Human Reproduction vol.7 no.5 pp.597-600, 1992
In-vitro fertilization and the ovarian hyperstimulation syndrome
MJ.MacDougaU1-2, S.L.Tan1-3 and H.S.Jacobs2 'The Hallam Medical Centre, 112 Harley Street, London WIN 8AA, 2Department of Reproductive Endocrinology, The Middlesex Hospital, Mortimer Street, London WIN 1AF and 3 Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, UK •'To whom correspondence should be addressed
Eight patients who developed severe ovarian hyperstimulation syndrome (OHSS) were identified among 1302 patients undergoing in-vitro fertilization (IVF) over a 1 year period (prevalence of 0.6%); 63% had uttrasonically diagnosed polycystic ovaries (PCO) and 75% were undergoing their first attempt at IVF. Pretreatment with a superactive luteinizing hormone-releasing hormone (LHRH) analogue significantly increased the prevalence of severe OHSS (1.1% versus 0.2%, P < 0.05) compared with ovarian stimulation with clomiphene citrate and human menopausal gonadotrophin (HMG). The mean serum oestradiol concentration on the day of human chorionk gonadotrophin (HCG) administration was 8200 ± 2300 pmol/1. A mean of 19.6 ± 6.8 follicles had been aspirated and 13.1 ± 7.7 oocytes recovered at transvaginal ultrasound-directed oocyte recovery. All patients had an embryo transfer and luteal support in the form of HCG. The clinical pregnancy rate was 88%, multiple pregnancy rate 71% and implantation rate 63.5 ± 41.3%. In a group of seven patients who were hospitalized for moderate OHSS during the same period, peak oestradiol levels were significantly lower than in those with severe OHSS (P < 0.05). Of the group with moderate OHSS, 57% had PCO, the clinical pregnancy rate was 100% and multiple pregnancy rate 43%. Patients with ultrasound-diagnosed PCO have an increased risk of developing OHSS and the dose of HMG administered to them should be minimized. In patients at risk of developing OHSS, progesterone instead of HCG should be used for luteal support. Transfer of a maximum of two embryos or freezing all embryos for transfer in a subsequent cycle may reduce the likelihood of multiple pregnancy. Key words: in-vitro fertilization/ovarian hyperstimulation syndrome/polycystic ovaries
Introduction The ovarian hyperstimulation syndrome (OHSS) is a well recognized complication of ovulation induction. In its severe form, it is characterized by ascites, ovarian enlargement with cyst formation, pleural effusion and electrolyte disturbances © Oxford University Press
(Schenker and Weinstein, 1978). The pathogenesis of OHSS remains unclear. Ovulation appears to be necessary for its development and its severity is usually related to the number and size of ovarian follicles (Blackstein et al., 1987) and the plasma oestradiol level (Haning et al., 1985). Recent evidence has pointed to the existence of an ovarian renin—angiotensin system which may be a 'prime mover' in the generation of OHSS (Ong etal., 1991). OHSS is believed to be relatively rare in patients undergoing ovarian stimulation for in-vitro fertilization (IVF) because the ovarian follicles are aspirated at the time of oocyte collection (Friedman et al., 1984). Nevertheless, severe OHSS remains a major life-threatening complication of ovarian stimulation for FVF; it is therefore important to study the clinical features of these patients to identify high risk factors and allow strategies to be planned to minimize the risk of the condition. We report details of eight patients with severe OHSS and seven patients with moderate OHSS requiring hospitalization and compare them with a cohort of patients treated during the same period who did not develop OHSS. Materials and methods Between 1 July 1989 and 30 June 1990, 1302 patients underwent ovarian stimulation for FVF at the Hallam Medical Centre. Using the classification of Schenker and Weinstein (1978), we identified eight patients who developed severe OHSS and seven with moderate OHSS during this period. The clinical features of these two groups of patients, the methods of ovarian stimulation, the response to stimulation and the outcome of pregnancy were studied. A comparison was made with the remaining 1287 patients who did not develop OHSS. There was no significant difference in the mean age of those developing OHSS and those who did not (Table I). Thirteen patients were undergoing their first attempt at IVF and two patients, both of whom developed severe OHSS, were on their second attempt. The causes of infertility were comparable in both groups of patients. Of the 1302 patients, 625 (48%) had ovarian stimulation with human menopausal gonadotrophin (HMG, Pergonal; Serono, Welwyn Garden City, UK) and clomiphene citrate, while 633 (48.6%) had been administered the luteinizing hormone-releasing hormone (LHRH) analogue, buserelin (Suprefact; Hoechst, Hounslow, UK) and HMG; 76% of the latter group (483 patients) had been given a 'long' buserelin regimen to desensitize the pituitary prior to commencing HMG, while the remaining patients (n = 150) had been given various 'short' regimens. Four of the eight patients who developed severe OHSS had 597
MJ.MacDougall, S.L.Tan and H.SJacobs
Table I. Comparison of clinical details and results (mean ± SD) from patients who developed severe and moderate ovanan hyperstimulation syndrome (OHSS) with those who did not develop the condition
No. patients Age (years) PCO Day of HCG Total HMG (ampoules) Oestradiol (pmol/1) No. oocytes
Implantation rate Clinical pregnancy rate Multiple pregnancy rate Onset OHSS
Severe OHSS
Moderate OHSS
No OHSS
8 34.3 63% 10.0 23.9 8200 13.1 63.5 88% 71% 7.1
7 31.6 57% 9.4 17.6 5600 8.6 41.7 100% 43% 10.0
1287 33.4 ± 4.5
± 3.4 ± 0.9 ± 8.1 2300* ± 7.7** ± 41.3%
+ 3.7 da
± 2.8 ± ± ± ± ±
