Oocyte maturation defect in women undergoing IVF: contributing factors and effects on mature sibling oocyte outcomes

Abstract

Purpose

This study aimed to identify demographic and clinical factors associated with low maturation rates and to investigate if the rate of immature oocytes impacts the outcomes of mature sibling oocytes.

Methods

Women undergoing their first IVF-ICSI cycle between 2018 and 2022 at a fertility clinic were included. Cycles were classified into five groups according to the proportion of Metaphase II stage oocytes (MII): Null (0% MII, n = 46), Poor (1–25% MII, n = 44), Low (26–50% MII, n = 453), Acceptable (51–75% MII, n = 1641), and Optimal (76–100% MII, n = 2642). Demographic characteristics and clinical outcomes were compared between the five groups. In patients with a Null/Poor maturation rate, subsequent cycle outcomes were also evaluated.

Results

A total of 4826 cycles were included in the study; 69,909 oocytes were recovered, and 53,065 were MIIs (75.9%). The Null group was older, had lower levels of anti-Müllerian hormone (AMH), needed more gonadotropins and days of stimulation, had higher follicle stimulating hormone (FSH) levels on day 3, and had less follicles > 15 mm on the day of trigger. When the outcomes of mature oocytes were compared, fertilization, usable blastocyst, aneuploidy, and life birth rates were comparable among groups. A binary logistic regression model using number of oocytes, paternal age, and trigger type with live birth rate endpoint found no differences between the categories and the base line Poor category. When patients whose maturation rate was Null/Poor, 42 (47.0%) carried out a second cycle; the maturation rate increased (56.9 ± 31.5 vs. 11.6 ± 11.2%, P < 0.0001).

Conclusion

Our data suggest that poor responders are more likely to have low rates of oocyte maturation. The proportion of immature oocytes does not impact the outcomes of mature sibling oocytes. In patients with Null/Poor maturation in their first cycle, the subsequent cycle is often associated with improved maturation rates.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10815-024-03353-w.

Introduction

Since the early days of in vitro fertilization (IVF), ovarian stimulation has been an integral part of assisted reproductive techniques (ARTs). The purpose of ovarian stimulation is to induce development of multiple dominant follicles and to mature several oocytes to improve chances for conception in a given cycle [1]. Oocyte maturation involves a complex sequence of steps to achieve nuclear and cytoplasmic maturity [2]. Nuclear maturation encompasses meiotic resumption at Prophase I and driving the progression is to Metaphase II. Cytoplasmic maturation refers to the processes that prepare the oocyte for activation and preimplantation development [3]. This involves the accumulation of mRNA, proteins, substrates, and nutrients that are required to achieve oocyte and early embryo developmental competence.

Oocyte denudation is an essential step in the ART laboratory, consisting of the removal of the cumulus cells that surround the gamete allowing the verification of the state of maturity of oocytes [4]. This technique is required in preparation for intracytoplasmic sperm injection (ICSI), for which the indications have been expanded beyond the diagnosis of severe male factor to include poor ovarian response, prior fertilization failure with conventional insemination, and preimplantation genetic testing (PGT) [5].

Evidence indicates that retrieving a higher number of mature oocytes maximizes the chances of achieving a live birth by increasing the number of available blastocysts. Unfortunately, it has been reported that between 15 and 23% of oocytes are immature at the time of denudation, found to be either at the prophase I or metaphase I stage [6–8]. Moreover, in some cycles the number of mature oocytes on retrieval after a hormone-stimulated cycle is lower than expected. Although some studies have used rescued in vitro matured Metaphase II (MII) oocytes, they suggest a lower capacity for embryo development than the oocytes that were mature at the time of denudation [9–11].

The etiology of decreased oocyte maturation rate remains largely unknown. While previous studies suggest that female age might be linked to lower maturation rates [12], serum human chorionic gonadotropin (hCG) levels do not seem to correlate with oocyte maturity [13] and delayed oocyte maturation trigger increases maturation rates [14]. Furthermore, it is still controversial whether a lower maturation rate is associated with poorer clinical outcomes with sibling mature oocytes, as the available data on this topic includes a limited number of patients undergoing day 3 embryo transfers and does not include the ploidy status of the transferred embryos [15, 16].

