The Egyptian IVFET Center, 3, Road 161 Hadayek El-Maadi, Cairo 11431, Egypt
1 To whom correspondence should be addressed. E-mail: ivf{at}link.net
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: assisted reproductive technology/coasting ovarian hyperstimulation syndrome/ovulation induction/prevention
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As we gained more experience with coasting, and the numbers of cycles became very large, we wished to report our experience using coasting with a detailed description of the protocol that reduced the incidence of OHSS. This is a retrospective analysis of a large series of patients at risk of developing severe OHSS who underwent coasting and were successfully managed to prevent the occurrence of OHSS without jeopardizing their chances of pregnancy. Analysis of the data was done to clarify when we stopped HMG and for how many days.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
When patients were considered at risk of developing OHSS, coasting protocol was applied as follows. When the leading follicle reached 16 mm in mean diameter, the HMG injections were stopped and GnRH agonist continued. Daily serum E2 was estimated and HCG was given when serum E2 fell to 3000 pg/ml. Ovum retrieval was performed 36 h after HCG administration. When we first started applying this protocol, before gaining enough experience, some patients (n = 86) were given HCG before the E2 level fell to 3000 pg/ml.
Two embryologists simultaneously examined the follicular fluid to identify the oocytecumulus complexes (OCC). It should be noted that more time and attention was needed in order to identify OCC because of the diminished number of granulosa cells surrounding the oocytes in these cases. The OCC were transferred to tissue culture media and incubated until the time of insemination. Oocyte-denuding and ICSI was done as previously described (Mansour et al., 1996). Embryo transfer was performed 4872 h later replacing two or three embryos according to the patients age and embryo quality. In some cases with previous IVF/ICSI failures, or patients aged
40 years, embryo transfer was done replacing four embryos. Serum
HCG was estimated 2 weeks after embryo transfer and ultrasound was scheduled 3 weeks later for positive cases. For ethical reasons we could not use a group of these patients as a control and expose them to the risk of developing OHSS. All data are presented as mean ± SD, unless otherwise stated.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
The data were analysed according to the number of coasting days into two groups: group I (n = 983) when coasting was done for up to 3 days only, and group II (n = 240) when coasting was done for 4 days. There was no significant difference in the mean age, infertility period, HMG ampoules and E2 level on day of HCG injection (Table I). The numbers of oocytes retrieved and MII oocytes were significantly higher in group I as compared to group II. However, the fertilization rate was not significantly different (P = 0.06). The mean number of embryos transferred was not different. The implantation and clinical pregnancy rates were significantly higher in group I as compared to group II.
When we first started applying this protocol, before gaining enough experience, some patients (n = 86) were given HCG before the E2 level fell to 3000 pg/ml. Their serum E2 on the day of starting coasting and on the day of HCG injection was 6568 ± 2166 and 4817 ± 1268 pg/ml respectively.
Severe OHSS occurred in 16 patients, which is 0.13% (16/12 494) of stimulated cycles and 1.3% (16/1223) of patients at risk of developing OHSS, and these underwent coasting (data are shown in Table II). It should be noted that all patients who developed OHSS were among the early cases to participate in this protocol and were given HCG before the E2 level fellped to <3000 pg/ml. All 16 patients who developed severe OHSS had bilateral enlargements of the ovaries >10 cm and tense ascites. They complained of abdominal pain, dyspnoea, nausea and vomiting. In addition, one patient had severe vulval edema. Active management of these patients was performed using a combination of transvaginal ultrasound-guided aspiration of the ascitic fluid and intravenous fluids and albumin (Aboulghar et al., 1993). Daily monitoring was done for urine output, haematocrit, serum electrolytes, creatinine, liver enzymes and albumin.
