gonadotropin and embryo transfer was performed (group 3). The incidence in our IVF population was 38 out of 1002 (3.8%). The overall incidence of OHSS for those who had an estradiol level >2500 pg/ml was 20.2% (38 out of 188), and none of the patients in group 1 developed OHSS; 13 out of 32 patients in group 2 (40.6%) and 25 out of 135 (18.5%) patients in group 3 developed OHSS. The live birth rate was 38%, 40%, and 45% in groups 1, 2, and 3, respectively, and the cumulative live birth rate was 52%, 75%, and 59%, respectively. Conclusion(s): Elective cryopreservation of embryos with subsequent frozen embryo transfer and coasting are effective ways of maximizing pregnancy and limiting severe OHSS. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Coasting, elective embryo cryopreservation, OHSS, ovarian hyperstimulation syndrome Although considerable improvement has been seen in the pregnancy outcomes with the introduction of new stimulation protocols, the incidence of ovarian hyperstimulation syndrome (OHSS) has failed to decrease over time. Ovarian hyperstimulation syndrome is a potentially life-threatening complication associated with controlled ovarian hyperstimulation and in vitro fertilization (IVF). Increased vascular permeability and fluid shifts cause hemoconcentration, which may be complicated by renal failure, thromboembolic episodes, respiratory distress, and death. The enlarged ovaries after controlled ovarian hyperstimulation can potentially rupture, hemorrhage, or undergo torsion (1, 2). Received August 26, 2008; revised February 11, 2009; accepted February 13, 2009; published online April 7, P.S.G. has nothing to disclose. L.L.T. has nothing to disclose. M.C.A. is on the speaker s bureau for Organon. M.A.W. has nothing to disclose. C.C.C. has nothing to disclose. Poster presented at the 62nd Annual Meeting of American Society for Reproductive Medicine, New Orleans, Louisiana, October 21 25, Reprint requests: Charles C. Coddington, M.D., Director, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, 200, 1st Street SW, Rochester, MN (FAX: ; coddington.charles@ mayo.edu). Despite extensive research, the pathogenesis of this syndrome is unclear. The variables closely related to OHSS are beta human chorionic gonadotropin (b-hcg), serum estradiol (E 2 ), the number of follicles, vascular endothelial growth factor (VEGF), interleukin-6, the ovarian renin angiotensin system, and prostaglandins (1, 3 5). Though high serum E 2 levels are most often associated with an increased risk of OHSS (6), the syndrome has been reported to occur with extremely low E 2 levels as well (7, 8). Various strategies have been proposed to reduce the occurrence of this syndrome, but none can eliminate the risk completely while maintaining optimum pregnancy outcome. Cycle cancellation lowers the risk of OHSS but at the expense of losing the cycle (9). Withholding the hcg injection until the serum E 2 falls below an acceptable level, commonly called coasting, decreases the incidence of OHSS and, although the implantation rate in a coasted cycle is reported to be lower, the pregnancy rates still reach 38.5% (10). Likewise, elective cryopreservation of the embryos with subsequent transfer at a later time has also been shown to reduce OHSS, and the cumulative live birth rate per patient with this technique approaches 82% (11) /$36.00 Fertility and Sterility â Vol. 94, No. 1, June doi: /j.fertnstert Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 We performed a retrospective data analysis at the Division of Reproductive Endocrinology and Infertility of the Mayo Clinic in Rochester, Minnesota, to ascertain whether we could minimize the incidence and severity of ovarian hyperstimulation while maximizing the chances of a successful pregnancy outcome in patients thought to be at risk for OHSS. MATERIALS AND METHODS The medical records of all consecutive patients who underwent fresh IVF cycles between 2000 and 2004 with long luteal gonadotropin-releasing hormone (GnRH) down-regulation protocol were screened. All patients with peak serum E 2 levels of >2500 pg/ml were presumed to be at increased risk for OHSS based on prior clinical observation, and they constituted our study population. Out of a total of 1002 IVF patients, 188 patients were considered to be at increased risk for OHSS. Informed consent was obtained by use of prior authorization for research, and approval was granted by the institutional review board. The data collected from these patients were then analyzed to determine [1] what percentage of patients thought to be at increased risk for OHSS based on their E 2 value of >2500 pg/ml were actually diagnosed with the