The use of an embryo transfer simulator to compare transfer techniques and pregnancy outcomes among physicians.

Objective: To evaluate the association between embryo transfer techniques and pregnancy outcomes. Design: This is a prospective observational study with a retrospective cohort. Setting: University Clinic. Patients: Patients underwent embryo transfers between 2015 and 2020. Intervention/Exposure: Fourteen physicians performed 25 mock embryo transfers on the embryo transfer simulator and completed a questionnaire assessing preferred embryo transfer techniques. Quantitative performance metrics on the embryo transfer simulator were measured. Individual physician embryo transfer success rates were retrospectively collected from all fresh and cryopreserved embryo transfers between January 1, 2015, and January 1, 2020. Associations between embryo transfer techniques (preferred technique and simulator performance metrics) and each physician's historical patient pregnancy outcomes were assessed. Main Outcome Measures: Associations between embryo transfer techniques and live births were assessed. Results: There were significant differences in embryo transfer techniques between physicians, including touches to the fundus, distance to the fundus, duration of embryo transfer, duration of the complete procedure, time spent navigating the cervical canal, velocity of embryo expulsion, time waited after embryo expulsion, and total score on the embryo transfer simulator. After controlling for confounders and multiple transfers per physician, the duration of embryo transfer was significantly associated with live birth, with longer durations associated with decreased live birth rates. Shorter placement distance to the fundus and higher velocity of embryo expulsion were both significantly associated with higher rates of ectopic pregnancy. Conclusions: This study revealed significant differences in transfer techniques among physicians. The use of the embryo transfer simulator for physicians in practice can elucidate differences and create opportunities for data-driven improvement in embryo transfer success rates.

The prevalence of sporadic and recurrent pregnancy loss.

This manuscript reports on the prevalence of early pregnancy loss. The impact of improved pregnancy diagnosis and influence of increased age and body mass index at first birth are discussed.

Embryo transfer success: It is in our hands.

Embryo transfer (ET) is considered as a critical step in the process of in vitro fertilization. Interestingly, studies have consistently shown significant outcome differences between physicians. Although the outcome of ET is not related to the physician's experience and specifically not different between fellows and attending physicians, certain techniques have been found to affect the success rate. This review summarizes the existing evidence regarding the impact of the individual physician performing ET and the techniques used.

Retained pregnancy tissue after miscarriage is associated with high rate of chronic endometritis.

The objective of this study was to evaluate prevalence of chronic endometritis in a cohort of patients with retained pregnancy tissue (RPT) following miscarriage, with and without a history of recurrent pregnancy loss (RPL). In a cohort of our single academic fertility centre, we evaluated women with unexplained RPL (two or more losses) without evidence of RPT and women undergoing hysteroscopic resection of RPT following miscarriage. Endometrial samples underwent staining with H and E and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high power fields (HPF) and the presence or absence of endometrial stromal changes. Our main outcome measure was to measure the prevalence of chronic endometritis. Endometrial samples from 50 women with RPT following miscarriage and 50 women with unexplained RPL without evidence of RPT were reviewed. The prevalence of chronic endometritis was significantly higher in the RPT cohort (62% versus 30%). A multivariable regression demonstrated significantly higher odds of chronic endometritis in the RPT cohort, aOR 7.3 (95% CI 2.1, 25.5). We conclude that women with RPT following pregnancy loss have a high rate of chronic endometritis, suggesting that RPT is a risk factor for this disorder. Impact StatementWhat is already known on this subject? Known risk factors for chronic endometritis include a history of pelvic inflammatory disease, intrauterine polyps and fibroids. The aetiology for increased chronic endometritis among women with RPL is unknown.What do the results of this study add? The prevalence of chronic endometritis is significantly higher among women with retained pregnancy tissue (RPT) following miscarriage compared to women with RPL. These data presented suggest that RPT is associated with chronic endometritis among women with a history of miscarriage.What are the implications of these findings for clinical practice and/or further research? We suggest a pathologic evaluation for chronic endometritis be performed on all patients who undergo hysteroscopic resection of RPT following miscarriage. Our findings also suggest that a uterine cavity evaluation with hysteroscopy to evaluate for RPT may be reasonable in women with a history of miscarriage who are found to have chronic endometritis on endometrial biopsy. Further research is needed to determine if resection of retained tissue is sufficient to treat RPOC associated chronic endometritis, or if additional antibiotic treatment is necessary.

