1 Fertility Centre, St Bartholomew's Hospital, West Smithfield, London, EC1A 7BE, UK and 2 Department of Obstetrics and Gynaecology, St Bartholomew's and The Royal London School of Medicine and Dentistry, Royal London Hospital, Whitechapel, London, E1 1BB, UK
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Abstract |
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Key words: coasting/oestradiol/ovarian hyperstimulation syndrome/ovarian stimulation/ultrasound
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Introduction |
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High serum concentrations of oestradiol (Schenker, 1993; Enskog et al., 1999
), large numbers of follicles (Haning et al., 1984
; Blankstein et al., 1987
; Enskog et al., 1999
) and a large number of oocytes retrieved (Asch et al., 1991
), are associated with increased risk of OHSS. However, none of these factors is completely reliable in predicting OHSS. Consequently, various strategies have been developed in an attempt to prevent severe OHSS, including aspiration of follicles prior to human chorionic gonadotrophin (HCG) administration (Aboulghar et al., 1992
; Egbase et al., 1997
), repeated aspiration of ovarian cysts after oocyte retrieval (Amit et al., 1993
), follicular aspiration of one ovary at, or 1012 h after, HCG administration (Tomazevic and Meden-Vrtovec, 1996
), freezing of all resulting embryos after IVF (Amso et al., 1990
), administration of concentrated human albumin (Asch et al., 1993
), pre-ovarian stimulation ovarian diathermy (Fukaya et al., 1995
; Rimington et al., 1997
; Egbase et al., 1998
) and cycle cancellation before HCG administration (Schenker and Weinstein, 1978
; Forman et al., 1990
). None of these strategies is ideal, as at best (with the exception of cycle cancellation prior to HCG administration) there may be a small reduction in the incidence of OHSS, but all are costly both emotionally and financially.
A report has been made on the `controlled drift period' in patients undergoing ovulation induction who are at risk of OHSS (Urman et al., 1992). This involved withholding gonadotrophin stimulation until serum oestradiol concentrations declined to a certain `safe' level, before the administration of HCG. Others (Sher et al., 1995
) subsequently confirmed the value of this preventative strategynow termed `coasting'as another method for preventing severe OHSS in patients undergoing IVF and embryo transfer. The `coasting' strategies reported so far have been based on routine serum oestradiol measurements in all patients undergoing ovarian stimulation. This, however, is inconvenient to patients and leads to increased costs and workload.
Here, the results of a modified coasting strategy in patients undergoing ovarian stimulation for IVF with or without intracytoplasmic sperm injection (ICSI) are reported. This prospective observational study describes the systematic application of oestradiol measurements only in patients who met preset ultrasound criteria. Subsequently, serum oestradiol concentrations and follicular size dictated the gonadotrophin dose and the timing of HCG administration in these patients.
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Materials and methods |
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If at any stage of ovarian stimulation, a total of >20 follicles (mean diameter 5 mm) was identified on ultrasound scan, the patient was considered to be at increased risk of developing severe OHSS, and a serum oestradiol concentration was obtained. Serum oestradiol was measured by a Bayer immuno-1 automated analyser (Bayer, Newbury, Bucks, UK) with <5% coefficient of variation in the range 7513 200 pmol/l. If serum oestradiol concentrations were <3000 pmol/l, the dose of FSH was maintained. If serum oestradiol concentrations were
3000 pmol/l but <13 200 pmol/l and at least 25% of the total number of follicles had a mean diameter of
13 mm, the FSH dose was halved and monitoring was continued with ultrasound scans and serum oestradiol concentrations every 23 days. If serum oestradiol concentrations were
13200 pmol/l and at least 25% of the follicles had a mean diameter of
15 mm, gonadotrophin injections were withheld. In the coasted group, serum oestradiol concentrations were monitored on a daily basis (except for weekends) and the HCG trigger was withheld until serum oestradiol concentrations declined to <10000 pmol/l.
OHSS was classified into three categories based on clinical symptoms (Navot et al., 1992). Patients were encouraged to contact the centre if they experienced symptoms of OHSS or required hospitalization elsewhere. Pregnant women were followed up until 12 weeks gestation.
