The Effectiveness and Safety of Artificial Oocyte Activation With Calcium Ionophore in Low Prognosis Women Classified as POSEIDON Group 4: a Randomized Clinical Trial

Brief Summary

Detailed Description

Poor ovarian response (POR) remains one of the significant challenges of Assisted Reproductive Technology (ART). Patients with POR yield a low number of oocytes, leading to a low number of useable embryos and a decline in the live birth rate. According to the consensus of the European Society of Human Reproduction and Embryology (ESHRE) in 2011, POR was diagnosed using Bologna criteria. However, some recent studies show the classification by Bologna is not efficient, because the oocyte number should be combined with female age since the likelihood of achieving a live birth among patients with similar oocyte yield ultimately depends on the age of the patient. In 2016, POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) Group was established and released the new criteria. The POSEIDON criteria proposed a shift from the terminology of POR to the concept of low prognosis. According to POSEIDON criteria, low prognosis account for 30-40% of all stimulated in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. The low prognosis patient is classified into four groups according to the results of ovarian reserve markers (AMH, AFC, or both), female age, and the number of oocytes retrieved in previous cycles, such as: maternal age \< 35, AMH ≥ 1,2 ng/ml and AFC ≥ 5 (subgroup 1a: \< 4 oocytes; subgroup 1b: 4-9 oocytes); maternal age ≥ 35, AMH ≥ 1,2 ng/ml and AFC ≥ 5 (subgroup 2a: \< 4 oocytes; subgroup 2b: 4-9 oocytes); maternal age \< 35, AMH \< 1,2 ng/ml and AFC \< 5; maternal age ≥ 35, AMH \< 1,2 ng/mL and AFC \< 5. Although many efforts have been made to improve treatment outcomes in this group of patients, such as researching, understanding, and modifying clinical ovarian stimulation regimens, the results are still not feasible. Especially, group 4, which have advanced maternal age (≥ 35) and seized for 14.4% of low prognosis, has a low cumulative live birth rate (11% in group 4). Female age is a critical element in the POSEIDON classification because age is crucially related to embryo ploidy and more importantly live birth outcome. The probability of having embryo ploidy sharply declined after the age of 34 and was lower than 50% in women aged 35 years and over. Therefore, patients in group 4 will have an increased risk of aneuploidy embryos, decreasing the live birth rate in these groups of patients. A recent study evaluated cumulative live birth rates per cycle, there was a remarkable difference between POSEIDON patients (21, 43, 10, 25, 29, and 17% in groups 1a, 1b, 2a, 2b, 3, and 4, respectively) and non-POSEIDON counterparts (52%). Facing difficulties related to clinical practice, optimizing the embryo culture process is necessary to improve the embryo number and quality in the POR group. Potential techniques include follicular size at the trigger, dual trigger, artificial oocyte activation (AOA), blastocyst transfer, and the role of preimplantation genetic testing for aneuploidy (PGT-A). In Vietnam, AOA was first reported in 2011, performing on 1588 oocytes, and said the fertilization rate was higher in the ICSI - AOA than in the ICSI group (80.8% vs 74.3%, respectively; p\<0.002). AOA is expected to improve treatment outcomes for low prognosis patients, especially in group 4 by the POSEIDON criteria with the potential for clinical efficacy and safety. Therefore, this study aims to evaluate the effectiveness and safety of AOA on treatment outcomes in low prognosis patients defined by the POSEIDON criteria (2016).

Primary Outcomes

Secondary Outcomes

• Cumulative ectopic pregnancy at 12 months(12 months after randomization)
• Fertilization failure rate(One day after oocyte retrieval)
• Total embryos blastocyst(Five days after oocyte retrieval)
• Cumulative clinical pregnancy at 12 months(12 months after randomization)
• Cumulative ongoing pregnancy at 12 months(12 months after randomization)
• High birth weight(At birth)
• Very low birth weight(At birth)
• Admission to NICU(At birth)
• Good quality day 3 embryo rate(Three days after oocyte retrieval)
• Positive pregnancy test(At 2 weeks after embryo placement)
• Implantation rate(At 3 weeks after embryo placement)
• Fertilization rate(One day after oocyte retrieval)
• Abnormal fertilization rate(One day after oocyte retrieval)
• Clinical pregnancy(At 7 weeks after embryo placement])
• Ongoing pregnancy(At 12 weeks after embryo placement)
• Miscarriage(At 12 weeks of gestation)
• Cumulative multiple pregnancy(12 months after randomization)
• Vanishing twins(At 12 weeks' gestation)
• Hypertensive disorders of pregnancy(At 20 weeks of gestation or beyond after the completion of the first transfer)
• Low birth weight(At birth)
• Major congenital abnormalities(At birth)
• Multiple pregnancy(At 6 to 8 weeks' gestation)
• Antepartum haemorrhage(At birth)
• Total embryos on day 3(Three days after oocyte retrieval)
• Good quality blastocyst rate(Five days after oocyte retrieval)
• Cumulative implantation rate at 12 months(12 months after randomization)
• Ectopic pregnancy(At 12 weeks of gestation)
• Cumulative miscarriage(12 months after randomization)
• Cumulative vanishing twins(12 months after randomization)
• Multiple delivery(At 24 weeks' gestation)
• Cumulative live birth rate(At 24 weeks of gestation)
• Birth weight(At the time of delivery)
• Large for gestational age(At birth)
• Cumulative multiple delivery(12 months after randomization)
• Gestational diabetes mellitus(At 24 to 28 weeks of gestation)
• small for gestational age(At birth)
• Very high birth weight(At birth)
• Perinatal mortality(24 weeks of gestation to the end of the neonatal period of 4 weeks after birth)