This case report describes the use of smooth endoplasmic reticulum aggregates-positive (SERa+) oocytes along with intracytoplasmic sperm injection (ICSI), supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF), aiming to enhance fertilization rates and reproductive outcomes. A 39-year-old woman, facing primary infertility for the past seven years, received assisted reproductive treatment (ART), which included adding GM-CSF to the culture medium and culture SERa+ oocytes before ICSI. Clinical results, embryo quality, fertilization rates, and other fertility parameters were used to track the patient\'s progress toward this individualized approach that led to a positive twin pregnancy and healthy twin babies.

To investigate whether the euploidy rate of blastocysts derived from smooth endoplasmic reticulum aggregates (SERa) positive cycles and oocytes are impacted.
Retrospective cohort study.
A total of 601 preimplantation genetic testing (PGT) cycles with at least one oocyte retrieved in our center between April 2017 and May 2021 were initially included in the study. Women>35 years and PGT cycles with chromosomal structural rearrangements (PGT-SR) were excluded. Embryological and blastocyst ploidy outcomes were compared among SERa+ oocyte, sibling SERa- oocytes and oocytes in SERa- cycles.
No significant difference was observed among the SERa+ oocyte group, sibling SERa- oocyte group, and SERa- cycle group in the normal fertilization rate (82.1% vs. 77.8% vs. 83.1%, respectively, P=0.061), blastocyst formation rate (71.0% vs. 72.5% vs. 68.4%, respectively, P=0.393), good quality blastocyst formation rate (46.4% vs. 48.3% vs. 42.6%, respectively, P=0.198). No significant difference was observed in the euploidy rate (50.0% vs. 62.5% vs. 63.3%, respectively, P=0.324), mosaic rate (12.5% vs. 9.7% vs. 13.4%, respectively, P=0.506), and aneuploidy rate (37.5% vs. 27.8% vs. 23.2%, respectively, P=0.137) among the three groups.
Our results suggest that the euploidy rate of blastocysts derived from SERa+ cycles and oocytes may not be impacted.

To investigate whether the reproductive outcomes of oocytes with smooth endoplasmic reticulum aggregates (SERa) are impaired.
A total of 2893 intracytoplasmic sperm injection (ICSI) cycles were performed between January 2010 and December 2019 in our center. In 43 transfer cycles, transferred embryos were totally derived from SERa+ oocytes. Each of the 43 cycles was matched with a separate control subject from SERa- patient of the same age ( ± 1 year), embryo condition, main causes of infertility, type of protocols used for fresh or frozen embryo transfer cycles. The clinical pregnancy, implantation, ectopic pregnancy and live birth rate were compared between the two groups.
43 embryo transfer cycles from SERa- patient were matched to the 43 transferred cycles with pure SERa+ oocytes derived embryos. No significant difference was observed in clinical pregnancy rate (55.81% vs. 65.11%, p=0.5081), implantation rate (47.89% vs. 50.70%, p=0.8667) and live birth rate (48.84% vs. 55.81%, p=0.6659) between the SERa+ oocyte group and the matched group. No congenital birth defects were found in the two groups.
Our results suggest that the implantation, clinical pregnancy, live birth and birth defects rate of embryos derived from oocytes with SERa are not impaired.

Is there any association between the appearance of smooth endoplasmic reticulum aggregates (SERa) in oocytes and ovarian stimulation, embryological, clinical and neonatal outcomes of ICSI and IVF cycles?
A suboptimal prolonged ovarian stimulation is detrimental to oocytes by inducing the occurrence of SERa, which reduces the reproductive potential of oocytes.
Controlled ovarian stimulation recruits oocytes of different qualities. Based on current evidence, it was agreed that non-homogeneous cytoplasm may represent the normal variability among oocytes rather than a dysmorphism with developmental significance. The only exception is the appearance of SERa within the ooplasm. Owing to the lack of univocal evidence in this literature about the safety of injecting oocytes with SERa and the mechanism responsible for the occurrence of SERa, this topic is still a matter of debate.
