Main findings
We have shown that there was a significant decrease in clinical outcomes for patients in the CS-ICF group compared with the CS-noICF and VD groups, while no significance was found between the CS-noICF and VD groups, which may be explained by Salker’s research outcome of impaired decidualization [16]. These differences still existed when baseline characteristics were matched after PSM. Excessive intra-uterine fluid has been found to result in changes in the expression of genes related to endometrium receptivity, such as integrin α and β in mice [17]. Most patients with a CS history may experience prolonged menstrual periods, or a weakened barrier of cervical mucus, which may cause uterine inflammation and impaired decidualization. Another explanation may lie in the presence of the scar, which may change the myometrial contractility and influence embryo implantation. The scar may destroy the continuity of the muscle fibers and those with severe impacts may result in ICF and further extremely early pregnancy loss [18].
Our data show a negative effect between ICF and clinical pregnancy rather than an impact based on merely the presence of a scar and the clinical pregnancy rate. Most studies have suggested that women with ICF have low implantation and pregnancy rates in IVF cycles [10, 19, 20]. Our data confirm that CS history is not the major cause of uncompromised clinical outcome during IVF cycle; however, the presence of ICF may explain the phenomenon. We were not concerned about the association of ICF and the scar defect, as a previous study conducted by Lawrenz et al. had indicated similar reproductive outcomes between patients with and without an isthmocele when ICF was cured [7].
There were fewer embryos transferred in the CS-ICF group than in the CS-noICF and VD groups according to clinicians’ tendency to employ a single blastocyst transfer strategy with smaller residue muscular thickness. Though it was not recorded with objective data, the proportions of one embryo transferred and one blastocyst transferred were highest among the three groups (59.2% of one embryo and 72.2% of one blastocyst). However, the ectopic pregnancy rates were similar among the three groups. This is inconsistent with previous studies among patients with a history of CS, as it has been reported that CS is a risk factor for ectopic pregnancies [21, 22]. The difference could be explained by the high proportion of blastocyst transfers, as a single blastocyst transfer may be a good intervention implemented to reduce the ectopic pregnancy rate compared with cleavage stage embryo transfer [23]. The potential effects of CS or ICF on ectopic pregnancy may be masked by the high ratio of blastocyst transfers.
With subgroup analysis, interesting findings can be seen between fresh cycles and frozen embryo transfer cycles. It seems the impacts of ICF disappeared in fresh embryo transfer cycles (a difference was shown only in biochemical pregnancy), while the adverse impact of ICF was still apparent in frozen embryo transfer cycles. However, there were a downward trend in clinical pregnancy and live birth rates, as the rates were lowest in the CS-ICF group almost 10% lower than that in the CS-noICF group. The fact that differences did not reach statistical significance may be due to the reduction in sample size after matching. The number of frozen thaw embryo transfer cycles enrolled for analysis was more than 4 times that of fresh cycles, which may be explained by clinicians’ prioritizing frozen strategy when the presence of ICF was obvious. However, the adverse impact of ICF still existed in FET cycles since it was difficult to treat under the current level of medical technology, and we failed to analyse the treatment of isomocele or ICF in the following FET cycle as a retrospective study.
ICF may be cause by many factors, such as hydrosalpinges, polycystic ovarian disease, subclinical uterine infections and endometriosis [10, 19]. Our data show that the proportion of ICF associated with hydrosalpinx or OHSS was less than 5%, as fluid associated with hydrosalpinx [19] and PCOS [24] has been confirmed to impact clinical outcomes, and most such patients underwent a frozen protocol in our centre. The potential cause of ICF may be explained by endometriosis, a finding that is supported by two other studies in non-tubal factor patients [25, 26]. The possible mechanism is stenosis of the cervical canal and formation of isthmocele, which may induce fluid accumulation mechanically or menstrual dripping and can cause difficulty in embryo transfer.
Changes in the endometrial microenvironment caused by the presence of ICF may be the main cause of implantation failure. The occurrence of ICF during IVF is generally considered to be related to fallopian tube factors, hormone levels in superphysiological states and related changes in the uterine microenvironment. In addition, the CS isthmocele may cause iatrogenic adenomyosis, which may result in toxic environment and impair endometrial receptivity and cervicouterine microbiota [27]. ICF with a history of CS may result in effusion from the ectopic endometrium in the scar, which has been confirmed pathologically in 28% of hysterectomy specimens of 51 patients in Morris’ study [28]. Gurbuz et al. provided an indirect evidence by describing a non-invasive isthmocele treatment in which patients were treated with gonadotropin-releasing hormone agonist for 3 months before hormone replacement treatment in FET cycles, which results in 25% of live birth [26].
We compared clinical outcomes among patients who had a history of CS with or with ICF, as well as patients who underwent vaginal delivery and were convinced that the clinical pregnancy rate was lower in the CS-ICF group than in the CS-noICF and VD groups, while the outcomes were equal between the CS-noICF and VD groups. Vissers et al. [29] also reported an impact on clinical pregnancy and implantation of CS, but they did not perform further analysis of the scar and its associated effects. In the recent study by Lawrenz et al. [7], an association between ICF and uncompromised clinical outcomes was mentioned, and the researchers conducted a detailed analysis of the possible factors of the production of effusion. Another study concluded that a subgroup of patients with symptomatic isthmocele may benefit from hysteroscopic isthmoplasty, which can help confirm the effect of ICF on pregnancy from another perspective [30].
Limitations and strengths
A potential criticism of this study is that we did not record the association of ICF with scar defect, as our focus was on the presence of ICF rather than the defect. Our study also has another limitation as we could not determine the degree of separation and the time of ICF development, since no data were collected on the amount of ICF; however, this does not affect our analysis, as in our clinical routine management, if the ICF was more than 3mm, we adopt an embryo freezing strategy rather than fresh embryo transfer, which can be supported by Andersen et al.’s study [31]. We also acknowledge that another limitation may lie in the cancellation cycles, which may include additional patients with ICF. In addition, these data do not allow us to determine the initial factors of the decrease in live births following CS in patients with or without ICF, as the study was retrospective in design, and we were unable to obtain inflammation information for the ICF, which remains for further research in the future. With these limitations, our strength lies in the group design, comparing the presence of ICF as well as delivery mode. In addition, our study contains the largest sample size in a retrospective study of this subject to date.
Further study
Our study proposed an added analysis for the uncompromised clinical outcomes of patients with a history of CS. We cannot say definitely that with the presence of a CS scar has an impact on clinical outcomes with the mere presence of ICF, but we can say that the effect of the scar on the endometrium environment can lead to an unfavorable outcome, but not the scar itself. The association between ICF and delivery mode is novel, and verifying whether the same association applies to general patients with or without scar defects and whether the association is affected by the amount of effusion would be interesting. At this time, we have no way to clarify the nature of the effusion, as the study was retrospective in design. In future research, we may focus on the bacterial analysis of effusion to explore the direct mechanism and propose improved protocols by way of a large prospective cohort study. Further study is being undertaken to ascertain why a history of CS is associated with fewer clinical pregnancies.
Implications of our findings
Even with the limitations, our results are still of great clinical significance. With the increasing CS rate worldwide, more infertile women are seeking to become pregnant with a scar on their uterus. Many studies have confirmed an uncompromised clinical outcome in patients with a history of CS and reported an even lower pregnancy rate when a niche was mentioned [7, 24, 30, 32, 33]. Previous studies agere that there is an impact in clinical outcomes, though some of them focus on isthmocele, and they describe blood or mucus on catheter[34]. ICF may be a new, effective, treatable factor that should be paid attention to achieve better pregnancy outcomes in patients with a history of CS.