Relationship between paternal factors and embryonic aneuploidy of paternal origin.

OBJECTIVE: To determine if there is a relationship between paternal factors and embryonic aneuploidy of paternal origin using preimplantation genetic testing for aneuploidy (PGT-A). DESIGN: Retrospective cohort. SETTING: Academic. PARTICIPANTS: Couples undergoing in vitro fertilization with PGT-A. INTERVENTIONS: None. MAIN OUTCOME MEASURE: To determine if there is an association between paternal age, body mass index (BMI), or semen analysis parameters and paternal aneuploidy. RESULTS: From January 2015-2020, 453 in vitro fertilization cycles (1,720 embryos) underwent PGT-A using single nucleotide polymorphism microarrays with parental support bioinformatics. The mean (±SD) was 36.5 (±3.5) years for maternal age, 39.5 (±5.5) years for paternal age, 24.7 (±5.0) kg/m2 for maternal BMI, and 27.6 (±4.3) kg/m2 for paternal BMI. Embryonic aneuploidy of paternal origin was found in 8.4% (144/1,720) embryos. There were 1,533 embryos with a recorded paternal BMI. Rates of embryonic aneuploidy of paternal origin were similar between men across BMI groups: BMI 18-24.9 kg/m2 was 7.2% (referent); BMI 25-29.9 kg/m2 was 8.4% (odds ratio [OR], 1.12; 95% confidence interval [CI], 0.79-1.82); and BMI ≥30 kg/m2 was 9.1% (OR, 1.31; 95% CI, 0.83-2.08). There were 854 embryos from men with a normal and 866 from men with an abnormal semen analysis. No differences were found in the rate of embryonic aneuploidy of paternal origin between men with normal and abnormal sperm concentration, total count, motility, progressive motility, or morphology. No significant difference was seen in rates of aneuploidy between men aged <50 years and those aged ≥50 years (OR, 1.69; 95% CI, 0.96-2.98). CONCLUSION: No association was found between paternal age, BMI, or semen analysis parameters and paternal aneuploidy.

Maternal body mass index is not associated with increased rates of maternal embryonic aneuploidy.

OBJECTIVE: To evaluate the relationship between maternal body mass index (BMI) and embryonic aneuploidy of maternal origin. DESIGN: Retrospective cohort analysis. SETTING: University hospital-based reproductive center. PATIENTS: Maternal origin of aneuploidy was available for 453 cycles and 1,717 embryos. INTERVENTIONS: Data regarding BMI were collected before egg retrieval. Comparison groups included underweight (BMI, <18.5 kg/m2), normal weight (BMI, 18.5-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥30 kg/m2). Overall embryonic aneuploidy and maternal aneuploidy rates were compared. The aneuploidy rate was the number of embryos with either maternal or mixed (maternal and paternal) aneuploidy divided by the total number of embryos tested. MAIN OUTCOME MEASURES: Overall embryonic aneuploidy and maternal aneuploidy rates. RESULTS: Maternal aneuploidy rate was 51.5% for BMI of ≥30 kg/m2 and 39.3% for BMI of <30 kg/m2. Female age as well as several in vitro fertilization characteristics were significantly different across groups and were included in the adjusted model. Both the overall embryonic aneuploidy rate (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.11-1.59) and the maternal aneuploidy rate (OR, 1.64; 95% CI, 1.25-2.16) increased with increasing maternal BMI. However, after controlling for significant confounders, BMI did not significantly predict the rate of maternal aneuploidy (OR, 1.16; 95% CI, 0.85-1.59). CONCLUSIONS: Maternal BMI did not correlate with embryonic aneuploidy of maternal origin after adjusting for confounders.

