Psychosocial outcomes of children born via embryo donation.

STUDY QUESTION: What are parents' perceptions of their relationships with and the psychosocial adjustments of their children who are born via embryo donation? SUMMARY ANSWER: Families created through embryo donation have well-adjusted parent-child relationships and reassuring child psychosocial outcomes. WHAT IS KNOWN ALREADY: Embryo donation is an effective and growing form of third-party reproduction, but there is limited research in this field. Prior studies suggest that families created through gamete donation function well regarding parent-child relationship quality and child behavioral and socioemotional adjustment. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional survey study with 187 total participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parents of children born via embryo donation were recruited nationally by contacting all embryo donation programs registered with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) as well as medically directed embryo donation or 'embryo adoption' centers. Participants completed three online Qualtrics questionnaires. The first was a survey including 33 questions on demographics, the procurement process, and self-reported obstetric outcomes. Participants also completed two standardized measures assessing children's behavior and parents' adjustment to parenthood: the Strengths and Difficulties Questionnaire (SDQ) and the Parental Acceptance-Rejection Questionnaire (PARQ). Scoring of the SDQ and PARQ was totaled and compared to standardized values (SDQ) or previously published results on other forms of gamete donation (PARQ), such as oocyte donation and sperm donation. MAIN RESULTS AND THE ROLE OF CHANCE: On the SDQ (n = 46), the average total difficulties scores by age were: 8.2 ± 0.98 for ages 2-4, 7.6 ± 0.93 for ages 5-10, and 3.5 ± 0.77 for ages 11-17; this is compared to the normal reported range of 0-13, which indicates that clinically significant psychosocial problems are unlikely. Across all ages and individual categories (emotional symptoms, conduct problem, hyperactivity, peer problem, prosocial), scores on the SDQ were within the normal ranges. The average PARQ score (n = 70) for all respondents was 27.5 ± 1.18 (range: 24-96), suggesting perceived parental acceptance. LIMITATIONS, REASONS FOR CAUTION: Because this study was cross-sectional, it could not capture familial relationships over time. This survey-based study design allows for potential selection bias (parents of well-adjusted children may be more likely to participate). Additionally, the overall sample size is relatively small; however, it remains one of the largest published to date. Another significant limitation to this study is the lack of generalizability: most participants were recruited from private, faith-based, embryo donation programs who are demographically similar. WIDER IMPLICATIONS OF THE FINDINGS: Though embryo donation is an established form of third-party reproduction, it is significantly less robustly studied compared to other forms of gamete donation (oocyte or sperm donation). This study provides a larger data set with a more expanded age range of children compared to the limited number of previously published studies. Furthermore, these findings indicate a high parental disclosure rate with respect to the use of embryo donation which contrasts previous findings. STUDY FUNDING/COMPETING INTEREST(S): No external funding source was utilized for the completion of this study. No conflicts are disclosed. TRIAL REGISTRATION NUMBER: N/A.

Sleep and obstructive sleep apnea in women with infertility.

PURPOSE: Obstructive sleep apnea (OSA) is associated with polycystic ovarian syndrome (PCOS), a common cause of infertility. Understanding predictors and outcomes of OSA in women with infertility may guide treatment. METHODS: A descriptive cross-sectional survey was performed to assess OSA in women presenting to an infertility clinic using validated sleep questionnaires to assess sleep and fertility outcomes. An Infertile-C group (controls with male or tubal factors) and an Infertile-S group (unknown/other infertile causes) were analyzed to assess OSA risk and other sleep disorders (e.g., restless legs syndrome (RLS) and insomnia) with fertility outcomes (time to pregnancy, PCOS, irregular menstruation, and miscarriage). RESULTS: In 258 women, occurrences of OSA diagnosis (6%) and RLS (10%) were reported similar to women of child-bearing age in the general population. PCOS was unassociated with OSA risk. Predictors of OSA risk were BMI, insomnia symptoms, and sleep aid use. Obese women with high OSA risk were more likely to have other comorbidities (e.g., depression). In adjusted models, prior clinical OSA diagnosis was associated with miscarriage (odds ratio: 6.17 (1.24, 30.62), p = 0.026). RLS was associated with irregular menstruation (odds ratio: 3.73 (1.21, 11.53), p = 0.022). CONCLUSIONS: Similar to other populations, women with infertility and OSA risk have more health comorbidities and higher BMI and may present with insomnia symptoms. While the data are limited, this study supports the potential associations of OSA and miscarriage. Further work is needed to evaluate OSA in female infertility.