syndrome, and [2] what the strategies were used to decrease the risk of OHSS and their impact on pregnancy and live birth rates (LBR). Patients with OHSS were also divided into three categories on the basis of symptoms, signs, and limitation of activity. Mild manifestations of OHSS included nausea, vomiting, and diarrhea abdominal discomfort and distension; moderate OHSS included worsening of symptoms, ascites, and ovarian enlargement up to 12 cm; and severe OHSS constituted pain accompanied by rapid weight gain, tense ascites, hemodynamic instability, respiratory difficulty, progressive oliguria, and laboratory abnormalities. Placement of patients in group 1, 2, or 3 was decided with respect to increased symptoms (as described for moderate/severe OHSS). If the symptoms and signs were milder, the patients were in group 1; whereas if the symptoms were more severe, patients were included in group 2. Patients were placed in group 3 when there was an increased level of E 2, increased follicles, and few OHSS symptoms. Statistical analysis was performed using the JMP 9.0 software (SAS Institute, Cary, NC). Analysis of variance was used, and P<.05 was considered statistically significant. RESULTS The overall incidence of OHSS in our study population was 20.2% (38 out of 188). Out of 188 patients, 21 (11.1%) had their cycles coasted (group 1), and elective embryo cryopreservation was done in 32 (17%) patients (group 2). In the remaining 135 (71.8%) patients, who had no risk factors other than a high E 2, ovulation was triggered with hcg, and embryo transfer (ET) was performed (group 3). The decision to coast, cryopreserve, or trigger ovulation was based upon the developing follicles, serum E 2 level, and clinical judgment. The age, infertility diagnosis, and basal level of follicle-stimulating hormone (FSH) of the patients in all the three groups were similar. Peak E 2 levels on the day of hcg injection were also comparable (P>.05, not statistically significant). Although none of the patients in group 1 developed OHSS, 13 out of 32 (40.6%) in group 2 and 25 out of 135 (18.5%) patients in group 3 developed OHSS (Tables 1 and 2). In group 1 (n ¼ 21), coasting was done if E 2 levels were >2500 pg/ml with a large cohort of small developing follicles (>30). The aim was to allow the follicles to develop without stimulating more E 2 production and still permit retrieval. The peak E 2 level was pg/ml, and the mean number of days of coasting was It is our policy to cancel a cycle if a >30% drop in E 2 levels occurs during coasting, but none of the patients in this group had their cycles canceled for this reason. The serum E 2 value on the day of hcg administration was pg/ml. The average number of oocytes retrieved in group 1 was , and embryos were transferred. The biochemical pregnancy rate (BPR) was 52.4%, LBR per ET was 38%, and none of the patients developed OHSS, as determined by clinical symptoms (see Table 1). The embryo cryopreservation group (group 2, n ¼ 32) had a peak E 2 level of pg/ml, and the average number of oocytes retrieved equaled The embryos were then frozen at pronuclear stage for use at a later date (see Table 1). Three out of 32 patients did not undergo frozen embryo transfer (FET); two conceived spontaneously, and one was an overseas patient who was lost to follow-up observation. A total of 55 FETs were performed in 29 patients. On average, each patient underwent FET cycles. The postthaw pronuclear embryo survival rate was 94.2%, and embryos were transferred. The overall LBR per transfer was 40%. The cumulative LBR to date per patient has approached 75%. In this group, 48.2% of the patients (14 out of 29) had a live birth on the first attempt at FET. The mean number of days from retrieval to first FET was 90 38, and by day 581, all patients had used all their frozen embryos (Table 3). Although 13 out of 32 patients developed OHSS in this group, none developed severe OHSS (see Table 2). In the final group (group 3, control, n ¼ 135), who underwent routine stimulation and fresh ET, the peak E 2 level was pg/ml. The average number of oocytes retrieved was , and embryos were transferred. The BPR was 65.9%, and the LBR per ET was 45%. It is interesting that 25 out of 135 (18.5%) patients developed OHSS. Severe OHSS occurred in two patients: one patient developed middle cerebral artery occlusion, and one patient had ovarian torsion (see Tables 1 and 2). DISCUSSION The published incidence of OHSS is 20% to 33 % for mild, 3% to 6 % for moderate, and 0.1% to 2.0% for severe OHSS, and our results agreed with this range (12 14). 