Body mass index, not race, may be associated with an alteration in early embryo morphokinetics during in vitro fertilization.

OBJECTIVE: To assess the relationship between maternal body mass index (BMI) and embryo morphokinetics on time-lapse microscopy (TLM). DESIGN: Retrospective cohort study. METHODS: All IVF cycles between June 2015 and April 2017 were reviewed. Female BMI prior to egg retrieval was collected through chart review. BMI (kg/m2) classification included underweight (< 18.5), normal weight (18.5-25), overweight (25-30), and obese (≥ 30). Embryos' morphokinetic parameters were assessed with TLM and included time to syngamy, 2-cell, 3-cell, 4-cell, and 8-cell. A generalized linear mixed model was used to control for potential confounders and multiple embryos resulting from a single IVF cycle. RESULTS: A total of 2150 embryos from 589 IVF cycles were reviewed and included in the analysis. Classification based on BMI was as follows: underweight (N = 56), normal weight (N = 1252), overweight (N = 502), and obese (N = 340). After adjusting for race and use of intracytoplasmic sperm injection, the mean time to the 8-cell stage in the underweight group was 4.3 (95% CI: - 8.31, - 0.21) h less than in the normal weight group (P = 0.025) and 4.6 (95% CI: - 8.8, - 0.21) h less than in the obese group (p = 0.022). No significant difference was noted between race and TLM after controlling for possible confounders. CONCLUSIONS: Embryos from underweight women were demonstrated to have a faster time to the 8-cell stage than normal weight or obese women. No significant difference was noted for race. This study demonstrates that weight can be a factor contributing to embryo development as observed with TLM.

Mean differences in maternal body mass index and recurrent pregnancy loss: a systematic review and meta-analysis of observational studies.

OBJECTIVE: To investigate the association of maternal body mass index (BMI) and recurrent pregnancy loss (RPL). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): A total of 3,833 women with RPL and 4,083 women as controls. INTERVENTION(S): Studies were identified through a search of PubMed, Embase, Scopus, and Cochrane. MAIN OUTCOME MEASURE(S): The primary outcome of interest was RPL using the mean differences in maternal BMI as the predictor variable. The results of the meta-analysis were reported as the mean difference with a 95% confidence interval. RESULT(S): In total, 892 studies were reviewed. Pooled data from 25 studies suggested that the maternal BMI of women with a history of recurrent pregnancy loss was significantly higher than the BMI of controls, mean difference 0.7 kg/m2 [95% confidence interval 0.2-1.3]. CONCLUSION(S): These findings supported an association between maternal BMI and RPL. Large prospective studies are needed to evaluate the influence of maternal BMI on pregnancy outcomes in women with RPL.

Novel ploidy analysis in ectopic pregnancy.

OBJECTIVE: To study whether a single-nucleotide polymorphism (SNP) array could be used to test tissue from ectopic pregnancy to distinguish whether ectopic pregnancies were aneuploid. DESIGN: Case series report. SETTING: Academic medical center. PATIENTS: One hundred seventy-eight women who underwent surgery for ectopic pregnancy at Northwestern Memorial Hospital between 2015 and 2018 were eligible for participation; written consent was obtained from 33 patients. Eight subjects had sufficient DNA samples and were included in the analysis. Maternal and paternal DNA samples were self-collected by buccal swab. Archived paraffin tissue containing chorionic villi from each surgically removed ectopic specimen was analyzed using SNP microarray technology to determine chromosome number and evaluate for maternal cell contamination. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Prevalence of aneuploidy in ectopic pregnancy specimens as well as success of SNP array technology in formalin-fixed and paraffin-embedded specimens. RESULTS: Subjects had a mean (±SD) age of 33.4 ± 5.4 years, body mass index of 23.4 ± 5.7 kg/m2, 3.3 ± 1.8 prior pregnancies, and 1.5 ± 1.4 live births. Genetic testing revealed that all eight tested samples were euploid, 6 female and 2 male (two arr(1-22)x2, (X,Y)x1 and 6 arr(1-22, X)x2); maternal cell contamination was ruled out in all cases. CONCLUSIONS: This study showed proof of concept for the use of routinely stored formalin-fixed, paraffin-embedded tissue blocks with DNA extraction for SNP array to detect ploidy status of ectopic pregnancy. Although all tested samples were euploid, further research is needed to gain a definitive answer to this question and better understand the mechanism that leads to ectopic implantation.

