by failure to recover oocytes despite repeated aspiration and flushing of mature ... Table I. Fertilization data for each of three ICSI treatment cycles. Cycle no.
Human Reproduction vol.14 no.7 pp.1707–1709, 1999
CASE REPORT
Severe ovarian hyperstimulation syndrome following salvage of empty follicle syndrome
I.O.Evbuomwan1, J.D.Fenwick, R.Shiels, M.Herbert and A.P.Murdoch Centre for Reproductive Medicine, RVI Trust, Newcastle upon Tyne, NE1 4LP, UK 1To
whom correspondence should be addressed
We report a case of severe ovarian hyperstimulation syndrome (OHSS) following a rescue of empty follicle syndrome (EFS). This suggests that the risk of developing OHSS remains unaltered even in the presence of EFS. The case supports the possibility of obtaining oocytes that fertilize and cleave normally after a second dose of human chorionic gonadotrophin (HCG) and a repeat oocyte retrieval. It supports the suggestion that the follicles are not necessarily empty in EFS. It demonstrates further that OHSS cannot be prevented by aspiration of follicular fluid and patients with large numbers of follicles and EFS must be warned of this potential complication. Key words: EFS/gonadotrophins/ICSI/ovarian hyperstimulation
Introduction The empty follicle syndrome (EFS) is a condition characterized by failure to recover oocytes despite repeated aspiration and flushing of mature follicles after ovulation induction for invitro fertilization treatment (Coulam et al., 1986; ZegersHochschild et al., 1995; Ndukwe et al., 1996; Ubaldi et al., 1997; Awonuga et al., 1998). The reported incidence varies from 2–7% (Ben-Shlomo et al., 1991; Meniru and Craft, 1997; Hassan et al., 1998). There are no predisposing factors and it has not been possible to predict it by the pattern of ovarian response to stimulation either endocrinologically or sonographically (Ben-Shlomo et al., 1991), although a useful simple test to confirm its presence by measuring serum human chorionic gonadotrophin (HCG) concentration on the day of oocyte recovery has been reported (Ndukwe et al., 1996). Its pathophysiology is unclear. Evidence has been provided (Zegers-Hochschild et al., 1995; Ndukwe et al., 1997) to suggest that EFS is more likely to represent a defect in the invivo bioactivity of HCG rather than being an intrinsic patient problem (Tsuiki et al., 1988), although Awonuga has recently demonstrated its occurrence in the presence of normal HCG concentrations (Awonuga et al., 1998). A second dose of HCG to trigger ovulation followed by a © European Society of Human Reproduction and Embryology
second attempt at oocyte recovery has been shown to be successful in rescuing these cases (Ndukwe et al., 1997; Ubaldi et al., 1997; Awonuga et al., 1998). What has not previously been considered, however, is the possibility of the patient subsequently developing severe ovarian hyperstimulation syndrome (OHSS) following such rescue protocols. In this case, we report the development of severe OHSS following a rescue of EFS in a patient who was otherwise considered to be at high risk of OHSS (.20 follicles pre-HCG).
Case report The patient was 33 years old with a 4 year history of secondary subfertility (she had a previous spontaneous miscarriage). She was undergoing her second cycle of intracytoplasmic sperm injection (ICSI) because of her husband’s severe asthenoteratozoospermia and intermittent oligozoospermia. In her first ICSI treatment (undertaken 6 months before), pituitary down-regulation was achieved with a gonadotrophinreleasing hormone analogue (GnRHa) buserelin acetate (Suprefact®; Shire Pharmaceuticals, UK) at a daily dose of 800 µg for 3 weeks. Stimulation of the ovaries was then commenced using purified recombinant follicle stimulating hormone (FSH) (Gonal-F®; Serono Laboratories, Welwyn Garden City, Herts, UK), administered s.c. at a daily constant dose of 225 IU for 10 days. Ovulation was induced with s.c. 10ˆ000 IU purified urinary HCG (Profasi®; Serono Laboratories) and follicular aspiration was performed 38 h later. Eight oocytes were retrieved from 13 follicles (16–20 mm diameter). Seven of the eight metaphase-II (MII) oocytes fertilized normally following injection with her husband’s spermatozoa and two of the resulting embryos were transferred 48 h later. No pregnancy occurred. In her second ICSI cycle, the patient had the same stimulation regime except that she had urinary follicle stimulating hormone (FSH) (Metrodin HP; Serono Laboratories) to stimulate ovulation. A total of 20 follicles (16–24 mm diameter) was visualized on ultrasound examination before 10 000 IU HCG was self administered s.c. Surprisingly, aspiration and repeated flushing 38 h later of all 11 follicles in the right ovary and three of the nine follicles in the left ovary failed to yield an oocyte. Further attempts by another experienced operator also failed. We therefore suspended further aspiration, leaving six follicles intact in the left ovary. A satisfactory response was obtained following an inquiry into the timing of administration, storage and expiry date of 1707
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Discussion Table I. Fertilization data for each of three ICSI treatment cycles Cycle no.