Uterine Transplantation: Recipient Patient Populations.

Uterine transplantation is an emerging treatment for patients with uterine factor infertility (UFI). In order to determine patient candidacy for transplant, it is imperative to understand how to identify, counsel and treat uterine transplant recipients. In this article, we focus on patient populations with UFI, whether congenital or acquired, including Mayer-Rokitansky-Kuster-Hauser, complete androgen insensitivity syndrome, hysterectomy, and other causes of nonabsolute UFI. Complete preoperative screening of recipients should be required to assess the candidacy of each individual prior to undergoing this extensive treatment option.

Excision versus Ablation for Management of Minimal to Mild Endometriosis: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this systematic review and meta-analysis was to perform an updated analysis of the literature in regard to the surgical management of minimal to mild endometriosis. This study evaluated women of reproductive age with superficial endometriosis to determine if the results of surgical excision compared with those of ablation in improved pain scores postoperatively. DATA SOURCES: The following databases were searched from inception to May 2020 for relevant studies: Cochrane Central Register of Controlled Trials, PubMed (MEDLINE), Ovid (MEDLINE), Scopus, and Web of Science. METHODS OF STUDY SELECTION: From our literature search, a total of 2633 articles were identified and screened. Ultimately, 4 randomized controlled trials were selected and included in our systematic review. The combined total number of subjects was 346 from these 4 studies, with sample sizes ranging from 24 to 170 participants. Data from 3 of the included studies were able to be compared and analyzed for a meta-analysis. The primary outcome was reduction in the visual analog scale (VAS) score for endometriosis-associated pain (dysmenorrhea, dyschezia, and dyspareunia), with follow-up time ranging from 6 to 60 months postoperatively. TABULATION, INTEGRATION, AND RESULTS: Data extracted from each study included the mean reduction in the VAS score from baseline. A random-effects model was used owing to significant heterogeneity across the studies. Statistical analyses were performed using Review Manager 5.3 software (Cochrane Collaboration, London, United Kingdom). The meta-analyses showed no significant differences between the excision and ablation groups in the mean reduction in VAS scores from baseline to 12 months postoperatively for dysmenorrhea (mean difference [MD] -0.03; 95% confidence interval [CI], -1.27 to 1.22; p = .97), dyschezia (MD 0.46; 95% CI, -1.09 to 2.02; p = .56), and dyspareunia (MD 0.10; 95% CI, -2.36 to 2.56; p = .94). In addition, there were no significant differences between the excision and ablation groups in mean VAS scores at the 12-month follow-up and beyond for dysmenorrhea (MD -0.11; 95% CI, -2.14 to 1.93; p = .92), dyschezia (MD 0.01; 95% CI, -0.70 to 0.72; p = .99), and dyspareunia (MD 0.34; 95% CI, -1.61 to 2.30; p = .73). CONCLUSION: On the basis of the data from our systematic review and pooled meta-analysis, no significant difference between laparoscopic excision and ablation was noted in regard to improving pain from minimal to mild endometriosis. However, to make definitive conclusions on this topic, larger randomized controlled trials are needed with longer follow-up.

Guidelines for standardized nomenclature and reporting in uterus transplantation: An opinion from the United States Uterus Transplant Consortium.