Disparities among infertility patients regarding genetic carrier screening, sex selection, and gene editing.

PURPOSE: The purpose of this study is to evaluate the perspectives of infertility patients regarding genetic carrier screening, embryo sex selection, embryo research, and gene editing. METHODS: An anonymous 32-question survey was distributed electronically to all patients who seen at a single academic fertility center for at least one visit between June 2018 and September 2019. Survey questions evaluated patient perspectives on genetic carrier screening, embryo sex selection, embryo research, and gene editing. RESULTS: There were 1460 survey responses (32.0% response rate). There were significant differences in the proportion of respondents receiving genetic carrier screening between racial groups, 73.1% of White, 45.5% of Black, 49.4% of Hispanic, and 62.8% of Asian respondents. The likelihood of having genetic carrier screening was also significantly influenced by respondent income, insurance status, and religion. Religion significantly influenced the acceptance of embryonic research and embryonic sex selection. While only 8.9% felt that genetically modifying embryos for physical traits should be allowed, 74.1% felt that genetic modification to correct disease should be allowed. CONCLUSION: Racial, religious, and socioeconomic factors significantly impacted respondents' likelihood to have genetic carrier screening and views on embryo sex selection, embryo research, and gene editing. These findings highlight the importance of tailoring genetic counseling to the individual, acknowledging individual and cultural differences in agreement with genetic testing and emerging genetic therapies.

Redefining chronic endometritis: the importance of endometrial stromal changes.

OBJECTIVE: To develop diagnostic criteria for chronic endometritis and compare the prevalence of chronic endometritis between women with recurrent pregnancy loss (RPL) and controls. DESIGN: Cohort study. SETTING: Single academic fertility center. PATIENTS: Women with unexplained RPL (two or more pregnancy losses) and prospectively recruited controls without a history of RPL or infertility. INTERVENTIONS: Endometrial samples were stained with hematoxylin and eosin and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high-power fields (HPFs). In addition, the presence or absence of endometrial stromal changes was documented. MAIN OUTCOME MEASURE: Prevalence of chronic endometritis. RESULTS: Endometrial samples from 50 women with unexplained RPL and 26 controls were evaluated. When chronic endometritis was defined as the presence of one or more plasma cells per 10 HPFs, 31% of controls and 56% of women with RPL met the criterion. When both endometrial stromal changes and plasma cells were required for a diagnosis of chronic endometritis, no controls and 30% of women with RPL met the criteria. CONCLUSIONS: Although rare plasma cells were found in biopsy samples from controls, the presence of both plasma cells and endometrial stromal changes was limited to the RPL cohort. We propose that chronic endometritis be defined as the presence of one or more plasma cells per 10 HPFs in the setting of endometrial stromal changes. With the use of these strict diagnostic criteria, women with RPL have a significantly higher rate of chronic endometritis, supporting an association between chronic endometritis and RPL.

Psychological distress and postponed fertility care during the COVID-19 pandemic.

