Risks of Placental Abruption and Preterm Delivery in Patients Undergoing Assisted Reproduction.

Importance: Patients using assisted reproductive technology (ART) may need additional counseling about the increased risks of placental abruption and preterm delivery. Further investigation into the potential additive risk of ART and placental abruption is needed. Objective: To ascertain the risk of placental abruption in patients who conceived with ART and to evaluate if placental abruption and ART conception are associated with an increased risk of preterm delivery (<37 weeks' gestation) over and above the risks conferred by each factor alone. Design, Setting, and Participants: This cross-sectional study used data from the National Inpatient Sample, which includes data from all-payer hospital inpatient discharges from 48 states across the US. Participants included women aged 15 to 54 years who delivered from 2000 through 2019. Data were analyzed from January 17 to April 18, 2024. Exposures: Pregnancies conceived with ART. Main Outcomes and Measures: Risks of placental abruption and preterm delivery in ART conception compared with spontaneous conceptions. Associations were expressed as odds ratios (ORs) and 95% CIs derived from weighted logistic regression models before and after adjusting for confounders. The relative excess risk due to interaction (RERI) of the risk of preterm delivery based on ART conception and placental abruption was also assessed. Results: Of 78 901 058 deliveries, the mean (SD) maternal age was 27.9 (6.0) years, and 9 212 117 patients (11.7%) were Black individuals, 14 878 539 (18.9%) were Hispanic individuals, 34 899 594 (44.2%) were White individuals, and 19 910 807 (25.2%) were individuals of other races and ethnicities. Of the total hospital deliveries, 98.2% were singleton pregnancies, 68.8% were vaginal deliveries, and 52.1% were covered by private insurance. The risks of placental abruption among spontaneous and ART conceptions were 11 and 17 per 1000 hospital discharges, respectively. After adjusting for confounders, the adjusted OR (AOR) of placental abruption was 1.42 (95% CI, 1.34-1.51) in ART pregnancies compared with spontaneous conceptions, with increased odds in White women (AOR, 1.42; 95% CI, 1.31-1.53) compared with Black women (AOR, 1.16; 95% CI, 0.93-1.44). The odds of preterm delivery were significantly higher in pregnancies conceived by ART compared with spontaneous conceptions (AOR, 1.46; 95% CI, 1.42-1.51). The risk of preterm delivery increased when patients had both ART conception and placental abruption (RERI, 2.0; 95% CI, 0.5-3.5). Conclusions and Relevance: In this cross-sectional study, patients who conceived using ART and developed placental abruption had a greater risk of preterm delivery compared with spontaneous conception without placental abruption. These findings have implications for counseling patients who seek infertility treatment and obstetrical management of ART pregnancies.

Gestational diabetes mellitus in pregnancies conceived after infertility treatment: a population-based study in the United States, 2015-2020.

