In the coming years, during which both unmet need and overuse are anticipated to coexist, the usage of cesarean sections (CS) is expected to continue rising globally [1]. Despite being a frequently necessary surgical procedure, CS may lead to increased risk of several obstetric complications in subsequent pregnancies. These complications include infection, hemorrhage, malplacentation, cesarean scar pregnancy, morbidly adherent placenta, and uterine rupture [2]. CS has been suggested to potentially increase a woman’s susceptibility to subfertility or even infertility [3,4]. This detrimental effect on fertility could be attributed to infection, the formation of adhesions, disruption of the placental bed [5], or the hostile uterine environment created by the presence of the CS niche [6].

In assisted reproductive treatment (ART) cycles, embryos are directly transferred into the uterine cavity, eliminating the need for the tubal component. Consequently, the implantation process is considered the most critical factor in predicting pregnancy outcomes [7]. The current understanding of the impact of prior CS on intracytoplasmic sperm injection (ICSI) outcomes is limited, with inconsistencies observed in the clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR). Several studies, including those by Diao et al. [8] in 2021, Patounakis et al. [9] in 2016, and Zhang et al. [10] in 2016, have found no detrimental effect of previous CS on ICSI outcomes. However, other researches have indicated significant reductions in the LBR and CPR in patients with prior CS, including the studies of Riemma et al. [11] in 2021, Zhao et al. [7] in 2021, Wang et al. [12] in 2020, Vissers et al. [6] in 2020, and van den Tweel et al. [13] in 2019. Given these conflicting results, a clear need exists for more robust studies. Therefore, this study was undertaken to investigate the influence of prior delivery mode on ICSI outcomes. Notably, the majority of the aforementioned studies were retrospective, making the prospective nature of our study its most distinctive feature.

No significant differences in baseline characteristics were present between the two groups, as shown in Table 1. In terms of the ICSI outcome parameters, no statistically significant differences were observed between groups in the number of oocytes retrieved, the number of mature (metaphase II) oocytes, or the fertilization rate, as shown in Table 2. The embryos were evaluated and graded based on the criteria established by Gardner, which consider blastocoel expansion as well as the quality of the inner cell mass and the trophectoderm. Subsequently, blastocysts were assigned a grade ranging from excellent to poor, reflecting their quality from highest to lowest. This grading system was designed to facilitate the input of scores into numerical databases and to aid in statistical analysis. The grading scale is as follows [18]: excellent (≥3AA); good (3,4,5,6 AB, 3,4,5,6 BA, and 1,2 AA); average (3–6BB, 3–6AC, 3–6CA, 1–2AB, and 1–2BA); and poor (1–6BC, 1–6CB, 1–6CC, and 1–2BB). When comparing the quality of transferred embryos between the two groups under study, no statistically significant difference was found (Table 2). The maximum number of embryos transferred in any given procedure was two.

Regarding the implantation rate (Table 3), the CD group had a rate of 40.4%, while the NVD group had a value of 41.7%. This difference was not statistically significant (p=0.842). The CPR was 50% in the CD group and 49.3% in the NVD group, which was also not a statistically significant distinction (p=0.932). In the CD group, six cases were diagnosed as chemical pregnancies, making up 14.6% of the group, while in the NVD group, eight cases were diagnosed as such, accounting for 19%. Again, no significant difference was present between the groups (p=0.591). Regarding the MR, 20% of the CD patients experienced a miscarriage, compared to 17.6% in the NVD group. This difference was not statistically significant (p=0.803). One case of tubal ectopic pregnancy arose in the NVD group (1.4%), but no significant difference was present between groups. In the NVD group, one case was withdrawn before the pregnancy results were obtained. The CD group was also divided into two subgroups (Table 4): subgroup (a), which consisted of 56 cases for which no niche could be detected during ultrasound examination, and subgroup (b), consisting of 14 cases for which a niche was identified. In subgroup (a), pregnancy occurred in 32 cases (57.1%), while in subgroup (b), nine cases (64.3%) resulted in pregnancy. No statistically significant difference was found between the two subgroups in terms of pregnancy outcome. In subgroup (a), chemical pregnancy occurred in four cases (12.5%), clinical pregnancy in 28 cases (87.5%), and miscarriage in five cases (15.6%). In subgroup (b), chemical pregnancy occurred in two cases (22.2%), clinical pregnancy in seven cases (77.8%), and miscarriage in two cases (22.2%).

For the past 25 years, the global rate of CS has been increasing [19]. It is crucial to assess the long-term effects of this trend on women’s health. The underlying causes of reduced fertility and unfavorable pregnancy outcomes after prior CS have been extensively researched, revealing a significant decrease in the likelihood of a subsequent pregnancy after a previous CS [20-22]. Many factors could detrimentally impact future fertility following CS. These may lead to post-surgical complications such as intrauterine adhesions, CS niche, or the effects of uterine rupture, in addition to intra-abdominal adhesions, Fallopian tube dysfunction, and uterine abnormalities induced by the cesarean scar [20]. However, the relationship between CS and the outcomes of ART has remained ambiguous, with conflicting findings reported [9-12]. Therefore, we conducted this study to examine the influence of prior delivery mode on ICSI outcomes.

Our findings align with the 2022 results of Bayram et al. [23], who found that the potential negative effects of CS can be mitigated when a euploid frozen ET is performed, following the exclusion of intracavitary fluid. Similarly, Diao et al. [8] proposed in 2021 that a previous CS without a niche does not impair pregnancy outcomes after IVF or ICSI relative to a previous NVD. Our results also concur with the research conducted by Patounakis et al. [9] and Zhang et al. [10], who determined that a previous CS does not influence embryo implantation and pregnancy outcomes in IVF cycles.

In contrast, in 2021, two systematic reviews and meta-analyses conducted by Riemma et al. [11] and Zhao et al. [7] indicated that a history of CS was associated with significantly reduced CPR and LBR, as well as an increased MR, after ART compared with women with previous vaginal deliveries. This could be attributed to the diminished contractility of the fibrotic tissue and myometrium at the scar site, which can lead to an accumulation of intracavitary fluid. In addition, findings have indicated that a scarred area at the site of a previous CS typically exhibits significantly reduced vascularization, decreased leukocyte infiltration, and delayed endometrial maturation compared to a non-scarred uterus. This suggests that regulation of endometrial receptivity may be impaired following CS [24]. These findings could potentially account for the decreased pregnancy and implantation rates observed in women with a prior CS. Similar findings have been reported by multiple retrospective clinical studies, indicating that the LBR and CPR in women with previous CS are lower than in those with previous vaginal delivery [6,25,26].

A major strength of our study lies in its prospective nature, as most studies assessing the impact of CS on ICSI outcomes have been retrospective. Another advantage is that we matched cases in both groups by age, body mass index, and ovarian reserve, further enhancing the validity of the findings. However, the present study does have limitations. To obtain more reliable data, the sample size should be expanded. Additionally, we did not gather detailed information about the category of CS (emergency vs. elective) [27], the type of CS incision, or the influence of previous CS on LBR. Therefore, further research is required to clarify these aspects.

In conclusion, the mode of previous delivery did not significantly impact pregnancy outcomes following frozen-thawed ET. Our findings may be explained by the fact that transfers only took place in frozen (more physiological) cycles, rather than fresh ones, once intracavitary fluid had been eliminated [23]. As the patients in the CS group had a history of only one previous CS, another possible explanation could be that the risk involved is minimized relative to multiple CS procedures.