Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy

Ali Abbara, Channa N Jayasena, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Gurjinder M K Nijher, Alexander N Comninos, Deborah Peters, Adam Buckley, Risheka Ratnasabapathy, Julia K Prague, Rehan Salim, Stuart A Lavery, Stephen R Bloom, Matyas Szigeti, Deborah A Ashby, Geoffrey H Trew, Waljit S Dhillo, Ali Abbara, Channa N Jayasena, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Gurjinder M K Nijher, Alexander N Comninos, Deborah Peters, Adam Buckley, Risheka Ratnasabapathy, Julia K Prague, Rehan Salim, Stuart A Lavery, Stephen R Bloom, Matyas Szigeti, Deborah A Ashby, Geoffrey H Trew, Waljit S Dhillo

Abstract

Context: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS).

Objective: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Setting and design: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom.

Intervention: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS.

Main outcome measure: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy.

Results: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS.

Conclusion: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Trial registration: ClinicalTrials.gov NCT01667406.

Figures

Figure 1.
Figure 1.
Patient flow diagram showing the number of patients assessed for eligibility, study enrolment, and kisspeptin-54 dose allocation. The study had a prospective adaptive design whereby the first 15 patients were randomly assigned 1:1:1 to receive kisspeptin-54 at doses of 3.2, 6.4, or 12.8 nmol/kg (n = 5 per group) to trigger oocyte maturation during IVF treatment. After interim analysis of oocyte maturation, subsequent patients were randomly assigned 1:1:1 to receive 6.4, 9.6, or 12.8 nmol/kg (n = 15 per group). No patients were lost to followup and no patients discontinued the intervention.
Figure 2.
Figure 2.
IVF study protocol using kisspeptin-54 to trigger oocyte maturation. The timeline shows the day of menstrual cycle for a typical patient. On day 2 or 3 of the menstrual cycle, daily sc recombinant FSH (Gonal F, 112.5 IU) was commenced. Daily GnRH antagonist injections (cetrotide, 0.25 mg) were commenced after 5 d of recombinant FSH injections. If serum LH was undetectable ( 10 miU/mL) was assessed 11 d following embryo transfer and clinical pregnancy was assessed by ultrasonography at 6 weeks' gestation.

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