A SART data cost-effectiveness analysis of planned oocyte cryopreservation versus in vitro fertilization with preimplantation genetic testing for aneuploidy considering ideal family size.

OBJECTIVE: To determine the cost-effectiveness of planned oocyte cryopreservation (OC) as a strategy for delayed childbearing to achieve 1 or 2 live births (LB) compared with in vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A) at advanced reproductive age. DESIGN: Decision tree model with sensitivity analyses using data from the Society for Assisted Reproductive Technology Clinical Outcome Reporting System and other clinical sources. SETTING: Not applicable. PATIENT(S): A data-driven simulated cohort of patients desiring delayed childbearing with an ideal family size of 1 or 2 LB. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Probability of achieving ≥1 or 2 LB, average and maximum cost per patient, cost per percentage point increase in chance of LB, and population-level cost/LB. RESULT(S): For those desiring 1 LB, planned OC at age 33 with warming at age 43 decreased the average total cost per patient from $62,308 to $30,333 and increased the likelihood of LB from 50% to 73% when compared with no OC with up to 3 cycles of IVF/PGT-A at age 43. For those desiring 2 LB, 2 cycles of OC at age 33 and warming at age 40 yielded the lowest cost per patient and highest likelihood of achieving 2 LB ($51,250 and 77%, respectively) when compared withpursuing only 1 cycle of OC ($75,373 and 61%, respectively), no OC and IVF/PGT-A with embryo banking ($79,728 and 48%, respectively), or no OC and IVF/PGT-A without embryo banking ($79,057 and 19%, respectively). Sensitivity analyses showed that OC remained cost-effective across a wide range of ages at cryopreservation. For 1 LB, OC achieved the highest likelihood of success when pursued before age 32 and remained more effective than IVF/PGT-A when pursued before age 39, and for 2 LB, 2 cycles of OC achieved the highest likelihood of success when pursued before age 31 and remained more effective than IVF/PGT-A when pursued before age 39. CONCLUSION(S): Among patients planning to postpone childbearing, OC is cost-effective and increases the odds of achieving 1 or 2 LB when compared with IVF/PGT-A at a more advanced reproductive age.

The parent trap: desire for multifetal gestation among patients treated for infertility.

OBJECTIVE: To evaluate predictors for patient preference regarding multifetal or singleton gestation among women presenting for infertility care. DESIGN: Cross-sectional study. SETTING: Academic university hospital-based infertility clinic. PATIENT(S): Five hundred thirty-nine female patients with infertility who presented for their initial visit. MAIN OUTCOME MEASURE(S): Demographic characteristics, infertility history, insurance coverage, desired treatment outcome, acceptability of multifetal reduction, and knowledge of the risks of multifetal pregnancies were assessed using a previously published 41-question survey. Univariate analysis was performed to assess patient factors associated with the desire for multiple births. Independent factors associated with this desire were subsequently assessed by multivariate logistic regression analysis. RESULT(S): Nearly a third of women preferred multiples over a singleton gestation. Nulliparity, lower annual household income, older maternal age, marital status, larger ideal family size, openness to multifetal reduction, and lack of knowledge of the maternal/fetal risks of twin pregnancies were associated with pregnancy desire. Older age (OR (95% CI) 1.66 (1.20-2.29)), nulliparity (OR (95% CI) 0.34 (0.20-0.58)), larger ideal family size (OR (95% CI) 2.34 (1.73-3.14)), and lesser knowledge of multifetal pregnancy risk (OR (95% CI) 0.67 (0.55-0.83)) were independently associated with desire. CONCLUSION(S): A large number of patients undergoing fertility treatment desire multifetal gestation. Although a lack of understanding of the risks associated with higher order pregnancies contributes to this desire, additional individual specific variables also contribute to this trend. Efforts to reduce the incidence of multiples should focus not only on patient education on comparative risks of multiples vs singleton pregnancies but also account for individual specific reservations.

Knowledge of Fertility and Perspectives About Family Planning Among Female Physicians.