In light of the imperative to gain a deeper understanding of the factors contributing to impaired oocyte maturation, our study’s primary aim was to clarify whether there are associated demographic and clinical parameters. Additionally, we explored the prognostic implications of low oocyte maturation by examining whether the proportion of immature oocytes within a cohort influences outcomes of mature sibling oocytes, including fertilization rates, embryo development, embryo ploidy, clinical pregnancy rates, and live birth rates. Furthermore, we investigated whether patients with a null or low maturation rate in their initial cycle were more likely to experience similar outcomes in a subsequent cycle.

Material and methods

Study design and population

This was a retrospective cohort study including 4826 consecutive patients who underwent their first ICSI cycles at a single academic-affiliated private practice between October 2018 and March 2022.

The inclusion criteria for the analysis were (i) First cycles with at least one oocyte recovered after vaginal oocyte retrieval (VOR), (ii) Body mass index between 18 and 30 kg/m², and (iii) Cases in which fresh ejaculated sperm was used for insemination. Exclusion criteria were (i) Diagnosis of polycystic ovarian syndrome and/or endometriosis, (ii) Use of preimplantation genetic testing for monogenetic disorders (PGT-M) or preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR).

For analysis, the patients were categorized according to the rate of MII oocytes at the time of ICSI as the following: Null (0% MII), Poor (1–25% MII), Low (26–50% MII), Acceptable (51–75% MII) and Optimal (76–100% MII). This methodology was based on a previous study that classified cycles into four groups based on the proportion of MII oocytes at the time of retrieval: minimal (1–25%), partial (26–50%), adequate (51–75%), optimal (76–100%) and found that a high proportion of immature sibling oocytes in the retrieved cohort affected the fertilization rate and embryo developmental competence of MII inseminated [16]. In order to gain a more comprehensive understanding of the impact, we opted to include a group where no MII oocytes were obtained (Null) to examine the potential outcomes if a cycle were to be repeated.

The definition of a MII oocyte was used as it is described in The International Glossary on Infertility and Fertility Care [17] which were those exhibiting the first polar body (PB) at the time of denudation. Immature oocytes were defined as (i) Prophase I (Germinal Vesicle-GV) when they showed an intracytoplasmic nucleus characteristic of prophase of the first meiotic division or (ii) Metaphase I (MI) in the absence of a visible GV or a PB.

The parameters that were compared among groups were maturation rate (MII oocytes/recovered oocytes), fertilization rate (two pronuclei (2PN) zygotes/metaphase II oocytes), and usable blastocyst rate (frozen or biopsied blastocyst/2PN zygotes). The center had implemented a blastocyst freeze-all policy, resulting in no fresh transfers being carried out.

Euploidy rate was calculated in cycles where PGT-A was performed using a next-generation sequencing-based platform to identify embryos without a whole chromosome aneuploidy. Clinical outcomes were calculated in patients who underwent single euploid frozen embryo transfer (FET). The data on clinical pregnancy rate (ultrasound-confirmed pregnancy/embryo transfer) and live birth rate (number of live births/embryo transfer) were collected.

Additional analyses were made to study the demographic characteristics and other clinical factors, such as the initial value of AMH and Estradiol (E₂) and serum FSH measurements on day 3 of the menstrual cycle. The doses and days of stimulation were noted as well.

Ovarian stimulation and oocyte retrieval

Monitoring of IVF cycles was per practice routine. Patients underwent ovarian stimulation with injectable gonadotropins using a Gonadotropin Releasing Hormone (GnRH) antagonist protocol as determined by their primary physician. Gonadotropin dosing was also decided by each patient’s primary physician and titrated according to the results of serial monitoring of follicular development using transvaginal sonography, and serum E₂ and progesterone throughout stimulation. Final oocyte maturation was triggered by administration of either a GnRH agonist, hCG, or a combination of the two, when the lead follicle was observed to be > 17 mm visualized on ultrasound scan. Transvaginal ultrasound–guided retrieval was performed 36 h after trigger.

IVF laboratory procedures

On the morning of the oocyte retrieval, a sperm sample was collected by the male partner. The semen was prepared for ICSI by first undergoing a simple wash with Quinn’s™ Sperm Washing Medium and centrifugation followed by a density gradient wash (1:1 ratio) and centrifugation. The sample was then assessed for immotility, progressive and non-progressive motility, according to the WHO Manual for the Examination and Processing of Human Semen [18], and the pellet was set aside for ICSI.

