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Prevention of severe ovarian hyperstimulation by coasting
FERTILITY AND STERILITYt VOL. 70, NO. 5, NOVEMBER 1998 Copyright ©1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Prevention of severe ovarian hyperstimulation by coasting Marc Dhont, M.D., Frauke Van der Straeten, M.D., and Paul De Sutter, M.D. Department of Obstetrics and Gynaecology, University Hospital, Ghent, Belgium
Objective: To evaluate the efficiency of withholding gonadotropins and deferring the administration of hCG until E2 levels start dropping (coasting) in the prevention of ovarian hyperstimulation syndrome (OHSS) in a high-risk population. Design: Retrospective case-control study. Setting: In vitro fertilization program at a university center. Patient(s): The case group consisted of 120 women undergoing ovarian stimulation for IVF who were considered to be at risk for ovarian hyperstimulation (serum E2 levels .2,500 pg/mL or .20 follicles at the time of hCG administration). Intervention(s): Gonadotropin administration was withheld when serum E2 levels exceeded 2,500 pg/mL, and hCG administration was delayed until E2 levels dropped below 2,500 pg/mL. Outcomes were compared with those from 120 matched patients in whom serum E2 levels and the number of follicles at the time of hCG administration were comparable to those at the beginning of coasting (control group). Main Outcome Measure(s): Incidence of moderate and severe OHSS. The number of oocytes retrieved and pregnancy rate (PR) were compared in both groups. Result(s): Coasting decreased the incidence of moderate and severe OHSS. The odds ratio of severe OHSS in the coasting group was 0.11 (95% confidence interval 0.01– 0.86). Although the number of oocytes was significantly lower in the coasting group (19.7 6 0.6 versus 22.1 6 0.6), coasting did not affect the PR (37.5% versus 36.7%). Conclusion(s): Our study indicates that coasting is an efficient method for reducing the incidence and severity of OHSS without compromising the PR. (Fertil Sterilt 1998;70:847–50. ©1998 by American Society for Reproductive Medicine.) Key Words: OHSS, coasting, IVF, gonadotropins, GnRH agonists
Received February 27, 1998; revised and accepted June 10, 1998. Reprint requests: Marc Dhont, M.D., University Hospital, De Pintelaan 185, B-9000 Gent, Belgium (FAX: 32-9-240-3831). 0015-0282/98/$19.00 PII S0015-0282(98)00280-5
The ovarian hyperstimulation syndrome (OHSS) is a common complication in patients undergoing gonadotropin stimulation for IVFET, and the severe form is estimated to occur in about 0.5% of patients (1). Several curative methods have been suggested, but prevention is the most important step to consider. However, despite the fact that much is known about the pathogenesis of OHSS, there is still no fail-safe method available for its prediction and complete prevention. Withholding hCG administration and cancelling oocyte pick-up is the most efficient method of preventing OHSS, but it can have considerable financial and emotional costs for the patient. Several less drastic preventive measures have been proposed, but none of them appear to be fully satisfying. Sher et al. (2) described “prolonged” coasting in 17 patients at risk of OHSS. They stopped hMG administration in patients with E2 levels of .6,000 pg/mL and .30 follicles and deferred hCG administration until the
plasma E2 concentration dropped below 3,000 pg/mL while continuing the administration of GnRH agonists. Although signs or symptoms of grade 2 or 3 OHSS developed in all their patients, there were no severe complications. From 1994 until 1996, during which period nearly 2,000 IVF cycles were performed in our center, we used coasting as the only measure to prevent OHSS. With the use of this method, no IVF cycles had to be cancelled and the pregnancy rate (PR) remained unchanged. To confirm the efficacy of coasting, we performed a case-control study in which we matched every case with a “non-coasted” IVF patient who had comparable risk factors. The aim of our study was to compare the incidence of moderate and severe OHSS in high-risk patients who underwent coasting with that in a matched series of patients who were at a comparable risk of OHSS. In addition, we investigated whether PRs were affected by coasting. 847