Importance: Pervasive gender disparities exist in medicine regarding promotion, achievement of academic rank, and appointment to leadership positions. Fertility and childbearing concerns may contribute to these disparities. Objective: To assess fertility knowledge and concerns and evaluate barriers to family building and impact on academic attrition reported by female physicians. Design, Setting, and Participants: This qualitative study used mixed methods; first, structured 1:1 interviews exploring fertility knowledge and family-building concerns were conducted among 16 female physicians between November 2019 and May 2020. Transcripts were coded in Dedoose and used to develop a survey instrument with subsequent pilot testing conducted among 24 female physicians between April 2020 and September 2020. Data analysis was performed from January 2021 to March 2021. Main Outcomes and Measures: Fertility knowledge, perceptions of peer and institutional support surrounding childbearing, factors contributing to delayed childbearing, and impact of family planning on career decisions. Results: Among 16 women who completed qualitative interviews, 4 (25%) were Asian, 1 (6%) was Black, 1 (6%) was multiracial, and 10 (63%) were White; mean (SD) age was 34.9 (4.0) years. Evaluation of fertility knowledge revealed 3 notable themes: (1) inadequate formal fertility education, (2) informal learning through infertility experiences of patients, peers, or personal struggles, and (3) desire to improve medical education through early introduction and transparent discussions about infertility. Exploration of childbearing concerns similarly revealed several salient themes: (1) high incidence of delayed childbearing, (2) perceived lack of peer and administrative support, and (3) impact of family building on career trajectory. These themes were borne out in pilot testing of the survey instrument: of 24 female physicians (7 Asian women [27%], 1 Black woman [4%], 1 Hispanic or Latinx woman [4%], 1 multiracial woman [4%], 15 White women [58%]; mean [SD] age, 36.1 [6.7] years), 17 (71%) had delayed childbearing and 16 (67%) had altered their career for family-building reasons. Conclusions and Relevance: Qualitative interviews identified fertility and family building concerns among female physicians and were used to develop a tailored survey for women in medicine. These findings suggest that female physicians may delay childbearing and make substantial accommodations in their careers to support family building. A large-scale national survey is needed to better characterize the unique fertility, childbearing, and parenting needs of women in academic medicine to better understand how these concerns may contribute to academic attrition.

Disposition preferences in oocyte preservation patients.

PURPOSE: To characterize the frozen oocyte disposition preferences of patients undergoing medical and planned fertility preservation. METHODS: All oocyte cryopreservation (OC) patients were identified between 2015 and 2018. Demographic information and fertility preservation (FP) indication (medical or planned) were identified for each patient. Oocyte disposition options included disposal, donation to research, or donation to a specified third party, which was decided at the time of initial consent and made available in the electronic medical record. The primary outcome was the disposition selection. Secondary outcomes included differences in demographic variables and disposition selections between medical and planned FP patients using chi-squared analysis. RESULTS: A total of 336 OC patients with a documented oocyte disposition preference were identified in the study timeframe. Patients were on average 34.5 years old (SD = 5.1) and were predominantly White (70.2%), nulliparous (83.0%), with a BMI of 24.7 (SD = 5.4). A total of 101 patients underwent OC for medical FP and 235 for planned FP. In both groups, the most commonly selected disposition option was donation to research (50% planned, 52% medical), followed by donation to a specified third party (30% planned, 30% medical), and finally disposal of oocytes (20% planned, 18% medical). There were no significant differences in disposition selection between each group. When comparing patient variables between groups, medical FP patients were more likely to be under the age of 35 and were less likely to be nulliparous (p < .001). CONCLUSION: This study shows that oocyte disposition choices are similar in patients undergoing OC for medical and planned indications. As donation to research was the most commonly selected option in both groups, it is time to start thinking of streamlining ways to utilize this potential research material in the future.

Tryptophan 2,3-Dioxygenase-2 in Uterine Leiomyoma: Dysregulation by MED12 Mutation Status.

Uterine leiomyomas (fibroids) are common benign tumors in women. The tryptophan metabolism through the kynurenine pathway plays important roles in tumorigenesis in general. Leiomyomas expressing mutated mediator complex subunit 12 (mut-MED12) were reported to contain significantly decreased tryptophan levels; the underlying mechanism and the role of the tryptophan metabolism-kynurenine pathway in leiomyoma tumorigenesis, however, remain unknown. We here assessed the expression and regulation of the key enzymes that metabolize tryptophan. Among these, the tissue mRNA levels of tryptophan 2,3-dioxygenase (TDO2), the rate limiting enzyme of tryptophan metabolism through the kynurenine pathway, was 36-fold higher in mut-MED12 compared to adjacent myometrium (P < 0.0001), and 14-fold higher compared to wild type (wt)-MED12 leiomyoma (P < 0.05). The mRNA levels of other tryptophan metabolizing enzymes, IDO1 and IDO2, were low and not significantly different, suggesting that TDO2 is the key enzyme responsible for reduced tryptophan levels in mut-MED12 leiomyoma. R5020 and medroxyprogesterone acetate (MPA), two progesterone agonists, regulated TDO2 gene expression in primary myometrial and leiomyoma cells expressing wt-MED12; however, this effect was absent or blunted in leiomyoma cells expressing G44D mut-MED12. These data suggest that MED12 mutation may alter progesterone-mediated TDO2 expression in leiomyoma, leading to lower levels of tryptophan in mut-MED12 leiomyoma. This highlights that fibroids can vary widely in their response to progesterone as a result of mutation status and provides some insight for understanding the effect of tryptophan-kynurenine pathway on leiomyoma tumorigenesis and identifying targeted interventions for fibroids based on their distinct molecular signatures.