Objective: To evaluate the risk of gestational diabetes mellitus (GDM) in singleton pregnancies conceived using infertility treatment and examine the influence of race and ethnicity as well as prepregnancy body mass index (BMI). Design: Cross-sectional study using the US vital records data of women that delivered singleton births. Setting: United States, 2015-2020. Interventions: Any infertility treatment was divided into two groups: those that used fertility-enhancing drugs, artificial insemination, or intrauterine insemination, and those that used assisted reproductive technology (ART). Main Outcome Measuress: Gestational diabetes mellitus, defined as a diagnosis of diabetes mellitus during pregnancy, includes both diet-controlled GDM and medication-controlled GDM in singleton pregnancies conceived with infertility treatment or spontaneously and delivered between 20- and 44-weeks' gestation. We also examined whether the infertility treatment-GDM association was modified by maternal race and ethnicity as well as prepregnancy BMI. Associations were expressed as a rate ratio (RR) and 95% confidence interval (CI), derived from log-linear models after adjustment for potential confounders. Results: A total of 21,943,384 singleton births were included, with 1.5% (n = 318,086) undergoing infertility treatment. Rates of GDM among women undergoing infertility treatment and those who conceived spontaneously were 11.0% (n = 34,946) and 6.5% (n = 1,398,613), respectively (adjusted RR 1.24, 95% CI 1.23, 1.26). The RRs were adjusted for maternal age, parity, education, race and ethnicity, smoking, BMI, chronic hypertension, and year of delivery. The risk of GDM was modestly increased for those using fertility-enhancing drugs (adjusted RR 1.28, 95% CI 1.27, 1.30) compared with ART (adjusted RR 1.18, 95% CI 1.17, 1.20), and this risk was especially apparent for non-Hispanic White women (adjusted RR 1.29, 95% CI 1.26, 1.31) and Hispanic women (adjusted RR 1.35, 95% CI 1.29, 1.41). The number of women who needed to be exposed to infertility treatment to diagnose one case of GDM was 46. Prepregnancy BMI did not modify the infertility treatment-GDM association overall and within strata of race and ethnicity. These general patterns were stronger after potential corrections for misclassification of infertility treatment and unmeasured confounding. Conclusions: Infertility treatment, among those who received fertility-enhancing drugs, is associated with an increased GDM risk. The persistently higher risk of GDM among women who seek infertility treatment, irrespective of prepregnancy weight classification, deserves attention. Infertility specialists must be vigilant with preconception counseling and ensure that all patients, regardless of race and ethnicity or BMI, are adequately tested for GDM early in pregnancy using a fasting blood glucose level or a traditional 50-g oral glucose tolerance test. Testing may be completed by the infertility specialist or deferred to the primary prenatal care provider at the first prenatal visit.

Infertility treatment is associated with increased risk of postpartum hospitalization due to heart disease.

BACKGROUND: Cardiovascular disease is a major cause of maternal mortality, but the extent to which infertility treatment is implicated in heart disease remains unclear. OBJECTIVE: To evaluate the association between infertility treatment and postpartum heart disease. METHODS: We designed a retrospective cohort study of patients who delivered in the United States between 2010 and 2018. The primary outcome was hospitalization within 12-month post-delivery due to heart disease (including ischemic heart disease, atherosclerotic heart disease, cardiomyopathy, hypertensive disease, heart failure, and cardiac dysrhythmias). We estimated the rate difference (RD) of hospitalizations among patients who conceived with infertility treatment and those who conceived spontaneously. Associations were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs), derived from Cox proportional hazards regression after adjustment for potential confounders. RESULTS: Infertility treatment was recorded in 0.9% (n = 287,813) of 31,339,991 deliveries. Rates of heart disease hospitalizations with infertility treatment and with spontaneous conception were 550 and 355 per 100,000, respectively (RD 195, 95% CI: 143-247; adjusted HR 1.99, 95% CI: 1.80-2.20). The most important increase in risk was observed for hypertensive disease (adjusted HR 2.16, 95% CI: 1.92-2.42). This increased risk was apparent as early as 30-day post-delivery (HR 1.61, 95% CI: 1.39-1.86), with progressively increasing risk up to a year. CONCLUSIONS: Although the absolute risk of postpartum heart disease hospitalization is low, infertility treatment is associated with an increased risk, especially for hypertensive disease. These findings highlight the importance of timely postpartum follow-ups in patients who received infertility treatment.

Risk of Stroke Hospitalization After Infertility Treatment.