1.3 4.7 + 1800* 3.9* 19 4%
10 1 ± 1 3 28.2 ± 17.7 + 5.3 ± 5.2**/* 16 4%$ 24.9%
± 9.5 da
+
*P < 0.05, **P < 0.01, P < 0.001, tP < 0.0001. PCO = polycystk ovaries; HCG = human chononic gonadotrophin; HMG = human menopausal gonadotrophin
received the 'long' protocol of buserelin, one had received a 'short' protocol (Tan et al., 1992a) in which buserelin and HMG were concomitantly administered from the beginning of the menstrual cycle, two had been administered a 3-day 'ultrashort' regimen of buserelin (Macnamee et al., 1989) and one had been given clomiphene citrate and HMG. In the seven patients with moderate OHSS, one had received a 'long' regimen of buserelin, four had received clomiphene citrate and HMG and two patients had been treated with HMG alone. All patients had had a pelvic ultrasound scan performed in the early follicular phase of the treatment cycle to determine if they had polycystic ovaries (PCO) (Adams et al., 1985). All patients received 5000 IU of human chorionic gonadotrophin (HCG) when there were at least three follicles > 14 mm diameter and when the mean diameter of the largest follicle reached 17 mm for patients receiving HMG and clomiphene citrate or 18 mm for those receiving buserelin and HMG. Transvaginal ultrasound-directed oocyte recovery was scheduled 35 h after the administration of HCG. All 15 patients received luteal support in the form of HCG, 2000 IU administered on the day of embryo transfer and repeated 3 days later. Statistical analyses were by two-sample /-tests, Fisher's exact and chi-square tests.
Results The overall prevalence of severe OHSS was 0.6% (8/1302). The prevalence of severe OHSS among patients who had had ovarian stimulation with HMG and clomiphene citrate was significantly lower compared with those who had treatment with buserelin (0.2% versus 1.1%, P < 0.05). The prevalence in patients treated with the long regimen was 0.8% compared with 2.0% in those receiving the short regimens. This difference was not, however, statistically significant. The mean total dose of HMG received by patients who developed moderate or severe OHSS was lower than in those who did not (Table I). The mean serum oestradiol concentration on the day of HCG administration in those who developed severe OHSS was 8200 ± 2300 pmol/1 which was significantly higher than that in the moderate OHSS group (5600 ± 1800 pmol/1, P < 0.05). 598
Table D. Comparison of severe and moderate ovanan hyperstimulation syndrome (OHSS) by number (mean ± SD) and size of follicles Severe OHSS (n = 8)
Moderate OHSS (" = 7)
No. follicles on day of HCG > 14 mm 9.6 ± 6.5 12-13 mm 3.5 ± 2.5 < 12 mm 3.5 ± 2.6 Total 16.9 ± 7.4
6.0 4.0 6.1 16.4
No. follicles on day of oocyte collection > 14 mm 8.8 ± 5.2 < 14 mm 13.5 ± 7.6 Total 22.4 ± 12.4
6.4 ± 1.9 7.0 ± 2.8* 13.4 ± 3.2
± ± ± ±
2.7 2.7 5.2 5.7
*P < 0.05. HCG = human chorionic gonadotrophin.
The mean day of HCG administration was similar in all patients (Table I). Similar numbers of follicles were detected by ultrasound on the day of HCG administration in patients developing moderate or severe OHSS (Table U). However, on the day of oocyte collection, patients developing severe OHSS had more follicles < 14 mm compared with patients who developed moderate OHSS. Except for one patient in whom there was technical difficulty at oocyte retrieval, all the observed follicles were aspirated at collection. The mean number of oocytes collected was highest in the severe OHSS group and was significantly greater in both hyperstimulated groups compared with nonhyperstimulated patients (P < 0.01, Table I). The mean oocyte recovery rate was 61.6 ± 22.2% in the severe and 63.9 ± 24% in the moderate OHSS group. The mean fertilization and cleavage rates were similar in the two groups (73.6 ± 14.8% and 82.5 ± 20.8% respectively in the severe group compared with 56 ± 27% and 90 ± 14% in the moderate group). All patients developing OHSS had an embryo transfer, with a mean of 3.5 ± 0.5 embryos transferred in the severe group and 3.4 ± 0.5 in the moderate group. Seven of the eight patients with severe OHSS and all seven with moderate OHSS became pregnant. The clinical pregnancy rate per cycle was significantly lower in patients who did not
IVF and OHSS
develop OHSS (P < 0.0001, Table I). Two patients in each of the moderate and severe OHSS groups, all of whom had polycystic ovarian syndrome, miscarried. The multiple pregnancy rate was increased in both hyperstimulated groups when compared with controls (Table I). In the severe group, there were five multiple pregnancies, consisting of one set of twins, three sets of triplets and one of quadruplets, giving a multiple pregnancy rate of 71 % which was significantly higher than the rate observed in the nonhyperstimulated patients (Table I). The implantation rate was 63.5 ± 41.3% in the severe group compared with 41.7 ± 19.4% in the moderate group. The mean onset of OHSS was 7.1 ± 3.7 days (range 3 - 1 4 days) after embryo transfer in the patients with severe OHSS. Ovarian enlargement with multiple cyst formation and ascites were present in all these patients and the maximum ovarian volume recorded was 3350 ml (range 11 -3350 ml). The mean duration of hospitalization was 11.4 ± 8.8 days (range 4 - 2 1 days) and one patient required admission to an intensive care unit for 3 days because of oliguria. All settled with conservative management and no patient required paracentesis. Patients with moderate OHSS tended to present later (mean 10.0 ± 9.5 days after embryo transfer) than those with severe OHSS. They remained in hospital for a mean of 6.0 ± 4.9 days (range 2—14 days) and in all cases the symptoms resolved on conservative management. Discussion Friedman et al. (1984) described the