Risk factors and human chorionic gonadotropin trends in patients with ruptured tubal ectopic pregnancies despite methotrexate treatment.

This retrospective cohort study investigates the risk factors and beta-human chorionic gonadotropin (ß-hCG) trends in patients with ruptured tubal ectopic pregnancies (EPs) despite methotrexate (MTX) treatment. All patients receiving MTX for sonographically confirmed tubal EPs at our fertility center between 2004 and 2014 were included. Baseline demographics and ß-hCG trends of patients with EP rupture after MTX were compared to patients with resolved EPs after MTX. One-hundred-thirty-seven patients with EPs were treated with MTX during the study duration; 27 experienced EP rupture and 110 EP resolution. There was no difference in the baseline demographics or ß-hCG levels on the day of MTX between the groups. Patients with ruptured EPs after MTX had higher ß-hCG levels on day-4 (1223.9 ± 243.5 vs. 1111.2 ± 179.7 mIU/mL; p < .001) and day-7 (1156.9 ± 206.2 vs. 872.4 ± 690.2 mIU/mL; p < .001). The odds of EP rupture compared to EP resolution was 6.2 (95% CI 2.1-19.1), 13.7 (95% CI 4.8-38.9), and 3.0 (95% CI 1.2-7.2) times higher when the change in ß-hCG levels was <5% between day-7 vs. day of MTX, day-7 vs. day-4, and day-4 vs. day of MTX, respectively. Our results demonstrate that ruptured tubal EPs despite MTX have <5% change in ß-hCG levels between the day of MTX and day-4 or day-7 after MTX.

Impact of FMR1 Pre-Mutation Status on Blastocyst Development in Patients Undergoing Pre-Implantation Genetic Diagnosis.

BACKGROUND/AIMS: The study aimed to investigate the impact of fragile X mental retardation 1 (FMR1) pre-mutation status on blastocyst development in patients undergoing pre-implantation genetic diagnosis (PGD). METHODS: Case-control study of patients <40 years undergoing PGD at blastocyst stage for FMR1 pre-mutation status. Age-matched patients undergoing PGD for other single gene disorders were considered controls. Blastocyst development, calculated per metaphase II (MII) oocyte retrieved and per 2 pronuclear (2PN) embryos, was compared between the 2 groups. Pregnancy outcomes after embryo transfer were also compared. RESULTS: Eighty-one and 791 patients were included in the FMR1 and control groups, respectively. FMR1 pre-mutation carriers had lower indicators of ovarian reserve, required higher gonadotropin doses, and had fewer MII oocytes retrieved. Mean blastocyst development per MII oocyte (12.6 vs. 29.4%; p < 0.001) and per 2PN embryos (21.5 vs. 41.7%; p < 0.001) was lower in the FMR1 group. An inverse correlation between the number of FMR1 CGG repeats and blastocyst development per MII oocyte (ρ = -0.63; p < 0.001) was observed. There was no difference in the rates of clinical pregnancy, spontaneous abortion, or live birth among the groups. CONCLUSION: Our study suggests lower rates of blastocyst development in patients with FMR1 pre-mutation status and an inverse correlation between the number of FMR1 CGG repeats and blastocyst development.

Temporal trends in minimally invasive myomectomy before and after the US Food and Drug Administration recommendation against electric morcellation.