Uterus transplantation is a nascent but growing field. To support this growth, the United States Uterus Transplant Consortium proposes guidelines for nomenclature related to operative technique, vascular anatomy, and donor, recipient, and offspring outcomes. In terms of anatomy, the group recommends reporting donor arterial inflow and recipient anastomotic site delivering inflow to the graft and offers standardization of the names for the 4 veins originating from the uterus because of current inconsistency in this particular nomenclature. Seven progressive stages with milestones of success are defined for reporting on uterus transplantation outcomes: (1) technical, (2) menstruation, (3) embryo implantation, (4) pregnancy, (5) delivery, (6) graft removal, and (7) long-term follow-up. The 3 primary metrics for success are recipient survival (as reported for other organ transplant recipients), graft survival, and uterus transplant live birth rate (defined as live birth per transplanted recipient). A number of secondary outcomes should also be reported, most of which capture stage-specific milestones, as well as data on graft failure. Outcome metrics for living donors include patient survival, survival free of operative intervention, and data on complications and hospitalizations. Finally, we make specific recommendations on follow-up for offspring born from uterine grafts, which includes specialty surveillance as well as collection and reporting of routine pediatric outcomes. The goal of standardization in reporting is to create consistency and improve the quality of evidence available on the efficacy and value of the procedure.

60S acidic ribosomal protein P1 (RPLP1) is elevated in human endometriotic tissue and in a murine model of endometriosis and is essential for endometriotic epithelial cell survival in vitro.

Endometriosis is a female disease which is defined as the presence of ectopic endometrial tissue and is dependent on estrogen for its survival in these ectopic locations. Expression of the ribosomal protein large P1 (RPLP1) is associated with cell proliferation and invasion in several pathologies, but a role in the pathophysiology of endometriosis has not been explored. In this study, we aimed to evaluate the expression and function of RPLP1 with respect to endometriosis pathophysiology. RPLP1 protein was localised by immunohistochemistry (IHC) in eutopic and ectopic tissue from 28 subjects with confirmed endometriosis and from 20 women without signs or symptoms of the disease, while transcript levels were evaluated by qRT-PCR in 77 endometriotic lesions and 55 matched eutopic endometrial biopsies, and protein expression was evaluated using western blotting in 20 of these matched samples. To evaluate the mechanism for enhanced lesion expression of RPLP1, an experimental murine model of endometriosis was used and RPLP1 expression was localized using IHC. In vitro studies using an endometriosis cell line coupled with shRNA knockdown was used to demonstrate its role in cell survival. Expression of RPLP1 mRNA and protein were significantly higher in ectopic lesion tissue compared to paired eutopic endometrium and immunohistochemical localisation revealed predominant localisation to epithelial cells. This pattern of lesion RPLP1 was recapitulated in mice with experimentally induced endometriosis. Stable knockdown of RPLP1 protein resulted in a significant decrease in cell survival in vitro. These studies reveal that RPLP1 is associated with cell proliferation and/or survival and may play a role in the pathophysiology of endometriosis.

Evolving ethical issues with advances in uterus transplantation.

While uterus transplantation was once considered only a theoretical possibility for patients with uterine factor infertility, researchers have now developed methods of transplantation that have led to successful pregnancies with multiple children born to date. Because of the unique and significant nature of this type of research, it has been undertaken with collaboration not only with scientists and physicians but also with bioethicists, who paved the initial path for research of uterus transplantation to take place. As the science of uterus transplantation continues to advance, so too must the public dialogue among obstetrician/gynecologists, transplant surgeons, bioethicists, and other key stakeholders in defining the continued direction of research in addition to planning for the clinical implementation of uterus transplantation as a therapeutic option. Given the rapid advances in this field, the time has come to revisit the fundamental questions raised at the inception of uterus transplantation and, looking forward, determine the future of this approach given emerging data on the procedure's impact on individuals, families, and society.

First birth from a deceased donor uterus in the United States: from severe graft rejection to successful cesarean delivery.