PURPOSE: To evaluate perceptions of delayed fertility care secondary to the COVID-19 pandemic. METHODS: This was a cross-sectional anonymous survey of N = 787/2,287 patients (response rate = 42.6%) from a single academic fertility center. Participants were randomized 1:1 to receive supplemental educational explaining the rationale behind recommendations to delay fertility treatments due to the COVID-19 pandemic. Assessment of well-being was conducted via the Personal Health Questionnaire Depression Scale, the Generalized Anxiety Disorder-7, the Ways of Coping-Revised, the Appraisal of Life Events Scale, and influence of supplemental education on agreement with ASRM COVID-19 Taskforce recommendations and associated distress. RESULTS: Participants in the education v. no education groups were 35.51 (SD = 4.06) and 37.24 (SD = 5.34) years old, married (90.8% v. 89.8%), had a graduate degree (53.9% v. 55.4%), > 1 year of infertility (73.4% v. 74.4%), and were nulliparous (69.0% v. 72.6%), with moderate to high distress (64.9% v. 64.2%) (ns). Distress was related to age, duration of infertility, and engagement in social support seeking and avoidant coping strategies (P < 0.001). Agreement with recommendations was related to receipt of supplemental education, history of pregnancy loss, and use of cognitive coping (P = 0.001). CONCLUSION: Most participants were distressed by the delay of treatments. Supplemental education increased acceptance of recommendations but did not decrease distress. Future treatment delays should include education related to and assessment of understanding of recommendations, and inclusion of mental health professionals in patient care.

Luteinizing Hormone Surge More Accurately Correlates With Ultrasound Dating of Early Pregnancy Compared to the Last Menstrual Period.

OBJECTIVES: To compare the use of the luteinizing hormone (LH) surge versus the last menstrual period (LMP) for the accuracy of pregnancy dating in fertile women with a diagnosis of recurrent early pregnancy loss (REPL). METHODS: This was an observational cohort study using prospectively collected data at 2 academic REPL programs between 2005 and 2018. Women with a history of REPL and at least 1 subsequent live birth after the evaluation were included. All patients conceived by intercourse timed to the LH surge. Transvaginal ultrasound was examinations were performed 2 weeks after missed menses. The gestational age (GA) was calculated by the LH surge (GALH ), LMP (GALMP ), and first crown-rump length (CRL) that measured 5 mm or greater (GACRL ). A secondary analysis compared GA based on the first measurable CRL of less than 5 mm versus GA based on the first CRL of 5 mm or greater. The GALH and GALMP were compared to determine which measure showed greater concordance with the CRL. The mean absolute difference in days between the GACRL versus GALH and GACRL versus GALMP was determined. RESULTS: A total of 115 women with 118 subsequent pregnancies resulting in live birth were included, with a mean age at delivery of 35.5 years and a mean of 3.6 prior pregnancy losses. The GALH showed a stronger correlation with the CRL (0.77) than the GALMP (0.63; P = .002). The GALH was more similar to the GACRL than the GALMP , with a mean absolute difference of 2.0 versus 3.1 days (P < .0001). CONCLUSIONS: When known, the LH surge appears to be more accurate than the LMP and should be used preferentially for dating of early pregnancy.

Can embryo morphokinetic parameters predict euploid pregnancy loss?

OBJECTIVE: To use time-lapse imaging to compare embryo morphokinetic parameters between embryos resulting in euploid pregnancy loss and euploid embryos resulting in live birth. DESIGN: Retrospective cohort study. SETTING: Single academic fertility center. PATIENT(S): All euploid single embryo transfers between October 2015 and January 2018. INTERVENTION(S): Collection and analysis of baseline characteristics, cycle parameters, and outcomes. MAIN OUTCOME MEASURE(S): Embryo morphokinetic measurements assessed with time-lapse imaging for time to syngamy (TPNf), time to two cells, time to three cells, time to four cells, time to eight cells, time to morula, and time to blastocyst. RESULT(S): The study included 192 euploid single-embryo transfers. Of these, the pregnancy rate was 78% (150 of 193) and the live-birth rate was 63% (121 of 193). There were 43 transfers that did not result in pregnancy, 15 biochemical pregnancy losses, 13 clinical losses, and 121 live births. There was no statistically significant difference in age, body mass index, or number of oocytes retrieved between the groups. Unadjusted and adjusted models revealed no differences in the morphokinetics of embryos resulting in euploid miscarriage compared with those resulting in live birth. CONCLUSION(S): Embryos that resulted in a euploid miscarriage did not display evidence of abnormal morphokinetics on time-lapse imaging. Euploid pregnancy loss is likely multifactorial, including both embryo and endometrial factors. Further research is needed to identify factors that can predict and prevent euploid loss.