A retrospective, longitudinal cohort study performed at a tertiary level public infertility center. We included 1662 cycles (180 SERa+ and 1482 SERa-) from 1129 women (age: 20-44 years) who underwent IVF/ICSI treatments in 2012-2019. The SERa+ cycles had at least one SERa+ oocyte in the oocyte cohort. The SERa- cycles had morphologically unaffected oocytes.
We collected stimulation data and embryological, clinical, neonatal outcomes of SERa- and SERa+ cycles and oocytes.
Overall, 347 out of 12 436 metaphase II oocytes (2.8%) were affected by SER. We performed only 12 transfers involving at least one SERa+ embryo. Stimulation length (P = 0.002), serum progesterone (P = 0.004) and follicle size (P = 0.046) at trigger, number of retrieved (P = 0.004) and metaphase II (P = 0.0001) oocytes were significantly higher in SERa+ than SERa- cycles. Fertilization rate was significantly (P < 0.0001) reduced in SERa+ cycles and oocytes compared to SERa- counterparts. Embryos of SERa+ cycles had a lower blastocyst formation rate compared to embryos of SERa- cycles (P = 0.059). Statistical analysis according to a generalized estimating equation model performed at patient level demonstrated that the duration of ovarian stimulation was predictive of SERa+ oocytes appearance. The clinical success of SERa+ cycles was lower than SERa- cycles, although no differences in neonatal birthweights or malformations were recorded in sibling unaffected oocytes of SERa+ cycles.
Given that SERa+ oocytes were discarded in our center for years and transfers of embryos originating from affected oocytes were generally avoided, clinical outcomes of SERa+ cycles are largely attributable to the transfer of embryos derived from unaffected oocytes of SERa+ cycles and we did not have data about newborns from affected oocytes, since none of the transfers involving SERa+ embryos resulted in a progressive clinical pregnancy.
For the first time, we speculate that the late-follicular phase elevated serum progesterone caused by a suboptimal prolonged ovarian stimulation may be detrimental to the oocytes by inducing the occurrence of SERa, resulting in negative effects on their reproductive potential. This raises the question of whether some stimulation regimens could be worse than others and a change in stimulation protocol would reduce the possibility of producing oocytes with suboptimal maturation. In particular, our data highlight the importance of correct timing of the trigger in order to maximize oocyte collection, not only in terms of numerosity but also their reproductive potential.
None.
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UNASSIGNED: The aims of this study were to compare the live birth, embryological and pregnancy outcomes after intracytoplasmic sperm injection (ICSI) in patients who have oocytes with smooth endoplasmic reticulum aggregates (SERa+ cycles) and patients with normal oocytes and to compare the pregnancy outcomes based on the observed frequency of SERa.
UNASSIGNED: The current study was a retrospective case record review of patients undergoing ICSI from 2012 to 2016 in a specialty fertility center.
UNASSIGNED: The patients were divided into two groups based on the presence of SERa: patients with at least one oocyte containing SERa (SERa+ cycles) (n = 112) and patients with normal oocytes (n = 839). The primary outcome measure was live birth rate. The secondary outcome measures were fertilization rate, cleavage rate, blastocyst formation rate, clinical pregnancy rate, miscarriage rate, and anomalies in children born.
UNASSIGNED: Women with SERa+ cycles showed similar live birth rates, fertilization rates, cleavage rates, blastocyst formation rates, clinical pregnancy rates, miscarriage rates, and abnormalities in children compared to women with normal oocytes. A gradual reduction in live birth rates was observed when the percentage of oocytes containing SERa increased. The group containing >50% of oocytes with SERa demonstrated no live births.
UNASSIGNED: Presence of SERa had no major overall negative impact on key embryological and live birth outcomes. A reduction in the live birth rate with increasing proportion of SERa oocytes was observed, with no live births in the group with >50% or all affected oocytes.

