Uterus Transplant in Women With Absolute Uterine-Factor Infertility.

Importance: Uterus transplant in women with absolute uterine-factor infertility offers the possibility of carrying their own pregnancy. Objective: To determine whether uterus transplant is feasible and safe and results in births of healthy infants. Design, Setting, and Participants: A case series including 20 participants with uterine-factor infertility and at least 1 functioning ovary who underwent uterus transplant in a large US tertiary care center between September 14, 2016, and August 23, 2019. Intervention: The uterus transplant (from 18 living donors and 2 deceased donors) was surgically placed in an orthotopic position with vascular anastomoses to the external iliac vessels. Participants received immunosuppression until the transplanted uterus was removed following 1 or 2 live births or after graft failure. Main Outcomes and Measures: Uterus graft survival and subsequent live births. Results: Of 20 participants (median age, 30 years [range, 20-36]; 2 Asian, 1 Black, and 16 White), 14 (70%) had a successful uterus allograft; all 14 recipients gave birth to at least 1 live-born infant. Eleven of 20 recipients had at least 1 complication. Maternal and/or obstetrical complications occurred in 50% of the successful pregnancies, with the most common being gestational hypertension (2 [14%]), cervical insufficiency (2 [14%]), and preterm labor (2 [14%]). Among the 16 live-born infants, there were no congenital malformations. Four of 18 living donors had grade 3 complications. Conclusions and Relevance: Uterus transplant was technically feasible and was associated with a high live birth rate following successful graft survival. Adverse events were common, with medical and surgical risks affecting recipients as well as donors. Congenital abnormalities and developmental delays have not occurred to date in the live-born children. Trial Registration: ClinicalTrials.gov Identifier: NCT02656550.

Deceased Donor Uterus Transplantation: A Narrative Review of the First 24 Published Cases.

Uterus transplantation is the surgical treatment for absolute uterine factor infertility (AUFI), a congenital or acquired condition characterized by the absence of a uterus. More than 80 transplants have been performed worldwide, resulting in more than 30 live births, originating both from living and deceased donors. The collection of published articles on deceased donor uterus transplantations was performed in PubMed and SCOPUS by searching for the terms "Uterus transplantation" AND "deceased donor"; from the 107 articles obtained, only case reports and systematic reviews of deceased donor uterus transplantations and the resulting live births were considered for the present manuscript. The extracted data included the date of surgery (year), country, recipient (age and cause of AUFI) and donor (age and parity) details, outcome of recipient surgery (hysterectomy), and live births (date and gestational age). The search of peer-reviewed publications showed 24 deceased donor uterus transplantations and 12 live births (a birth rate of 66%) with a 25% occurrence of graft loss during follow-up (6 of 24). Among this series, twelve transplants were performed in the USA (seven births), five in the Czech Republic (one birth), three in Italy (one birth), two in Turkey (two births), and two in Brazil (one birth). The median recipient age was 29.8 years (range 21-36), while the median donor age was 36.1 years (range 20-57). Of 24 recipients, 100% were affected by MRKH (Mayer-Rokitanski-Kuster-Hauser) syndrome. Two live births were reported from nulliparous donors. Deceased donor uterus transplantation birth rates are very similar to the living donor rates reported in the literature, but ethical implications could be less important in the first group. It is necessary to register every case in the International Registry for Uterus Transplantation in order to perform a systematic review and comparison with living donor rates.

Unique Lessons From the Natural Progression of Rejection in Human Uterine Allografts.

INTRODUCTION: Uterus transplantation (UTx) is a novel treatment for absolute uterine infertility. Acute T cell-mediated rejection (TCMR) can be monitored only through serial cervical biopsies. METHODS: This study, the first of its kind in human transplantation, evaluated clinical, serological, and pathophysiological manifestations of allograft rejection from immunosuppression withdrawal (ISW) to graft hysterectomy (Hx). RESULTS: Following live birth, immunosuppression was abruptly withdrawn from six living-donor UTx recipients. ISW occurred at a median of 7.4 weeks before graft Hx. Post-ISW signs of rejection included: (1) discoloration of the cervix; (2) increased uterine size compared to day of ISW; (3) serological evidence of eosinophilia and progressive development of donor-specific antibodies (DSA) or child-specific antibodies (CSA); (4) histopathological evidence of TCMR in cervical biopsies preceding the development of antibodies in serum; and (5) C4d deposition in tissue before formation of DSA or CSA in all but two recipients. At graft Hx, endometrial glands were preferentially targeted for destruction over stroma while parametrial arteries displayed variable arteritis and fibrointimal hyperplasia. CONCLUSION: Recognition of the progression of uterine allograft rejection may be important for other human organ recipients and drive research on modulation of immunosuppression and the paradoxical relationship between adaptive cellular and humoral immunity in natural pregnancies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656550.