Statistical analysis was performed with the aid of the analysis of variation (ANOVA) and Student's t-test for the different parameters. Fisher's and chi-square tests were used to compare proportions; differences seen were considered to be statistically significant if P < 0.05.
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Results |
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The demographic characteristics of the three high-risk groups and the low-risk group are described in Table I. The mean age, baseline FSH concentrations, aetiology of infertility and distribution of primary or secondary infertility (data not shown) were similar in all high-risk groups. The mean BMI was significantly higher in the maintenance group (27.4 ± 6.9kg/m2) and in the reduced group (25.9 ± 4.7kg/m2) compared with the coasted group (23.9 ± 4.3kg/m2; P = 0.03). In the study group (123 cycles), a total of 81 patients were having their first IVF with or without ICSI cycle (15 in the maintenance group, 32 in the reduced group, and 34 in the coasted group). In total, 245 low-risk cycles were in patients having their first IVF with or without ICSI treatment cycle. Seven patients (16.3%) were identified who had previous severe OHSS despite preventative measures, such as freezing all embryos (four patients) and intravenous albumin (all patients). In addition, four further patients had had their cycles abandoned (Table II
).
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There were no cases of moderate or severe OHSS in the 457 cycles that were not considered to be at high risk. Table IV summarizes the incidence of OHSS in the different high-risk groups. Overall, four patients developed moderate OHSS and one patient developed severe OHSS, all being early-onset OHSS (3.3% and 0.8% of the high-risk population and 0.7% and 0.2% of the total cycles respectively). The woman who developed severe OHSS was triggered when the serum oestradiol concentration was >13200 pmol/l, only made known after the HCG trigger injection; thus the HCG was given in violation of the protocol. This was her first cycle of ovarian stimulation for ICSI because of male factor infertility, and the patient was hospitalized for 10 days and required paracentesis and supportive therapy. She did not conceive. There were two women with moderate OHSS in the coasted group, the diagnosis being tubal infertility in one and polycystic ovarian syndrome (PCOS) in the other. There was one case of moderate OHSS in the maintenance group (tubal), and one in the reduced group (male factor and PCOS).
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The treatment outcome is described in Table IV. There was no statistical difference between the groups.
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Discussion |
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Serum oestradiol concentrations 13200 pmol/l in the presence of an adequate number of mature follicles (
15 mm) for the commencement of coasting, and <10000 pmol/l for HCG trigger administration, seemed to be effective in our programme, resulting in a low incidence of moderate and severe OHSS of 0.7% (4/580) and 0.2% (1/580) respectively. In the coasted patients (n = 50) in whom the risk of severe OHSS has been estimated as high as 80% (Asch et al., 1991
), the incidence of moderate and severe OHSS was 4% and 2% respectively. The various ovarian stimulation protocols, types of gonadotrophins used, timing of gonadotrophin administration and serum oestradiol testing (Waldenström et al., 1999
), as well as differences in assay availability of serum oestradiol concentrations, may account for the differences between the results presented here and those of others, and it is advised that each centre should establish its own threshold level for serum oestradiol.
The duration of coasting that is effective in reducing the incidence of severe OHSS without a significant reduction in the number of oocytes retrieved and without affecting pregnancy rate is still to be determined, and has been debated extensively. It has been suggested (Waldenström et al., 1999) that a coasting period of
4 days does not compromise outcome, but longer periods may. It has been suggested that the coasting duration is inversely related to the clinical pregnancy rate (Tortoriello et al., 1998b
), but a `safe' duration of coasting has not been determined. A window for collecting fertilizable oocytes of up to 6 days has been reported (Dhont et al., 1998
). In the current study it was observed that women in the coasted group who conceived were coasted between 2 to 6 days. The coasting interval depends on the serum oestradiol threshold level used for withholding gonadotrophins, and it is notable that others (Benadiva et al., 1997
), using a step-down protocol, withheld gonadotrophins for a mean duration of 1.9 ± 0.9 days but still had to cancel five cycles because of a >20% drop in serum oestradiol after HCG administration.