Embryo transfer training in fellowship: national and institutional data.

OBJECTIVE: To evaluate current national practices in embryo transfer (ET) training in United States reproductive endocrinology and infertility (REI) fellowship programs and live birth rates after ET performed by fellows versus attending physicians. DESIGN: Cross-sectional survey of U.S. fellowship program directors and fellows in 2019 and retrospective cohort study of IVF cycle outcomes after ET performed by fellows versus attending physicians. SETTING: Not applicable. PATIENT(S): Fellowship program directors and fellows completed a survey. Embryo transfers from 2015-2018 were analyzed. INTERVENTION(S): A survey assessed experiences with ET training. Cycle outcomes were analyzed. MAIN OUTCOME MEASURE(S): Proportion of fellows performing ET during training, and live birth rate following fellow and faculty ETs. RESULT(S): Anonymous surveys were sent to 51 REI fellowship program directors and 142 fellows. Twenty-one percent (15/73) reported that no ETs were performed by fellows. Forty-four percent of third-year fellows had performed fewer than ten ETs during fellowship training. Retrospective review of 940 blastocyst ETs revealed no difference in live birth rates between fellows and attending physicians: 51.6% (131/254) versus 49.4% (339/686), respectively. CONCLUSION(S): This study revealed striking differences between fellowship programs regarding the adequacy of ET training; nearly one-half of third-year fellows had performed fewer than ten ETs. With appropriate supervision, there is no difference in live birth rate between ETs performed by fellows and attending physicians. Efforts should be made to address barriers and set minimums for the number of transfers performed during fellowship.

Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known?

OBJECTIVE: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. DESIGN: Review of English publications in PubMed and Embase to April 6, 2020. METHOD(S): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. RESULT(S): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. CONCLUSION(S): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility.

Black recipients of oocyte donation experience lower live birth rates compared with White recipients.

RESEARCH QUESTION: Is minority race associated with worse oocyte donation outcomes? DESIGN: Retrospective analysis of 926 oocyte recipients who underwent a donor cycle with fresh embryo transfer at a single fertility centre between January 2009 and June 2015. Race was self-reported. To adjust for repeat donors within the sample, mixed models were used to analyse donor parameters and recipient outcomes. The recipient outcome models were adjusted for age, body mass index and primary infertility diagnosis. RESULTS: The study consisted of 767 (82.8%) White, 41 (4.4%) Black, 63 (6.8%) Asian and 55 (5.9%) Hispanic women. Compared with White recipients, the adjusted odds ratio (aOR) for clinical pregnancy was 0.39 (95% confidence interval [CI] 0.19-0.79) for Black, 0.55 (95% CI 0.31-0.98) for Hispanic and 0.88 (95% CI 0.51-1.53) for Asian recipients. The aOR for live birth was 0.47 (95% CI 0.23-0.98) for Black, 0.58 (95% CI 0.32-1.06) for Hispanic and 0.62 (95% 0.35-1.09) for Asian recipients. A subgroup analysis restricted to cycles with racially concordant donors and recipients showed that the odds of clinical pregnancy and live birth were further reduced among Black recipients, with aOR of 0.28 (95% CI 0.09-0.81) and 0.30 (95% CI 0.09-0.98), respectively. CONCLUSIONS: Black and Hispanic oocyte donation recipients experience lower clinical pregnancy rates and Black recipients experience lower live birth rates compared with White recipients. Racially discordant donor oocyte cycles involving donors and recipients of different races present an opportunity to further investigate the cause of disparity.