Derivation and validation of the first web-based nomogram to predict the spontaneous pregnancy after reproductive surgery using machine learning models.

Objective: Infertility remains a significant global burden over the years. Reproductive surgery is an effective strategy for infertile women. Early prediction of spontaneous pregnancy after reproductive surgery is of high interest for the patients seeking the infertility treatment. However, there are no high-quality models and clinical applicable tools to predict the probability of natural conception after reproductive surgery. Methods: The eligible data involving 1013 patients who operated for infertility between June 2016 and June 2021 in Yantai Yuhuangding Hospital in China, were randomly divided into training and internal testing cohorts. 195 subjects from the Linyi People's Hospital in China were considered for external validation. Both univariate combining with multivariate logistic regression and the least absolute shrinkage and selection operator (LASSO) algorithm were performed to identify independent predictors. Multiple common machine learning algorithms, namely logistic regression, decision tree, random forest, support vector machine, k-nearest neighbor, and extreme gradient boosting, were employed to construct the predictive models. The optimal model was verified by evaluating the model performance in both the internal and external validation datasets. Results: Six clinical indicators, including female age, infertility type, duration of infertility, intraoperative diagnosis, ovulation monitoring, and anti-Müllerian hormone (AMH) level, were screened out. Based on the logistic regression model's superior clinical predictive value, as indicated by the area under the receiver operating characteristic curve (AUC) in both the internal (0.870) and external (0.880) validation sets, we ultimately selected it as the optimal model. Consequently, we utilized it to generate a web-based nomogram for predicting the probability of spontaneous pregnancy after reproductive surgery. Furthermore, the calibration curve, Hosmer-Lemeshow (H-L) test, the decision curve analysis (DCA) and clinical impact curve analysis (CIC) demonstrated that the model has superior calibration degree, clinical net benefit and generalization ability, which were confirmed by both internal and external validations. Conclusion: Overall, our developed first nomogram with online operation provides an early and accurate prediction for the probability of natural conception after reproductive surgery, which helps clinicians and infertile couples make sensible decision of choosing the mode of subsequent conception, natural or IVF, to further improve the clinical practices of infertility treatment.

Endometrioma surgery: Hit with your best shot (But know when to stop).

Ovarian endometriomas (OEs) are commonly detected by ultrasound in individuals affected by endometriosis. Although surgery was widely regarded in the past as the gold standard for treating OEs, especially in the case of large cysts, the surgical management of OEs remains debated. Firstly, OEs often represent the "tip of the iceberg" of underlying deep endometriosis, and this should be considered when treating OEs to ameliorate patients' pain for focusing on the surgical objectives and providing better patient counseling. In the context of fertility care, OEs may have a detrimental effect on ovarian reserve through structural alterations, inflammatory responses, and oocyte reserve depletion. Conversely, the surgical approach may exacerbate the decline within the same ovarian reserve. While evidence suggests no improvement in in-vitro fertilization (IVF) outcomes following OE surgery, further studies are needed to understand the impact of OE surgery on spontaneous fertility. Therefore, optimal management of OEs is based on individual patient and fertility characteristics such as the woman's age, length of infertility, results of ovarian reserve tests, and surgical background. Among the available surgical approaches, cystectomy appears advantageous in terms of reduced recurrence rates, and traditionally, bipolar coagulation has been used to achieve hemostasis following this approach. Driven by concerns about the negative impact on ovarian reserve, alternative methods to obtain hemostasis include suturing the cyst bed, and novel methodologies such as CO2 laser and plasma energy have emerged as viable surgical options for OEs. In instances where sonographic OE features are non-reassuring, surgery should be contemplated to obtain tissue for histological diagnosis and rule out eventual ovarian malignancy.

Uterus Transplantation: the Translational Evolution of a Clinical Breakthrough.

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important preclinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore criteria and describe the different procedures of preparation, surgeries, postoperative monitoring, and use of assisted reproduction in human uterus transplantation. We review the worldwide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore criteria and strict alignment with the IDEAL concept have resulted in the establishment of uterus transplantation as a novel, safe, and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.