first case of severe OHSS following oocyte collection for IVF. Since then the prevalence of severe OHSS has been reported to vary between 0.6 and 1.9% (Smitz et al., 1990; Forman et al., 1990) and the prevalence of 0.6% in the present study is consistent with previous reports. It has been suggested that follicular puncture and aspiration of follicular fluid protects patients undergoing IVF from developing OHSS (Rabinowitz et al., 1987). However, recent reports suggest that follicular aspiration does not necessarily prevent the occurrence of OHSS (Golan et al., 1988; Magnus et al., 1988) and the results of this study support this view. There are three possible approaches to reducing the risk of OHSS—identify patients at risk, reduce stimulation for the patients so identified, and careful follow-up to allow early diagnosis and symptomatic treatment should OHSS occur. Prevention of OHSS is difficult because OHSS is not easily predicted. It has been suggested that patients who are young (Navot et al., 1988), those with PCO (Magnus et al., 1988; Smitz et al., 1990) and those with high oestradiol levels and multiple ovarian follicles at the time of HCG administration (Navot et al., 1988; Golan et al., 1988; Forman et al., 1990) are at increased risk. Our results emphasize the importance of PCO as a risk factor for the development of OHSS in IVF. Sixty-three per cent of those with severe and 57 % of those with moderate OHSS had PCO compared with a prevalence of 33 % among patients referred to the Hallam Medical Centre for IVF (unpublished data) and a prevalence of 22% in volunteers (Poison et al., 1988). Once ovarian stimulation has been commenced, there is no single factor that will reliably predict all patients who will develop
OHSS (Delvigne et al., 1991). In the present study, the oestradiol levels, number of follicles on the day of collection and number of oocytes collected were all greater in the severely hyperstimulated patients. However, it is difficult to recommend levels at which treatment ought to be abandoned or alternative protocols adopted, as there was a significant overlap in these parameters with patients who only had moderate OHSS and those who did not become hyperstimulated at all. It would be reasonable, however, to consider patients with PCO who have serum oestradiol levels > 8000 pmol/1 on the day of HCG administration as being at higher risk. The number of small follicles < 14 mm on the day of oocyte collection was significantly greater in those who developed severe OHSS. This may also be of some predictive value. The use of LHRH agonists was previously recommended in the hope that by converting the patient to a hypogonadal state, OHSS could be prevented (Salat-Baroux et al., 1988). Unfortunately, this has not proved to be the case (Smitz et al., 1990) and, in fact, a number of recent reports suggest that OHSS may be more common when LHRH agonists are used (Forman et al., 1990), especially if the patient has PCO (Charbonnel et al., 1987). Our data clearly confirm this suggestion. In this study, patients who developed severe or moderate OHSS had received lower doses of gonadotrophins compared with patients not developing OHSS, which suggests that they were very sensitive to stimulation, presumably because they had PCO. We, therefore, consider it important to assess ovarian morphology before stimulating the ovaries. If PCO are identified by ultrasound, we consider it prudent to initiate ovarian stimulation with a lower dose of HMG. The rationale of this approach is the observation that during induction of ovulation for anovulatory infertility, a 'low' dose protocol significantly reduces the incidence of OHSS (Shoham et al., 1991). All patients in this study had received HCG injections for luteal support. Interestingly, the usual practice during the period of this study was to use progesterone pessaries instead of HCG in patients with serum oestradiol levels > 10 000 pmol/1 and none of these patients developed moderate or severe OHSS. It would therefore appear that progesterone rather than HCG should be used for luteal support in high risk patients. The use of glucocorticoids for the prevention of OHSS in high risk patients produces no benefit (Tan et al., 1992b). The risk of multiple pregnancy with its attendant obstetric risks (Tan et al., 1992c) is significantly higher in patients with severe OHSS. Of the seven patients in our study who had three embryos transferred and who developed severe OHSS, five had multiple pregnancies. It may, therefore, be advisable to transfer only two embryos if the patient is at a high risk of developing OHSS. Other strategies include freezing all embryos for transfer in a subsequent cycle (Amso et al., 1990) and, in the case of patients on LHRH analogues, continuing the analogue until the onset of menstruation. In conclusion, OHSS is iatrogenic, difficult to prevent and can cause significant morbidity. Patients with PCO should be started on a lower dose of gonadotrophins. Use of LHRH analogues and HMG increase the risk of OHSS and close monitoring of oestrogen levels and follicle numbers should be performed. Patients who develop a large number of follicles with very high 599
MJ.MacDougaU, S.L.Tan and H.SJacobs
oestrogen levels should have their HCG withheld or embryos cryopreserved for elective transfer in a subsequent cycle. If a decision is made to proceed with fresh embryo transfer, the use of HCG for luteal support should be avoided and a reduction should be considered in the number of embryos transferred. Acknowledgements We wish to thank Mr B.Rizk and Mr Z.Shoham for their helpful comments, and colleagues at the Hallam Medical Centre who helped to manage many of the hyperstimulated patients.