Oocytes were denuded from cumulus cells by mechanical pipetting in 80 U/mL Hyaluronidase (SAGE) strictly 3.5 h after the oocyte retrieval. Then, oocytes were washed thoroughly, and the maturity status was determined. ICSI was performed on Metaphase II oocytes 5 h after oocyte retrieval. The inseminated oocytes were placed into incubators overnight. The Panasonic MCO-170AICUVL-PA CO2 standard boxes were set with 5.0% CO₂ and 5.0% O₂ to achieve a controlled pH value within the 7.27–7.34 range, which was monitored weekly. After 16–18 h, oocytes were assessed for the formation of two pronuclei, signifying fertilization. Embryos were cultured in Sage Cleavage® media drops covered with OVOIL from Vitrolife. Laser zona breaching was performed using a Cronus laser (Research Instruments, Falmouth, UK) on day 3 of embryo culture, and embryos were transferred to fresh drops of ORIGIO® Sequential Blast™. In PGT-A cases, biopsy of five to ten cells from the extruding portion of the trophectoderm was performed on day 5, 6, or 7. The results of each biopsy were categorized as being euploid or aneuploid, being the low-risk mosaic embryos clustered together with the euploid ones.

Embryo transfer

A programmed single euploid FET cycle was performed using daily administration of estradiol with the goal of obtaining a trilaminar endometrium measuring at least 7 mm. Daily intramuscular progesterone was then initiated, with transfer occurring on the sixth day of progesterone administration. Embryos were thawed on the day of replacement and transferred with ultrasound-confirmed intrauterine placement of the catheter.

Statistical analysis

The Statistical Package for Social Sciences (SPSS 16.0 for Windows; IBM, USA) was used for all statistical analyses. One-way analysis of variance (ANOVA) was used for comparison of mean values of quantitative variables, using post hoc tests to conclusively identify which specific groups showed significant differences from each other. Fisher’s exact test was used to compare the percentages of categorical variables. Statistically significant findings (P < 0.05) were identified in the tables and graphs; otherwise, they were only identified as non-significant (NS). Binary logistic regression models were proposed, using number of oocytes, paternal age, and trigger type as control variables.

As only patients undergoing their initial IVF cycle were included, each patient was only included once in the primary analysis. However, in a subset of patients who did not retrieve any mature oocytes and subsequently underwent a new cycle, paired comparisons were carried out.

Results

During the study time, 69,909 oocytes were recovered from the 4826 stimulation cycles, in which an overall maturity of 75.9% (n = 53,063) was found. The maturation frequencies were distributed in the five groups: 0.9% Null (n = 46), 0.9% Poor (n = 44), 9.4% Low (453), 34% Acceptable (n = 1641), and 54.7% Optimal (n = 2642).

Table 1 describes the demographic characteristics of the cases. Both the BMI and the history of previous pregnancy were comparable among the study groups. However, the Null group was older, had higher FSH levels on day 3 of the menstrual cycle, and had lower levels of AMH. The male factor (Table 2) was analyzed under the parameters of sperm concentration and the assessment of total progressive motility, and we found comparable values in all groups.

Table 1.

Comparison of baseline patient characteristics according to the rate of Metaphase II oocytes at the time of ICSI as the following: Null (0% MII), Poor (1–25% MII), Low (26–50% MII), Acceptable (51–75% MII), and Optimal (76–100% MII). The data are expressed as the mean (95% confidential interval), and P value * is based on ANOVA test comparisons. The superscripts are used to indicate pairwise comparisons; different superscripts indicate statistically significant differences (P < 0.05). Superscripts: a = Null, b = Poor, c = Low, d = Acceptable, e = Optimal. E2: Estradiol; FSH: Follicular follicle-stimulating hormone; AMH: Anti-Mullerian Hormone; D + 3: third day of a menstrual cycle; NS: Non-significant