MATERIALS AND METHODS All patients underwent an IVF treatment at the Infertility Center at the University Hospital in Ghent, Belgium. All procedures pertaining to the clinical aspects of IVF were approved by the institutional review board. Ovarian stimulation was performed with the use of a combination of a GnRH agonist (Decapeptyl; Ipsen Biotech, France), 0.1 mg SC, and an individually adjusted hMG regimen in a short protocol, usually starting with 3 ampules of hMG (Humegon; Organon, Oss, the Netherlands), 75 IU IM. Stimulation was continued until at least one half of the follicles reached a mean diameter of 20 mm, at which time a single dose of 10,000 IU of hCG (Pregnyl; Organon) was injected. When E2 levels were .2,500 pg/mL in the presence of at least 20 follicles, hMG administration was discontinued. The serum E2 level subsequently was determined every morning until it dropped below 2,500 pg/mL, at which time hCG was given. Between December 1993 and January 1997, 120 patients met the criteria for coasting and were treated accordingly. The duration of the coasting period varied from 1– 6 days (mean, 1.94 days). Serum E2 concentrations were determined with the use of a commercially available RIA kit (BioMe´rieux, France). The luteal phase was supported by IM progesterone (50 mg/d) or intravaginal progesterone (600 mg/d) because it is well established that additional hCG to support the luteal phase is associated with a higher incidence of OHSS. A control group was selected from patients who had been stimulated for IVF before coasting had been introduced between 1989 and 1993 (n 5 120). The main difference in the treatment protocol of the control group was that, in most of the patients, stimulation was performed with the use of a long protocol (goserelin; Zeneca, Belgium), starting with four ampules per day after complete pituitary desensitization was obtained. The luteal phase also was supported by IM progesterone (50 mg/d) in all patients who had .20 mature follicles. All controls were matched with patients from the coasting group as closely as possible for the number of follicles and the E2 level at the time of hCG administration. The outcome parameters were the mean number of oocytes, the yield of oocytes per follicle, oocyte maturity, the number of embryos transferred, the incidence of OHSS, PRs, implantation rates, and progesterone levels in the luteal phase. We used the classification of OHSS described by Schenker and Weinstein (3). The three main categories of OHSS (mild, moderate, and severe) are determined on the basis of clinical symptoms and ultrasonographic and laboratory findings. Because mild forms of OHSS are frequently unnoticed, we only registered the incidence of moderate and severe OHSS. The symptoms of moderate OHSS include abdominal heaviness, tension and pain, ascites, nausea, and vomiting. 848
Dhont et al.
Communications-in-brief
TABLE 1 Hormonal and IVF data for the coasting and control groups. Hormonal and IVF data Age (y) Maximum level of E2 (pg/mL) Level of E2 on day of hCG administration (pg/mL) No. of follicles E2 level per follicle (pg/mL) No. of oocytes* Oocyte yield per follicle (%)* No. of mature oocytes* No. of embryos transferred* Incidence of OHSS (%)† (moderate and severe) No. of patients with severe OHSS Median duration of hospitalization in d (range) Pregnancy rate (%) Proportion of twins (%) Implantation rate (%) Level of progesterone in the luteal phase (ng/mL)
Coasting group (n 5 120)
Control group (n 5 120)
30.2 6 0.4 3,834.3 6 79.6 2,348.5 6 43.1
30.4 6 0.4 3,833.3 6 79.2 3,833.3 6 79.2
24.5 6 0.7 170.5 6 5.8 19.7 6 0.6 80.5 18.5 6 0.7 2.3 6 0.1 5.8
24.7 6 0.7 167.0 6 5.1 22.1 6 0.6 89.5 20.5 6 0.7 2.9 6 0.1 18.3
1
9
5
7 (3–18)
37.5 20.5 20.0 150.0 6 8.9
36.7 27.3 17.0 137.6 6 10.5
Note: All values are means 6 SE unless otherwise indicated. *P,.05. † P,.01.
Severe OHSS is always associated with clinical and laboratory signs of hypovolemia and sometimes with hepatorenal functional disturbance, electrolyte imbalance, and respiratory problems due to pleural effusion. Patients who required hospitalization were considered to have severe OHSS. Indications for hospitalization were gross abdominal discomfort due to ascites and/or signs of hemoconcentration (hematocrit .45% and/or reduced diuresis). Statistical analysis was performed with the use of the statistical package Statistica Anova Manova. We compared the different parameters between the case group and the control group with the use of the Mann-Whitney U test and the Student’s t-test. For comparison of proportions, we used Fisher’s exact test.