References AdamsJ., Poison,D.W., Abdulwahid.N., Morris.D.V., Franks,S., Mason.H., Tucker,M., Priced, and Jacobs.H.S. (1985) MultifoUicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet, ii, 1375-1378. Amso,N.N., Ahuja.K.K., Morris,N. and Shaw.R.W. (1990) The management of predicted ovarian hyperstimulation involving gonadotropin releasing hormone analog with elective cryopreservation of all pre-embryos. Fertil. Steril, 53, 1087-1090. Blackstein.J., Shalev.J., Saadon.T., Kukia.E.E., Rabinovici.J., Pariente,C, Lunenfeld.B., Serr.D.M. and Mashiach.S. (1987) OHSS: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597-602. Charbonnel.B., Krempf.M., Blanchare.P., Dano,F. and Delage.C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of a luteinising hormone releasing hormone analog and exogenous gonadotropins. Fertil. Steril, 47, 920—924. Delvigne.A., Vandromme,J., Bariow,P., Lejeune.B. and Leroy.L. (1991) Are there predictive criteria of complicated ovarian hyperstimulation in IVF? Hum. Reprod., 6, 959 -962. Friedman.C.I., Schmidt.G.E., Chang.F.E. and Kim.M.H. (1984) Severe ovarian hyperstimulation following follicular aspiration. Am. J. Obstet. Gynccol, 150, 436-437. Forman.R.G., Frydman.R., Egan.D., Ross.C. and Barlow,D.H. (1990) Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in-vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502-509. Golan.A., Ron-FJ,R., Herman,A., Weinraub.Z., Soffer.Y. and Caspi.E. (1988) Ovarian hyperstimulation syndrome, D-Trp-6 luteinizing hormone releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil. Steril, 50, 912-916. Haning.R.V., Strawn.E.Y. and Noltne.W.E. (1985) Pathophysiology of the ovarian hyperstimulation syndrome. Obstet. Gynecol, 66, 220-224. Macnamee.M.C, Howles.C.M., Edwards.R.G., Taylor,P.J. and Elder,K.T. (1989) Short term LHRH agonist treatment: a prospective trial of a novel ovarian stimulation regimen for in vitro fertilization.
Fertil Steril, 52, 264-268. Magnus.O., Tanbo.T., Henricksen.M.D. and Abyholm.T. (1988) Severe ovarian hyperstimulation syndrome. Case reports. Ada Europ. Fertil., 19, 8 9 - 9 2 . Navot.D., Relou.A., Birkenfeld.A., Rabinowitz.T., Brzezinski.A. and Margalioth.E.J. (1988) Risk factors and prognostic variables in ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol, 159, 210-215. Ong.A., Eisen.V., Rennie.D.P., Homburg.R., Lachelin.G., Jacobs.H.S. and Slater.D. (1991) The pathogenesis of the ovarian hyperstimulation syndrome: a possible role for renin. Gin. Endocrinol, 34, 4 3 - 4 8 . Polson.D.W., WadsworthJ., AdamsJ. and Franks.S. (1988) Polycystic ovaries: a common finding in normal women. Lancet, ii, 870-872. Rabinowitz.R., Laufer,N., Lewin.A., Simon,A., Margalioth.E. and Schenker,J. (1987) Rate of ovarian hyperstimulation syndrome after
600
high dose hMG for induction of ovulation in IVF cycles. Hum. Reprod., 2 (Suppl. 1), 18. Salat-Baroux.J., Alvarez.S., Antoine,J.M., Tibi.C, Cornet.D., Mandelbaum,J., Plachot.M. and Junca.A.M. (1988) Comparison between long and short protocols of LHRH agonist in the treatment of polycystic ovarian disease by IVF. Hum. Reprod., 3, 535-539. Schenker.J.G. and Weinstein.D. (1989) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril, 30, 255-262. Shoham.Z., Patel.A. and Jacobs,H.S. (1991) Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified follicle-stimulating hormone. Fertil. Steril., 55, 1051-1056. Smitz.J., Camus.M., Devroey,P., Erard.P., Wisanto.A. and Van Steirteghem.A.C. (1990) Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization. Hum. Reprod., 5, 933-937. Tan.S.L., Kingsland.C, Campbell.S., Mills.C, BradfiekU., YovichJ. and Jacobs.H.S. (1992a) The long protocol of administration of GnRH agonists are superior to the short protocol for ovarian stimulation in IVF. Fertil. Steril, 57, 810-814. Tan.S.L., Balen.A., Hussein.El., Campbell.S. and Jacobs,H.S. (1992b) The use of glucocorticoids for the prevention of ovarian hyperstimulation in IVF. Fertil. Steril., in press. Tan,S.L., Doyle,P., Campbell,S., Beral,V., Rizk.B., Brinsden.P., Mason,P. and Edwards.R.G. (1992c) Obstetric outcome of pregnancies resulting from in vitro fertilization compared to normally conceived pregnancies. Am. J. Obstet. Gynecol, in press. Received on December 12, 1991; accepted on February 20, 1992
In-vitro fertilization and the ovarian hyperstimulation syndrome
MJ.MacDougaU1-2, S.L.Tan1-3 and H.S.Jacobs2 'The Hallam Medical Centre, 112 Harley Street, London WIN 8AA, 2Department of Reproductive Endocrinology, The Middlesex Hospital, Mortimer Street, London WIN 1AF and 3 Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX, UK •'To whom correspondence should be addressed
Eight patients who developed severe ovarian hyperstimulation syndrome (OHSS) were identified among 1302 patients undergoing in-vitro fertilization (IVF) over a 1 year period (prevalence of 0.6%); 63% had uttrasonically diagnosed polycystic ovaries (PCO) and 75% were undergoing their first attempt at IVF. Pretreatment with a superactive luteinizing hormone-releasing hormone (LHRH) analogue significantly increased the prevalence of severe OHSS (1.1% versus 0.2%, P < 0.05) compared with ovarian stimulation with clomiphene citrate and human menopausal gonadotrophin (HMG). The mean serum oestradiol concentration on the day of human chorionk gonadotrophin (HCG) administration was 8200 ± 2300 pmol/1. A mean of 19.6 ± 6.8 follicles had been aspirated and 13.1 ± 7.7 oocytes recovered at transvaginal ultrasound-directed oocyte recovery. All patients had an embryo transfer and luteal support in the form of HCG. The clinical pregnancy rate was 88%, multiple pregnancy rate 71% and implantation rate 63.5 ± 41.3%. In a group of seven patients who were hospitalized for moderate OHSS during the same period, peak oestradiol levels were significantly lower than in those with severe OHSS (P < 0.05). Of the group with moderate OHSS, 57% had PCO, the clinical pregnancy rate was 100% and multiple pregnancy rate 43%. Patients with ultrasound-diagnosed PCO have an increased risk of developing OHSS and the dose of HMG administered to them should be minimized. In patients at risk of developing OHSS, progesterone instead of HCG should be used for luteal support. Transfer of a maximum of two embryos or freezing all embryos for transfer in a subsequent cycle may reduce the likelihood of multiple pregnancy. Key words: in-vitro fertilization/ovarian hyperstimulation syndrome/polycystic ovaries