Proposal for individual treatment by tubal occlusion factor based on the results of salpingoscopic salpingoplasty.

AIM: As a treatment for tubal infertility, falloposcopic tuboplasty (FT) is one of the options for patients who wish to conceive naturally. Based on the results of FT, we propose an appropriate time of transitioning to assisted reproductive technology (ART) for tubal infertility. OBJECTS AND METHODS: We examined the outcomes of cases of tubal infertility during the period from June 1999 through March 2021 who were performed tuboplasty at our hospital using the FT catheter system under laparoscopy. RESULTS: The number of treated cases was 828. There were 243 cases of endometriosis and 119 cases of genital chlamydial infection. By FT, 712 cases (86.0%) were successfully recanalized. Of the 712 cases, 189 conceived naturally (26.5%) and miscarriages were 23 cases (12.2%), ectopic pregnancies were 8 cases (4.2%). The mean duration from FT to pregnancy was 6.5 months in natural pregnancy group, 90% of them were pregnant within 14 months. In endometriosis cases, the pregnancy rate after FT did not change significantly among clinical stage. CONCLUSIONS: Even when the fallopian tube was recanalized by FT, if the couple is unable to conceive naturally, they had better to consider switching to ART at about 14 months. When the couples with endometriosis consider switching to ART, we suggest deciding without considering the rASRM stage.

Uterus Transplantation: A Future Issue for the French Legislator?

Uterus transplantation (UT) is a surgical procedure that seeks to correct absolute uterine infertility. As such, it is coupled with assisted reproductive technologies (ART). Currently performed as an investigational procedure in France, this technique could be subject to a legal framework in the future. Given its specificities, the French legislator will need to state their position on several matters. Regarding the donor, they will need to determine whether the benefits for the infertile woman justify exposure of a living person to the risks of the removal procedure. If necessary, they will have full freedom to set the criteria for selecting the living donor based on age, the existence or not of past pregnancies or the nature of the donor-recipient relationship. On the other side, the conditions for becoming a recipient should be consistent with the existing rules for ART. Other considerations could include age and past pregnancies again. Lastly, the legislator will also need to address the possible desire for UT without the endpoint of pregnancy.

Impact of surgery on reproductive outcomes in women with deep endometriosis and proven presurgical infertility: Facts and controversies.

In women with proven infertility and deep endometriosis (DE), optimal management is controversial. To date, there is no clear evidence on the association between infertility and different stages of rASRM, nor is there clear guidance from leading scientific societies for surgical treatment of DE patients. A comprehensive literature search was conducted on the main databases for English-language trials describing the effectiveness of surgery for DE in patients with proven infertility; 16 studies were deemed eligible for inclusion in this systematic review (CRD42024498888). Quantitative analysis was not possible because of the heterogeneity of the data. A descriptive summary of the results according to location of pathology, surgical technique used, and whether assisted reproductive technology (ART) was needed or not was provided. A total of 947 infertile women were identified, 486 of whom became pregnant, with an average pregnancy rate of 51.3%. Our review suggests that surgery can be of valuable help in improving reproductive outcomes by improving the results of ART. It has not been possible to reach robust conclusions on the outcomes of surgery based on the location of DE because of the heterogeneity of evidence available to date. Overall, although some data encourage first-line surgical management, further investigation is needed to determine its effective application before or after ART failure.

Natural conception and term pregnancy after hysteroscopic incision of complete septate uterus with septate cervix: A case report and literature review.

OBJECTIVE: To discuss several techniques of hysteroscopic surgery for complete septate uterus. CASE REPORT: A 40-year-old female with unexplained primary infertility was diagnosed with complete septate uterus with septate cervix. Hysteroscopic incision of complete septate uterus was performed by using ballooning technique. The patient conceived naturally shortly after the operation and delivered a healthy, term infant. CONCLUSION: Hysteroscopic incision of complete septate uterus is a safe and prompt way of metroplasty. With the knowledge obtained from a pre-operative MRI, it can be completed without laparoscopy and the need for hospitalization.

First-line surgery versus first-line assisted reproductive technology for women with deep infiltrating endometriosis: a systematic review and meta-analysis.