RESULTS The duration of coasting was a mean (6SD) of 1.9 6 0.8 days. A comparison of all relevant data between the case and control groups is given in Table 1. Estradiol levels at the moment that coasting was started were comparable to E2 levels at the time hCG was given to the control patients (mean [6SD], 3,834.3 6 872.3 pg/mL versus 3,833.6 6 867.6 pg/mL). The mean (6SD) level of E2 at the time hCG was given in the case group was 2,348.5 6 472.2 pg/mL. Vol. 70, No. 5, November 1998
The mean (6SD) number of follicles with a diameter of .15 mm was comparable in both groups (24.5 6 7.3 in the case group and 24.7 6 7.1 in the control group). The mean (6SD) number of retrieved oocytes was significantly lower in the case group (19.7 6 6.4 versus 22.1 6 6.8; P,.05). There was no statistically significant difference, however, in oocyte maturity (93.6% of the retrieved oocytes in the coasting group were mature versus 93.2% in the control group). The mean (6SD) number of embryos transferred was 2.3 6 0.8 and 2.9 6 1.2 in the coasting group and the control group, respectively. This statistically significant difference is due to the fact that in recent years we have transferred two embryos. The PRs per cycle were 37.5% and 36.7%, respectively, in the coasting and control groups, whereas the overall PRs per cycle during the coasting and control periods were 34.1% and 30.9%, respectively. The implantation rates also were similar (20% in the case group versus 17% in the control group). Progesterone levels during the luteal phase were not different. The incidence of moderate and severe OHSS was 5.8% in the coasting group versus 18.3% in the control group (P,.005; odds ratio [OR] 0.27, 95% confidence interval [CI] 0.11– 0.67). Only one patient in the coasting group had to be hospitalized because of severe OHSS, whereas nine patients in the control group required hospitalization (P,.01; OR 0.11, 95% CI 0.01– 0.86). No case of moderate or severe OHSS was recorded in the remainder of the patients who did not meet the criteria of coasting. Hence, the overall incidence of moderate and severe OHSS during this period was 0.4% compared with 1.7% during the previous period.
DISCUSSION Several procedures to prevent hyperstimulation short of cancelling the cycle have been proposed. A few reports have indicated that withholding gonadotropin stimulation for 1 or more days can prevent severe OHSS (3, 4). The results of our large case-control study confirm that coasting is a valuable method for reducing the incidence and severity of OHSS in patients at risk. The fact that the control group was treated during a different period than the case group might seem to be a methodologic limitation of this study, but it does not invalidate its conclusions for several reasons. Patients from both groups were matched for the main determinants of the risk for OHSS (i.e., the number of follicles and the E2 level), PRs and luteal support in both groups were comparable, and the definition and treatment of moderate and severe OHSS did not change during the two periods. Several cut-off levels for the number of follicles and the serum E2 level used to predict severe OHSS have been proposed. The threshold we selected for coasting (E2 .2,500 pg/mL and/or .20 follicles) is rather low. However, the fact that moderate to severe hyperstimulation did not develop in any of the patients who were not considered to be at risk FERTILITY & STERILITYt
proves the high specificity of the selected cut-off levels. Premature reduction of the dose of hMG can lead to complete arrest of follicular maturation. It is therefore important to start coasting only after a number of follicles have reached maturity. The reasons why coasting is effective in preventing OHSS are speculative. Although high estrogen levels are associated with OHSS, it is unlikely that they are causally involved in its development. Hence, reduction of E2 levels in itself is not the main goal of coasting. Although our study does not clarify how long stimulation can be interrupted before oocytes from mature follicles will be lost, there is evidence that the window for collecting fertilizable oocytes from mature follicles can be extended up to 6 days. We also cannot determine from our data whether waiting for a more substantial and/or prolonged drop of E2 levels would have been more successful in preventing OHSS without compromising the PR. In patients in whom coasting lasted for .2 days, E2 levels initially increased before dropping, notwithstanding the fact that the endogenous secretion of gonadotropins was suppressed by the cotreatment with a GnRH