Introduction The ovarian hyperstimulation syndrome (OHSS) is a well recognized complication of ovulation induction. In its severe form, it is characterized by ascites, ovarian enlargement with cyst formation, pleural effusion and electrolyte disturbances © Oxford University Press
(Schenker and Weinstein, 1978). The pathogenesis of OHSS remains unclear. Ovulation appears to be necessary for its development and its severity is usually related to the number and size of ovarian follicles (Blackstein et al., 1987) and the plasma oestradiol level (Haning et al., 1985). Recent evidence has pointed to the existence of an ovarian renin—angiotensin system which may be a 'prime mover' in the generation of OHSS (Ong etal., 1991). OHSS is believed to be relatively rare in patients undergoing ovarian stimulation for in-vitro fertilization (IVF) because the ovarian follicles are aspirated at the time of oocyte collection (Friedman et al., 1984). Nevertheless, severe OHSS remains a major life-threatening complication of ovarian stimulation for FVF; it is therefore important to study the clinical features of these patients to identify high risk factors and allow strategies to be planned to minimize the risk of the condition. We report details of eight patients with severe OHSS and seven patients with moderate OHSS requiring hospitalization and compare them with a cohort of patients treated during the same period who did not develop OHSS. Materials and methods Between 1 July 1989 and 30 June 1990, 1302 patients underwent ovarian stimulation for FVF at the Hallam Medical Centre. Using the classification of Schenker and Weinstein (1978), we identified eight patients who developed severe OHSS and seven with moderate OHSS during this period. The clinical features of these two groups of patients, the methods of ovarian stimulation, the response to stimulation and the outcome of pregnancy were studied. A comparison was made with the remaining 1287 patients who did not develop OHSS. There was no significant difference in the mean age of those developing OHSS and those who did not (Table I). Thirteen patients were undergoing their first attempt at IVF and two patients, both of whom developed severe OHSS, were on their second attempt. The causes of infertility were comparable in both groups of patients. Of the 1302 patients, 625 (48%) had ovarian stimulation with human menopausal gonadotrophin (HMG, Pergonal; Serono, Welwyn Garden City, UK) and clomiphene citrate, while 633 (48.6%) had been administered the luteinizing hormone-releasing hormone (LHRH) analogue, buserelin (Suprefact; Hoechst, Hounslow, UK) and HMG; 76% of the latter group (483 patients) had been given a 'long' buserelin regimen to desensitize the pituitary prior to commencing HMG, while the remaining patients (n = 150) had been given various 'short' regimens. Four of the eight patients who developed severe OHSS had 597
MJ.MacDougall, S.L.Tan and H.SJacobs
Table I. Comparison of clinical details and results (mean ± SD) from patients who developed severe and moderate ovanan hyperstimulation syndrome (OHSS) with those who did not develop the condition
No. patients Age (years) PCO Day of HCG Total HMG (ampoules) Oestradiol (pmol/1) No. oocytes
Implantation rate Clinical pregnancy rate Multiple pregnancy rate Onset OHSS
Severe OHSS
Moderate OHSS
No OHSS
8 34.3 63% 10.0 23.9 8200 13.1 63.5 88% 71% 7.1
7 31.6 57% 9.4 17.6 5600 8.6 41.7 100% 43% 10.0
1287 33.4 ± 4.5
± 3.4 ± 0.9 ± 8.1 2300* ± 7.7** ± 41.3%
+ 3.7 da
± 2.8 ± ± ± ± ±
1.3 4.7 + 1800* 3.9* 19 4%
10 1 ± 1 3 28.2 ± 17.7 + 5.3 ± 5.2**/* 16 4%$ 24.9%
± 9.5 da
+
*P < 0.05, **P < 0.01, P < 0.001, tP < 0.0001. PCO = polycystk ovaries; HCG = human chononic gonadotrophin; HMG = human menopausal gonadotrophin
received the 'long' protocol of buserelin, one had received a 'short' protocol (Tan et al., 1992a) in which buserelin and HMG were concomitantly administered from the beginning of the menstrual cycle, two had been administered a 3-day 'ultrashort' regimen of buserelin (Macnamee et al., 1989) and one had been given clomiphene citrate and HMG. In the seven patients with moderate OHSS, one had received a 'long' regimen of buserelin, four had received clomiphene citrate and HMG and two patients had been treated with HMG alone. All patients had had a pelvic ultrasound scan performed in the early follicular phase of the treatment cycle to determine if they had polycystic ovaries (PCO) (Adams et al., 1985). All patients received 5000 IU of human chorionic gonadotrophin (HCG) when there were at least three follicles > 14 mm diameter and when the mean diameter of the largest follicle reached 17 mm for patients receiving HMG and clomiphene citrate or 18 mm for those receiving buserelin and HMG. Transvaginal ultrasound-directed oocyte recovery was scheduled 35 h after the administration of HCG. All 15 patients received luteal support in the form of HCG, 2000 IU administered on the day of embryo transfer and repeated 3 days later. Statistical analyses were by two-sample /-tests, Fisher's exact and chi-square tests.