Did the revised Alpha/ESHRE consensus (Vienna, 2017) bring a real answer on managing oocytes with aggregates of smooth endoplasmic reticulum (SERa)?
According to the currently available literature, a case by case approach on the time of injecting/inseminating SERa+ oocytes may be not helpful for embryologists making a decision, so we suggest fertilizing both SERa+ and SERa- oocytes and prioritizing embryos derived from SERa- oocytes.
In 2011, the Istanbul consensus recommended not to inject/inseminate SER+ oocytes due to adverse foetal outcomes reported in literature. At the end of 2017, a panel of experts reconsidered this recommendation and advised a case by case approach. Hence, with a lack of clear recommendations, in-vitro fertilization practitioners still have heterogeneous attitudes when managing SERa+ oocytes. In this context of controversy, an updated review could be helpful in (i) forming a common language for managing cases of SERa+ oocytes and (ii) offering the most ethical practice and best care for patients seeking infertility treatment or fertility preservation.
This review (with a last literature search on 1 June 2018) evaluated the effect of the SER dysmorphism on embryological and neonatal outcomes.
Studies were considered for inclusion if they were prospective or retrospective cohort or case-control studies. Electronic searches of the Pubmed and Embase databases were done using the keyword combination: smooth endoplasmic reticulum, SER, oocyte and zygote. Abstracts and articles written in English and limited to humans were included.
The search returned a total of 726 studies among which 21 met the inclusion criteria. The literature does not unanimously support a negative association between SERa and embryogenesis, implantation or assisted reproductive therapy outcomes. The reviewed studies reported 112 neonatal outcomes after transfers where at least one embryo originated from oocyte affected by SERa. They included 101 healthy babies, three live births with malformations, three neonatal deaths, one stillbirth and four medical interruptions of pregnancy. After transfer of embryos exclusively derived from SERa+ oocytes, a total of 48 healthy newborns were reported along with four babies with perinatal complications (including one ventricular septal defect), one stillbirth, one neonatal death and one pregnancy termination for multiple malformations.
As with any review, this review was limited by the quality of the included studies especially in terms of possible methodological limitations, the limited sample size and the retrospective aspect of the studies. Among the 21 selected studies, seven were abstracts and two were case reports. Of the remaining 14 studies, only three were prospective. The tools used in identifying SERa+ oocytes may have varied from one study to another and a consequent misclassification cannot be excluded. Considering the poor resolution of light microscopy in detecting SER aggregates, we are not sure that apparently SERa- oocytes do not really exhibit such a dysmorphism if they were analysed under electronic microscopy or a time lapse system.
In the light of the existing data and the lack of a real link between fertilizing SERa+ oocytes and the occurrence of embryo aneuploidy/malformations, we think that discarding SERa+ oocytes may be not the most ethical approach even in patients with large cohorts on the day of oocyte retrieval. Avoiding the wastage of oocytes and embryos with respect to medical ethics remains a constant concern in daily IVF practice. Thus, we recommend that all mature oocytes could be fertilized and embryos originating from SERa- oocytes would be preferably transferred, even if they come from a cohort with SERa+ oocytes. The remaining embryos derived from SERa+ oocytes could be considered with a lower priority for transfer after obtaining consent from the couple if a strict follow-up of the pregnancy and the baby is performed.
We have no conflict of interest to declare and no funding was received.
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OBJECTIVE: The present study aimed to gather information on the impact of Alpha/European Society of Human Reproduction and Embryology (ESHRE) consensus regarding oocytes with aggregates of smooth endoplasmic reticulum (SERa) on in vitro fertilization outcome. In particular, we investigated if patients undergoing intracytoplasmic sperm injection (ICSI) and whose oocytes are discarded due to SERa have a higher chance of embryo transfer cancellation compared to patients without SERa oocytes.