agonist. This illustrates that at least dominant follicles can continue their growth in the face of a virtually absent stimulus, whereas intermediate follicles will undergo atresia. This presumably is one of the reasons for the efficacy of coasting in preventing OHSS. From ovulation induction with gonadotropins in patients with polycystic ovary syndrome, it is well known that the number of intermediate but growing follicles at the time of hCG administration predicts the risk of subsequent OHSS. Whether the dominant follicles that have been starved for a few days also have a reduced expression of the presumed mediators of OHSS is an interesting topic for further investigation. We would have expected the maturity of retrieved oocytes to have been higher in the coasting group, but our results do not show a statistically significant difference. Despite the decreased number of retrieved oocytes, the PR was not compromised. The PR was 37.5% in the coasting group and 36.7% in the control group, despite the fact that we transferred significantly fewer embryos in the coasting group. This is due to a deliberate policy of restricting the number of transferred embryos in recent years. Moderate and severe OHSS occurred more frequently in the control group. This is of particular relevance for the incidence of severe OHSS. Only one patient in the coasting group was hospitalized with severe OHSS, in contrast with nine patients in the control group; thus, the overall incidence of severe OHSS in our IVF-ET program declined to ,0.1% after coasting was introduced. In conclusion, this case-control study demonstrates that coasting is the treatment of choice in patients at risk for 849
OHSS because it reduces the incidence of OHSS without compromising the PR. References 1. Forman RG, Frydman R, Egan D. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990;53:502–9.
850
Dhont et al.
Communications-in-brief
2. Sher G, Zouves C, Feinman M, Maassarani G. “Prolonged coasting”: an effective method for preventing severe ovarian hyperstimulation syndrome in patients undergoing in-vitro fertilization. Hum Reprod 1995; 10:3107–9. 3. Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1978;30:255– 68. 4. 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.
Vol. 70, No. 5, November 1998
Prevention of severe ovarian hyperstimulation by coasting Marc Dhont, M.D., Frauke Van der Straeten, M.D., and Paul De Sutter, M.D. Department of Obstetrics and Gynaecology, University Hospital, Ghent, Belgium
Objective: To evaluate the efficiency of withholding gonadotropins and deferring the administration of hCG until E2 levels start dropping (coasting) in the prevention of ovarian hyperstimulation syndrome (OHSS) in a high-risk population. Design: Retrospective case-control study. Setting: In vitro fertilization program at a university center. Patient(s): The case group consisted of 120 women undergoing ovarian stimulation for IVF who were considered to be at risk for ovarian hyperstimulation (serum E2 levels .2,500 pg/mL or .20 follicles at the time of hCG administration). Intervention(s): Gonadotropin administration was withheld when serum E2 levels exceeded 2,500 pg/mL, and hCG administration was delayed until E2 levels dropped below 2,500 pg/mL. Outcomes were compared with those from 120 matched patients in whom serum E2 levels and the number of follicles at the time of hCG administration were comparable to those at the beginning of coasting (control group). Main Outcome Measure(s): Incidence of moderate and severe OHSS. The number of oocytes retrieved and pregnancy rate (PR) were compared in both groups. Result(s): Coasting decreased the incidence of moderate and severe OHSS. The odds ratio of severe OHSS in the coasting group was 0.11 (95% confidence interval 0.01– 0.86). Although the number of oocytes was significantly lower in the coasting group (19.7 6 0.6 versus 22.1 6 0.6), coasting did not affect the PR (37.5% versus 36.7%). Conclusion(s): Our study indicates that coasting is an efficient method for reducing the incidence and severity of OHSS without compromising the PR. (Fertil Sterilt 1998;70:847–50. ©1998 by American Society for Reproductive Medicine.) Key Words: OHSS, coasting, IVF, gonadotropins, GnRH agonists
Received February 27, 1998; revised and accepted June 10, 1998. Reprint requests: Marc Dhont, M.D., University Hospital, De Pintelaan 185, B-9000 Gent, Belgium (FAX: 32-9-240-3831). 0015-0282/98/$19.00 PII S0015-0282(98)00280-5
