Coasting—what is the best formula?

O. Levinsohn-Tavor, S. Friedler, M. Schachter, A. Raziel, D. Strassburger and R. Ron-El1

IVF and Infertility Unit, Department of Obstetrics and Gynecology, Assaf-Harofeh Medical Center, Zerifin, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

1 To whom correspondence should be addressed. rronel{at}asaf.health.gov.il


    Abstract
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Coasting is a method to decrease the incidence of ovarian hyperstimulation syndrome (OHSS), which involves withdrawing exogenous gonadotrophins until the serum estradiol (E2) level decreases. The application of this strategy, as it appears in the literature, has been variable, with heterogeneous criteria for initiating and ending the coasting process and as a result, reports of efficacy are inconsistent. In attempt to establish a recommended protocol for coasting we reviewed and analysed 10 relevant studies, found by a Medline search. Based on the data collected, coasting should be initiated when the serum E2 concentration exceeds 3000 pg/ml, but not unless the leading follicles reach a diameter of 15–18 mm. Its duration should be limited to <4 days, thus, preventing the decrease in implantation and pregnancy rates that occur after longer periods of coasting. Administration of hCG should be withheld until serum E2 falls below 3000 pg/ml. Based on the published data, these suggested guidelines result in an acceptably low incidence of severe OHSS (<2%) and provide satisfactory fertilization and pregnancy rates (55–71% and 36.5–63% respectively). A multicentre randomized prospective study would help to confirm the effectiveness of this approach.

Key words: coasting/guidelines/IVF/ovarian hyperstimulation syndrome


    Introduction
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Coasting is a strategy for the prevention of severe ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. It involves withdrawing exogenous gonadotrophins and postponing hCG administration until the patient’s serum estradiol (E2) level decreases to a ‘safer’ level. Coasting was first described by Rabinovici et al. (1987Go) and was first applied in IVF by Sher et al. (1993Go). Different studies employed different cut-off limits for serum E2 concentrations and leading follicle size for initiating and ending of the coasting period. The reported efficacy of preventing severe OHSS has not been uniformly consistent, probably due to the different criteria for using coasting. Although most studies support its use, the optimal coasting procedure regarding these cut-off limits and the maximal duration of the process without adverse effect on success rate, remain obscure. We reviewed the literature in an attempt to establish the optimal protocol for coasting.


    When should coasting be employed?
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Coasting should be considered in patients with excessive follicular response to ovarian stimulation by gonadotrophins, who are anticipated to be at risk of developing severe OHSS. Since the size of the active granulosa cell population determines the incidence and severity of OHSS (Asch et al., 1993Go), monitoring of plasma E2 concentration and the number of follicles help to identify patients at risk. When serum E2 is >3000 pg/ml and more than 30 follicles are seen by ultrasound, the risk of severe OHSS is elevated (Asch et al., 1991Go) and coasting should be considered.


    Methods
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
We used a Medline search (Webspirs Silver Platter Information N.V. Version 4.3 Build 20001206) to find studies evaluating the outcome of IVF cycles in patients at risk for OHSS, in whom coasting was implemented in their treatment (Table I). The studies were heterogeneous in their design, selection criteria for coasting, patients’ characteristics and control groups. Therefore, to attempt meta-analysis was inappropriate. A qualitative review of the relevant articles was done in order to find recommended guidelines for coasting based on the data available. All coasted patients in the studies reviewed were treated by long protocol, except in one study, which used a short protocol (Dhont et al., 1998Go). Pituitary down-regulation was carried out using GnRH analogue (short-acting preparations in all studies, except two which lack this information). hMG or recombinant FSH were used for ovarian stimulation, with initial doses individualized according to patients’ characteristics. hCG was administered at a dose of 5000 or 10 000 IU. All patients received progesterone supplementation i.m. or by vaginal suppositories for luteal support.


View this table:
[in this window]
[in a new window]
 
Table I. Comparison of criteria used for coasting
 

    When to initiate and terminate coasting by administering hCG?
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Three factors should be considered; plasma E2 concentration (which reflects the total functional granulosa cell population), the number of ovarian follicles (which predicts the potential for further granulosa cell proliferation and rise in E2) and the diameter of the leading follicles. Table I summarizes criteria of the reviewed reports.

Most of the clinicians publishing their experience with coasting chose to initiate the procedure at an E2 concentration of 2500–3000 pg/ml (Sher et al., 1995Go; Benavida et al., 1997Go; Dhont et al., 1998Go; Lee et al., 1998Go; Tortoriello et al., 1998Go; Fluker et al., 1999Go; Al-Shawaf et al., 2001Go). This relatively low threshold for coasting has proven to be effective in reducing the incidence of OHSS without compromising the cycle outcome. Higher cut-off levels (such as 6000 pg/ml) are associated with higher incidence of OHSS and the need for longer periods of coasting, leading to a lower pregnancy and implantation rate (Waldenstrom et al., 1999Go).