|
Analysis of the results was done to compare ICSI outcome with 3 coasting days to 4, 5, 6 and 7 days separately (Table III). The numbers of cases undergoing coasting for 6 and 7 days was too small to be significant, 13 and 7 respectively. Coasting for 4 and 5 days significantly reduced the number of oocytes retrieved, MII oocytes, and the implantation and pregnancy rates. The more days of coasting, the more adverse effects on the results.
|
Two cases of OHSS developed in our centre during this time that were not diagnosed as high risk and did not undergo coasting.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Withholding HMG until E2 level falls to a safe level before giving HCG, known as coasting, was first introduced for non-IVF cycles by Rabinovici et al. (1987). The authors stopped HMG for 210 days to rescue 12 cycles that were at risk of OHSS. This idea was also applied in an attempt to avoid cancellation of 40 cycles in PCO patients with impending OHSS (Urman et al., 1992
). The authors withheld gonadotrophins and followed the patients by daily E2 and ultrasound. After a drift period of 2.8 days, HCG was given and only one patient developed OHSS. The idea of coasting in IVF cycles was advocated by Sher et al. (1993
, 1995
) when they withheld gonadotrophins between 4 and 9 days in 68 patients until E2 levels fell to <3000 pg/ml. In their work they produced 27 viable pregnancies and none of the patients developed severe OHSS. Another study reported coasting in 66 patients at risk of developing OHSS, but only four patients developed OHSS (Ben-Nun et al., 1993
).
Coasting is widely used by many IVF centres and a number of publications have appeared in the literature, demonstrating that coasting was effective in reducing OHSS (Benadiva et al., 1997; Awonuga et al., 1997
; Dhont et al., 1998
; Lee et al., 1998
; Waldenstrom et al., 1999
; Aboulghar et al., 2000
; Ohata et al., 2000
; Al-Shawaf et al., 2001
, 2002
; Egbase et al., 2002
).
Despite the large number of studies available in the literature about coasting, there are no definite criteria for a specific protocol on how to apply it (Delvigne and Rozenberg, 2002a; Ulug et al., 2004
).
In this work we aimed at reporting our experience in detail for a large series of coasted patients. Analysis of our data was done to clarify some practical points: (i) when we stopped HMG; (ii) how many days of coasting; (iii) special laboratory precautions for coasted patients.
The timing of stopping HMG and starting coasting is very important. In our study coasting was started according to the size of the leading follicles rather than the level of E2. When the leading follicles reached 16 mm in mean diameter, HMG was stopped. After stopping the HMG, the follicles continued to grow while the E2 first increased and then started falling. We then waited as long as it took (27 days) for the E2 to fall to 3000 pg/ml before giving HCG. Large follicles (pre-ovulatory) have the function of maximizing the diminishing circulating gonadotrophins, and they continue to enlarge despite the diminished levels of gonadotrophins (Sher et al., 1993). If HMG is stopped earlier when the leading follicles are <16 mm in mean diameter they undergo atresia. It was demonstrated that mature follicles can survive for a few days without exogenous FSH/HMG, while small follicles will undergo apoptosis/necrosis (Garcia-Velasco et al., 2004
). Gonadotrophins up-regulate gonadotrophin receptors and also inhibit granulosa cell apoptosis (Chun et al., 1996
). Accordingly, during coasting, the small immature follicles, being less receptive to FSH, will undergo arrest and necrosis. It has been recently demonstrated that when coasting was started early, the percentage of mature oocytes was smaller compared with late onset of coasting (Ulug et al., 2004
).