The ovarian hyperstimulation syndrome (OHSS) is a common complication in patients undergoing gonadotropin stimulation for IVFET, and the severe form is estimated to occur in about 0.5% of patients (1). Several curative methods have been suggested, but prevention is the most important step to consider. However, despite the fact that much is known about the pathogenesis of OHSS, there is still no fail-safe method available for its prediction and complete prevention. Withholding hCG administration and cancelling oocyte pick-up is the most efficient method of preventing OHSS, but it can have considerable financial and emotional costs for the patient. Several less drastic preventive measures have been proposed, but none of them appear to be fully satisfying. Sher et al. (2) described “prolonged” coasting in 17 patients at risk of OHSS. They stopped hMG administration in patients with E2 levels of .6,000 pg/mL and .30 follicles and deferred hCG administration until the
plasma E2 concentration dropped below 3,000 pg/mL while continuing the administration of GnRH agonists. Although signs or symptoms of grade 2 or 3 OHSS developed in all their patients, there were no severe complications. From 1994 until 1996, during which period nearly 2,000 IVF cycles were performed in our center, we used coasting as the only measure to prevent OHSS. With the use of this method, no IVF cycles had to be cancelled and the pregnancy rate (PR) remained unchanged. To confirm the efficacy of coasting, we performed a case-control study in which we matched every case with a “non-coasted” IVF patient who had comparable risk factors. The aim of our study was to compare the incidence of moderate and severe OHSS in high-risk patients who underwent coasting with that in a matched series of patients who were at a comparable risk of OHSS. In addition, we investigated whether PRs were affected by coasting. 847
MATERIALS AND METHODS All patients underwent an IVF treatment at the Infertility Center at the University Hospital in Ghent, Belgium. All procedures pertaining to the clinical aspects of IVF were approved by the institutional review board. Ovarian stimulation was performed with the use of a combination of a GnRH agonist (Decapeptyl; Ipsen Biotech, France), 0.1 mg SC, and an individually adjusted hMG regimen in a short protocol, usually starting with 3 ampules of hMG (Humegon; Organon, Oss, the Netherlands), 75 IU IM. Stimulation was continued until at least one half of the follicles reached a mean diameter of 20 mm, at which time a single dose of 10,000 IU of hCG (Pregnyl; Organon) was injected. When E2 levels were .2,500 pg/mL in the presence of at least 20 follicles, hMG administration was discontinued. The serum E2 level subsequently was determined every morning until it dropped below 2,500 pg/mL, at which time hCG was given. Between December 1993 and January 1997, 120 patients met the criteria for coasting and were treated accordingly. The duration of the coasting period varied from 1– 6 days (mean, 1.94 days). Serum E2 concentrations were determined with the use of a commercially available RIA kit (BioMe´rieux, France). The luteal phase was supported by IM progesterone (50 mg/d) or intravaginal progesterone (600 mg/d) because it is well established that additional hCG to support the luteal phase is associated with a higher incidence of OHSS. A control group was selected from patients who had been stimulated for IVF before coasting had been introduced between 1989 and 1993 (n 5 120). The main difference in the treatment protocol of the control group was that, in most of the patients, stimulation was performed with the use of a long protocol (goserelin; Zeneca, Belgium), starting with four ampules per day after complete pituitary desensitization was obtained. The luteal phase also was supported by IM progesterone (50 mg/d) in all patients who had .20 mature follicles. All controls were matched with patients from the coasting group as closely as possible for the number of follicles and the E2 level at the time of hCG administration. The outcome parameters were the mean number of oocytes, the yield of oocytes per follicle, oocyte maturity, the number of embryos transferred, the incidence of OHSS, PRs, implantation rates, and progesterone levels in the luteal phase. We used the classification of OHSS described by Schenker and Weinstein (3). The three main categories of OHSS (mild, moderate, and severe) are determined on the basis of clinical symptoms and ultrasonographic and laboratory findings. Because mild forms of OHSS are frequently unnoticed, we only registered the incidence of moderate and severe OHSS. The symptoms of moderate OHSS include abdominal heaviness, tension and pain, ascites, nausea, and vomiting. 848
Dhont et al.