Results The overall prevalence of severe OHSS was 0.6% (8/1302). The prevalence of severe OHSS among patients who had had ovarian stimulation with HMG and clomiphene citrate was significantly lower compared with those who had treatment with buserelin (0.2% versus 1.1%, P < 0.05). The prevalence in patients treated with the long regimen was 0.8% compared with 2.0% in those receiving the short regimens. This difference was not, however, statistically significant. The mean total dose of HMG received by patients who developed moderate or severe OHSS was lower than in those who did not (Table I). The mean serum oestradiol concentration on the day of HCG administration in those who developed severe OHSS was 8200 ± 2300 pmol/1 which was significantly higher than that in the moderate OHSS group (5600 ± 1800 pmol/1, P < 0.05). 598
Table D. Comparison of severe and moderate ovanan hyperstimulation syndrome (OHSS) by number (mean ± SD) and size of follicles Severe OHSS (n = 8)
Moderate OHSS (" = 7)
No. follicles on day of HCG > 14 mm 9.6 ± 6.5 12-13 mm 3.5 ± 2.5 < 12 mm 3.5 ± 2.6 Total 16.9 ± 7.4
6.0 4.0 6.1 16.4
No. follicles on day of oocyte collection > 14 mm 8.8 ± 5.2 < 14 mm 13.5 ± 7.6 Total 22.4 ± 12.4
6.4 ± 1.9 7.0 ± 2.8* 13.4 ± 3.2
± ± ± ±
2.7 2.7 5.2 5.7
*P < 0.05. HCG = human chorionic gonadotrophin.
The mean day of HCG administration was similar in all patients (Table I). Similar numbers of follicles were detected by ultrasound on the day of HCG administration in patients developing moderate or severe OHSS (Table U). However, on the day of oocyte collection, patients developing severe OHSS had more follicles < 14 mm compared with patients who developed moderate OHSS. Except for one patient in whom there was technical difficulty at oocyte retrieval, all the observed follicles were aspirated at collection. The mean number of oocytes collected was highest in the severe OHSS group and was significantly greater in both hyperstimulated groups compared with nonhyperstimulated patients (P < 0.01, Table I). The mean oocyte recovery rate was 61.6 ± 22.2% in the severe and 63.9 ± 24% in the moderate OHSS group. The mean fertilization and cleavage rates were similar in the two groups (73.6 ± 14.8% and 82.5 ± 20.8% respectively in the severe group compared with 56 ± 27% and 90 ± 14% in the moderate group). All patients developing OHSS had an embryo transfer, with a mean of 3.5 ± 0.5 embryos transferred in the severe group and 3.4 ± 0.5 in the moderate group. Seven of the eight patients with severe OHSS and all seven with moderate OHSS became pregnant. The clinical pregnancy rate per cycle was significantly lower in patients who did not
IVF and OHSS
develop OHSS (P < 0.0001, Table I). Two patients in each of the moderate and severe OHSS groups, all of whom had polycystic ovarian syndrome, miscarried. The multiple pregnancy rate was increased in both hyperstimulated groups when compared with controls (Table I). In the severe group, there were five multiple pregnancies, consisting of one set of twins, three sets of triplets and one of quadruplets, giving a multiple pregnancy rate of 71 % which was significantly higher than the rate observed in the nonhyperstimulated patients (Table I). The implantation rate was 63.5 ± 41.3% in the severe group compared with 41.7 ± 19.4% in the moderate group. The mean onset of OHSS was 7.1 ± 3.7 days (range 3 - 1 4 days) after embryo transfer in the patients with severe OHSS. Ovarian enlargement with multiple cyst formation and ascites were present in all these patients and the maximum ovarian volume recorded was 3350 ml (range 11 -3350 ml). The mean duration of hospitalization was 11.4 ± 8.8 days (range 4 - 2 1 days) and one patient required admission to an intensive care unit for 3 days because of oliguria. All settled with conservative management and no patient required paracentesis. Patients with moderate OHSS tended to present later (mean 10.0 ± 9.5 days after embryo transfer) than those with severe OHSS. They remained in hospital for a mean of 6.0 ± 4.9 days (range 2—14 days) and in all cases the symptoms resolved on conservative management. Discussion Friedman et al. (1984) described the first case of severe OHSS following oocyte collection for IVF. Since then the prevalence of severe OHSS has been reported to vary between 0.6 and 1.9% (Smitz et al., 1990; Forman et al., 1990) and the prevalence of 0.6% in the present study is consistent with previous reports. It has been suggested that follicular puncture and aspiration of follicular fluid protects patients undergoing IVF from developing OHSS (Rabinowitz et al., 1987). However, recent reports suggest that follicular aspiration does not necessarily prevent the occurrence of OHSS (Golan et al., 1988; Magnus et al., 1988) and the results of this study support this view. There are three possible approaches to reducing the risk of OHSS—identify patients at risk, reduce stimulation for the patients so