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3 TABLE 1 General patient characteristics and pregnancy outcome in three patient groups. Cycles coasted (n [ 21) Cryopreservation of all embryos (n [ 32) Ovulation triggered with subsequent embryo transfer (n [ 135) (control) Age (y) a Serum E 2 on day of hcg (pg/ml) a No. of oocytes retrieved a Embryos transferred (day 3) a BPR 52.4% 63.6% 65.9% a Clinical pregnancy 38% 50.9% 54.8% a LBR 38% (per fresh ET) 40% (per FET) 45% (per fresh ET) Cumulative LBR per patient 52% 75% 59% Notes: BPR ¼ biochemical pregnancy rate; LBR ¼ live birth rate. a P>.05, not statistically significant (analysis of variance). Gera. OHSS: maximizing success, minimizing effect. Fertil Steril incidence in this IVF population was 3.8% (38 out of 1002). It is difficult to define the categories of OHSS because the signs and symptoms exhibit a continuum of severity. We divided our patients with OHSS were divided into three categories on the basis of symptoms, signs, and limitation of activity. Mild manifestations of OHSS included nausea, vomiting, diarrhea, and abdominal discomfort and distension; moderate OHSS included worsening of symptoms, ascites, and ovarian enlargement up to 12 cm; and pain accompanied by rapid weight gain, tense ascites, hemodynamic instability, respiratory difficulty, progressive oliguria, and laboratory abnormalities constituted severe OHSS. Hospital admission alone was not used to define severe OHSS. Although mild OHSS can be managed by monitoring symptoms, the management of the moderate form requires more intensive patient monitoring of daily weight, urine output, abdominal girth charting, and laboratory evaluation for evidence of hemoconcentration as well as serum electrolyte monitoring. Some patients with moderate OHSS may also require hospital admission for pain management, abdominal paracentesis, intravenous rehydration, and prophylactic heparin therapy when clinically indicated (15). Some investigators have advocated albumin administration, but this was not provided for our patients (16). The preferred management of patients with potential for severe OHSS is prevention by early recognition of risk factors and timely management. Selecting one preventive approach for a large cohort of patients undergoing controlled ovarian hyperstimulation is often challenging because the benefits and risks associated with each strategy vary with each individual. At present, cycle cancellation, coasting, and elective embryo cryopreservation continue to be the primary options for OHSS prevention. Newer data suggest that for some patients treatment with cabergoline can also decrease hemoconcentration and ascites by blocking the vascular endothelial growth factor 2 (VEGF-2) receptor (17, 18). TABLE 2 Occurrence of ovarian hyperstimulation syndrome (OHSS) in various patient groups. OHSS Cycles coasted (0/21) Cryopreservation of embryos (13/32) Ovulation triggered with subsequent embryo transfer (25/135) (control) Mild Moderate (outpatient management) Moderate (hospital admission) Paracentesis 2 2 IV hydration þ prophylactic 2 6 heparin therapy Severe Ovarian torsion Gera. OHSS: maximizing success, minimizing effect. Fertil Steril Fertility and Sterility â 175

4 TABLE 3 Characteristics of 55 cryopreserved-thawed embryo-transfer cycles in 29 patients. Characteristic Value No. of FETs Embryos thawed before ET Embryos survived with cleavage Post-thaw survival rate 94.2% Embryos transferred Blastomeres at day 2 ET (n ¼ 54) Blastomeres at blastocyst 100 transfer (n ¼ 1) Grade at ET (0 ¼ highest, ¼ poorest) Days from retrieval to first ET (n ¼ 29) Second ET (n ¼ 15) Third ET (n ¼ 5) Fourth ET (n ¼ 4) Fifth ET (n ¼ 1) 476 Sixth ET (n ¼ 1) 581 BPR 63.6% Clinical pregnancy rate 50.9% Spontaneous abortion rate 10.9% Implantation rate 28% Cumulative LBR per patient 75% Notes: BPR ¼ biochemical pregnancy rate; ET ¼ embryo transfer; FET ¼ frozen embryo transfer; LBR ¼ live birth rate. Gera. OHSS: maximizing success, minimizing effect. Fertil Steril Monitoring the E 2 levels helps in decision making during the IVF cycle to prevent the occurrence of this syndrome. The choice of approach and exact clinical levels are not fixed and may vary from one center to another. Although an E 2 value of 3000 pg/ml has been selected as a safe value for hcg administration in most previous studies (19, 20), severe OHSS has been observed in patients with very low E 2 levels of 475 pg/ml (7). Based on previous clinical experience of IVF-ET at our center, a cutoff level of 2500 pg/ml was selected for patients during the study period who needed admission and aggressive therapy for OHSS prevention and treatment. The literature supports increased concern for OHSS when advancing levels of E 2 are observed, and