Importance: Stroke accounts for 7% of pregnancy-related deaths in the US. As the use of infertility treatment is increasing, many studies have sought to characterize the association of infertility treatment with the risk of stroke with mixed results. Objective: To evaluate the risk of hospitalization from hemorrhagic and ischemic strokes in patients who underwent infertility treatment. Design, Setting, and Participants: This population-based, retrospective cohort study used data abstracted from the Nationwide Readmissions Database, which stores data from all-payer hospital inpatient stays from 28 states across the US, from 2010 and 2018. Eligible participants included individuals aged 15 to 54 who had a hospital delivery from January to November in a given calendar year, and any subsequent hospitalizations from January to December in the same calendar year of delivery during the study period. Statistical analysis was performed between November 2022 and April 2023. Exposure: Hospital delivery after infertility treatment (ie, intrauterine insemination, assisted reproductive technology, fertility preservation procedures, or use of a gestational carrier) or after spontaneous conception. Main Outcomes and Measures: The primary outcome was hospitalization for nonfatal stroke (either ischemic or hemorrhagic stroke) within the first calendar year after delivery. Secondary outcomes included risk of stroke hospitalization at less than 30 days, less than 60 days, less than 90 days, and less than 180 days post partum. Cox proportional hazards regression models were used to estimate associations, which were expressed as hazard ratios (HRs), adjusted for confounders. Effect size estimates were corrected for biases due to exposure misclassification, selection, and unmeasured confounding through a probabilistic bias analysis. Results: Of 31 339 991 patients, 287 813 (0.9%; median [IQR] age, 32.1 [28.5-35.8] years) underwent infertility treatment and 31 052 178 (99.1%; median [IQR] age, 27.7 [23.1-32.0] years) delivered after spontaneous conception. The rate of stroke hospitalization within 12 months of delivery was 37 hospitalizations per 100 000 people (105 patients) among those who received infertility treatment and 29 hospitalizations per 100 000 people (9027 patients) among those who delivered after spontaneous conception (rate difference, 8 hospitalizations per 100 000 people; 95% CI, -6 to 21 hospitalizations per 100 000 people; HR, 1.66; 95% CI, 1.17 to 2.35). The risk of hospitalization for hemorrhagic stroke (adjusted HR, 2.02; 95% CI, 1.13 to 3.61) was greater than that for ischemic stroke (adjusted HR, 1.55; 95% CI, 1.01 to 2.39). The risk of stroke hospitalization increased as the time between delivery and hospitalization for stroke increased, particularly for hemorrhagic strokes. In general, these associations became larger for hemorrhagic stroke and smaller for ischemic stroke following correction for biases. Conclusions and Relevance: In this cohort study, infertility treatment was associated with an increased risk of stroke-related hospitalization within 12 months of delivery; this risk was evident as early as 30 days after delivery. Timely follow-up in the immediate days post partum and continued long-term follow-up should be considered to mitigate stroke risk.

Trocar site hernia after laparoscopy: Early recognition prevents catastrophic sequelae.

BACKGROUND: Trocar site hernia is a rare but potentially serious complication of laparoscopic surgery that may lead to bowel incarceration and strangulation. Prompt diagnosis by emergency physicians facilitates timely intervention that prevents bowel necrosis. We report a case of trocar site hernia presenting to the emergency department (ED) with abdominal pain that was correctly diagnosed and promptly managed. CASE REPORT: A 25-year-old woman, gravida 2, abortion 2, underwent outpatient surgery and laparoscopic removal of a ruptured right-sided tubal pregnancy without any intraoperative difficulties. However, 48 h later, she presented to the ED complaining of acute abdominal pain and nausea. Computed tomography revealed a loop of small bowel herniating through a 12-mm right lower quadrant trocar site defect in the fascia. She was taken back to the operating room, where the computed tomography findings were confirmed and the entrapped bowel was successfully reduced and the fascial defect repaired. The patient was discharged home feeling much improved. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trocar site hernia is a rare but potentially dangerous complication that can present with acute symptoms or be asymptomatic if late in onset. Intestinal necrosis begins as soon as 6 h after constriction of blood flow to entrapped bowel, so timely intervention is critically important. Therefore, trocar site hernias should be considered in patients presenting with abdominal complaints after laparoscopic surgery and included in the differential diagnosis of bowel obstruction.

Fertility preservation in transgender men and the need for uniform, comprehensive counseling.