Metaphase-II eggs (n)
0 PN 1 PN 2 PN 3 PN No. oocytes degenerated
1 2 (EFS cycle) 3
8 9 12
0 4 0
0 0 0
7 2 8
0 0 1
1 3 3
EFS 5 empty follicle syndrome; PN 5 pronuclear; ICSI 5 intracytoplasmic sperm injection.
the HCG administered. Unfortunately, HCG concentration was not measured on the day of EFS occurrence. Serum progesterone concentration was 4 nmol/l on the day of follicle aspiration (day EFS occurred) compared with 6 nmol/l obtained on the day of HCG administration (38 h earlier). Concomitant oestradiol concentrations were 3285 and 1472 pmol/l respectively. These results would be consistent with absent HCG bioactivity. After counselling, the patient received a second dose of 10 000 IU HCG and a second oocyte retrieval session was scheduled for 38 h later. Progesterone concentration on the day of the second follicle aspiration was 102 nmol/l, oestradiol concentration was 1133 pmol/l and HCG was 116 IU/L. A total of nine oocytes was retrieved from 13 follicles (16–20 mm) and these included previously punctured follicles. ICSI was performed by an experienced embryologist who carried out all the treatments for this couple. Of the six MII eggs injected with the husband’s spermatozoa, only two fertilized normally and subsequently cleaved. The two resulting embryos were later transferred and the patient received two doses of 2000 IU HCG, 48 h apart for luteal support. Four days later, the patient complained of abdominal pain and distension, nausea, vomiting, thirst and decreased urine output. Blood tests confirmed haemoconcentration (haematocrit 5 45%) and hypo-osmolality (serum osmolality 283 mOsm/kg). A diagnosis of severe OHSS (Navot et al., 1992) was made. She was admitted to hospital and managed according to our unit’s protocol (Stewart et al., 1997). Her condition improved over the next 4 days following admission and she was allowed home on the fifth day. When reviewed 3 days later, her clinical improvement was sustained and her ascites almost completely resolved. Her serum osmolality was 290 mOsm/kg and her haemoconcentration had resolved (haematocrit 5 34%). She was unfortunately not pregnant. In her third ICSI cycle, the patient had the same stimulation regime as in her second except that she self-administered a s.c. 5000 IU ovulation triggering dose of HCG and she used progesterone pessaries for luteal support. The egg retrieval procedure conducted 38 h after the HCG administration was uneventful and 14 oocytes were retrieved from 21 follicles. Eight of the 12 MII oocytes injected with the husband’s spermatozoa fertilized and cleaved normally, two of the resulting embryos were transferred and at the time of writing she has an ongoing twin pregnancy at 33 weeks gestation. Table I summarizes the embryological information obtained in the three ICSI cycles. 1708
EFS, defined as the failure to retrieve oocytes from mature follicles following ovulation induction for assisted reproductive treatments, occurs infrequently with a suggested incidence of 0.6–7% (Ben-Shlomo et al., 1991; Meniru and Craft, 1997; Hassan et al., 1998; Awonuga et al., 1998). Nevertheless, it is a frustrating condition when it occurs, as the patients and the healthcare personnel involved have invested time, effort and money to reach the stage of oocyte retrieval (Awonuga et al., 1998). There is cumulative evidence to suggest that EFS may be a multifactorial problem with the common manifestation being a lack of oocyte retrieval at operation (Coulam et al., 1986; Ashkenazi et al., 1987; Tsuiki et al., 1988; Asch et al., 1992; Zegers-Hochschild et al., 1995; Khalaf and Braude, 1997; Awonuga et al., 1998). It is also possible that there is an individual susceptibility to the genesis of the EFS because some patients have EFS while others who have been administered the same batch of drugs, including HCG, during the same period, in the same centre and using the same