Maturation rate	Null (0%)a	Poor (1–25%)b	Low (26–50%)c	Acceptable (51–75%)d	Optimal (76–100%)e	P value*
No. of patients	46	44	453	1641	2642	-
Age (years)	37.5 (36.0–39.1)d,e	35.7 (34.4–37.0)	36.6 (36.2–37.0)d,e	35.5 (35.2–35.7)a,c	35.6 (35.4–35.8)a,c	P < 0.001
Body Mass Index	23.6 (22.8–24.5)	23.6 (22.7–24.5)	24.0 (23.7–24.3)	23.9 (23.7–24.0)	23.8 (23.7–4.0)	NS
Gravidity	0.1 (− 0.01–0.1)	0.2 (0.0–0.3)	0.1 (0.1–0.1)	0.1 (0.1–0.2)	0.1 (0.1–0.1)	NS
E2 (pg/mL) D + 3	53.3 (47.9–49.9)	50.3 (37.2–69.4)	51.0 (40.1–60.5)	48.0 (46.6–49.5)	50.6 (47.5–50.3)	NS
FSH (mIU/mL) D + 3	14.1 (11.7–16.4)b,c,d,e	10.4 (9.0–11.7)a,d,e	9.3 (8.1–8.4)a,d,e	8.2 (8.1–8.4)a,b,c,e	8.6 (8.5–8.8)a,b,c,d	P < 0.001
AMH level (ng/mL)	0.7 (0.5–0.8)c,d,e	2.0 (1.5–2.6)	2.3 (2.0–2.5)a,d,e	3.3 (3.2–3.5)a,c	3.1 (3.0–3.3)a,c	P < 0.001

Table 2.

Patient’s semen characteristics comparison according to the rate of Metaphase II oocytes at the time of ICSI: Null (0% MII), Poor (1–25% MII), Low (26–50% MII), Acceptable (51–75% MII), and Optimal (76–100% MII). The data are expressed as the mean (95% confidential interval), and P value * is based on ANOVA test comparisons

Maturation rate	Null (0%)	Poor (1–25%)	Low (26–50%)	Acceptable (51–75%)	Optimal (76–100%)	P value*
No. of patients	46	44	453	1641	2642	-
Sperm concentration	62.7 (48.9–76.5)	71.7 (58.2–85.2)	59.0 ± (55.1–62.8)	61.7 (59.5–63.8)	64.5 (58.9–70.0)	NS
TMPS	108.3 (176.5–140.2)	165.4 (123.7–207.1)	149.3 (136.2–162.3)	150.4 (143.7–157.2)	154.1 (144.9–163.2)	NS

TPMS total motile progressive motile sperm count, NS non-significant

As summarized in Table 3, when overall characteristics of ovarian stimulation were studied, significant differences were observed in the null maturation group. The Null group had less follicles > 15 mm on the day of trigger, had lower levels of estradiol on the day of trigger, needed more gonadotropins and more days of stimulation. Finally, the number of retrieved oocytes was lower.

Table 3.

Cycle parameters according to the rate of Metaphase II oocytes at the time of ICSI: Null (0% MII), Poor (1–25% MII), Low (26–50% MII), Acceptable (51–75% MII), and Optimal (76–100% MII). The data are expressed as the mean (95% confidential interval). *P value is based on ANOVA test comparisons. The superscripts are used to indicate pairwise comparisons; different superscripts indicate statistically significant differences (P < 0.05). Superscripts: a = Null, b = Poor, c = Low, d = Acceptable, e = Optimal. E2: Estradiol; P4: Progesterone; NS: Non-significant

Maturation rate		Null (0%)a	Poor (1–25%)b	Low (26–50%)c	Acceptable (51–75%)d	Optimal (76–100%)e	P value*
No. of patients		46	44	453	1641	2642	-
15 mm follicles on trigger		2.5 (2.1–3.0)b,c,d,e	6.2 (5.0–7.4)a,d,e	5.9 (5.6–6.3)a,d,e	8.7 (8.5–9.0)a,b,c,	8.6 (8.4–8.8)a,b,c	P < 0.001
E2 (pg/mL) on trigger		857.9 (704.2–1011.6)b,c,d,e	1956.8 (1602.9–2310.6)a,d,e	2103.8 (1971.5–2236.1)a,d,e	2795.5 (2717.4–2873.7)a,b,c	2766.6 (2703.2–2830.1)a,b,c	P < 0.001
P4 (ng/mL) on trigger		1.1 (0.7–1.4)	1.3 (1.1–1.5)	1.2 (1.1–1.3)	1.2 (1.2–1.3)	1.2 (1.1–1.2)	NS
Total dose gonadotropin		4646.7 (3414.7–3480.8)b,c,d,e	3725.0 (3322.6–4127.3)a	3694.2 (2358.7–3801.7)a,d,e	3372.9 (3318.8–3426.9)a,c	3426.6 (3381.8–3471.4)a,c	P < 0.001
Days stimulation		10.4 (9.3–11.4)c,d,e	9.4 (8.7–10.1)	9.1 (8.9–9.2)a	9.0 (8.9–9.0)a,e	9.1 (9.1–9.2)a,d	P < 0.001
Trigger medication	HCG	1349 (27.9%)	30 (65.0%)	24 (54.5%)	170 (37.5%)	456 (27.7%)	P < 0.001
	Lupron®	1169 (24.2%)	0 (0.0%)	4 (9.0%)	64 (14.1%)	418 (25.4%)
	Both	2308 (47.8%)	16 (35.0%)	16 (36.4%)	219 (48.3%)	769 (46.8%)
Number of oocytes retrieved		1.9 (1.5–2.4)b,c,d,e	8.9 (7.0–10.9)a,d,e	11.0 (10.2–11.8) a,d,e	16.0 (15.5–16.5)a,b,c,e	14.4 (14.0–14.8)a,b,c,d	P < 0.001