Objective: To review the literature to assess best practices for counseling transgender men who desire gender-affirming surgery on fertility preservation options. Design: A scoping review of articles published through July 2021. Setting: None. Patients: Articles published in Cochrane, Web of Science, PubMed, Science Direct, SCOPUS, and Psychinfo. Interventions: None. Main Outcome Measures: Papers discussing transgender men, fertility preservation (FP), and FP counseling. Results: The primary search yielded 1,067 publications. After assessing eligibility and evaluating with a quality assessment tool, 25 articles remained, including 8 reviews, 5 surveys, 4 consensus studies, 3 retrospective studies, 3 committee opinions, and 2 guidelines. Publications highlighted the importance of including the following topics during counseling: (1) FP and family building options; (2) FP outcomes; (3) effects of testosterone therapy on fertility; (4) contraception counseling; (5) attitudes toward family building; (6) consequences of transgender parenting; and (7) barriers to success. Conclusions: Currently, there is a lack of standardization for comprehensive counseling about FP for transgender men. Standardized approaches can facilitate conversation between physicians and transgender men and ensure patients are making informed decisions regarding pelvic surgery and future family building plans.

lncRNA Malat1 and miR-26 cooperate in the regulation of neuronal progenitor cell proliferation and differentiation.

Neurogenesis is a finely tuned process, which depends on the balanced execution of expression programs that regulate cellular differentiation and proliferation. Different molecular players ranging from transcription factors to chromatin modulators control these programs. Adding to the complexity, also non-coding (nc)RNAs take part in this process. Here we analyzed the function of the long non-coding (lnc)RNA Malat1 during neural embryonic stem cell (ESC) differentiation. We find that deletion of Malat1 leads to inhibition of proliferation of neural progenitor cells (NPCs). Interestingly, this co-insides with an increase in the expression of miR-26 family members miR-26a and miR-26b in differentiating ESCs. Inactivation of miR-26a/b rescues the proliferative phenotype of Malat1 knockout (KO) cells and leads to accelerated neuronal differentiation of compound Malat1KO/mir-26KO ESCs. Together our work identifies a so far unknown interaction between Malat1 and miR-26 in the regulation of NPC proliferation and neuronal differentiation.

Altmetric and bibliometric analysis of influential articles in reproductive biology, 1980-2019.

RESEARCH QUESTION: What are the most influential articles in reproductive biology journals from 1980 to 2019 according to Altmetric Attention Score (AAS), number of citations and Relative Citation Ratio (RCR)? DESIGN: Cross-sectional study of reproductive biology articles indexed in the National Institutes of Health Open Citation Collection from 1980 to 2019. Data were downloaded on 20 May 2021. The 100 articles with highest AAS, RCR and number of citations were analysed. RESULTS: Twenty-one reproductive biology journals were identified, including 120,069 articles published from 1980 to 2019. In total 227 reproductive biology classics were identified due to some overlap between the three lists. Compared with the 100 articles with the highest AAS (after excluding articles featured on both lists), the 100 top-cited articles were older (2014 versus 2001, mean difference [95% confidence interval] 13.5 [11.5, 15.5]), less likely to be open access (64% versus 85%), more likely to be reviews (42% versus 12%) and less likely to be observational studies (9% versus 51%) and randomized clinical trials (0% versus 5%). These same trends were observed in analyses comparing the 100 articles with highest AAS to the 100 articles with highest RCR. The most common topic was assisted reproduction, but prominent topics included infertility for top AAS articles, reproductive technology in animals for top-cited articles, and polycystic ovary syndrome for top RCR articles. CONCLUSIONS: Formerly, influential articles in reproductive biology journals were evaluated by absolute citation rates and subject to limitations of conventional bibliometric analysis. This is the first comprehensive study to use altmetrics and citation-based metrics to identify reproductive biology classics.

Peritoneal hernia following abdominal hysterectomy: A case report.