protocol, have successful oocyte retrieval operations. Our case demonstrates that any proposed individual susceptibility must be variable since the problem was present in only one of three treatment cycles. Despite the uncertain aetiology a consistent feature of EFS is the possibility of successfully retrieving oocytes following a repeat ovulation triggering dose of HCG and a second oocyte recovery procedure in the majority of reported cases (ZegersHochschild et al., 1995; Ndukwe et al., 1996, 1997; Ubaldi et al., 1997; Hassan et al., 1998; Awonuga et al., 1998). Previously, however, the possibility of subsequently developing severe OHSS after such a rescue protocol has not been considered. To our knowledge, this is the first reported case of severe OHSS following a rescue of EFS. We speculate that our patient subsequently developed severe OHSS following exposure to high doses of biologically active HCG as she was already at high risk of OHSS, having developed .20 follicles. The dosage of HCG she received (10 000 IU) is consistent with our routine policy for women who have ,20 follicles aspirated, whereas we normally give 5000 IU HCG and support the luteal phase with progesterone pessaries if .20 follicles are aspirated. Further evidence is given by our more cautious management of her third cycle when she was again at high risk of OHSS (21 mature follicles at oocyte retrieval). This time we reduced the ovulation triggering dose of HCG to 5000 IU and gave progesterone pessaries for luteal support. She did not develop OHSS. Similar cases of EFS (but without OHSS) have been reported (Zegers-Hochschild et al., 1995; Ndukwe et al., 1997). The serum progesterone concentration (4 nmol/l) obtained on the day of EFS occurrence clearly indicated that the peri-ovulatory events as described by others (Seibel et al., 1982; ItskoizEldor et al., 1993; Ndukwe et al., 1997) had not occurred. This would be consistent with an initial lack of HCG bioactivity. The presence of subsequent HCG bioactivity is supported by the markedly elevated concentration of serum progesterone obtained on the day of the second oocyte retrieval (102 nmol/l).
OHSS after salvage of EFS
We did not have a serum β-HCG result on the day of EFS occurrence to compare with the concentration obtained after the repeat dose of HCG (116 IU/l). Nevertheless, the serum progesterone concentrations obtained on these days (4 versus 102 nmol/l) strongly indicated that the concentration of the serum β-HCG on the day of EFS would have been significantly lower. Retrieval of mature oocytes after the second dose of HCG, subsequent development of severe OHSS and non-incidence of EFS in the first and third cycles suggests that EFS in this case occurred as a result of abnormalities in the bioactivity of a particular batch of HCG rather than an intrinsic patient abnormality. This supports the suggestion (Hassan et al., 1998) that the follicles in EFS are not empty after all, as oocytes were retrieved both from previously aspirated follicles which had refilled, as well as from follicles which were left intact. We speculate further that the low fertilization rate in the second ICSI cycle may reflect compromised oocyte quality caused by a lack of FSH during the inadvertent period of ‘coasting’ which occurred between the first and second HCG administration. Evidence to support our speculation is provided by the decreasing serum oestradiol concentration at this time. The lesson from this case is that the risk of OHSS is unaltered even in the presence of EFS. We therefore suggest taking the usual precautions, including giving the minimum dose of HCG (5000 IU) required to trigger ovulation and administering progesterone for luteal support, when rescuing EFS in patients otherwise considered to be at high risk of OHSS (MacDougall et al., 1992; Schenker, 1993; Mathur et al., 1996; Elchalal and Schenker, 1997).