Background: The efficiency of different first-line treatments, such as first-line surgery and assisted reproductive technology (ART), in women with deep infiltrating endometriosis (DIE) is still unclear due to a lack of direct comparative trials. This systematic review and meta-analysis aim to elucidate and compare the efficacies of first-line treatments in patients with DIE, with an emphasis on fertility outcomes. Methods: An exhaustive search of PubMed Central, SCOPUS, EMBASE, MEDLINE, Cochrane trial registry, Google Scholar, and Clinicaltrials.gov databases was done to identify studies directly comparing first-line surgery and assisted reproductive technology (ART) for DIE, and reporting fertility-related outcomes. Pooled estimates for each of the binary outcomes were reported as odds ratios (ORs) with 95% confidence intervals (CIs). The results were pooled using a random-effects model with the Mantel-Haenszel technique. Results: Our results show that pregnancy rate per patient (OR, 1.47; 95% CI, 0.59 to 3.63), pregnancy rate per cycle (OR, 1.16; 95% CI, 0.45 to 2.99), and live births per patient (OR, 1.66; 95% CI, 0.56 to 4.91) were comparable in DIE patients, treated with surgery or ART as a first line of treatment. When both complete and incomplete surgical DIE excision procedures were taken into account, surgery was associated with a significant enhancement in the pregnancy rate per patient (OR, 1.63; 95% CI, 1.11 to 2.40). Conclusion: The available evidence suggests that both first-line surgery and ART can be effective DIE treatments with similar fertility outcomes. However, further analysis reveals that excluding studies involving endometriomas significantly alters the understanding of treatment efficacy between surgery and ART for DIE-associated infertility. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=426061, identifier CRD42023426061.

Analysis of factors affecting pregnancy rate after laparoscopic surgery for infertility associated with endometriosis.

OBJECTIVE: To analyze the factors that might influence the pregnancy rate in patients with infertility related to endometriosis (EMs) after undergoing laparoscopic surgery, providing guidance for our clinical diagnostic and therapeutic decision-making. METHODS: A retrospective analysis was conducted on clinical records and 1-year postoperative pregnancy outcomes of 335 patients diagnosed with endometriosis-related infertility via laparoscopic surgery, admitted to our department from January 2018 to December 2020. RESULTS: The overall pregnancy rate for patients with endometriosis (EMs) related infertility 1-year post-surgery was 57.3 %, with the highest pregnancy rate observed between 3 to 6 months after surgery. Factors such as Body Mass Index (BMI) (P = 0.515), presence of dysmenorrhea (P = 0.515), previous pelvic surgery (P = 0.247), type of EMs pathology (P = 0.893), and preoperative result of serum carbohydrate antigen 125 (CA125)（P = 0.615）had no statistically significant effect on postoperative pregnancy rates. The duration of infertility (P = 0.029), coexistence of adenomyosis (P = 0.042), surgery duration (P = 0.015), intraoperative blood loss (P = 0.050), preoperative result of serum anti-Müllerian hormone (AMH) (P = 0.002) and age greater than 35 (P = 0.000) significantly impacted postoperative pregnancy rates. The post-surgery pregnancy rate in patients with mild (Stage I-II) EMs was notably higher than those with moderate to severe (Stage III-IV) EMs (P = 0.009). Age (P = 0.002), EMs stage (P = 0.018), intraoperative blood loss (P = 0.010) and adenomyosis (P = 0.022) were the factors that affected the postoperative live birth rate. CONCLUSION: For patients with EMs-related infertility undergoing laparoscopic surgery, factors such as age > 35 years, infertility duration > 3 years, concurrent adenomyosis, severe EMs, surgery duration ≥ 2 h, intraoperative blood loss ≥ 50 ml, and low AMH before surgery are detrimental for the pregnancy rate within the first postoperative year. However, BMI, dysmenorrhea, past history of pelvic surgery, EMs pathology types (ovarian, peritoneal, deep infiltrating),and preoperative result of serum CA125 barely show any statistical difference in their effect on postoperative pregnancy rates. In terms of postoperative live birth rate, age > 35 years, severe EMs, intraoperative blood loss ≥ 50 ml, and adenomyosis were adverse factors.

Impact of surgery for endometriosis on the outcomes of in vitro fertilization.