BACKGROUND: Internal hernias rarely lead to bowel obstruction; they are caused by a natural or unnatural opening within the peritoneal cavity. Defects in the peritoneum are extremely rare. Patients present with features of intestinal obstruction and most cases are diagnosed during surgery. CASE PRESENTATION: A 47-year-old woman with a history of multiple abdominal surgeries had a small bowel hernia through a peritoneal defect of the anterior abdominal wall. She presented with abdominal pain and distension and was taken to the operating room, where findings revealed an intact fascia and small bowel herniation through a midline peritoneal defect. CONCLUSION: Herniation of small bowel through the peritoneum is a rare type of internal hernia that can manifest in a patient with extensive history of abdominal surgeries. This type of clinical picture warrants a high degree of suspicion for prompt and proper management. Surgery should not be delayed, to avoid increased morbidity and mortality.

Infertility treatment and the risk of small for gestational age births: a population-based study in the United States.

OBJECTIVE: To evaluate the association between infertility treatments and small for gestational age (SGA) births. DESIGN: Cross-sectional study. SETTING: United States, 2015-2019. PATIENTS: Women (n = 16,836,228) who delivered nonmalformed, singleton live births (24-44 weeks' gestation). INTERVENTIONS: Any infertility treatment, including assisted reproductive technology (ART) and prescribed fertility-enhancing medications. MAIN OUTCOME MEASURES: Small for gestational age birth, defined as sex-specific birth weight <10% for gestational age. Associations between SGA and infertility treatment were derived from Poisson regression with robust variance. Risk ratios (RR) and 95% confidence intervals (CI) were derived after adjusting for confounders. In a sensitivity analysis, we corrected for nondifferential exposure misclassification and unmeasured confounding biases. RESULTS: Subsequently, 1.4% (n = 231,177) of pregnancies resulted from infertility treatments (0.8% ART and 0.6% fertility-enhancing medications). Of these, SGA births occurred in 9.4% (n = 21,771) and 11.9% (n = 1,755,925) of pregnancies conceived with infertility treatment and naturally conceived pregnancies, respectively (adjusted RR, 1.07; 95% CI, 1.06, 1.08). However, after correction for misclassification bias and unmeasured confounding, infertility treatment was associated with a 27% reduced risk of SGA (bias-corrected RR, 0.73; 95% CI, 0.53, 0.85). Similar trends were seen for analyses stratified by exposure to ART and fertility-enhancing medications, as well as for SGA <5th and <3rd percentiles. CONCLUSIONS: Exposure to infertility treatment is associated with a reduced risk of SGA births. These findings, which are contrary to some published reports, may reflect changes in the modern practice of infertility care, maternal lifestyle, and compliance with prenatal care within the infertile population. Until these findings are corroborated, the associations must be cautiously interpreted.

Singleton pregnancies conceived with infertility treatments and the risk of neonatal and infant mortality.

OBJECTIVES: To examine the risks of neonatal and infant mortality in relation to infertility treatment and to quantify the extent to which preterm delivery mediates this relationship. DESIGN: Cross-sectional study. SETTING: United States, 2015-2018. PATIENT(S): A total of 14,961,207 pregnancies resulting in a singleton live birth. INTERVENTION(S): Any infertility treatment, including assisted reproductive technology and fertility-enhancing drugs. MAIN OUTCOME MEASURE(S): Neonatal (<28 days) mortality. The effect measure, risk ratio (RR), and 95% confidence interval (CI) were derived from log-linear Poisson models. A causal mediation analysis of the relationship between infertility treatment and mortality associated with preterm delivery (<37 weeks) was performed. The effects of exposure misclassification and unmeasured confounding biases were assessed. RESULT(S): Any infertility treatment was documented in 1.3% (n = 198,986) of pregnancies. Infertility treatment was associated with a 51% increased risk of neonatal mortality (RR 1.51, 95% CI 1.39-1.64), with a slightly higher risk for early neonatal mortality (RR 1.57, 95% CI 1.43-1.73) than late neonatal mortality (RR 1.33, 95% CI 1.11-1.58). These risks were similar for pregnancies conceived through assisted reproductive technology and fertility-enhancing drugs. The mediation analysis showed that 72% (95% CI 59-85) of the total effect of infertility treatment on neonatal mortality was mediated through preterm delivery. In a sensitivity analysis, following corrections for exposure misclassification and unmeasured confounding biases, these risks were higher for early, but not for late, neonatal mortality. CONCLUSION(S): Pregnancies conceived with infertility treatment are associated with increased neonatal mortality, and this association is largely mediated through preterm delivery. However, given the substantial underreporting of infertility treatment, these associations must be cautiously interpreted.