identified, and careful follow-up to allow early diagnosis and symptomatic treatment should OHSS occur. Prevention of OHSS is difficult because OHSS is not easily predicted. It has been suggested that patients who are young (Navot et al., 1988), those with PCO (Magnus et al., 1988; Smitz et al., 1990) and those with high oestradiol levels and multiple ovarian follicles at the time of HCG administration (Navot et al., 1988; Golan et al., 1988; Forman et al., 1990) are at increased risk. Our results emphasize the importance of PCO as a risk factor for the development of OHSS in IVF. Sixty-three per cent of those with severe and 57 % of those with moderate OHSS had PCO compared with a prevalence of 33 % among patients referred to the Hallam Medical Centre for IVF (unpublished data) and a prevalence of 22% in volunteers (Poison et al., 1988). Once ovarian stimulation has been commenced, there is no single factor that will reliably predict all patients who will develop
OHSS (Delvigne et al., 1991). In the present study, the oestradiol levels, number of follicles on the day of collection and number of oocytes collected were all greater in the severely hyperstimulated patients. However, it is difficult to recommend levels at which treatment ought to be abandoned or alternative protocols adopted, as there was a significant overlap in these parameters with patients who only had moderate OHSS and those who did not become hyperstimulated at all. It would be reasonable, however, to consider patients with PCO who have serum oestradiol levels > 8000 pmol/1 on the day of HCG administration as being at higher risk. The number of small follicles < 14 mm on the day of oocyte collection was significantly greater in those who developed severe OHSS. This may also be of some predictive value. The use of LHRH agonists was previously recommended in the hope that by converting the patient to a hypogonadal state, OHSS could be prevented (Salat-Baroux et al., 1988). Unfortunately, this has not proved to be the case (Smitz et al., 1990) and, in fact, a number of recent reports suggest that OHSS may be more common when LHRH agonists are used (Forman et al., 1990), especially if the patient has PCO (Charbonnel et al., 1987). Our data clearly confirm this suggestion. In this study, patients who developed severe or moderate OHSS had received lower doses of gonadotrophins compared with patients not developing OHSS, which suggests that they were very sensitive to stimulation, presumably because they had PCO. We, therefore, consider it important to assess ovarian morphology before stimulating the ovaries. If PCO are identified by ultrasound, we consider it prudent to initiate ovarian stimulation with a lower dose of HMG. The rationale of this approach is the observation that during induction of ovulation for anovulatory infertility, a 'low' dose protocol significantly reduces the incidence of OHSS (Shoham et al., 1991). All patients in this study had received HCG injections for luteal support. Interestingly, the usual practice during the period of this study was to use progesterone pessaries instead of HCG in patients with serum oestradiol levels > 10 000 pmol/1 and none of these patients developed moderate or severe OHSS. It would therefore appear that progesterone rather than HCG should be used for luteal support in high risk patients. The use of glucocorticoids for the prevention of OHSS in high risk patients produces no benefit (Tan et al., 1992b). The risk of multiple pregnancy with its attendant obstetric risks (Tan et al., 1992c) is significantly higher in patients with severe OHSS. Of the seven patients in our study who had three embryos transferred and who developed severe OHSS, five had multiple pregnancies. It may, therefore, be advisable to transfer only two embryos if the patient is at a high risk of developing OHSS. Other strategies include freezing all embryos for transfer in a subsequent cycle (Amso et al., 1990) and, in the case of patients on LHRH analogues, continuing the analogue until the onset of menstruation. In conclusion, OHSS is iatrogenic, difficult to prevent and can cause significant morbidity. Patients with PCO should be started on a lower dose of gonadotrophins. Use of LHRH analogues and HMG increase the risk of OHSS and close monitoring of oestrogen levels and follicle numbers should be performed. Patients who develop a large number of follicles with very high 599
MJ.MacDougaU, S.L.Tan and H.SJacobs
oestrogen levels should have their HCG withheld or embryos cryopreserved for elective transfer in a subsequent cycle. If a decision is made to proceed with fresh embryo transfer, the use of HCG for luteal support should be avoided and a reduction should be considered in the number of embryos transferred. Acknowledgements We wish to thank Mr B.Rizk and Mr Z.Shoham for their helpful comments, and colleagues at the Hallam Medical Centre who helped to manage many of the hyperstimulated patients.
