The reasons for recurrent implantation failure (RIF) comprises chronic endometritis, cesarean scar syndrome, and embryo-endometrial asynchrony during implantation. The general treatment for chronic endometritis and cesarean scar syndrome is a broad-spectrum antibiotic and hysteroscopic surgery. The optimal window of implantation can be identified using an endometrial receptivity array (ERA) or a nuclear system test (NST).
In recent years, the quality and frequency of in vitro fertilization (IVF) have grown rapidly. However, overcoming recurrent implantation failure and multiple IVF failures with high quality or chromosomally normal embryos is difficult with general IVF procedures. Hereafter, we briefly describe three maternal causes of implantation failure.
Chronic endometritis occurs in approximately 30-60% of women with a history of recurrent implantation failure. Chronic endometritis, which is asymptomatic and undetectable by general fertility tests, is characterized by the presence of plasma cells in the endometrial biopsy samples. The wide variety of microorganisms responsible for chronic endometritis. Some endometrial biopsy samples in patients with chronic endometritis only contain plasma cells, whilst bacteria were not found.
The general diagnosis of chronic endometritis is histopathological verification via immunostaining with the plasmacyte marker. Hysteroscopy is also a reliable tool for diagnosing of chronic endometritis. The diagnostic accuracy of hysteroscopy is >90% when important findings are present.
The general treatment for chronic endometritis is a broad-spectrum antibiotic against a broad spectrum of bacteria. General indicators of the treatment for chronic endometritis in patients with a history of recurrent implantation failure after antibiotic therapy are 92.3% and 99.1% after the first-line therapy, and combined second-line therapy, respectively.
Cesarean Scar Syndrome
A higher frequency of secondary infertility is observed in patients with a record of cesarean section than in those who deliver vaginally. Secondary infertility in women with abnormal postmenstrual uterine bleeding and a prior delivery by cesarean section can be caused by bloody fluid from a cesarean scar defect (CSD), which outlaws implantation. The trapped blood in a cesarean scar can flow into the vagina in the form of a genital spot and intrauterine cavity, affecting the nature of the cervical mucus, sperm transfer and implantation.
The prevalence of cesarean scar defect is 24-84% in women with a record of one or more deliveries by cesarean section. In addition, 29-82% of women with cesarean scar defect have postmenstrual uterine spotting.
Transvaginal ultrasound, saline sonohysterography, or magnetic resonance imaging can identify cesarean scar defects. Hysteroscopy also provides reliable data for direct confirmation of cesarean scar defects.
The general treatment for cesarean section scar syndrome is hysteroscopic surgery for resection of the lower and upper edges of a cesarean scar defect and cauterization of its neovascularity. If the residual myometrial cesarean scar defect is extremely thin, the scar should be resected and sutured laparoscopically. The procedure is limited to patients with 2.5-mm residual thickness of the myometrium. When the thickness is <2.5 mm, the cesarean scar defect is cut and stitched using a combination of laparoscopy and hysteroscopy.
Embryonic implantation requires mutual interaction and synchronization between the morphologically and developmentally competent embryo, and the optimally decidualized endometrium. The window of implantation occurs through the decidual transformation of the endometrium. The window of implantation can be subjectively identified using the endometrial dating of immunostained endometrial tissues.
The endometrial receptivity array is a tool for objective identification of the optimal window of implantation based on 238 genes identified from microarray analysis of the decidualizing human endometrium. However, the endometrial receptivity array is expensive. Therefore, before using it, it is necessary to take into account economic efficiency.
The nuclear channel system includes membranous organelles of the nuclei of epithelial cells that appear for a short time during implantation. The concordance between endometrial receptivity array and the results of immunofluorescence staining of the nuclear system of window of implantation was confirmed. The identification of the nuclear system is as effective as the endometrial receptivity array for detecting the optimal window of implantation.
The general treatment for recurrent implantation failure associated with suspected asynchrony of embryo-endometrial is first confirmed by hysteroscopy. Chronic endometritis is one of the causes of endometrial decidualization. When intrauterine finding is normal, an endometrial receptivity array or nuclear channel system can be used to determine whether a decidualized endometrium is optimal for implantation. If endometrial receptivity array or nuclear channel system testing indicates that the endometrium is “non-receptive”, it is necessary to check the optimal window of implantation, and the timing of embryo transfer should be rescheduled.
When the endometrium is “receptive,” we recommend the transfer of a single frozen-warmed blastocyst. Controlled ovarian stimulation for multiple follicle development negatively affects the endometrial receptivity due to the influence of supraphysiologic levels of abnormal endocrine hormones on the proliferative and decidualizing processes of the endometrium.
When a pregnancy test is negative after the transfer of a cleaved embryo, determining whether cleavage arrest or impaired endometrial receptivity is responsible for implantation failure is impossible. Therefore, embryos used to treat recurrent implantation failure should be cultured to the blastocyst stage. The implantation rate after double embryo transfer with low- and high- quality embryos is lower than after elective transfer of a single embryo. Thus, embryo transfer with several embryos is not recommended.
In conclusion, the best treatment strategy for patients with a history of recurrent implantation failure is a frozen-warmed embryo transfer of single high quality (or, chromosomally normal) blastocyst to a receptive endometrium.