The miR-26 family regulates neural differentiation-associated microRNAs and mRNAs by directly targeting REST.

Repressor element 1-silencing transcription factor (REST) plays a crucial role in the differentiation of neural progenitor cells (NPCs). C-terminal domain small phosphatases (CTDSPs) are REST effector proteins that reduce RNA polymerase II activity on genes required for neurogenesis. miR-26b regulates neurogenesis in zebrafish by targeting ctdsp2 mRNA, but the molecular events triggered by this microRNA (miR) remain unknown. Here, we show in a murine embryonic stem cell differentiation paradigm that inactivation of miR-26 family members disrupts the formation of neurons and astroglia and arrests neurogenesis at the neural progenitor level. Furthermore, we show that miR-26 directly targets Rest, thereby inducing the expression of a large set of REST complex-repressed neuronal genes, including miRs required for induction of the neuronal gene expression program. Our data identify the miR-26 family as the trigger of a self-amplifying system required for neural differentiation that acts upstream of REST-controlled miRs.

Postpartum hemorrhage caused by uterine artery pseudoaneurysm: A case report.

BACKGROUND: Uterine artery pseudoaneurysms (UAPs) are a rare life-threatening complication presenting as vaginal bleeding. Transvaginal ultrasound doppler scans can diagnose UAPs in the immediate and later postpartum period. This case report highlights UAP management using minimally invasive interventions for fertility preservation. CASE: A 21-year-old woman presented on post-operative day 10 following a primary cesarean section with heavy vaginal bleeding and a UAP was confirmed on doppler sonography. A multidisciplinary approach determined the optimal management taking the patient's fertility into consideration. Initially, the UAP was injected directly with thrombin under ultrasound guidance. However, due to a subsequent hemorrhage, a uterine artery embolization was performed. CONCLUSION: Recognition of UAP is critical in the management of postpartum vaginal bleeding. Patient goals should be balanced with the severity of UAPs to determine optimal management.

Epidemiology of coronavirus disease 2019 in pregnancy: risk factors and associations with adverse maternal and neonatal outcomes.