As more follicles are recruited in response to FSH stimulation, the mass of the granulosa cells increases and the cells gain functional maturation. These two factors, acting synergistically, cause a concomitant increase in serum oestradiol and in, as yet poorly defined, vasoactive substances (Agrawal et al., 1999). Although oestradiol does not cause OHSS, its serum concentrations are currently the best endocrine, albeit surrogate, marker available to estimate the maturing granulosa cell mass function. In the current study, the number of small follicles (<14 mm) was significantly higher in the coasted patients compared with the non-coasted groups, but the number of larger follicles (>14 mm) was lower in this group. This suggests that it is the small and medium (<14 mm) size follicles that are mostly responsible for the high serum oestradiol concentrations (and vasoactive compounds) (Enskog et al., 1999
).
A large number of follicles has been associated with a high risk of developing severe OHSS (Blankstein et al., 1987; Enskog et al., 1999
). In patients who developed a severe form of the syndrome, 95% of pre-ovulatory follicles were <16 mm and most were <9 mm (Enskog et al., 1999
), while others (Navot et al., 1988
) found that patients who developed OHSS had an increased number of follicles measuring 1216 mm and >18 mm.
It has been postulated that follicles of varying sizes have a different threshold to gonadotrophins, with smaller follicles having a higher threshold than larger follicles (Fluker et al., 1999). Therefore, withholding gonadotrophins will initially cause apoptosis of the granulosa cells and atresia of a large number of small follicles. Longer periods of coasting will cause a further reduction in FSH concentrations, followed by atresia of medium-sized follicles. It is plausible that if the FSH concentration falls further, mature follicles (>15 mm) will also undergo atresia, resulting in large follicular cysts with poor-quality oocytes and lower number. We have noticed this phenomenon where, in one case, only one oocyte was collected.
There are other mechanisms that can explain the reduced incidence of severe OHSS in coasted cycles. FSH is known to induce LH receptors on the granulosa cells. Withholding gonadotrophin with the resultant drop in FSH concentrations leads to down-regulation of the LH receptors (Waldenström et al., 1999). This will reduce the number of granulosa cells available for luteinization, hence a reduction in the concentration of vasoactive substances thought to be responsible for OHSS (Sher et al., 1995
). Furthermore, granulosa cell growth is dependent on FSH, and a sharp decline in the FSH concentration may increase the rate of granulosa cell apoptosis (Tortoriello et al., 1998b
) adding to the reduction in vasoactive substances considered to be the initiators of the increased capillary permeability. This may also explain the lower number of oocytes retrieved in coasted patients in the present study.
Various strategies for eliminating or reducing OHSS have been introduced recently, and apart from withholding HCG (with its cost and psychological implications), they have only partially reduced the incidence of severe OHSS. The most widely used strategy of freezing all embryos (Amso et al., 1990) has not been found to prevent OHSS (Salat-Baroux et al., 1990
; Shaker et al., 1996
; Chen et al., 1997
; Queenan et al., 1997
). Furthermore, not all patients have embryos suitable for freezing (Waldenström et al., 1999
). Administering concentrated albumin (Asch et al., 1993
; Shoham et al., 1994
) has also had variable outcome (Mukherjee et al., 1995
; Ng et al., 1995
; Shaker et al., 1996
; Ndukwe et al., 1997
). To determine if coasting is a strategy that will become established as a viable, cost-effective option may require larger, prospective randomized studies. The difficulties in conducting a controlled study in this area (Fluker et al., 1999
) should not preclude centres from reporting on their experience.
In conclusion, the strategy of individualizing ovarian stimulation, vigilance in identifying patients at risk of developing OHSS by ultrasound, and reducing or withholding gonadotrophins depending on serum oestradiol concentrations and ultrasound findings, resulted in a low incidence of moderate (0.7%) and severe (0.2%) OHSS. However, four cases of moderate OHSS were still encountered in the study group (n = 123), indicating the need for further vigilance. The only case that developed severe OHSS was one of the coasted patients and was managed in violation of the protocol without information about serum oestradiol measurements, highlighting the importance of this parameter. Nevertheless, the strategy of coasting has not compromised the clinical pregnancy rate (40.0% per cycle) or the implantation rates (25.6%) in coasted patients, and appears to have reduced inconvenience to patients, costs and workload. Moreover, strict adherence to a defined and simple protocol will enable easier comparison and more meaningful interpretation of results in coasted patients, thus permitting further opportunities to reduce the incidence of severe OHSS.
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Notes |
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References |
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Submitted on June 12, 2000; accepted on October 4, 2000.