OBJECTIVE: To investigate the temporal trends in minimally invasive myomectomy at one reproductive medicine center before and after the US Food and Drug Administration (FDA) recommendation against electric morcellation. METHODS: A retrospective chart review was undertaken of patients undergoing minimally invasive myomectomy between April 1, 2012, and April 30, 2016, at a center in New York. Temporal trends in laparoscopic myomectomy (LM), robot-assisted laparoscopic myomectomy (RAM), and laparoscopically assisted myomectomy (LAM), and intraoperative and postoperative outcomes before and after the April 2014 recommendation were compared. RESULTS: Minimally invasive myomectomy was performed in 73 patients. No difference was noted in the rates of minimally invasive myomectomy 2 years before (35/74 [47.3%]) and after (38/79 [48.1%]) the FDA's recommendation. The ratio of abdominal to minimally invasive myomectomy remained relatively constant before (68/59=1.15) and during the study period (80/73=1.10). There was a significant decrease in LM and RAM and a corresponding rise in LAM immediately after the recommendation (P<0.001). CONCLUSION: The rates of minimally invasive myomectomy before and after the FDA's recommendation did not differ, indicating that technical modifications to laparoscopic technique can allow surgeons to offer minimally invasive myomectomy to patients with symptomatic leiomyomas.

Increased odds of live birth in fresh in vitro fertilization cycles with shorter ovarian stimulation.

OBJECTIVE: To investigate the impact of prolonged ovarian stimulation on pregnancy outcomes in IVF cycles with fresh day 3 ET. DESIGN: Retrospective cohort study. SETTING: University-affiliated center. PATIENT(S): All patients initiating their first IVF cycle with fresh day 3 ET. Prolonged ovarian stimulation was defined as a duration of more than two standard deviations (95th percentile) for the study cohort (i.e., >13 days). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth rate was considered the primary outcome and was compared between patients undergoing ovarian stimulation for ≤13 days and >13 days. Odds ratios (OR) with 95% confidence intervals (CI) for all pregnancy outcomes after day 3 ET were calculated. The OR for live birth was adjusted using logistic regression. RESULT(S): A total of 6,410 and 339 patients underwent ovarian stimulation for ≤13 days and >13 days, respectively. There were no differences in the demographics or mean number of day 3 embryos transferred between the two groups. Ovarian stimulation ≤13 days was associated with increased odds of clinical pregnancy (OR 2.15, 95% CI 1.19-3.89) and live birth (OR 2.35, 95% CI 1.25-4.43). The increased odds for live birth in the ≤13-day group remained unchanged after logistic regression. Patients with clinical pregnancies in the >13-day group were younger (34.6 ± 4.91 years) compared with those who did not conceive (38.2 ± 4.72 years). CONCLUSION(S): Our findings suggest that ovarian stimulation ≤13 days is associated with increased odds of clinical pregnancy and live birth. In patients undergoing ovarian stimulation >13 days, younger age is associated with live birth.

Antibiotic Prophylaxis for Gynecologic Procedures prior to and during the Utilization of Assisted Reproductive Technologies: A Systematic Review.

The use of assisted reproductive technologies (ART) has increased steadily. There has been a corresponding increase in the number of ART-related procedures such as hysterosalpingography (HSG), saline infusion sonography (SIS), hysteroscopy, laparoscopy, oocyte retrieval, and embryo transfer (ET). While performing these procedures, the abdomen, upper vagina, and endocervix are breached, leading to the possibility of seeding pelvic structures with microorganisms. Antibiotic prophylaxis is therefore important to prevent or treat any procedure-related infections. After careful review of the published literature, it is evident that routine antibiotic prophylaxis is generally not recommended for the majority of ART-related procedures. For transcervical procedures such as HSG, SIS, hysteroscopy, ET, and chromotubation, patients at risk for pelvic infections should be screened and treated prior to the procedure. Patients with a history of pelvic inflammatory disease (PID) or dilated fallopian tubes are at high risk for postprocedural infections and should be given antibiotic prophylaxis during procedures such as HSG, SIS, or chromotubation. Antibiotic prophylaxis is recommended prior to oocyte retrieval in patients with a history of endometriosis, PID, ruptured appendicitis, or multiple prior pelvic surgeries.

5-millimeter Trocar-site Hernias After Laparoscopy Requiring Surgical Repair.