The number of days without HMG that is needed before giving HCG is variable. Different investigators withheld HMG from 2 to 9 days (Sher et al., 1993, 1995; Aboulghar et al., 2000
; Al-Shawaf et al., 2001
). We did not limit the duration of coasting to an arbitrary number of days. Instead, we allowed patients to coast until their E2 reached safe levels As soon as it fell to <3000 pg/ml, HCG was given. A more sensitive method was investigated to determine when to decrease, or even stop, HMG injections (Al-Shawaf et al., 2002
) by measuring E2 and FSH levels. It was found that FSH decreased by 25% during the coasting period, and
5 mIU/ml was safe to trigger ovulation. Therefore reduction of circulating FSH may be the mechanism of reducing OHSS (Meldrum, 2002
), which can take from 2 to 9 days. Furthermore, it was demonstrated that the duration of coasting did not have an impact on the IVF outcome (Delvigne and Rozenberg 2002b). It has also been demonstrated that the rate of decrease in E2 level during coasting was not important (Ulug et al., 2004
). The authors concluded that the criteria for initiating coasting can be flexible, and once follicles passed the threshold of increasing in size, irrespective of E2 level, coasting can be started without compromising the outcome (Ulug et al., 2004
). Similarly it has been found that the rate of E2 decrease did not alter the pregnancy rate (Delvigne and Rozenberg, 2002b
). However, in one study (Isaza et al., 2002
), it has been suggested that if coasting required >5 days, or if an abrupt fall was observed in serum E2 levels (<1000 pg/ml), the oocyte quality might be affected. Other studies demonstrated that prolonged coasting for >4 days reduced IVF outcome (Tortoriello et al., 1998
; Izaza et al., 2002). In our study the number of coasting days affected the ICSI outcome. When coasting was done for >3 days, the mean number of oocytes retrieved, the implantation and clinical pregnancy rates were significantly reduced. The more the days of coasting, the more pronounced the adverse effects on the results. In 80% of the coasted cases, the E2 level fell to <3000 pg/ml in <4 days (group I). Only 20% of the cases needed
4 days for the E2 level to fall to <3000 pg/ml (group II). Although the implantation and clinical pregnancy rates were significantly reduced in group II, this group of patients achieved a 36% clinical pregnancy rate, which is very acceptable. However, because safety comes first, we should not be restricted by the number of coasting days and give HCG before the E2 level falls to <3000 pg/ml.
The OHSS cases that occurred during the 5 year period of this study were given HCG before E2 fell to 3000 pg/ml. These cases were among the first to participate in this protocol of coasting, before we gained enough experience. It is interesting to note that there were two cases of OHSS in our centre during this time that were not diagnosed to be high risk and did not undergo coasting. In both of them the E2 level did not exceed 3000 pg/ml. This protocol of coasting was very effective in markedly reducing the incidence of severe OHSS in our centre. During the 5 year period of this study, controlled ovarian stimulation was performed in 12 494 ICSI cycles and only 16 patients developed OHSS (0.13%), and it was only 1.3% in patients who were at risk of developing OHSS. It should be noted, however, that all these 16 cases were patients with polycystic ovary syndrome (PCOS). It is well recognized that patients with PCOS are more prone to develop OHSS (Bider et al., 1989; Navot et al., 1992
; Aboulghar and Mansour, 2003
). It is also important to note that all these 16 cases received HCG when the E2 level was >3000 pg/ml (4916 ± 2704) after coasting.
In the laboratory, these coasted patients needed extra time and care. It should be noted that the OCC could not be visualized easily due to the diminished number of granulosa cells around the oocytes. It is advisable to have two embryologists working simultaneously during the oocyte retrieval procedure to identify the OCC. Otherwise no special precautions were required in the ovum retrieval technique itself.
