|Year : 2012 | Volume
| Issue : 1 | Page : 32-36
Prediction of ovarian hyperstimulation syndrome in coasted patients in an IVF/ICSI program
Fatimah Y Aljawoan1, Linda P Hunt2, Uma D Gordon3
1 Consultant Obstetrician and Gynaecologist, Alyamamah Hospital, Riyadh, Saudi Arabia
2 Senior Lecturer in Medical Statistics, School of Clinical Sciences, University of Bristol Institute of Child Life and Health, UBHT Education Centre, Bristol, United Kingdom
3 Consultant Gynaecologist and Subspecialist in Reproductive Medicine, Bristol Centre for Reproductive Medicine, Southmead Hospital, Bristol, United Kingdom
|Date of Submission||06-May-2011|
|Date of Decision||01-Aug-2011|
|Date of Acceptance||07-Jan-2012|
|Date of Web Publication||2-Jul-2012|
Fatimah Y Aljawoan
P.O. Box 225151, Riyadh 11324
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: To determine why a subgroup of coasted patients developed moderate/severe ovarian hyperstimulation syndrome (OHSS) in an assisted reproduction setting. Materials and Methods: Retrospective study of 2948 in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycles with 327 patients requiring coasting. Long protocol gonadotrophin releasing hormone analogue (GnRH-a) regimen was used and serum estradiol (E 2 ) checked when ≥20 follicles were noted on follicular tracking. Coasting was initiated when leading three follicles were ≥15mm with E 2 ≥1635pg/ml. Results: The incidence of moderate/severe OHSS was 10.4% in coasted patients (equivalent 1.15% of the total IVF/ICSI cycles in the Center). Coasted patients who subsequently developed OHSS showed a significantly higher number of retrieved oocytes, higher serum E 2 level on the day of human chorionic gonadotrophin (hCG) administration, and multiple pregnancies. No significant differences were noted with female age, BMI, cause of infertility, gonadotrophin dosage, coasting duration, and % of E 2 drop. Conclusion: Moderate/severe OHSS might be predicted in coasted patients by a combination of total oocyte numbers and E 2 level on the day of hCG. Multiple pregnancies also significantly increased the risk.
Keywords: Coasted patients, IVF treatment cycle, ovarian hyperstimulation syndrome
|How to cite this article:|
Aljawoan FY, Hunt LP, Gordon UD. Prediction of ovarian hyperstimulation syndrome in coasted patients in an IVF/ICSI program. J Hum Reprod Sci 2012;5:32-6
|How to cite this URL:|
Aljawoan FY, Hunt LP, Gordon UD. Prediction of ovarian hyperstimulation syndrome in coasted patients in an IVF/ICSI program. J Hum Reprod Sci [serial online] 2012 [cited 2021 May 11];5:32-6. Available from: https://www.jhrsonline.org/text.asp?2012/5/1/32/97795
| Introduction|| |
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian hyperstimulation (COH) used in assisted reproduction treatment (ART). Evidence suggests that the pathogenesis of OHSS may involve the immune system; however, the crucial event appears to be an increase in capillary permeability. Human chorionic gonadotrophin (hCG) stimulation plays a key role in triggering the syndrome. 
Coasting involves withdrawing exogenous gonadotrophin injections and withholding hCG until the patient's serum estradiol (E 2 ) level decreases to a "safe" level. ,
The purpose of this study was to analyze why a subgroup of over-responsive patients who needed coasting developed moderate-to-severe OHSS.