BACKGROUND: Coronavirus disease 2019 may be associated with adverse maternal and neonatal outcomes in pregnancy, but there are few controlled data to quantify the magnitude of these risks or to characterize the epidemiology and risk factors. OBJECTIVE: This study aimed to quantify the associations of coronavirus disease 2019 with adverse maternal and neonatal outcomes in pregnancy and to characterize the epidemiology and risk factors. STUDY DESIGN: We performed a matched case-control study of pregnant patients with confirmed coronavirus disease 2019 cases who delivered between 16 and 41 weeks' gestation from March 11 to June 11, 2020. Uninfected pregnant women (controls) were matched to coronavirus disease 2019 cases on a 2:1 ratio based on delivery date. Maternal demographic characteristics, coronavirus disease 2019 symptoms, laboratory evaluations, obstetrical and neonatal outcomes, and clinical management were chart abstracted. The primary outcomes included (1) a composite of adverse maternal outcome, defined as preeclampsia, venous thromboembolism, antepartum admission, maternal intensive care unit admission, need for mechanical ventilation, supplemental oxygen, or maternal death, and (2) a composite of adverse neonatal outcome, defined as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, 5-minute Apgar score of <5, persistent category 2 fetal heart rate tracing despite intrauterine resuscitation, or neonatal death. To quantify the associations between exposure to mild and severe or critical coronavirus disease 2019 and adverse maternal and neonatal outcomes, unadjusted and adjusted analyses were performed using conditional logistic regression (to account for matching), with matched-pair odds ratio and 95% confidence interval based on 1000 bias-corrected bootstrap resampling as the effect measure. Associations were adjusted for potential confounders. RESULTS: A total of 61 confirmed coronavirus disease 2019 cases were enrolled during the study period (mild disease, n=54 [88.5%]; severe disease, n=6 [9.8%]; critical disease, n=1 [1.6%]). The odds of adverse composite maternal outcome were 3.4 times higher among cases than controls (18.0% vs 8.2%; adjusted odds ratio, 3.4; 95% confidence interval, 1.2-13.4). The odds of adverse composite neonatal outcome were 1.7 times higher in the case group than to the control group (18.0% vs 13.9%; adjusted odds ratio, 1.7; 95% confidence interval, 0.8-4.8). Stratified analyses by disease severity indicated that the morbidity associated with coronavirus disease 2019 in pregnancy was largely driven by the severe or critical disease phenotype. Major risk factors for associated morbidity were black and Hispanic race, advanced maternal age, medical comorbidities, and antepartum admissions related to coronavirus disease 2019. CONCLUSION: Coronavirus disease 2019 during pregnancy is associated with an increased risk of adverse maternal and neonatal outcomes, an association that is primarily driven by morbidity associated with severe or critical coronavirus disease 2019. Black and Hispanic race, obesity, advanced maternal age, medical comorbidities, and antepartum admissions related to coronavirus disease 2019 are risk factors for associated morbidity.

Beyond the "Jewish panel": the importance of offering expanded carrier screening to the Ashkenazi Jewish population.

OBJECTIVE: To assess whether or not the current American College of Obstetricians and Gynecologists (ACOG) recommendations regarding carrier screening are sufficiently robust in detecting mutations in the Ashkenazi Jewish (AJ) population. DESIGN: Cross-sectional study. SETTING: Outreach program at university community center. PATIENTS: Self-identified Jewish students, 18-24 years of age, interested in genetic carrier testing. INTERVENTIONS: Expanded carrier screening (ECS) with the use of a commercially available targeted genotyping panel including >700 mutations in 180 genes. MAIN OUTCOME MEASURES: Gene mutations found in this population were grouped into three categories based on ACOG's 2017 committee opinion regarding carrier screening: category 1: the four commonly recommended genetic conditions known to be a risk for this population; category 2: 14 genetic disorders that should be considered for more comprehensive screening, including those of category 1; and category 3: the ECS panel, which includes category 2. RESULTS: A total of 81 students underwent screening and 36 (44.4%) were ascertained to be carriers of at least one mutation. A total of 45 mutations were identified, as 8 students were carriers for more than one condition. If testing were limited to category 1, 84% of the mutations would not have been identified, and if limited to category 2, 55% of mutations would have gone undetected. CONCLUSIONS: Individuals of Ashkenazi Jewish descent are at significant risk for carrying a variety of single-gene mutations and therefore they should be offered panethnic ECS to increase the likelihood of detecting preventable disorders.

First PGT-A using human in vivo blastocysts recovered by uterine lavage: comparison with matched IVF embryo controls†.