In Table 4, embryological outcomes were compared among groups; both fertilization and usable blastocyst rates of mature sibling oocytes were similar between groups. Euploidy rates and pregnancy outcomes were compared in 3950 (81.8%) of the cycles where PGT-A was performed and were found to be comparable between the groups. Logistic regression was employed to assess the impact of potential confounders, including the number of oocytes, the age of male participants, and the triggering method, on LBR. Using the Poor category as baseline, the adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) for the remaining categories were as follows: Low category, OR 0.738 (95% CI: 0.535–1.019), P = 0.065; Acceptable category, OR 0.759 (95% CI: 0.554–1.014), P = 0.087; and Optimal category, OR 0.791 (95% CI: 0.578–1.084), P = 0.145.

Table 4.

Cycle outcomes according to the rate of Metaphase II oocytes at the time of ICSI: Null (0% MII), Poor (1–25% MII), Low (26–50% MII). Fertilization rate was obtained by dividing the number of 2PN (two pronuclei = by = the number of Metaphase II oocytes microinjected. The usable blastocyst rate was determined by dividing the number of biopsied or vitrified blastocysts by the total number of fertilized oocytes. The euploidy rate was calculated as the number of euploid embryos divided by the number of biopsied blastocysts. The clinical pregnancy rate was defined as the number of intrauterine gestational sacs with fetal heartbeat, divided by the total number of embryo transfers. The life birth rate was calculated as the number of live births per embryo transfers. P value * is based on FISHER’s exact test comparisons

Maturation rate	Poor (1–25%)	Low (26–50%)	Acceptable (51–75%)	Optimal (76–100%)	P value*
No. of patients	44	453	1641	2642	-
Fertilization rate % (n)	78.3 (65/83)	80.9 (1714/2119)	82.5 (14,440/17,509)	84.3 (28,130/33,354)	NS
Usable blastocyst rate % (n)	52.3 (34/65)	51.9 (889/1714)	50.8 (7333/14,440)	54.5 (15,322/28,130)	NS
Euploidy rate % (n)	80.8 (21/26)	67.4 (485/719)	68.4 (4068/5943)	67.2 (8243/12,261)	NS
No. of euploid blastocyst transfers	10	172	946	1639	NS
Clinical pregnancy rate % (n)	90.0 (9/10)	72.7 (125/172)	71.5 (676/946)	73.3 (1201/1639)	NS
Life birth rate % (n)	90.0 (9/10)	59.9 (103/172)	62.8 (594/946)	65.0 (1066/1639)	NS

Forty-two (47.0%) patients whose maturation rate was Null/Poor carried out a second cycle (Supplementary Fig. 1). The maturation rate increased statistically in the second cycle although it did not reach the mean global maturation rate (75.9%). Three of the cases (7.1%) with no MII in the first cycle also did not have MIIs in the subsequent cycle. When clinical and stimulation factors were compared between the two cycles (Supplementary Table 1), we observed that both the number of 15 mm follicles and the level of E2 on trigger were higher in the second cycle. In contrast, no significant differences were observed in the dose of gonadotropins, length of stimulation, and type of trigger used.

Discussion

According to our findings, patients' clinical characteristics have an impact on the rate of oocyte maturation. Nevertheless, our observations have led us to conclude that the potential of sibling mature oocytes is independent of the proportion of mature oocytes. Furthermore, our findings suggest that patients who experience null/poor maturation in their first cycle often exhibit improved maturation rates in their subsequent cycle.