| Materials and Methods|| |
The study was undertaken at a center for reproductive medicine. In addition to the Bristol Center departmental database medicine, Bristol, UK. Medical records of all 327 coasted patients between 1 st January 2004 and 31 st December 2007 were manually reviewed. Ethical and Institutional Review Board approval was not required for this retrospective analysis.The long gonadotrophin releasing hormone agonist (GnRH-a) protocol was used (as this is the standard protocol in the unit). Oral Norethisterone tablets 5mg twice daily for 7 days were started from Day 19 of the cycle. On Day 21, buserelin acetate nasal spray (Superfact; Hoeschst, UK Ltd, Hounslow, Middlesex) was started, 600 μg/day in five divided doses (100 μg every 4 h during the day time and 200 μg at bedtime) until the day of hCG injection. Serum E 2 was measured after 14 days of buserelin administration to confirm pituitary down-regulation. Gonadotrophins were started when the E 2 level was <54.5 pg/mL. The daily dose of gonadotrophin was 150 IU for patients aged less than 35 years and 300 IU for patients aged more than 35 years. In polycystic ovarian syndrome (PCOS) patients, the dose was reduced to 75 IU alternating with 150 IU daily for women below 35 years and 150 IU daily for above 35. The patient could choose the type of gonadotrophin; either Menopur (Ferring, Slough,UK) or Gonal-F (Serono, Maidenhead,UK). Cycle monitoring was performed by serial transvaginal ultrasound scans from stimulation Day 8 and repeated as necessary. When the scan revealed ≥20 follicles, serum E 2 was measured. Coasting was initiated when the E 2 level was >1635 pg/mL and the leading three follicles were ≥15mm in diameter. Once coasting was initiated, serum E 2 level was estimated daily along with follicular tracking scans as necessary. When the three leading follicles were ≥17mm, 5000 IU of hCG (Profasi, Serono, Rome, Italy) was administered, provided the E 2 levels were ≤4087 pg/mL. In our Center, E 2 level of ≤4087 pg/mL was considered the "maximum acceptable level" at which to proceed to egg collection. The decision to cancel the treatment was discussed with the patient if the E 2 was >8170.4pg/ml, if the E 2 drop was >60% in 24 h, or if coasting duration was >6 days. Oocyte retrieval was performed by transvaginal ultrasound guidance under intravenous sedation (Propafol and Alfentanyl). Two embryos (three if the patient was aged 40 years or more) were transferred on days 2-3 after oocyte retrieval. All patients had luteal support with cyclogest pessaries 400mg twice daily, starting from the day of embryo transfer. Patients were asked to undertake a urinary pregnancy test 2 weeks after embryo transfer if no period ensued. Transvaginal ultrasound examination was performed at 7 weeks' gestation to identify clinical pregnancy and viability. The occurrence and severity of OHSS after coasting was defined according to Golan's classification of OHSS. Patients with mild OHSS were not included in the study.
Incidence of OHSS amongst coasted patients and demographic and cycle characteristics in both OHSS and non-OHSS cases.
Chi-square test was used to compare categorical variables; Fisher's exact test was used for 2 × 2 Tables when frequencies were small. For continuous variables (age, BMI, FSH level, gonadotrophin requirements, E 2 values, number of follicles, and number of oocytes), unpaired Student's t-test or Mann Whitney U-test was used, depending on the distribution. A 5% level of significance was used. All analyses were performed using the computer program, Stats Direct (Stats Direct, Sale, UK). Data are presented as mean±SD or median with range.
| Results|| |
From January 2004 to December 2007, a total of 2948 treatment cycles (IVF/ICSI) were carried out. Coasting was undertaken in 327 (11%) patients considered to be at risk of developing OHSS. 34 (10.4%) of these coasted patients developed moderate or severe OHSS (1.15% of the total IVF/ICSI cycles). Severe OHSS occurred in seven patients, which was 2.1% of coasted patients, and 0.24% of all IVF/ICSI cycles. Moderate OHSS occurred in 27 patients, which was 8.3% of coasted patients (0.91% of all cycles). Patients showing mild OHSS were excluded. As illustrated in [Table 1], there were no statistically significant differences between OHSS and non-OHSS groups within the coasted patients in relation to age, BMI, percentage with previous pregnancy, FSH level, and duration of infertility. [Table 2] illustrates the cause of infertility; group sizes were too small here for Chi-square analysis.