STUDY QUESTION: After controlled ovarian stimulation (COS) and IUI, is it clinically feasible to recover in vivo conceived and matured human blastocysts by uterine lavage from fertile women for preimplantation genetic testing for aneuploidy (PGT-A) and compare their PGT-A and Gardner scale morphology scores with paired blastocysts from IVF control cycles? SUMMARY ANSWER: In a consecutive series of 134 COS cycles using gonadotrophin stimulation followed by IUI, uterine lavage recovered 136 embryos in 42% (56/134) of study cycles, with comparable in vivo and in vitro euploidy rates but better morphology in in vivo embryos. WHAT IS KNOWN ALREADY: In vivo developed embryos studied in animal models possess different characteristics compared to in vitro developed embryos of similar species. Such comparative studies between in vivo and in vitro human embryos have not been reported owing to lack of a reliable method to recover human embryos. STUDY DESIGN, SIZE, DURATION: We performed a single-site, prospective controlled trial in women (n = 81) to evaluate the safety, efficacy and feasibility of a novel uterine lavage catheter and fluid recovery device. All lavages were performed in a private facility with a specialized fertility unit, from August 2017 to June 2018. Subjects were followed for 30 days post-lavage to monitor for clinical outcomes and delayed complications. In 20 lavage subjects, a single IVF cycle (control group) with the same ovarian stimulation protocol was performed for a comparison of in vivo to in vitro blastocysts. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Women were stimulated with gonadotrophins for COS. The ovulation trigger was given when there were at least two dominant follicles ≥18 mm, followed by IUI of sperm. Uterine lavage occurred 4-6 days after the IUI. A subset of 20 women had a lavage cycle procedure followed by an IVF cycle (control IVF group). Recovered embryos were characterized morphologically, underwent trophectoderm (TE) biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using the next-generation sequencing technique. After lavage, GnRH antagonist injections were administered to induce menstruation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 134 lavage cycles were performed in 81 women. Uterine lavage recovered 136 embryos in 56 (42%) cycles. At the time of cryopreservation, there were 40 (30%) multi-cell embryos and 96 (70%) blastocysts. Blastocysts were of good quality, with 74% (70/95) being Gardener grade 3BB or higher grade. Lavage blastocysts had significantly higher morphology scores than the control IVF embryos as determined by chi-square analysis (P < 0.05). This is the first study to recover in vivo derived human blastocysts following ovarian stimulation for embryo genetic characterization. Recovered blastocysts showed rates of chromosome euploidy similar to the rates found in the control IVF embryos. In 11 cycles (8.2%), detectable levels of hCG were present 13 days after IUI, which regressed spontaneously in two cases and declined after an endometrial curettage in two cases. Persistent hCG levels were resolved after methotrexate in three cases and four cases received both curettage and methotrexate. LIMITATIONS, REASON FOR CAUTION: The first objective was to evaluate the feasibility of uterine lavage following ovarian stimulation to recover blastocysts for analysis, and that goal was achieved. However, the uterine lavage system was not completely optimized in our earlier experience to levels that were achieved late in the clinical study and will be expected in clinical service. The frequency of chromosome abnormalities of in vivo and IVF control embryos was similar, but this was a small-size study. However, compared to larger historical datasets of in vitro embryos, the in vivo genetic results are within the range of high-quality in vitro embryos. WIDER IMPLICATIONS OF THE FINDINGS: Uterine lavage offers a nonsurgical, minimally invasive strategy for recovery of embryos from fertile women who do not want or need IVF and who desire PGT, fertility preservation of embryos or reciprocal IVF for lesbian couples. From a research and potential clinical perspective, this technique provides a novel platform for the use of in vivo conceived human embryos as the ultimate benchmark standard for future and current ART methods. STUDY FUNDING/COMPETING INTEREST(S): Previvo Genetics, Inc., is the sole sponsor for the Punta Mita, Mexico, clinical study. S.M. performs consulting for CooperGenomics. J.E.B. and S.A.C. are co-inventors on issued patents and patents owned by Previvo and ownshares of Previvo. S.N. is a co-author on a non-provisional patent application owned by Previvo and holds stock options in Previvo. S.T.N. and M.J.A. report consulting fees from Previvo. S.T.N., S.M., M.V.S., M.J.A., C.N. and J.E.B. are members of the Previvo Scientific Advisory Board (SAB) and hold stock options in Previvo. J.E.B and S. M are members of the Previvo Board of Directors. A.N. and K.C. are employees of Previvo Genetics. L.V.M, T.M.M, J.L.R and S. S have no conflicts to disclose. TRIAL REGISTRATION NUMBER: Protocol Registration and Results System (PRS) Trial Registration Number and Name: Punta Mita Study TD-2104: Clinical Trials NCT03426007.