Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol

Abstract

Study question: What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels?

Summary answer: The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm.

What is known already: In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol.

Study design, size, duration: From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses.

Participants/materials, setting, methods: The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined.

Main results and the role of chance: The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS.

Limitations, reasons for caution: This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins.

Wider implications of the findings: For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy.

Trial registration: ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878.

Conflict of interest statement

Competing Interests: The authors have the following interests: Financial support for this study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., the manufacturer of corifollitropin alfa and rFSH. Pierre J. M. Verweij is a former employee of MSD BV, Oss, The Netherlands. Davis Gates, Keith Gordon, and Barbara J. Stegmann are current employees of Merck & Co., Inc., Kenilworth, NJ and may own stock or stock options in the company. Georg Griesinger has received consulting fees from MSD, Ferring, Glycotope, Serono, Finox, Vitrolife, IBSA, and ReprodWissen GmbH; board membership fee from MSD; and speakers’ bureau fees from MSD, Ferring, Serono, Vitrolife, and IBSA. Basil C. Tarlatzis declares unrestricted research and travel grants and honorarium from Merck Serono; unrestricted research and travel grants, honorarium, and speakers bureau fees from MSD; travel grants, honoraria, and advisory board fees from IBSA; and travel grants from Ferring. Paul Devroey has nothing to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Fig 1. ROC curves for the prediction of moderate to severe OHSS (69 cases) based on the number of follicles ≥11 mm on the day of hCG, the E2 level on the day of hCG or both.

AUCs: 0.728 (follicles); 0.678 (E2); 0.739 (follicles and E2).

Fig 2. ROC curves for the prediction of severe OHSS (35 cases) based on the number of follicles ≥ 11 mm on the day of hCG, the E2 level on the day of hCG or both.

AUCs: 0.769 (follicles); 0.731 (E2); 0.782 (follicles and E2).

Fig 3. Probabilities of moderate to severe OHSS and severe OHSS associated with the number of follicles ≥11 mm on the day of hCG.

Fig 4. Probabilities of moderate to severe OHSS and severe OHSS associated with the E2 level on the day of hCG.