Uterus transplantation is the only known potential treatment for absolute uterine factor infertility. It offers a unique setting for the investigation of immunologic adaptations of pregnancy in the context of the pharmacologic-induced tolerance of solid organ transplants, thus providing valuable insights into the early maternal-fetal interface. Until recently, all live births resulting from uterus transplantation involved living donors, with only 1 prior birth from a deceased donor. The Cleveland Clinic clinical trial of uterus transplantation opened in 2015. In 2017, a 35 year old woman with congenital absence of the uterus was matched to a 24 year old parous deceased brain-dead donor. Transplantation of the uterus was performed with vaginal anastomosis and vascular anastomoses bilaterally from internal iliac vessels of the donor to the external iliac vessels of the recipient. Induction and maintenance immunosuppression were achieved and subsequently modified in anticipation of pregnancy 6 months after transplant. Prior to planned embryo transfer, ectocervical biopsy revealed ulceration and a significant diffuse, plasma cell-rich mixed inflammatory cell infiltrate, with histology interpreted as grade 3 rejection suspicious for an antibody-mediated component. Aggressive immunosuppressive regimen targeting both cellular and humoral rejection was initiated. After 3 months of treatment, there was no histologic evidence of rejection, and after 3 months from complete clearance of rejection, an uneventful embryo transfer was performed and a pregnancy was established. At 21 weeks, central placenta previa with accreta was diagnosed. A healthy neonate was delivered by cesarean hysterectomy at 34 weeks' gestation. In summary, this paper highlights the first live birth in North America resulting from a deceased donor uterus transplant. This achievement underscores the capacity of the transplanted uterus to recover from a severe, prolonged rejection and yet produce a viable neonate. This is the first delivery from our ongoing clinical trial in uterus transplantation, including the first reported incidence of severe mixed cellular/humoral rejection as well as the first reported placenta accreta.

New Frontier: Role of the Radiologist in Uterine Transplantation.

Uterine transplantation (UT) is a novel treatment for absolute uterine factor infertility (AUFI) that is currently being performed under experimental protocols in multiple medical centers worldwide. At the time of this publication, there have been at least 10 live births by women with a transplanted uterus. As successful outcomes from this innovative procedure increase, it is likely that more centers will perform UT. Imaging is performed in multiple steps of the UT process, including preoperative imaging of potential donors and recipients, posttransplant surveillance, and monitoring of pregnancy. Fetal imaging is performed by maternal-fetal medicine professionals, but most imaging examinations in UT are performed by radiologists. Given the significant role of imaging in this groundbreaking surgery, radiologists must be familiar with the causes of AUFI and the role of imaging in establishing this diagnosis. Radiologists working in medical centers where UT is performed should understand the role of imaging in preoperative planning and postoperative surveillance. While data regarding complications of UT are preliminary at best, radiologists must be aware of the risk of vascular compromise and graft failure and their imaging features. The authors provide a brief history of UT and define the radiologist's role in pre- and postoperative imaging assessments.©RSNA, 2019.

Characterizing the endometrial fluid cytokine profile in women with endometriosis.

PURPOSE: To compare growth factor and cytokine profiles in the endometrial secretions of patients with and without endometriosis to determine whether a particular protein profile is predictive of the disease. METHODS: Patients undergoing laparoscopic gynecologic surgery for benign indications were recruited for this prospective cohort study. Prior to surgery, endometrial fluid was aspirated and multiplex immunoassay was used to quantify 7 cytokines and growth factors. During surgery, each patient was staged according to the ASRM staging system for endometriosis. Cytokines and growth factors were evaluated using the Mann-Whitney and Kruskal-Wallis tests. Combinations of cytokines were evaluated using logistic regression analysis, and ROC curves were generated to evaluate the predictive capacity of the assay. RESULTS: Endometrial secretions were analyzed from 60 patients. Nineteen had stage 3-4 endometriosis, 19 had stage 1-2 disease, and 22 had no endometriosis. There were no significant differences between controls and stage 1-2 endometriosis; however, levels of IL-1α and IL-6 were significantly increased in women with moderate-to-severe disease. A combination of IL-1α, IL-1ß, and IL-6 in endometrial secretions predicts stage 3-4 endometriosis with an AUC of 0.78. A threshold value of 118 pg/mL yields a sensitivity of 75% and specificity of 70%. CONCLUSION: Aspiration of endometrial fluid is a safe and effective approach for evaluating the endometrial profile of women with endometriosis. Women with moderate-to-severe endometriosis demonstrate a distinct cytokine profile compared to controls. A combination of IL-1α, IL-1ß, and IL-6 in the endometrial secretions is predictive of stage 3-4 endometriosis, but is not predictive of minimal-to-mild disease.

