O-007 Leveraging warning thresholds of oocyte immaturity rate to identify patients at risk of pathological endophenotypes. Analysis of 16,155 retrievals with implications for rescue-IVM
Authors: Maggiulli R , Cimadomo D , Innocenti F , Taggi M , Canosi T , Cermisoni G , Casciani V , Soscia D M , Fabozzi G , Albricci L , Coticchio G , Petrone P , Vaiarelli A , Ubaldi F M , Rienzi L 
Published: July 2024

Abstract

Study question
How to develop a robust strategy to pinpoint women exhibiting potential oocyte maturity defects, making them candidates for in-depth genetic investigations and rescue-IVM interventions?

Summary answer
Oocyte immaturity rate warning-limit was 51%. Within three retrievals, 7.8%, 1.5%, and 0.3% of the patients might exceed it once, twice and three times, respectively.

What is known already
Oocyte maturity involves cytoplasmic and nuclear aspects. While cytoplasmic maturity is challenging to define and monitor in IVF, nuclear maturation is evaluated through germinal vesicle breakdown and first polar body extrusion. Consensus suggests 10-20% immaturity rates post-OS is acceptable, but some patients exceed. From a diagnostic standpoint, women surpassing these rates may be eligible for additional genetic assessments; from a clinical standpoint, instead, exploring rescue-IVM is promising. However, guidelines for both practices are currently lacking.

Study design, size, duration
Retrospective study including retrievals with ≥1 cumulus-oocyte-complex (COC; years:2008-2022). The weighted-mean immaturity-rate (20%) and the outliers for COCs retrieved (&gt;22) were defined on the whole dataset (N = 16155). Confounders upon immaturity-rates were outlined among first retrievals with ≥5 COCs (N = 7963). Warning immaturity-rate limit was calculated as “weighted-average+2SD” among first retrievals with 5-22 COCs (N = 7523). Conservative and estimated prevalence of facing immaturity-rates higher than the warning limit across multiple retrievals were also calculated.

Participants/materials, setting, methods
All retrievals were conducted 35.5±0.5 hours after trigger and cumulus-cells were removed to assess oocyte maturity 3.7±1.2 hours later. Rescue-IVM was not conducted at our center, and immature oocytes were discarded. OS, time between pick-up and denudation, and maternal characteristics were tested as putative confounders through linear regressions.

Main results and the role of chance
Among all retrievals conducted between 2008 and 2022, the weighted-mean oocyte immaturity-rate was 20%, suggesting that normally ≥1 immature oocyte(s) might be obtained with ≥5 COCs.
Use of agonist trigger versus hCG (unstandardized coefficient-B: -2.1%,95%CI from -2.8% to -1.4%,adjusted-p&lt;0.001), length of OS (unstandardized coefficient-B:-0.6%,95%CI from -0.8% to -0.4%,adjusted-p&lt;0.001), and ratio COCs:follicles &gt;16 mm at ovulation induction (unstandardized coefficient-B:+4.6%, 95%CI from +3.8% to + 5.3%,adjusted-p&lt;0.001) were associated with the immaturity-rates in a multivariate linear regression.
Among first retrievals with ≥5 and ≤22 COCs, the immaturity-rates warning limit was defined as 51%.
In 3.6% (N = 286) of the 7962 first retrievals with ≥5 COCs the immaturity-rates were ≥51%. The same prevalence for second and third retrievals were 3.8% (N = 86/2232) and 2.1% (N = 14/667). The conservative prevalence of patients with immaturity-rates ≥51% once, twice and three times among three consecutive retrievals were 4.5% (N = 361/7962), 0.3% (N = 23/7962), and 0.03% (N = 2/7962). The same rates, assuming all patients would conduct three consecutive retrievals, were 7.8% (N = +257), 1.5% ( = +93), and 0.3% (N = +21). Out of the 667 patients that indeed conducted 3 retrievals between 2008-2022, these rates were 7.6% (N = 51), 0.9% (N = 6) and 0.4% (N = 3), supporting the reliability of the predicted estimates.

Limitations, reasons for caution
Both germinal-vesicles and metaphase-I immature oocytes were not deemed clinically useful here, although this is controversial. Well-designed studies to systematically monitor rescued oocytes’ developmental, chromosomal, and reproductive competence are still needed, especially in patients subject to high immaturity-rates.

Wider implications of the findings
Oocyte immaturity-rates ≥51% with ≥5 COCs especially when consistently experienced across multiple retrievals, is a statistically-sound criterion to candidate patients to whole-exome-screening. This aims at outlining gene associations with defective oocyte maturation. The clinical effectiveness of rescue-IVM should be primarily studied in these women (prevalence ≤1%).

Trial registration number
None