This narrative review aims to summarize available evidence on the IVF-associated outcomes after surgery for endometriosis. Only one retrospective study investigated if surgical treatment of superficial/peritoneal endometriosis may modify the outcomes of IVF; therefore, more data are needed to confirm the benefit of surgery for this type of disease for improving ART outcomes, and to be able to support it in routine practice. Solid evidence from several meta-analyses demonstrates that surgical treatment of endometriomas does not enhance the outcomes of IVF. In contrast, surgical treatment of ovarian endometriosis may lead to a reduction in ovarian reserve, especially in cases involving bilateral endometriomas or repeated surgical procedures. Some non-randomized studies have examined if surgical treatment on deep endometriosis may influence IVF outcomes. A systematic review with meta-analysis revealed that patients who underwent surgery before IVF exhibited significantly higher pregnancy rates per patient, pregnancy rates per cycle, and live birth rates per patient compared to those without prior surgery. However, the available data are insufficient to recommend surgical excision of deep endometriosis as the first-line treatment for asymptomatic patients to enhance IVF outcomes.

Bowel endometriosis: Surgical customization is demanding.

Bowel endometriosis is the most common form of severe deep endometriosis. Surgery is an option in case of infertility and/or chronic pain or in the presence of a stenotic lesion. Clinical examination and preoperative imaging must provide an identity card of the lesion so that customized surgery can be proposed. The primary objective of this tailor-made surgery will always be to preserve the organ. The surgeon then has three options: shaving, discoid resection and segmental resection. The more extensive the resection, the greater the risk of severe short- and long-term complications. Surgery must therefore be adapted to the patient's specific situation and needs. Moreover, personalized care must extend beyond surgery. It must begin before the operation, preparing the patient for the operation like an athlete before a race, and continue afterwards by adapting the follow-up to the surgery performed.

Management of patients with endometriosis and infertility: laparoscopic treatment and spontaneous pregnancy rate.

OBJECTIVE: To evaluate factors involved in spontaneous pregnancy rate after surgery for endometriosis in patients with endometriosis and infertility. METHODS: This retrospective study spanned from 2014 to 2020 and included a follow-up period of two years of patients with endometriosis-related infertility who underwent laparoscopic surgery. Women aged 25 to 43 years with patent tubes, no/mild male factor and no other infertility factors were selected and grouped according to fertility management as follows: patients immediately prescribed ART (16.5%, ART-p); patients who chose not to undergo ART (83.5%) and achieved spontaneous pregnancy (71.8% SP-p); and patients who first chose not to undergo ART but had it subsequently (28.2%, NSP-p). RESULTS: A total of 200 patients were analyzed. Of the 167 patients who waited for spontaneous pregnancy, 71.8% achieved it. We observed a tendency of higher endometriosis ASRM scores in the ART-p group compared with patients who waited for spontaneous pregnancy, and lower scores in individuals that achieved spontaneous pregnancy. When we looked at how long it took to achieve pregnancy, we found that individuals in the SP-p group achieved pregnancy in 5.7 months, while subjects in the NSP-p group took 1.8 times longer than their peers in the SP-p group (p<0.001). However, once prescribed ART, the individuals in the NSP-p group achieved pregnancy within a similar time when compared with subjects in the SP-p group. In order to identify individuals that might benefit from ART early on, we performed a multivariable analysis and developed a decision tree (81.3% accuracy and 53.3% sensitivity). CONCLUSIONS: The present results indicated that, after surgery, the majority of patients achieved spontaneous pregnancy. The decision tree proposed in this study allows the early identification of patients who might require ART, thus decreasing the time between surgery and pregnancy and improving overall outcomes.

Evidence-based diagnosis and treatment for uterine septum: a guideline.

OBJECTIVE: To provide evidence-based recommendations regarding the diagnosis and effectiveness of surgical treatment of a uterine septum. METHODS: This guideline provides evidence-based recommendations regarding the diagnosis and effectiveness of surgical treatment of a uterine septum. This replaces the last version of the same name (Fertil Steril. 2016 Sep 1;106(3):530-40). MAIN OUTCOME MEASURE(S): Outcomes of interest included the impact of a septum on underlying fertility, live birth, clinical pregnancy, and obstetrical outcomes. RESULT(S): The literature search identified relevant studies to inform the evidence for this guideline. CONCLUSION(S): The treatment of uterine septa and subsequent outcomes associated with infertility, recurrent pregnancy loss, and adverse obstetrical outcomes are summarized. Resection of a septum has been shown to improve outcomes in patients with recurrent pregnancy loss and to decrease the likelihood of malpresentation. In the setting of infertility, it is recommended to use a shared decision-making model after appropriate counseling to determine whether or not to proceed with septum resection.