References AdamsJ., Poison,D.W., Abdulwahid.N., Morris.D.V., Franks,S., Mason.H., Tucker,M., Priced, and Jacobs.H.S. (1985) MultifoUicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet, ii, 1375-1378. Amso,N.N., Ahuja.K.K., Morris,N. and Shaw.R.W. (1990) The management of predicted ovarian hyperstimulation involving gonadotropin releasing hormone analog with elective cryopreservation of all pre-embryos. Fertil. Steril, 53, 1087-1090. Blackstein.J., Shalev.J., Saadon.T., Kukia.E.E., Rabinovici.J., Pariente,C, Lunenfeld.B., Serr.D.M. and Mashiach.S. (1987) OHSS: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597-602. Charbonnel.B., Krempf.M., Blanchare.P., Dano,F. and Delage.C. (1987) Induction of ovulation in polycystic ovary syndrome with a combination of a luteinising hormone releasing hormone analog and exogenous gonadotropins. Fertil. Steril, 47, 920—924. Delvigne.A., Vandromme,J., Bariow,P., Lejeune.B. and Leroy.L. (1991) Are there predictive criteria of complicated ovarian hyperstimulation in IVF? Hum. Reprod., 6, 959 -962. Friedman.C.I., Schmidt.G.E., Chang.F.E. and Kim.M.H. (1984) Severe ovarian hyperstimulation following follicular aspiration. Am. J. Obstet. Gynccol, 150, 436-437. Forman.R.G., Frydman.R., Egan.D., Ross.C. and Barlow,D.H. (1990) Severe ovarian hyperstimulation syndrome using agonists of gonadotropin-releasing hormone for in-vitro fertilization: a European series and a proposal for prevention. Fertil. Steril., 53, 502-509. Golan.A., Ron-FJ,R., Herman,A., Weinraub.Z., Soffer.Y. and Caspi.E. (1988) Ovarian hyperstimulation syndrome, D-Trp-6 luteinizing hormone releasing hormone microcapsules and menotropin for in vitro fertilization. Fertil. Steril, 50, 912-916. Haning.R.V., Strawn.E.Y. and Noltne.W.E. (1985) Pathophysiology of the ovarian hyperstimulation syndrome. Obstet. Gynecol, 66, 220-224. Macnamee.M.C, Howles.C.M., Edwards.R.G., Taylor,P.J. and Elder,K.T. (1989) Short term LHRH agonist treatment: a prospective trial of a novel ovarian stimulation regimen for in vitro fertilization.
Fertil Steril, 52, 264-268. Magnus.O., Tanbo.T., Henricksen.M.D. and Abyholm.T. (1988) Severe ovarian hyperstimulation syndrome. Case reports. Ada Europ. Fertil., 19, 8 9 - 9 2 . Navot.D., Relou.A., Birkenfeld.A., Rabinowitz.T., Brzezinski.A. and Margalioth.E.J. (1988) Risk factors and prognostic variables in ovarian hyperstimulation syndrome. Am. J. Obstet. Gynecol, 159, 210-215. Ong.A., Eisen.V., Rennie.D.P., Homburg.R., Lachelin.G., Jacobs.H.S. and Slater.D. (1991) The pathogenesis of the ovarian hyperstimulation syndrome: a possible role for renin. Gin. Endocrinol, 34, 4 3 - 4 8 . Polson.D.W., WadsworthJ., AdamsJ. and Franks.S. (1988) Polycystic ovaries: a common finding in normal women. Lancet, ii, 870-872. Rabinowitz.R., Laufer,N., Lewin.A., Simon,A., Margalioth.E. and Schenker,J. (1987) Rate of ovarian hyperstimulation syndrome after
600
high dose hMG for induction of ovulation in IVF cycles. Hum. Reprod., 2 (Suppl. 1), 18. Salat-Baroux.J., Alvarez.S., Antoine,J.M., Tibi.C, Cornet.D., Mandelbaum,J., Plachot.M. and Junca.A.M. (1988) Comparison between long and short protocols of LHRH agonist in the treatment of polycystic ovarian disease by IVF. Hum. Reprod., 3, 535-539. Schenker.J.G. and Weinstein.D. (1989) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril, 30, 255-262. Shoham.Z., Patel.A. and Jacobs,H.S. (1991) Polycystic ovarian syndrome: safety and effectiveness of stepwise and low-dose administration of purified follicle-stimulating hormone. Fertil. Steril., 55, 1051-1056. Smitz.J., Camus.M., Devroey,P., Erard.P., Wisanto.A. and Van Steirteghem.A.C. (1990) Incidence of severe ovarian hyperstimulation syndrome after GnRH agonist/HMG superovulation for in-vitro fertilization. Hum. Reprod., 5, 933-937. Tan.S.L., Kingsland.C, Campbell.S., Mills.C, BradfiekU., YovichJ. and Jacobs.H.S. (1992a) The long protocol of administration of GnRH agonists are superior to the short protocol for ovarian stimulation in IVF. Fertil. Steril, 57, 810-814. Tan.S.L., Balen.A., Hussein.El., Campbell.S. and Jacobs,H.S. (1992b) The use of glucocorticoids for the prevention of ovarian hyperstimulation in IVF. Fertil. Steril., in press. Tan,S.L., Doyle,P., Campbell,S., Beral,V., Rizk.B., Brinsden.P., Mason,P. and Edwards.R.G. (1992c) Obstetric outcome of pregnancies resulting from in vitro fertilization compared to normally conceived pregnancies. Am. J. Obstet. Gynecol, in press. Received on December 12, 1991; accepted on February 20, 1992