Communications-in-brief
TABLE 1 Hormonal and IVF data for the coasting and control groups. Hormonal and IVF data Age (y) Maximum level of E2 (pg/mL) Level of E2 on day of hCG administration (pg/mL) No. of follicles E2 level per follicle (pg/mL) No. of oocytes* Oocyte yield per follicle (%)* No. of mature oocytes* No. of embryos transferred* Incidence of OHSS (%)† (moderate and severe) No. of patients with severe OHSS Median duration of hospitalization in d (range) Pregnancy rate (%) Proportion of twins (%) Implantation rate (%) Level of progesterone in the luteal phase (ng/mL)
Coasting group (n 5 120)
Control group (n 5 120)
30.2 6 0.4 3,834.3 6 79.6 2,348.5 6 43.1
30.4 6 0.4 3,833.3 6 79.2 3,833.3 6 79.2
24.5 6 0.7 170.5 6 5.8 19.7 6 0.6 80.5 18.5 6 0.7 2.3 6 0.1 5.8
24.7 6 0.7 167.0 6 5.1 22.1 6 0.6 89.5 20.5 6 0.7 2.9 6 0.1 18.3
1
9
5
7 (3–18)
37.5 20.5 20.0 150.0 6 8.9
36.7 27.3 17.0 137.6 6 10.5
Note: All values are means 6 SE unless otherwise indicated. *P,.05. † P,.01.
Severe OHSS is always associated with clinical and laboratory signs of hypovolemia and sometimes with hepatorenal functional disturbance, electrolyte imbalance, and respiratory problems due to pleural effusion. Patients who required hospitalization were considered to have severe OHSS. Indications for hospitalization were gross abdominal discomfort due to ascites and/or signs of hemoconcentration (hematocrit .45% and/or reduced diuresis). Statistical analysis was performed with the use of the statistical package Statistica Anova Manova. We compared the different parameters between the case group and the control group with the use of the Mann-Whitney U test and the Student’s t-test. For comparison of proportions, we used Fisher’s exact test.
RESULTS The duration of coasting was a mean (6SD) of 1.9 6 0.8 days. A comparison of all relevant data between the case and control groups is given in Table 1. Estradiol levels at the moment that coasting was started were comparable to E2 levels at the time hCG was given to the control patients (mean [6SD], 3,834.3 6 872.3 pg/mL versus 3,833.6 6 867.6 pg/mL). The mean (6SD) level of E2 at the time hCG was given in the case group was 2,348.5 6 472.2 pg/mL. Vol. 70, No. 5, November 1998
The mean (6SD) number of follicles with a diameter of .15 mm was comparable in both groups (24.5 6 7.3 in the case group and 24.7 6 7.1 in the control group). The mean (6SD) number of retrieved oocytes was significantly lower in the case group (19.7 6 6.4 versus 22.1 6 6.8; P,.05). There was no statistically significant difference, however, in oocyte maturity (93.6% of the retrieved oocytes in the coasting group were mature versus 93.2% in the control group). The mean (6SD) number of embryos transferred was 2.3 6 0.8 and 2.9 6 1.2 in the coasting group and the control group, respectively. This statistically significant difference is due to the fact that in recent years we have transferred two embryos. The PRs per cycle were 37.5% and 36.7%, respectively, in the coasting and control groups, whereas the overall PRs per cycle during the coasting and control periods were 34.1% and 30.9%, respectively. The implantation rates also were similar (20% in the case group versus 17% in the control group). Progesterone levels during the luteal phase were not different. The incidence of moderate and severe OHSS was 5.8% in the coasting group versus 18.3% in the control group (P,.005; odds ratio [OR] 0.27, 95% confidence interval [CI] 0.11– 0.67). Only one patient in the coasting group had to be hospitalized because of severe OHSS, whereas nine patients in the control group required hospitalization (P,.01; OR 0.11, 95% CI 0.01– 0.86). No case of moderate or severe OHSS was recorded in the remainder of the patients who did not meet the criteria of coasting. Hence, the overall incidence of moderate and severe OHSS during this period was 0.4% compared with 1.7% during the previous period.