Thickened Endometrium in Postmenopausal Women With an Initial Biopsy of Limited, Benign, Surface Endometrium: Clinical Outcome and Subsequent Pathologic Diagnosis.

Endometrial biopsy or curetting is indicated for postmenopausal women with abnormal uterine bleeding and/or thickened endometrium. Often, endometrial biopsy or curetting yields limited benign surface endometrium, which may indicate insufficient sampling. This study addresses the clinical outcome and subsequent pathologic diagnoses in postmenopausal women who received this initial diagnosis. Among a total of 370 endometrial biopsy or curetting between 2012 and 2015, 192 (52%) were diagnosed as limited benign surface endometrial epithelium. The women ranged in age from 55 to 91 yr old. Their clinical presentations mainly included postmenopausal bleeding, pelvic pain, and enlarged uterus. Primarily because the initial report was interpreted as "benign," 108 (57%) had no subsequent follow-up. Interestingly, women with an increased endometrial thickness were more likely to receive repeat evaluation. Among the 84 women who underwent follow-up endometrial sampling, 6 (7%) had hyperplasia with atypia or malignancy, 21 (25%) had a repeat diagnosis of limited surface sample, 4 (5%) had insufficient materials, and 53 (63%) had other benign findings. Among the subset of women who did receive subsequent follow-up, endometrial atypia or malignancies are more likely found in those with increased body mass index. In conclusion, a slight majority of women with postmenopausal bleeding and/or thickened endometrium had an initial limited surface endometrial sample. Most had no subsequent endometrial sampling. Among those with subsequent follow-up, the majority had benign findings. The study highlights the inconsistencies in adequacy criteria for endometrial sampling and the lack of standardization of subsequent management.

Uterine Factor Infertility: A Clinical Review.

Uterine factor infertility (UFI) may affect up to 1 in 500 reproductive age women. The uterus is an essential component of achieving pregnancy and carrying a pregnancy to term successfully. There are many etiologies of UFI which may be categorized into either congenital or acquired causes. In this review, we discuss the different causes of UFI as well as the treatment options, which now includes uterine transplant.

Fallopian tube perfusion in ex-vivo and in-vivo laparoscopic hysterectomy specimens: potential application for uterine transplantation.

STUDY QUESTION: Is there perfusion to the fallopian tubes in ex-vivo and in-vivo uteri at the time of total laparoscopic hysterectomy (TLH), as observed using laser angiography with indocyanine green (ICG)? SUMMARY ANSWER: The fallopian tubes may have perfusion from the utero-ovarian vasculature alone. WHAT IS KNOWN ALREADY: The fallopian tubes are perfused by the uterine and utero-ovarian vessels. Perfusion can be measured using laser angiography with ICG. STUDY DESIGN, SIZE, DURATION: This prospective pilot cohort study included 15 women, ages 32-59 years old, who underwent TLH with bilateral salpingectomy for benign indications. PARTICIPANTS/MATERIALS, SETTING, METHODS: In five participants, TLH was performed and the utero-ovarian artery was cannulated ex vivo and injected with ICG. The other 10 participants underwent the in-vivo protocol. The mesosalpinx and uterine vessels were transected in the partial protocol. Colpotomy was also performed in the complete protocol. All fallopian tubes were imaged using laser angiography with ICG. The relative fluorescence and the fluorescence intensity ratio (length of fluorescent fallopian tube/total length of fallopian tube) of the fallopian tubes were measured in the ex-vivo and in-vivo protocols, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: Ex vivo, the fimbria of the ipsilateral fallopian tube had 47% median relative fluorescence as compared to the contralateral fallopian tube, which had 2.4% median relative fluorescence. In vivo, the post-ICG fluorescence intensity ratios were 0.61 ± 0.40 for the partial protocol, and 0.78 ± 0.30 for the complete protocol, with mean differences of 0.37 (95% CI: 0.23-0.50, P < .0001) and 0.22 (95% CI: 0.12-0.31, P < 0.0001), respectively, between the pre-procedure and the post-ICG fluorescence intensity ratios. Greater than 0.75 fluorescence intensity ratios (i.e. >75% tubal length fluorescence) was seen in 60% of fallopian tubes. LIMITATIONS, REASONS FOR CAUTION: This is a pilot study with a small sample size and pathologic uteri, which would not be appropriate for uterine transplantation. No conclusions can be made regarding the functionality of the fallopian tubes. WIDER IMPLICATIONS OF THE FINDINGS: The fallopian tubes may have perfusion with the utero-ovarian vasculature alone, potentially allowing for future animal studies regarding tubal viability in recipients of uterine-tubal transplants. If successful, human uterine-tubal transplantation may allow for spontaneous conception rather than IVF. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. S.F., P.F.P., K.A.S. and R.F. have no conflicts of interest to report. M.L.S. is an educational consultant for Medtronic (Dublin, Republic of Ireland) and Applied Medical (Rancho Santa Margarita, CA, USA), as well as a stockholder for SynDaver Labs (Tampa, FL, USA). S.E.Z. is an educational consultant for Applied Medical (Rancho Santa Margarita, CA, USA) and is on the advisory board for AbbVie Inc. (Chicago, IL, USA). TRIAL REGISTRATION NUMBER: Not applicable.