Meniru, I.G. and Craft, I. (1997) Evidence from a salvaged treatment cycle supports an aetiology for the empty follicle syndrome that is related to terminal follicular developmental events. Hum. Reprod., 11, 2385–2387. Navot, D., Bergh, P.A. and Laufer, N. (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil. Steril., 58, 249–261. Ndukwe, G., Thornton, S., Fishel, S. et al. (1996) Predicting empty follicle syndrome. Fertil. Steril., 66, 845–847. Ndukwe, G., Thornton, S., Fishel, S. et al. (1997) ‘Curing’ empty follicle syndrome. Hum. Reprod., 12, 21–23. Schenker, J.G. (1993) Prevention and treatment of ovarian hyperstimulation. Hum. Reprod., 8, 653–659. Seibel, M.M., Smith, D.M., Levesque, L. et al. (1982) The temporal relationship between luteinizing hormone surge and the human oocyte maturation. Am. J. Obstet. Gynaecol., 142, 568–572. Stewart, J.A., Hamilton, P.J. and Murdoch, A.P. (1997) Upper limb thrombosis associated with assisted conception treatment. Hum. Reprod., 12, 2174–2175. Tsuiki, A., Rose, B.I., and Hung, T.T. (1988) Steroid profiles of follicular fluids from a patient with the empty follicle syndrome. Fertil. Steril., 49, 104–107. Ubaldi, F., Nagy, Z., Janssenwillen, C., et al. (1997) Ovulation by repeated human chorionic gonadotrophin in ‘empty follicle syndrome’ yields a twin clinical pregnancy. Hum. Reprod., 12, 454–456. Zegers-Hochschild, F., Fernandez, E., Mackenna, A. et al. (1995) The empty follicle syndrome: a pharmaceutical industry syndrome. Hum. Reprod., 10, 2262–2265. Received on December 23, 1998; accepted on April 16, 1999
References Asch, R.H., Li, H.P., Yovich, J. et al. (1992) Failed oocyte retrieval after lack of human chorionic gonadotrophin administration in assisted reproductive technology. Fertil. Steril., 58, 361–365. Awonuga, A., Govindbhai, J., Zierke, S. et al. (1998) Continuing the debate on empty follicle syndrome: can it be associated with normal bio-availability of beta-human chorionic gonadotrophin on the day of oocyte recovery? Hum. Reprod., 13, 1281–1284. Ashkenazi, J., Fieldberg, D., Shelef, M. et al. (1987) Empty follicle syndrome: an entity in the aetiology of infertility of unknown origin or a phenomenon associated with purified follicle stimulating hormone therapy? Fertil. Steril., 48, 152–154. Ben-Shlomo, I., Schiff, E., Levran, D. et al. (1991) Failure of oocyte retrieval during in vitro fertilisation: a sporadic event rather than a syndrome. Fertil. Steril., 48, 152–154. Coulam, C.B., Bustillo, M. and Schulman, J.D. (1986) Empty follicle syndrome. Fertil. Steril., 46, 1153–1155. Elchalal, U. and Schenker, J.G. (1997) The pathophysiology of ovarian hyperstimulation syndrome – views and ideas. Hum. Reprod., 12, 1129–1137. Hassan, A.H., Saleh, H.A., Kalil, O. et al. (1998) Double oocyte aspiration may be solution for empty follicle syndrome: case report. Fertil. Steril., 69, 138–139. Itskoiz-Eldor, J., Levron, J. and Kol. S. (1993) Use of gonadotrophin releasing hormone agonist to cause ovulation and prevent the ovarian hyperstimulation syndrome. Clin. Obstet. Gynaecol., 36, 701–710. Khalaf, Y. and Braude, P. (1997) ‘Curing’ empty follicle syndrome (letter). Hum. Reprod., 12, 1601. MacDougall, M.J., Tan, S.L, Jacobs, H.S. (1992) In-vitro fertilization and the ovarian hyperstimulation syndrome. Hum. Reprod., 7, 597–600. Mathur, R.S., Joels, L.A., Akande, V.A., and Jenkins, J.M. (1996) The prevention of ovarian hyperstimulation syndrome. Br. J. Obstet. Gynaecol., 103, 740–746.
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