the American Society for Reproductive Medicine (ASRM) Practice Committee recommends caution when the E 2 level is in excess of 2500 pg/ml as this indicates an increasing risk of OHSS (15). TheE 2 levels may be relative to the laboratory and the assay used. There could be a selection bias in our study as the decision to coast, cryopreserve, or trigger ovulation was based upon the developing follicles, serum E 2 level, and clinical judgment. Those patients who seemed to be at little clinical risk for development of OHSS were triggered and went to retrieval and ET, and those who were more symptomatic and were suspected to be at risk of developing OHSS were offered elective embryo cryopreservation or cycle coasting. Selection bias may have been at play in each IVF center as each group observed their patients, decided which patients were at risk, and developed subsequent treatment options for them. Prospective randomized studies are needed to assess outcome differentials and overcome this bias. Cycle cancellation can eliminate the risk for developing OHSS completely, as has been noted by others (2, 9), but at the same time it also eliminates the chance of a pregnancy in that cycle. The cost burden and the psychological impact of a canceled cycle are immense. None of the 188 patients in our study had their cycles canceled to prevent OHSS. Coasting by withholding gonadotropins is an effective method to reduce the incidence of OHSS. The E 2 levels at which coasting was initiated ranged between 2500 and 3500 pg/ml in most of the previous studies (20 22). We started coasting in our IVF cycles when the E 2 levels were >2500 pg/ml with >30 small developing follicles. This low cutoff level allowed for a low number of days required to coast ( ) while maintaining a LBR of 38%. Also, a study by Ulug et al. (23) found reduced implantation and pregnancy rates in cycles coasted for R4 days. They started coasting when either E 2 levels were >4000 pg/ml or there were at least 20 follicles of 10 mm diameter with 20% >15 mm present. Another recent study has supported good pregnancy results with coasting of 1 to 2 days (22); a longer duration of coasting seemed to affect the endometrial receptivity or its synchronization with embryonic age. The incidence of severe OHSS has been found to be low in high-risk patients who had their cycles coasted (21, 22, 24). In a study by Dhont et al. (25), 120 women considered to be at risk for OHSS were coasted when their serum E 2 levels exceeded 2500 pg/ml, and hcg was administered when the E 2 levels were <2500 pg/ml. When compared with 120 matched OHSS high-risk patients with noncoasted cycles, the study found that coasting significantly decreased the incidence of both moderate and severe OHSS (24). These studies are in agreement with ours. In our study, no coasted cycles resulted in cancellation, and none of these patients developed OHSS. However, coasting does appear to be associated with a reduced oocyte collection rate. The oocyte quality and endometrial receptivity in a coasted cycle are still a matter of debate. A reduction in the number and quality of oocytes retrieved in a coasted cycle has been reported by a large number of studies (23, 26). In our study, the average number of oocytes retrieved was in the coasted group versus in the elective embryo cryopreservation group versus in the no-intervention group (P>.05, not statistically significant). The numbers were not statistically significant among the three groups, but the trend toward increased embryos has 176 Gera et al. OHSS: maximizing success, minimizing effect Vol. 94, No. 1, June 2010

5 been a powerful factor in guiding clinical practice where the aim is to achieve maximum results without compromising patient health. Elective embryo cryopreservation is one of several options that may decrease the risk of OHSS by avoiding exposure to exogenous and endogenous hcg while preserving the chance for live birth. Elective embryo cryopreservation has been recommended when there is the highest concern for development of severe or critical OHSS. The highest mean peak E 2 of pg/ml was seen in group 2. Elective freezing of all embryos not only reduced the expected incidence of OHSS in these high-risk patients, it also reduced the duration and severity of the syndrome. Six out of 32 (18.7%) patients had symptoms consistent with mild form of OHSS, and 3 out of 32 (9.3%) were managed on an outpatient basis with careful monitoring of weight, abdominal girth, urine output, and hematologic parameters. There were 2 out of 32 (6.2%) hospital admissions for paracentesis and 2 out of 32 (6.2%) for intravenous rehydration and prophylactic heparin therapy. None