Various stimulation regimens have been utilized in ART with the objective of maximizing the quantity and quality of oocytes, thereby facilitating the development of a sufficient number of viable embryos to enhance the cumulative pregnancy rate associated with each cycle. However, the precise mechanism governing the individual responses of antral follicles to exogenous gonadotropins remains poorly understood. Early antral follicles may not exhibit synchronous growth in response to exogenous gonadotropins. The GnRH antagonist protocol has gained widespread acceptance in IVF due to its ease of application and efficacy, supplanting protocols that employed long suppressions with GnRH agonists [19]. However, since GnRH antagonist allows for a more natural recruitment of follicles in an unsuppressed ovary [20], it is less effective in achieving follicular synchronization [21]. This lack of synchronization could be a contributing factor to the overall maturation rate of 75.9% observed in our study, which aligns with the suggested benchmark value of 75.0% [22]. Fortunately, cycles with very low oocyte maturity are uncommon. Our study has revealed that the probability of obtaining a cycle with less than 25% oocytes maturity is 1.8%. This finding is consistent with a previous study that reported a maturation rate of less than 30% in only 1.3% of cycles [23].

Reaching an international consensus on the use of serum biomarkers predictive of a poor response to ovarian stimulation seems elusive. While the measurement of basal levels of FHS has been a long-standing standard practice, Antral follicle count (AFC) and Antimüllerian Hormone (AMH) have begun to dominate the clinical scene and are used in classifications outlined by the ESHRE Bologna consensus statement and POSEIDON group [24–26]. According to our results, patients with lower maturation rates showed lower AMH and higher early follicular phase FSH levels, indicating that they had a phenotype consistent with a poor responder. Our findings support the use of these two markers to predict having a suboptimal response to stimulation and collection of a low number of mature oocytes. This information could help patient counseling and optimize subsequent treatments by offering personalized treatment protocols [27].

Additionally, research has long indicated that female ovarian reserve declines progressively with increasing chronological age. As shown in Table 1, we observed that the group with Null maturation had a higher average age. Previous authors have also demonstrated a link between advanced maternal age and higher rates of oocyte immaturity [12, 15, 16, 28]. It is noteworthy that there is one study that did not find the association and the discrepant results might be caused by the study design, since they calculated the maturation rate at retrieval (including the MI oocytes) and 6 h after [29].

Regarding cycle characteristics, our study found that the Null maturation group had fewer 15 mm or larger follicles on the day of the trigger, lower maximum serum E2 levels, and required significantly more days of stimulation and total doses of gonadotropins than the other groups. The pattern we observed in the Null maturation group has also been observed in cases with low ovarian reserve [30]. A previous publication reported that the number of Metaphase I and GV oocyte is negatively correlated with gonadotropin dose [31]. However, comparing the current results with the previously published ones is challenging due to the lack of details provided in some studies about the ovarian stimulation process, or the inclusion of different protocols such as long agonist, mild-stimulation, short agonist, prolong agonist, and antagonist. In our case, only antagonist protocol was used, and patients who received this protocol for ovarian hyperstimulation were found to have a higher incidence of decreased oocyte maturation [23].

In the current study, we found that the maturation rate within a cohort of oocytes did not influence the embryological outcomes of the mature oocytes from the same cohort. Fertilization, blastulation, or euploidy rates remained unaffected. Some authors have raised concerns regarding potential abnormal cytoplasmic development in all oocytes from a cohort when a high percentage of their sibling oocytes are in the MI and GV stages at the time of retrieval. Such a scenario would imply cytoplasmic impairment in MII stage oocytes from that cohort. However, our results suggest that a mature oocyte will develop into a competent embryo regardless of the maturity of the rest of the cohort. Indeed, we observed no correlation between maturation rate and fertilization rate. This finding aligns with some previous studies [12, 29, 32], but not with others that reported higher fertilization rates when the ratio of mature oocytes was either high [15, 31, 33, 34] or low [35]. Discrepancies in findings could originate from the timing of maturation assessment (at the time of collection, after denudation, or at the time of ICSI). A higher maturation rate at collection translates into a greater number of in vivo matured metaphase II oocytes, potentially leading to more oocytes reaching full competence by the time of ICSI insemination. In our study, the maturation ratio was calculated at the time of ICSI, and we microinjected all available metaphase II oocytes, even if they had extruded the polar body during culture.