One should remember that even after withholding exogenous gonadotrophins, there is an additional subsequent rise in serum E2 for 1–2 days (Sher et al., 1995Go; Fluker et al., 1999Go; Egbase et al., 2000Go) and increase in follicular diameter. When Sher et al. (1995Go) initiated coasting at a plasma E2 level of >3000 pg/ml, the peak plasma concentration rose to > 6000 pg/ml during the coasting period.

Administrating hCG with an E2 level below 2500–3000 pg/ml, has also proven effective, placing the women at lower risk for OHSS (Sher et al., 1995Go; Benavida et al., 1997Go; Dhont et al., 1998Go; Tortoriello et al., 1998Go; Al-Shawaf et al., 2001Go). Dhont et al. (1998Go) compared a coasting group with a control group, both having similar number of follicles (24) and maximum E2 level (3830 pg/ml). On the day of hCG administration E2 concentration was 2348 pg/ml in the coasted group and 3833 pg/ml in the control group. Only one patient developed severe OHSS in the coasted group, compared with nine patients in the control group. When an appropriate threshold for administrating hCG is determined, serum E2 should be followed and not be allowed to fall too low below it. Waldenstrom et al. (1999Go) reported two cases in which hCG administration was delayed for an additional day after serum E2 had dropped below the threshold level (2724 pg/ml), leading to vaginal bleeding and cycle cancellation. In three other cases, serum E2 was allowed to fall below 272 pg/ml, resulting in the retrieval of only one to three oocytes of poor quality.

The size of the leading follicle is of importance because only follicles larger than a threshold size (diameter of >15 mm) can continue to grow for an interval without gonadotrophin support. It has been shown that after early withdrawal of gonadotrophins, when the leading follicle reached >=15 mm, follicular growth continued to a size of >18 mm, with normal fertilization, cleavage and clinical pregnancy rates (Egbase et al., 2002Go). Oocytes in smaller follicles may undergo maturation arrest or atresia following gonadotrophin withdrawal. If too many follicles are larger than the threshold size, cystic follicles and poor quality oocytes could result (Sher et al., 1995Go). In most studies the leading follicles reached 15–18 mm before initiating coasting, but optimal follicle threshold measurements is yet to be determined.


    What is the duration of coasting which is advantageous without compromising conception rate?
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Ulug et al. (2002Go) found that coasting for >=4 days reduces the implantation and pregnancy rate, while oocyte quality does not appear to be affected. Isaza et al. (2002Go) compared cycle outcome in recipients of oocyte donation, from donors who were initiated coasting, and donors who did not. The outcome of oocyte donation from donors undergoing coasting was not impaired, with comparable implantation and pregnancy rates. However, if coasting duration was >4 days a significant decrease in both implantation and pregnancy rates was found (37.5 versus 72.2% and 11.3 versus 30.5%, respectively). Waldenstrom et al. (1999Go) included in their study only patients with a minimum coasting period of 3 days. In a subgroup of patients with coasting periods of 3–4 days the pregnancy rate was 58% and when the coasting period reached 5–6 days, pregnancy rate decreased to 31%. Again, it was concluded, that coasting of <=4 days does not compromise cycle outcome. Tortoriello et al. (1998Go) also reported a lower implantation rate in a subgroup of coasted patients whose coasting interval was one day longer than a mean duration of 2.6 days. Other reports showed good pregnancy rates with longer coasting periods (mean 4.9–6.1 days, ranging up to 11 days), but did not analyse the results according to the interval of coasting (Sher et al., 1995Go; Egbase et al., 1999Go).

Although prolonged coasting (up to 11 days) was applied with acceptable pregnancy rates, when results were analysed according to the length of coasting, a duration of more than 4 days had less favourable outcome. Because comparable fertilization and cleavage rates were found among the groups of different coasting duration, it is likely that the interval of coasting mainly affects endometrial receptivity (Ulug et al., 2002Go).

The duration of coasting is determined by the serum E2 level and the diameter of the leading follicles when coasting is initiated. The larger the follicles are and the higher the serum E2 is, the longer the coasting period will be before reaching the target threshold of E2 for administrating hCG. If coasting is initiated when the largest follicles are not more than 17–18 mm and E2 concentration is not more than 6000 pg/ml, coasting periods of >4 days can be avoided (Waldenstrom et al., 1999Go; Egbase et al., 2000Go).