of the patients developed severe OHSS. Wada et al. (26) reported 27% incidence of OHSS after retrieval and cryopreservation, with severe syndrome occurring in 7%. Our results had lower incidence with a similar severe group. As pointed out by Queenan et al. (27), the pregnancy potential of the frozen embryos from hyperstimulated cycles is equal to that of the standard thawed ET. Ninety-four percent of our embryos survived the freeze-thaw process in the pronuclear phase (unpublished data). Fourteen out of 29 patients had a live birth after first FET in our study, and 15 patients had retreatment with a second FET. Six out of 15 patients had a live birth after the second FET. A third FET was performed in five patients out of whom one had a live birth. Four patients proceeded to fourth FET that resulted in one live birth. One patient had a fifth and a sixth FET but no live birth. From the data reviewed, it was difficult to determine what aspects of patient selection or embryo quality might have contributed to this result. The cumulative LBR was 52%; 75%, and 59% for coasting, freeze-all, and no action, respectively. These findings are consistent with our previous experience with embryo cryopreservation as reported by Tummon et al. (11) in The cryopreserved-thawed embryos show high survival, cleavage, and implantation rates. Queenan et al. (28) in a study of 15 patients at risk for OHSS showed that cryopreservation of all embryos with subsequent transfer resulted in an ongoing pregnancy rate of 67% per patient. Four patients developed OHSS in their study. Ferrareti et al. (29) did a prospective randomized study of 125 patients at risk of developing OHSS. All patients had a serum E 2 level of R1500 pg/ml on the day of hcg administration, and >15 oocytes were collected. The patients were divided in two groups with fresh ET in group 1 (n ¼ 67) and elective cryopreservation in group 2 (n ¼ 58). There were no differences in pregnancy and LBR rates between the two groups. Four patients developed OHSS in group 1 and none in group 2. Thus, cryopreservation of all embryos seemed to benefit these patients. In group 3 of our study, the peak serum E 2 level was pg/ml, and the patients had no other symptoms or signs; hcg injection was given with patient consent. The LBR was 45% in this group; 25 out of 135 patients developed OHSS. There were eight hospital admissions primarily for paracentesis, intravenous rehydration, and prophylactic heparin therapy. Severe OHSS occurred in two patients, with middle cerebral artery occlusion in one woman and ovarian torsion in another (which required surgery to save the ovary). The occurrence of middle cerebral artery occlusion as a complication of controlled ovarian hyperstimulation is a rare event, so we report it as such. The peak serum E 2 level on the day of hcg in this patient was 2852 pg/ml, 16 oocytes were retrieved, and three embryos were transferred (30). It seems that the E 2 level would not have predicted this complication. Because of the life-threatening nature of this catastrophic event, it is imperative to recognize and treat this complication of severe OHSS as early as possible. Anticoagulation therapy has remained the mainstay of treatment, with tissue plasminogen activator and heparin as the main agents (30). Early discontinuation of pregnancy may also be considered in selected patients to prevent progression of OHSS. The risk of adnexal torsion also is increased in hyperstimulated patients due to bilaterally enlarged ovaries with multiple follicular or luetin cysts. It should be suspected in every patient who has nausea, fever, and sudden onset abdominal pain as well as an increased white blood cell count. Conservative treatment with simple reduction of the torsion of the twisted adnexa results in optimum preservation of ovarian function and future fertility. CONCLUSION The morbidity associated with mild and moderate OHSS, the life-threatening nature of severe OHSS, and the cost involved in hospitalization of patients with controlled ovarian hyperstimulation complications are substantial; thus, we conclude that elective cryopreservation of embryos with subsequent FET is an effective way of maximizing pregnancy and limiting severe OHSS. The pregnancy potential of the frozen embryos remains excellent, and the cumulative LBR surpasses that achieved by coasting in a cycle. Although each of these strategies has been effective in reducing the chance for OHSS and may be used effectively for differing clinical cases, cryopreservation of embryos with subsequent FET offers a higher cumulative pregnancy rate as compared to coasting. 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