The cycle characteristics are shown in [Table 3]. A significantly higher number of oocytes were retrieved from the OHSS group as compared to non-OHSS group (mean number of eggs 17.4 vs 14.5; P = 0.004). Likewise, the mean E 2 level on day of hCG administration was significantly higher in the OHSS group as compared with non-OHSS group (3215 vs 2912 pg/mL P = 0.050). However, there were no significant differences between the OHSS and non-OHSS coasted patients with regard to duration of coasting, total units of gonadotrophin used, maximum E 2 , and % E 2 drop (E2 on day of hCG).
Pregnancy outcome is shown in [Table 4]. The multiple pregnancy rate was significantly higher in the OHSS group compared with non-OHSS (52.9% vs. 24.3%; P = 0.006).
| Discussion|| |
OHSS is a potentially life-threatening iatrogenic complication, the pathogenesis of which is not well understood. The syndrome is dependent on the administration of hCG. This led to the development of some of the preventive measures for OHSS such as cycle cancelation and coasting. Coasting is a method by which hCG administration is withheld until serum E 2 reaches a "safe" value. Coasting considerably reduces the incidence of OHSS in high-risk patients, but unlike cancellation of cycle, it does not completely prevent its occurrence. The incidence of severe OHSS in the present study was 2.4% among the 327 coasted patients and 0.24% of the total 2948 stimulated cycles during the 4-year study period. Delvige and Rozenberg, 2002, reported a similar incidence of 2.5% severe OHSS among 190 coasted patients.  For high-risk groups where the E 2 level is greater than 6000 pg/mL, the incidence of OHSS was 38%, while with more than 30 oocytes it was 22.7%.  A combination of both parameters led to a very high incidence at 80%. 
We looked at the patient/cycle characteristics to identify any predictive factors for OHSS. The mean age was similar with both OHSS and non-OHSS cases. This finding is different from other studies, , which showed that younger patients are more prone to develop OHSS. This might be related to the greater probability of achieving a pregnancy with younger patients and to higher response of the ovaries to exogenous gonadotrophins, both risk factors for OHSS. The overall mean age of coasted patients in our study was 34.3±4 years, which is higher than other studies. ,
BMI was also similar in both groups; several studies having reported no correlation between BMI or body weight and OHSS. , However, one study  reported a positive correlation between lean body mass and OHSS. As seen in our study, and in other studies, the duration and type of infertility (primary or secondary) had no influence on OHSS occurrence. 
Although several studies reported higher incidence of OHSS amongst PCOS patients, this was not seen in our study. This might be explained by the lower dose of gonadotrophins used from the outset in PCOS patients. Such a strategy is supported by other authors, , who conclude that severe OHSS is preventable in patients with PCOS when ovarian stimulation is accomplished with a low dose of gonadotrophins. The total dose of gonadrotrophins required has been reported to be lower in OHSS cycles.  Although it was not statistically significant, the number of IU used for non-OHSS cases was slightly higher than OHSS cases (1897.5 (750) vs. 1777.5 (750)), and this is particularly seen in PCOS patients who had the lowest dose of human menopausal gonadotrophins (hMG) (1687.5 (749)) among all coasted patients. Such a finding can be explained by the sensitivity of the PCOS patients to ovarian stimulation and the adjustment of gonadotrophin dose from the outset to avoid OHSS occurrence. This may further be reduced by the use of an antagonist compared with long protocol GnRH-a. According to the result of a Cochrane Review, GnRH antagonist protocol gives similar live birth rate as GnRH agonist, but with lower incidence of severe ovarian hyperstimulation.  Reducing the incidence of OHSS in a patient with PCOS emphasizes the value of recognizing a patient's risk factors and individualizing treatment regimens with careful monitoring.