To our knowledge, this is the first study evaluating the impact of maturation rates on clinical outcomes using a single euploid FET approach. Previous research has suggested that higher maturation rates may lead to improved outcomes, but this could potentially be attributed to the fact that embryologists are able to select the best embryo from larger cohorts (may not be many in case of poor maturity) or because more embryos are transferred in cases where a SET policy is not in place [12, 34]. This was the case in a study where 2.4 embryos were transferred in the optimal maturation group and only 1.0 embryos were transferred in the minimal maturation rate one in a published study [16]. Our findings indicate that once a euploid blastocyst is transferred, its likelihood of resulting in a pregnancy is not affected by the maturation rate of the oocytes from which it was derived. Interestingly, among the ten patients whose euploid embryo transfers derived from a cohort in the Poor category, nine achieved successful deliveries. The unusually elevated live birth rate can be attributed to the very low number of cycles included from this group in this particular analysis. However, given the infrequency of this event in IVF cycles and the substantial size of our database, we aimed to explore the outcomes within this category. Further research with larger sample sizes is essential to validate these results and to deepen our understanding of the factors contributing to the oocyte competence within such cohorts.

There is limited data available on how to effectively manage patients with null or poor maturation in their initial ovarian stimulation attempt. Previous studies have indicated that patients with a high rate of immature oocytes may experience similar outcomes in subsequent cycles [8], implying a potential underlying pathology in these cases. However, our findings present a more optimistic outlook, suggesting that patients with null or poor maturation rates in their first IVF cycle are likely to achieve better results in subsequent cycles. Our observations indicate that both the number of 15 mm follicles and the level of E2 on trigger were higher. Meanwhile, the dose of gonadotropins, length of stimulation, and type of trigger remained relatively unaltered. Unfortunately, due to our limited data, we were unable to determine whether the cycle was optimized by the physician or if there was a different response from the ovary in the subsequent cycle. Whether this improvement is simply a regression to the mean phenomenon or reflects a learning process enabling clinicians to manage these patients more effectively warrants further investigation. Based on our limited data, it seems undergoing a new cycle appears to be a beneficial approach.

The study is limited by its retrospective design and how the groups were organized based on maturation percentage, replicating previous studies (16). Furthermore, it is important to acknowledge that we included all cycles, irrespective of the number of oocytes retrieved. This inclusion criterion may have led to cycles with a single oocyte being categorized only within the Null or Optimal maturation rate groups, while those with two oocytes could only have been assigned to the Null, Acceptable, or Optimal maturation rate groups. Other studies have addressed this limitation by restricting analysis to larger cohorts (Ozgur et al., 2015), but we decided to incorporate all cycles in order to obtain a more comprehensive and representative understanding of the broader patient population. We repeated all analyses after categorizing those with 0% maturity into the Poor category and obtained similar results. Alternatively, categorizing the studied cycles into quartiles based on the number of oocytes obtained and then creating subgroups of maturity rates within those quartiles would have allowed for adjustment for ovarian response. However, given the low number of cycles with null or poor maturity, this would deem the resulting subgroups impossible to analyze with any meaningful power. However, the large sample size, the patient’s same stimulation scheme with antagonist, and strict exclusion criteria constitute the strengths of the article. In the current study, we excluded PCOS patients, since research showed that alteration of many factors might directly or indirectly impair the competence of maturating oocytes through endocrine and local paracrine/autocrine actions in those patients [36].

Our findings clarify the clinical observations linked to impaired oocyte maturation in patients undergoing IVF. Further research is necessary to identify modifiable factors that could enhance oocyte maturity, both in general and specifically in cases with poor maturation rates during initial attempts. Although we did not do rescue in vitro maturation in the present study, recent studies have noted that the process does not seem to affect the frequency of oocytes with normal chromosome copy numbers [37]. Therefore, additional research is warranted to determine whether this alternative approach can improve the success rate of IVF for women experiencing reduced oocyte maturation.

Conclusions

Patient’s clinical characteristics appear to have an impact on the oocyte maturation rate. The rate of immaturity had no repercussions on its sibling MII oocytes in their ability to produce usable blastocyst, implantation capacity, achieve pregnancy, and live birth rate; hence, oocyte sibling potential seems to be independent of the proportion of mature oocytes once they are fertilized. In patients with a null/poor maturation rate in their first cycle, the subsequent cycle is often associated with improved maturation rates.

Supplementary Information

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Declarations

Conflict of interest

E.S. was a consultant for and received research funding from the Foundation for Embryonic Competence. All other authors declare that they have no potential conflicts of interest and no financial support.