Trocar-site hernias are rare complications of laparoscopic surgery. Although trocar-site hernias occur more often at >10-mm sites, hernias can still develop at 5-mm sites after laparoscopy and can lead to serious complications. The primary objective of this review is to summarize the current medical literature pertaining to the clinical presentation and predisposing risk factors of trocar-site hernias at 5-mm sites after laparoscopy. A total of 295 publications were identified, 17 (5.76%) of which met the inclusion criteria. Twenty-seven patients with trocar-site hernias were identified after laparoscopic cases. The median age (interquartile range) for all adult patients with trocar-site hernias was 63 years (interquartile range, 39.5-66.5 years). Eight of the 18 patients (44.4%) undergoing gynecologic laparoscopy were parous although details of parity were not reported in most publications. Simple manual reduction or laparoscopic reduction with fascial closure (21 patients [84%]) was used more often compared with exploratory laparotomy (4 patients [16%], p < .001) to manage trocar-site hernias. There was no statistical difference in the location of trocar-site hernias (i.e., umbilical [14 patients, 56%] vs nonumbilical/lateral [11 patients, 44%], p = .12). Findings of this review suggest that increased operative times and excessive manipulation can extend 5-mm fascial incisions, thereby increasing the risk of trocar-site hernias. Parous women older than 60 years may have unrecognized fascial defects, which confer a higher risk of trocar-site hernias after laparoscopic surgery, even in the absence of incision manipulation or prolonged surgical duration. Such patients may benefit from closure of 5-mm fascial incisions although prospective data are required to validate the overall generalizability of this management strategy.

Is ABO blood type associated with ovarian stimulation response in patients with diminished ovarian reserve?

PURPOSE: Recent studies have explored the relationship between ABO blood type and serum markers of ovarian reserve, specifically follicle-stimulating hormone (FSH) and anti-mullerian hormone (AMH). The primary objective of this study is to investigate whether there is an association between ABO blood type and ovarian stimulation response in patients with serum markers of diminished ovarian reserve (DOR). METHODS: This is a retrospective study of all patients undergoing controlled ovarian stimulation (COS) for in vitro fertilization (IVF) between May 2010 and July 2013. Patients were sub-grouped, a priori, based on serum AMH levels: ≤1 ng/mL, ≤0.5 ng/mL and ≤0.16 ng/mL. Within each sub-group, demographic, baseline IVF characteristics and COS response parameters based on ABO blood types were compared. The number of mature oocytes retrieved was considered the primary outcome. Analysis of variance (ANOVA) and Chi-square tests were used to compare means and percentages between ABO blood types within groups. RESULTS: Complete data was available for 2575 patients. The mean (± SD) age and BMI of the study cohort was 38.9 (±3.97) years, 23.4 (±5.91) kg/m(2), respectively. The distribution of ABO blood types in the cohort was as follows: 36.8 % (A), 6.56 % (AB), 17.3 % (B), and 39.3 % (O). The demographics and baseline IVF characteristics were comparable among patients with blood types A, AB, B, and O within each AMH group. Within each AMH sub-group, no difference was found in the total days of COS, total gonadotropins administered, peak estradiol level, or number of mature oocytes retrieved based on blood type. CONCLUSIONS: Our results suggest no association between ABO blood type and ovarian stimulation response in patients with DOR. The predictive value of ABO blood type in determining ovarian stimulation response in such patients is currently limited.

Genes in the terminal regions of orthopoxvirus genomes experience adaptive molecular evolution.

BACKGROUND: Orthopoxviruses are dsDNA viruses with large genomes, some encoding over 200 genes. Genes essential for viral replication are located in the center of the linear genome and genes encoding host response modifiers and other host interacting proteins are located in the terminal regions. The central portion of the genome is highly conserved, both in gene content and sequence, while the terminal regions are more diverse. In this study, we investigated the role of adaptive molecular evolution in poxvirus genes and the selective pressures that act on the different regions of the genome. The relative fixation rates of synonymous and non-synonymous mutations (the d(N)/d(S) ratio) are an indicator of the mechanism of evolution of sequences, and can be used to identify purifying, neutral, or diversifying selection acting on a gene. Like highly conserved residues, amino acids under diversifying selection may be functionally important. Many genes experiencing diversifying selection are involved in host-pathogen interactions, such as antigen-antibody interactions, or the "host-pathogen arms race." RESULTS: We analyzed 175 gene families from orthopoxviruses for evidence of diversifying selection. 79 genes were identified as experiencing diversifying selection, 25 with high confidence. Many of these genes are located in the terminal regions of the genome and function to modify the host response to infection or are virion-associated, indicating a greater role for diversifying selection in host-interacting genes. Of the 79 genes, 20 are of unknown function, and implicating diversifying selection as an important mechanism in their evolution may help characterize their function or identify important functional residues. CONCLUSIONS: We conclude that diversifying selection is an important mechanism of orthopoxvirus evolution. Diversifying selection in poxviruses may be the result of interaction with host defense mechanisms.