    How successful is coasting in decreasing the incidence of OHSS?
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Severe OHSS is a serious complication of gonadotrophin administration, occurring in 0.5–2% of patients undergoing ovarian stimulation for IVF. The technique of coasting is used in patients at risk who are more likely to develop severe OHSS. Most studies demonstrate a low incidence of severe OHSS (<2%) in high-risk patients managed with coasting (Sher et al., 1995Go; Benavida et al., 1997Go; Dhont et al., 1998Go; Tortoriello et al., 1998Go; Fluker et al., 1999Go; Waldenstrom et al., 1999Go; Al-Shawaf et al., 2001Go; Egbase et al., 2002Go; Ulug et al., 2002Go). As shown in Table II the efficacy of coasting in decreasing severe OHSS is high but two studies found an exceptionally higher incidence of severe OHSS as compared to the others. Lee et al. (1998Go) treated 20 patients with coasting, which resulted in severe OHSS in 4 (20%). The hCG was administered as soon as serum E2 started to decrease with no specific threshold level mentioned. The hCG may have been administered too early to prevent OHSS. Egbase et al. (1999; 2000), in two different studies, demonstrated a high incidence of severe OHSS in patients treated with coasting (20%). The criteria for withholding the gonadotrophins were serum E2 >6000 pg/ml (exceedingly higher than other studies) and more than 15 follicles in each ovary. At such an advanced stage of overstimulation of the ovary, the granulosa cell mass may have become too large for the full effect of coasting to be achieved. Although coasting allowed serum E2 to fall below 3000 pg/ml, severe OHSS occurred, possibly because synthesis of vasoactive substances have already been induced. The development of more specific biochemical markers for prediction of OHSS could increase the efficacy of coasting in prevention of OHSS.


View this table:
[in this window]
[in a new window]
 
Table II. Comparison of the outcome in coasted cycles
 
According to Asch et al. (1991Go) when pre-ovulatory peak plasma E2 concentration exceeds 6000 pg/ml and more than 29 follicles are seen on sonogram, the risk of severe OHSS is >80%. Therefore, even the result of 20% severe OHSS in Egbase’s reports, could be regarded as an improvement after coasting.


    Conclusion
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Ovarian hyperstimulation syndrome is an iatrogenic and serious complication in IVF programmes and several approaches have been suggested to prevent it. The most successful prevention is by cancellation of the cycle before administration of hCG, but this approach has significant financial and emotional costs to the patient. A widely used strategy is cryopreservation of all embryos (Amso et al., 1990Go). However, this does not prevent the early form of OHSS and generally yields inferior pregnancy rates compared with fresh embryo transfer. The technique of coasting is appealing to both physicians and patients because it allows transfer of fresh embryos, without additional treatment cycles.

Coasting has proven to be an effective method to minimize the development of severe OHSS in a high-risk population. It addresses the fundamental event that leads to OHSS which is the excess of proliferation and activation of granulosa cells. Removing the FSH stimulation of granulosa cells inhibits their proliferation causing down regulation of their LH receptors, reducing the number of granulosa cells available for luteinization. It has been suggested that a sharp decline in the FSH concentration may increase the rate of granulosa cell apoptosis (Tortoriello et al., 1998Go). Withholding gonadotrophins will initially cause accelerated apoptosis of the granulosa cells and atresia of a large number of small follicles. It is the small follicles that are mostly responsible for the high serum E2 concentration and vasoactive compounds (Enskog et al., 1999Go). The end result is reduction of chemical mediators or precursors that augment fluid extravasation. As a result of the effects described above coasting leads to reduced number of retrieved oocytes, which is in direct relationship to the duration of coasting. However, there is no significant difference in oocyte maturity, fertilizability and cleavage rate (Dhont et al., 1998Go; Ulug et al., 2002Go). Information about the oocyte and embryo quality in coasted patients is not available in most reports but comparable fertilization, cleavage and pregnancy rates suggest no significant impairment of quality of the oocytes obtained. A recent study showed no difference in embryo quality between embryos obtained from oocyte donors who underwent coasting and embryos obtained from donors who did not (Isaza et al., 2002Go). Because candidates for coasting are high responders and have numerous follicles, many oocytes are still obtained after coasting, often leaving a large number of embryos for cryopreservation.

In this review we suggest some useful guidelines for management of high-risk patients by coasting. With appropriate use this method is effective in preventing severe OHSS and yet provides high pregnancy rates. An important decision to be made is the threshold level of E2 concentration at which coasting should be initiated. We recommend a limit of 3000 pg/ml since it leads to effective prevention of OHSS and keeps the overall duration of the coasting <4 days, which is safe and does not reduce implantation or pregnancy rates. However, coasting should not begin unless the leading follicles reach a diameter of 15–18 mm. It is important to delay hCG administration until the plasma E2 concentration falls below 3000 pg/ml. Failure to do so could lead to the false impression that coasting does not prevent OHSS. A large randomized prospective trial would help to validate the effectiveness of the suggested protocol.