In our study, the coasting duration was similar with both OHSS and non OHSS cases. It has been found that the period of coasting correlated with serum E 2 level at the beginning of coasting.  Prolonged coasting, more than 4 days, was found to be associated with a reduced oocyte numbers/quality, with a detrimental effect on implantation rate.  The data regarding the predictive value of maximum serum E 2 level on the development of OHSS is conflicting. While D'Angelo et al., in a retrospective case control study found that a cut-off value of serum E 2 level (3346 pg/mL) on Day 11 of ovarian stimulation could detect 85% of women at risk for OHSS,  Morris et al. reported that serum E 2 level is not an accurate predictive factor for OHSS development.  Mathur et al. referred the discrepancies between different studies to several factors: variations in the methods of serum E 2 assays, the small number of patients involved in each of these studies, the biological variability of OHSS, and the occurrence of OHSS in two distinct forms (early and late) where they differ in the time of onset and their predisposing factors. Added to this is the use of different classification of OHSS and the variation in the selected value of E 2 level. 
The number of oocytes retrieved was significantly higher in the coasted OHSS patients. The relationship between number of oocytes retrieved and incidence of OHSS was reported by Asch et al.  There were no cases of severe OHSS in cycles where less than 20 oocytes were retrieved while, with 30 or more oocytes, the incidence of severe OHSS was 22.7%. Morris et al. also found that 20% of cycles with 30 or more oocytes were complicated with OHSS. 
The importance of the timing of hCG administration was emphasized by several investigators, , as too early administration exposes the patients to increased risk of OHSS. Several studies considered a serum E 2 level of 3000 pg/mL as optimal level for hCG administration. ,, Most authors have continued coasting until the serum E 2 level reached a safe range (2500-3000 pg/mL. , In our study, hCG was administered if E 2 was less than 4087 pg/mL, provided that the percentage of serum E 2 drop in 24 h was less than 60%. E 2 level of 4087 pg/mL is higher than the safe level suggested by other authors, and the mean E 2 level on day of hCG was statistically significantly higher in the OHSS cases as compared with non-OHSS cases (3215 (710) pg/mL for OHSS as compared to non-OHSS where the mean E 2 level on day of hCG was 2912 (904) pg/mL with P value of 0.05). These findings suggest that the level of serum E 2 on the day of hCG could predict OHSS cases. Asch et al., showed that OHSS occurrence was related to the level of serum E 2 .  With serum E 2 <3500 pg/mL, none of the patients developed OHSS, compared with incidence of 1.5% when serum E 2 was in the range of 3500-5999 pg/mL and 38% when serum E 2 was 6000 pg/mL. Despite the higher E 2 cut-off, severe OHSS incidence is in our study is comparable to other reported studies, ,, which found that a combination of follicle count (18 or more follicles) and/or E 2 of more than 5000 pg/mL on the day of hCG can predict 83% of the severe OHSS cases with 84% specificity.
Continued stimulation by hCG is a well-recognized risk factor for OHSS occurrence, and several authors reported strong association between pregnancy and OHSS occurrence. , Our results showed a slightly higher pregnancy rate among OHSS cases compared with non-OHSS cases, although other authors have demonstrated a much higher pregnancy rate. The increase is reported to be mainly associated with higher incidence of late-onset OHSS,  which we could not delineate in our study as the data regarding onset of OHSS was lacking in patients' records. Several studies found that the occurrence of OHSS was two to five-fold higher when pregnancy occurred.  Our study demonstrates an overall pregnancy rate for coasted patient of 40%. This finding is in accordance with other studies which showed coasting does not reduce pregnancy rate. 
In accordance with previous studies,  multiple pregnancy was found to be more common with OHSS cases as compared with non-OHSS cases. This is explained by the higher level of hCG in multiple pregnancy. As both multiple pregnancy and OHSS are iatrogenic complications associated with ART, every effort must be made to reduce their incidence for the overall safety of our patients.