Uterine Transplantation: Surgical Innovation in the Treatment of Uterine Factor Infertility.

Uterine factor infertility (UFI) is a condition that affects thousands of women and is estimated to have a prevalence as high as one in five hundred reproductive-aged women. A wide range of circumstances can lead to UFI and include women with congenital absence of a uterus (Mayer Rokitansky Kuster Hauser or MRKH syndrome), women who have undergone iatrogenic removal of the uterus, or women who have uteri that are in situ but have been damaged by infection or surgical instrumentation. There have been 17 published reports of human uterine transplantation in the world. This article will summarize the history of human uterine transplantation and discuss our current understanding of the medical, surgical, and ethical considerations surrounding this innovative procedure.

Fertility and fertility preservation: knowledge, awareness and attitudes of female graduate students.

PURPOSE: To evaluate the general knowledge of female graduate students on reproductive aging and fertility preservation options, as well as to investigate the perceptions, personal beliefs, and desires regarding fertility and preservation modalities. MATERIALS AND METHODS: A cross-sectional online survey study of female graduate students and medical trainees from academic institutions in Ohio was performed. Women were excluded if the online survey was incomplete or if they were >45 years. RESULTS: Analysis of 590 surveys was performed (response rate of 26.3%). Ninety-four percent (557/590) of subjects were between 20 and 35 years. Our respondents tended to be nulliparous (87%), married or in a relationship (51%) and interested in future fertility (77%). The reasons cited for delaying childbearing were multi-factorial, with career building noted most commonly (69%). Nearly 60% of women reported they would consider fertility preservation in the future; however, the majority (87%) cited two or more barriers. When asked about their desire for information on fertility preservation, 28% desired to receive education on their choices and 36% wanted their Ob/Gyn to discuss fertility preservation options. Women >30 years were significantly more likely to desire future fertility, want more fertility preservation education and consider pursuing fertility preservation in the future. CONCLUSIONS: Graduate-level women often delay childbearing for professional pursuits. This study demonstrates a need for increased fertility preservation awareness and education, especially by Ob/Gyn providers.

Minimally Invasive Myomectomy.

Uterine fibroids can significantly impact a woman's health, fertility, and quality of life. When medical therapy fails, surgery is recommended; the gold standard in uterine-sparing surgery is myomectomy. The evidence-based benefits of minimally invasive myomectomy are detailed in this manuscript. Minimally invasive myomectomy techniques are reviewed, including laparoscopic, robotic-assisted, and laparoscopic or robotic-assisted with mini-laparotomy. Criteria for minimally invasive myomectomy are outlined and preoperative planning is discussed. Both institutional data and data from systematic reviews are included to compare outcomes. Each myomectomy case should take into account clinical characteristics of the myomas, patient preference, and surgeon skill and experience.