The pathogenesis of OHSS is not fully understood. However, the condition is triggered with HCG and is associated with very high E2 levels and a series of events that leads to increased capillary permeability and extravasations of fluid in the abdominal cavity (Rizk and Aboulghar, 1999). There are different mediators such as elevation of plasma rennin activity (Haning et al., 1985
), proinflammatory cytokines such as interleukin-6 and interleukin 1
(Fredhlander et al., 1993
), and vascular endothelial growth factor (VEGF) (Mclure et al., 1994
). In coasting, HMG is withheld and GnRH agonist is continued until E2 levels fall and possibly all other associated mediators will fall as well. Very recently an interesting study was published investigating the mechanism of coasting (Garcia-Velasco et al., 2004
). The authors demonstrated that the granulosa cells aspirated from coasted patients showed a ratio in favour of apoptosis, especially in smaller follicles. They also demonstrated that coasting reduces VEGF protein secretion and gene expression in granulosa cells especially in small and medium follicles. The idea of selectively inducing atresia in this follicle population without altering the delicate equilibrium with large mature follicles is the main factor in coasting (Garcia-Velasco et al., 2004
). It has been demonstrated that the small and medium-sized follicles are responsible for the high E2 concentration and vasoreactive compounds (Al-Shawaf et al., 2001
). Recently, a new therapeutic modality was introduced through the use of LH at the end of follicular maturation (Filicori et al., 2002
). It selectively induces atresia in a small follicle population and stimulates the growth of large follicles.
In vitro maturation of oocytes (IVM) has also been proposed recently as an alternative for prevention of OHSS in patients with PCOS (Child et al., 2002). The IVM pregnancy rate and live birth rates per retrieval were 26.2 and 15.9% compared to 38.3 and 26.2% for IVF. Compared to IVM, coasting allows in vivo maturation of the oocyte and results in a very satisfactory outcome. Why should we retrieve immature oocytes at the GV stage and mature them in vitro to reach the MII stage when we can allow complete maturation in vivo during the days of coasting, and in the mean time the E2 level will fall to a safe level?
In conclusion, the very small incidence of OHSS in this large-sized study adds to the existing indirect evidence of the efficacy of coasting in the prevention of OHSS. The protocol used in our centre started coasting for patients at risk according to the size of the leading follicles rather than the level of E2. The duration of coasting was determined according to the level of E2 to allow it to fall to a safe level. Special attention was given in the laboratory to give extra time and care for finding the OCC from coasted patients because they can be easily missed due to the diminished number of granulosa cells around the oocytes. The pregnancy rate was affected adversely as the number of coasting days increased; nevertheless, in the interests of safety it is recommended to wait until E2 falls to <3000 pg/ml.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aboulghar MA and Mansour RT (2003) Ovarian hyperstimulation syndrome: classifications and critical analysis of preventive measures. Hum Reprod Update 3,27589.[CrossRef]
Aboulghar MA, Mansour RT, Serour GI, Sattar M, Amin Y and Elattar I (1993) Management of severe ovarian hyperstimulation syndrome by ascetic fluid aspiration and intensive intravenous fluid therapy. Obstet Gynecol 81,108111.[Abstract]
Aboulghar MA, Mansour RT, Serour GI, Rhodes CA and Amin YM (2000) Reduction of human menopausal gonadotrophin dose followed by coasting in prevention of severe ovarian hyperstimulation syndrome. J Assist Reprod Genet 17,298301.[CrossRef][ISI][Medline]
Al-Shawaf T, Zosmer A, Hussain S, Tozer A, Panay N, Wilson C, Lower AM and Grudzinkas JG (2001) Prevention of severe ovarian hyperstimulation syndrome in IVF with or without ICSI and embryo transfer: a modified coasting strategy based on ultrasound for identification of high-risk patients. Hum Reprod 16,2430.
Al-Shawaf T, Zosmer A, Tozer A, Gillott C, Lower AM and Grudzinskas JG (2002) Value of measuring serum FSH in addition to serum estradiol in a coasting programme to prevent severe OHSS. Hum Reprod 17,12171221.
Asch RH, Ivery G, Goldsman M, Frederick JL, Stone SC and Balmaceda JP (1993) The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome. Hum Reprod 8,10151020.