DISCUSSION Several procedures to prevent hyperstimulation short of cancelling the cycle have been proposed. A few reports have indicated that withholding gonadotropin stimulation for 1 or more days can prevent severe OHSS (3, 4). The results of our large case-control study confirm that coasting is a valuable method for reducing the incidence and severity of OHSS in patients at risk. The fact that the control group was treated during a different period than the case group might seem to be a methodologic limitation of this study, but it does not invalidate its conclusions for several reasons. Patients from both groups were matched for the main determinants of the risk for OHSS (i.e., the number of follicles and the E2 level), PRs and luteal support in both groups were comparable, and the definition and treatment of moderate and severe OHSS did not change during the two periods. Several cut-off levels for the number of follicles and the serum E2 level used to predict severe OHSS have been proposed. The threshold we selected for coasting (E2 .2,500 pg/mL and/or .20 follicles) is rather low. However, the fact that moderate to severe hyperstimulation did not develop in any of the patients who were not considered to be at risk FERTILITY & STERILITYt
proves the high specificity of the selected cut-off levels. Premature reduction of the dose of hMG can lead to complete arrest of follicular maturation. It is therefore important to start coasting only after a number of follicles have reached maturity. The reasons why coasting is effective in preventing OHSS are speculative. Although high estrogen levels are associated with OHSS, it is unlikely that they are causally involved in its development. Hence, reduction of E2 levels in itself is not the main goal of coasting. Although our study does not clarify how long stimulation can be interrupted before oocytes from mature follicles will be lost, there is evidence that the window for collecting fertilizable oocytes from mature follicles can be extended up to 6 days. We also cannot determine from our data whether waiting for a more substantial and/or prolonged drop of E2 levels would have been more successful in preventing OHSS without compromising the PR. In patients in whom coasting lasted for .2 days, E2 levels initially increased before dropping, notwithstanding the fact that the endogenous secretion of gonadotropins was suppressed by the cotreatment with a GnRH agonist. This illustrates that at least dominant follicles can continue their growth in the face of a virtually absent stimulus, whereas intermediate follicles will undergo atresia. This presumably is one of the reasons for the efficacy of coasting in preventing OHSS. From ovulation induction with gonadotropins in patients with polycystic ovary syndrome, it is well known that the number of intermediate but growing follicles at the time of hCG administration predicts the risk of subsequent OHSS. Whether the dominant follicles that have been starved for a few days also have a reduced expression of the presumed mediators of OHSS is an interesting topic for further investigation. We would have expected the maturity of retrieved oocytes to have been higher in the coasting group, but our results do not show a statistically significant difference. Despite the decreased number of retrieved oocytes, the PR was not compromised. The PR was 37.5% in the coasting group and 36.7% in the control group, despite the fact that we transferred significantly fewer embryos in the coasting group. This is due to a deliberate policy of restricting the number of transferred embryos in recent years. Moderate and severe OHSS occurred more frequently in the control group. This is of particular relevance for the incidence of severe OHSS. Only one patient in the coasting group was hospitalized with severe OHSS, in contrast with nine patients in the control group; thus, the overall incidence of severe OHSS in our IVF-ET program declined to ,0.1% after coasting was introduced. In conclusion, this case-control study demonstrates that coasting is the treatment of choice in patients at risk for 849
OHSS because it reduces the incidence of OHSS without compromising the PR. References 1. Forman RG, Frydman R, Egan D. Severe ovarian hyperstimulation syndrome using agonists of gonadotropin releasing hormone for in vitro fertilization: a European series and a proposal for prevention. Fertil Steril 1990;53:502–9.
850
Dhont et al.
Communications-in-brief
2. Sher G, Zouves C, Feinman M, Maassarani G. “Prolonged coasting”: an effective method for preventing severe ovarian hyperstimulation syndrome in patients undergoing in-vitro fertilization. Hum Reprod 1995; 10:3107–9. 3. Schenker JG, Weinstein D. Ovarian hyperstimulation syndrome: a current survey. Fertil Steril 1978;30:255– 68. 4. 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.
Vol. 70, No. 5, November 1998