None of the currently employed strategies avoid severe OHSS when excessive multiple follicular growths are encountered in the course of COH. To-date, there is no consensus about when to start coasting or the exact protocol to be used for coasting. This, however, did not affect its use by clinicians. Delvigne and Rozenberg, 2002, found coasting to be the most popular preventive measure for OHSS, used by 573 members of the European Society of Human Reproduction and Embryology involved in the survey.  Such popularity may be related to the advantages of coasting mentioned earlier.
Successful prevention of OHSS requires full understanding of its etiology, predisposing factors, pathophysiological changes, means for early detection, and methods to intervene and reverse the pathophysiological changes. The present study identifies two of the factors that could predict the development of moderate/severe OHSS in coasted patients in an assisted reproduction setting.
| References|| |
|1.||Garcia-Velasco JA, Zuniga A, Pacheco A, Gomez R, Simon C, Remohi J, et al. Coasting acts through downregulation of VEGF gene expression and protein secretion. Hum Reprod 2004;19:1530-8. |
|2.||Mathur R, Evbuomwan I, Jenkins J. Prevention and management of ovarian hyperstimulation syndrome. Curr Obstet Gynacol 2000;12:111-6. |
|3.||Abulghar MA, Mansour RT. Ovarian hyperstimulation syndrome: Classifications and critical analysis of preventive measures. Hum Reprod Update 2003;9:275-89. |
|4.||Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): A review. Hum Reprod 2002;8:559-77. |
|5.||Asch RH, Li HP, Balmaceda JP, Weckstein LN, Stone SC. Severe ovarian hyperstimulation syndrome in assisted reproductive technology: Definition of high risk groups. Hum Reprod 1991;10:1395-9. |
|6.||Enskog A, Henriksson M, Unander M, Nilsson L, Brännström M. Prospective study of clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril 1999;71:808-14. |
|7.||Delvigne A, Dubois M, Batthe B, Bassil S, Meuleman C, De Sutter P, et al. The ovarian hyperstimulation syndrome in in-vitro fertilization: A Belgian multicentric study. II. Multiple discriminant analysis for risk prediction. Hum Reprod 1993;8:1361-6. |
|8.||Lyons CA, Wheeler CA, Frishman GN. Hackett RJ, Seifer DB, Haning RV Jr. Early and late presentation of the ovarian hyperstimulation syndrome: Two distinct entities with different risk factors. Hum Reprod 1994;9:792-9. |
|9.||Navot D, Relou A, Birkenfeld A, Rabinowitz R, Brzezinski A, Margalioth EJ. Risk factors and prognostic variables in the ovarian hyperstimulation syndrome. Am J Obstet Gynecol 1988;159:210-5. |
|10.||Balasch J, Creus M, Fabregues F, Carmona F, Casamitjana R, Ascaso C, et al. Inhibin, follicle-stimulating hormone and age as predictors of ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. Am J Obstet Gynecol 1996;127:1226-30. |
|11.||Edwards RG, Lobo RA, Bouchard P. Time to revolutionize ovarian stimulation. Hum Reprod 1996;11:917-9. |
|12.||Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, et al. Gonadotrophin-releasing hormone antagonists for assisted reprod.uction technology. Cochrane Database Syst Rev 2011;5: CD001750. |
|13.||Moreno L, Diaz I, Pacheco A, Zuñiga A, Requena A, Garcia-Velasco JA. Extended coasting duration exerts a negative impact on IVF cycle outcome due to premature luteinisation. Reprod Biomed Online 2004;9:500-4. |
|14.||Juan A, Veronica I, Guillermo Q, Antonio P. Coasting for the prevention of ovarian hyperstimulation syndrome: Much ado about nothing. Fertil Steril 2006;85:547-54. |