Awonuga AO, Pittrof RJ, Zaidi J, Dean N, Jacobe HS, Benadiva CA, Davis O, Kligman I, Moomjy M, Liu H-C and Rosenwaks Z (1997) Withholding gonadotrophin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 67,724727.[CrossRef][ISI][Medline]
Benadiva CA, Davis O, Kligman I, Moomjy M, Liu H-C and Rosenwaks Z (1997) Withholding gonadotrophin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 67,724727.[CrossRef][ISI][Medline]
Ben-Nun I, Shulman A, Ghetler Y, Shilon M, Maneti H and Beyth Y (1993) The significance of 17-estradiol levels in highly responding women during ovulation induction in IVF treatment: its impact and prognostic value with respect to oocyte maturation and treatment outcome. J Assist Reprod Genet 10,213215.[CrossRef][ISI][Medline]
Bider D, Menashe Y, Oelsner G, Serr DM, Mashiach S and Ben-Rafael Z (1989) Ovarian hyperstimulation due to exogenous gonadotrophin administration. Acta Obstet Gynecol Scand 68,511514.[ISI][Medline]
Bornestein R, Elhalah U, Lunenfeld B and Schwartz ZS (1989) Severe ovarian hyperstimulation syndrome: a reevaluated therapeutic approach. Fertil Steril 51,791795.[ISI][Medline]
Child TJ, Phillips SJ, Abdul-Jalil AK, Gulekli B and Tan SL (2002) A comparison of in vitro maturation and in vitro fertilization for women with polycystic ovaries. Obstet Gynecol 100,665670.
Chun S, Eisenhauer K, Minami S, Billig H, Perlas E and Hsueh A (1996) Hormonal regulation of apoptosis in early astral follicles: follicle-stimulating hormone as a major survival factor. Endocinology 137,14471456.[Abstract]
Delvigne A and Rozenberg S (2001) Preventive attitude of physicians to avoid OHSS in IVF patients. Hum Reprod 16,24912495.
Delvigne A and Rozenberg S (2002a) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 8,559577.
Delvigne A and Rozenberg S (2002b) A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update 8,291296.
Dhont M, Van der Straeten F and De Sutter P (1998) Prevention of severe ovarian hyperstimulation by coasting. Fertil Steril 70,847850.[CrossRef][ISI][Medline]
Egbase PE, Al Sharhan M and Grudzinskas JG (2002) Early coasting in patients with polycystic ovarian syndrome is consistent with good clinical outcome. Hum Reprod 17,12121216.
El-Sheikh MM, Hussein M, Fouad S, El-Sheikh R, Bauer O and Al-Hasani S (2001) Limited ovarian stimulation (LOS), prevents the recurrence of severe forms of ovarian hyperstimulation syndrome in polycystic ovarian disease. Eur J Obstet Gynecol Reprod Biol 94,245249.[CrossRef][ISI][Medline]
Filicori M, Cognini GE, Tabarelli C, Pocognoli P, Taraborrelli S, Spettoli D and Ciampaglia W (2002) Stimulation and growth of antral ovarian follicles by selective LH activity administration in women. J Clin Endocrinol Metab 87,11561161.
Fredhlander MA, De Mola JR and Goldfarb JM (1993) Elevated levels of interleukin 6 in ascites and serum from women with ovarian hyperstimulation syndrome. Fertil Steril 60,827.
Garcia-Velasco JA, Isaza V, Vidal C, Landazábal A, Remohi J, Simon C and Pellicer A (2004) Human ovarian steroid secretion in vivo: effects of GnRH agonist versus antagonist (cetrorelix). Hum Reprod 16,25332539.[CrossRef]
Golan A, Ron-El R, Herman A, Weinraub Z, Soffer Y and Caspi E (1988) Ovarian hyperstimulation syndrome following -Trp-6 luteinising hormone releasing hormone microcapsules and menotrophin for in vitro fertilization. Fertil Steril 50,912916.[ISI][Medline]
Haning RV, Strawn EY and Nolten WE (1985) Pathophysiology of ovarian hyperstimulation syndrome. Obstet Gynecol 66,220224.[Abstract]
Isaza V, Garcia-Velasco JA, Aragones M, Remhi J, Simon C and Pellicer A (2002) Oocyte and embryo quality after coasting: the experience from oocyte donation. Hum Reprod 17,17771782.