METHODS: This is a nested case-control study drawn from the cohort of women referring for in vitro fertilization with ICSI. Cases were patients showing at least one oocyte with SERa at the time of injection. Controls were subsequent patients showing no SERa oocytes and matched ratio 1:1 for age, clinical indication to in vitro fertilization (IVF), and body mass index. The main outcome was the rate of embryo transfer cancellation.
RESULTS: The percentage of women experiencing a transfer cancellation (absence of suitable oocytes or viable embryos) in their ICSI cycle were significantly higher in cases (18 %) compared to controls (8 %) (p = 0.02); however, adjusted odds ratio for FSH and number of SERa oocytes, of follicles, of retrieved oocytes, and of inseminated oocytes were not statistically significant.
CONCLUSIONS: We have shown that the exclusion of SERa oocytes from ICSI cycles causes an increased frequency of transfer cancellation. This effect is mostly due to the reduced number of available oocytes after exclusion of SERa oocytes.

OBJECTIVE: Should oocytes showing the presence of smooth endoplasmic reticulum aggregates (SER) be considered for embryo transfer?
CONCLUSIONS: The present study shows that embryos derived from metaphase II oocyte with visible SER (SER+MII) have the capacity to develop normally and may lead to newborns with no major malformations.
BACKGROUND: It has been reported that the presence of SER in the cytoplasm of oocytes has a negative impact on embryo development, and is associated with a decreased clinical outcome and an increased risk of congenital anomalies. Therefore, it has been recommended that embryos derived from SER-positive oocytes should not be transferred.
METHODS: Consecutive ICSI cycles with at least one SER+MII oocyte were retrospectively analyzed regarding embryological and pregnancy outcome and compared with ICSI cycles showing only oocytes without SER (SER-MII).
METHODS: In total, 394 SER-positive (SER+) cycles and 6845 SER-negative (SER-) cycles were analyzed. The Student\'s t-test, one-way analysis of variance test and χ(2) test were used for statistical analysis. P value of <0.05 was considered statistically significant.
RESULTS: Comparable fertilization rates were observed in SER+ (76.2%) and SER- (73.5%) cycles. In case of blastocyst culture, the cycle efficiency was lower in SER+ than in SER- cycles (mean 42.2 versus 62.8%, P < 0.001). The pregnancy and clinical pregnancy (CP) rates per embryo transfer (ET) were comparable for SER+ and SER- cycles (37.6 versus 37.8% and 33.0 versus 32.4%, respectively). In the SER+ cycles, the fertilization rates of SER+MII and SER-MII (72.9 versus 77.0%), as well as the capacity to develop into good-quality embryos on Days 3 (62.3 versus 63.7%) and 5 (45.4 versus 47.4%), were similar. In the 364 SER+ cycles, the ETs were subdivided in: ET with only SER+MII (n = 31; 8.5%), ET with only SER-MII (n = 235; 64.5%) and ET with mixed SER+ and SER-MII (n = 98; 26.9%). The pregnancy (25.8, 37.4 and 41.8%, respectively) and CP rates (22.6, 32.4 and 37.9%, respectively) were not different between the three subgroups. Among the cycles with known outcome, there was no difference in the rate of major malformations between SER+ cycles (5.3%) and SER- cycles (2.1%). Moreover, no major malformations were reported from the live borns definitely originating from SER+MII embryos. In addition, three newborns, from single ET with frozen-thawed embryos originating from SER+MII oocytes, were delivered and presented no major malformation.
CONCLUSIONS: Taking into account the previous publications and our neonatal data, a follow-up of the children born after ET with embryos originating from SER+ cycles is encouraged.
CONCLUSIONS: More studies should be performed to investigate the origin and effect of SER aggregates on the molecular status of oocytes and embryos.
BACKGROUND: No external funding was either sought or obtained for this study and there are no potential competing interests.
BACKGROUND: Not applicable.