    FOOTNOTES
 


    References
 Top
 Abstract
 Introduction
 When should coasting be...
 Methods
 When to initiate and...
 What is the duration...
 How successful is coasting...
 Conclusion
 References
 
Al-Shawaf, T., Zosmer, A., Hussain, S., Tozer, A., Panay, N., Wilson, C., Lowen, A.M. and Grudzinskas, J.G. (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, 24–30.[Abstract/Free Full Text]

Amso, N.N., Ahuja, K.K., Moris, N. and Shaw, R.W. (1990) The management of predicted ovarian hyperstimulation involving gonadotrophin-releasing hormone analogue with elective cryopreservation of all pre-embryos. Fertil. Steril., 53, 1087–1090.[ISI][Medline]

Asch, R.H., Li H.P., Balmaceda, J.P., Weckstein, L.N. and Stone, S.C. (1991) Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Hum. Reprod., 10, 1395–1399.

Asch, R., Ivery, G., Goldsman, M., Fredrick, J.L., Stone, S.C. and Balmaceda, J.P. (1993) The use of intravenous albumin in patients at high risk of ovarian hyperstimulation syndrome. Hum. Reprod., 8, 1015–1020.[Abstract]

Benavida, C.A., 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, 724–727.[CrossRef][ISI][Medline]

Dhont, M., Van der Straeten, F. and De Sutter, P. (1998) Prevention of severe ovarian hyperstimulation by coasting. Fertil. Steril., 70, 847–850.[CrossRef][ISI][Medline]

Egbase, P.E., Al Sharhan, M. and Grudzinskas, J.G. (1999) Early unilateral follicular aspiration compared with coasting for the prevention of severe ovarian hyperstimulation syndrome: a prospective randomized study. Hum. Reprod., 14, 1421–1425.[Abstract/Free Full Text]

Egbase, P.E., Al Sharhan, M., Berlingieri, P. and Grudzinskas, J.G. (2000) Serum estradiol and progesterone concentrations during prolonged coasting in 15 women at risk of ovarian hyperstimulation syndrome following ovarian stimulation for assisted reproductive treatment. Hum. Reprod., 15, 2082–2086.[Abstract/Free Full Text]

Egbase, P.E., Al Sharhan, M. and Grudzinskas, J.G. (2002). ‘Early coasting’ in patients with polycystic ovarian syndrome is consistent with good clinical outcome. Hum. Reprod., 17, 1212–1216.[Abstract/Free Full Text]

Enskog, A., Henriksson, M., Unander, M., Nilsson, L. and Brannstrom, M. (1999) Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil. Steril., 71, 808–814.[CrossRef][ISI][Medline]

Fluker, M.R., Hooper, W.M. and Yuzpe, A.A. (1999) Withholding gonadotrophin (‘coasting’) to minimize the risk of ovarian hyperstimulation during superovulation and in vitro fertilization-embryo transfer cycles. Fertil. Steril., 71, 294–301.[CrossRef][ISI][Medline]

Isaza, V., Garcia-Velasco, J.A., Aragones, M., Remohi, J., Simon, C. and Pellicer, A. (2002) Oocyte and embryo quality after coasting: the experience from oocyte donation. Hum. Reprod., 17, 1777–1782.[Abstract/Free Full Text]

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, 1157–1158.[Abstract]

Rabinovici, J., Kushnir, O., Shalev, J., Goldenberg, M. and Blankstein, J. (1987) Rescue of menotrophin cycles prone to develop ovarian hyperstimulation. Br. J. Obstet. Gynaecol., 94, 1098–1102.[ISI][Medline]

Sher, G., Salem, R., Feinman, M., Dodge, S., Zouves, C. and Knutzen, V. (1993) Eliminating the risk of life-endangering complications following overstimulation with menotrophin fertility agents: a report on women undergoing in vitro fertilization and embryo transfer. Obstet. Gynecol., 81, 1009–1011.[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, 3107–3109.[Abstract]

Tortoriello, D.V., McGovern, P.G., Colon, J.M., Loughlin, J. and Santoro, N. (1998) "Coasting" does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil. Steril., 69, 454–460.[CrossRef][ISI][Medline]

Ulug, U., Bahceci, M., Erden, H.F., Shalev, E. and Ben-Shlomo, Izhar. (2002) The significance of coasting duration during ovarian stimulation for conception in assisted fertilization cycles. Hum. Reprod., 17, 310- 313.

Urman, B., Pride, S.M. and Ho Yuen, B. (1992) Management of overstimulated gonadotrphin cycles with a controlled drift period. Hum. Reprod., 7, 213–217.[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, 294–297.[Abstract/Free Full Text]