Lee C, Tummon I, Martin J, Nisker J, Power S and Tekpetey F (1998) Does withholding gonadotrophin administration prevent severe ovarian hyperstimulation syndrome? Hum Reprod 13,11571158.[Abstract]
Macklon NS and Fauser BC (2000) Gonadotropin therapy for the treatment of anovulation and for ovarian hyperstimulation for IVF. Mol Cell Endocrinol 55,159161.[CrossRef]
Mansour RT, Aboulghar MA, Serour GI, Fahmy I, Ramzi AM and Amin YM (1996) Intracytoplasmic sperm injection using microsurgically retrieved epididymal sperms and testicular sperm. Fertil Steril 95,566572.
Mclure N, Healy D, Rogerrs P, Sullivan J, Beaton L, Haning RV Jr, Conolly D and Robertson DM (1994) Vascular endothelial growth factors as capillary permeability agent in ovarian hyperstimulation. Lancet 344,236.
Meldrum D (2002) Vascular endothelia growth factor, polycystic ovary syndrome, and ovarian hyperstimulation syndrome. Fertil Steril 78,11701171.[CrossRef][ISI][Medline]
Navot D, Bergh PA and Laufer N (1992) Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 58,249261.[ISI][Medline]
Ohata Y, Harada T, Ito M Yoshida S, Iwabe T and Terakawa N (2000) Coasting may reduce the severity of the ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome. Gynecol Obstet Invest 50,186188.[CrossRef][ISI][Medline]
Rabinovici J, Kushnir O, Shalev J, Goldenberg M and Blankstein J (1987) Rescue of menotropin cycles prone to develop ovarian hyperstimulation. Br J Obstet Gynecol 94,10981102.[ISI][Medline]
Rizk B and Aboulghar MA (1999) Classification, pathophysiology, and management of ovarian hyperstimulation syndrome. In Brinsden P (ed) In-Vitro Fertilization and Assisted Reproduction. Parthenon Publishing, New York/London, pp 131155.
Rizk B and Smitz J (1992) Ovarian hyperstimulation syndrome after superovulation for IVF and related procedures. Hum Reprod 7,320327.[Abstract]
Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y and Aboulghar H (1998) Complications of medically assisted conception in 3,500 cycles. Fertil Steril 4,638642.[CrossRef]
Sher G, Salem R, Feinman M, Dodge S, Zouves C and Knotzen V (1993) Eliminating the risk of life-endangering complications following overstimulation with menotropin fertility agents: a report on women undergoing in vitro fertilization and embryo transfer. Obstet Gynecol 81,10091011.[Abstract]
Sher G, Zouves C, Feinman M and Maassarani G (1995) Prolonged coasting: an effective method for preventing severe ovarian hyperstimulation syndrome in patients undergoing in-vitro fertilization. Hum Reprod 10,31073109.[Abstract]
Tortoriello DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K and Santoro N (1998) "Coasting" does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 69,454460.[CrossRef][ISI][Medline]
Ulug U, Ben-Shlomo I and Bahceci M (2004) Predictors of success during the coasting period in high-responder patients undergoing controlled ovarian stimulation for assisted conception. Fertil Steril 82,338342.[CrossRef][ISI][Medline]
Urman B, Pride SM and Ho Yuen B (1992) Management of overstimulated gonadotrophin cycles with a controlled drift period. Hum Reprod 7,213217.[Abstract]
Waldenstrom U, Kahn J, Marsk L and Nilsson S (1999) High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by prolonged coasting of very hyperstimulated patients: a multicentre study. Hum Reprod 14,294247.
Wheelan JG III and Vlahos NF (2000) The ovarian hyperstimulation syndrome. Fertil Steril 73,883896.[CrossRef][ISI][Medline]
Submitted on June 11, 2005; resubmitted on May 25, 2005; accepted on May 31, 2005.
|