|15.||D'Angelo A, Amso N. Coasting (withholding gonadotropins) for preventing ovarian hyperstimulation syndrome Review 2002; (3): CD 002811. |
|16.||Morris RS, Paulson RJ, Sauer MV, Lobo RA. Predictive value of serum oestradiol concentrations and oocyte number in severe ovarian hyperstimulation syndrome. Hum Reprod 1995;10:811-4. |
|17.||Mathur R, Evbuomwan I, Jenkins J. Prevention and management of ovarian hyperstimulation syndrome. Obstet Gynaecol Reprod Med 2008;18:18-22. |
|18.||Lee C, Tummon I, Martin J, Nisker J, Power S, Tekpetey F. Does withholding gonadotrophin administration prevent severe ovarian hyperstimulation syndrome? Hum Reprod 1998;13:1157-58. |
|19.||Waldenström U, Kahn J, Marsk L, Nilsson S. High pregnancy rates and successful prevention of severe ovarian hyperstimulation syndrome by ´prolonged coasting` of very hyperstimulated patients: A multicentre study. Hum Reprod 1996;14:294-7. |
|20.||Al-Shawaf T, Zosmer A, Hussain S, Tozer, A, Panay N, Wilson C, et al. 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 2001;16:24-30. |
|21.||Benavida CA, Davis O, Kligman I, Moomjy M, Liu HC, Rosenwaks Z. Withholding gonadotrophin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome. Fertil Steril 1997;67:724-7. |
|22.||Dhont M, Van der Straeten F, De Sutter P. Prevention of severe ovarian hyperstimulation by coasting. Fertil Steril 1998;70:847-50. |
|23.||Edwards RG, Lobo RA, Bouchard P.Time to revolutionize ovarian stimulation. Hum Reprod 1996;11:917-9. |
|24.||Levinsohn-Tavor O, Friedler S, Schachter M, Raziel A, Strassburger D, Ron-El R. Coasting-what is the best formula? Hum Reprod 2003;18:937-40. |
|25.||Tortoriello DV, McGovern PG, Colon JM, Skurnick JH, Lipetz K, Santoro N. Coasting does not adversely affect cycle outcome in a subset of highly responsive in vitro fertilization patients. Fertil Steril 1998;69:454-60. |
|26.||Grochowaskl D, Wozyski S, Kuczyski W, Szamatowicz J. Correctly timed coasting reduces the risk of ovarian hyperstimulation syndrome and gives good cycle outcome in an in vitro fertilization program. Gynecol Endocrinol 2001;15:234-8. |
|27.||Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM, et al. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril 2006;85:112-20. |
|28.||Papanikolau EG, Herman T, Willem V, Michel C, Valérie V, Andre V, et al. Early and late ovarian hyperstimulation syndrome: Early pregnancy outcome and profile. Hum Reprod 2005;20:636-41. |
|29.||Delvigne A, Rozenberg S. A qualitative systematic review of coasting, a procedure to avoid ovarian hyperstimulation syndrome in IVF patients. Hum Reprod Update 2002;8:291-6. |
|30.||McClure N, Leya J, Radwanska E, Rawlins R, Haning RV Jr. Luteal phase support and sever ovarian hyperstimulation syndrome. Hum Reprod 1992;7:758-64. |
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Effects of different doses of letrozole on the incidence of early-onset ovarian hyperstimulation syndrome after oocyte retrieval
| ||Qiaohua He,Linlin Liang,Cuilian Zhang,Hangsheng Li,Zhaojia Ge,Lu Wang,Shihong Cui |
| ||Systems Biology in Reproductive Medicine. 2014; : 1 |
|[Pubmed] | [DOI]|
||Ovarian Hiperstimulation Syndrome: incidence in a public service of assisted reproduction and literature review
| ||Ludmila Machado Neves,Flavia Machado Cella Kurobe,Jefferson Drezett,Márcia de Toledo Blake,Artur Dzik,Mario Cavagna,Luiz Henrique Gebrim |
| ||Reproducao & Climaterio. 2013; 28(1): 10 |
|[Pubmed] | [DOI]|