The chances of obtaining a euploid embryo and subsequent live birth remain consistent with national age-based rates after an in vitro fertilization cycle that produced only aneuploid embryos.

OBJECTIVE: To determine the prognosis of patients who were only able to obtain aneuploid embryos in their first in vitro fertilization (IVF) cycle if they attempted a second cycle. DESIGN: Case series and retrospective cohort study. SETTING: A single, large fertility center. PATIENT(S): All patients who obtained only aneuploid embryos after IVF with preimplantation genetic testing for aneuploidy during the initial cycle and returned for a second cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The percentage of patients who obtained a euploid embryo and live birth rates in the second cycle, stratified by Society for Assisted Reproductive Technology-defined age groups, was compared with that of controls from the same period. RESULT(S): A total of 538 patients with only aneuploid embryos in their first cycle were included. Three hundred (56%) patients obtained euploid blastocysts in the second cycle, with younger women having a higher chance of obtaining at least 1 euploid embryo (81% in women aged <35 years vs. 25% in women aged >42 years). The cumulative live birth rates were 71%, 62%, 46%, 27%, and 13% for the age groups <35, 35-37, 38-40, 41-42, and >42 years, respectively. The live birth rates per first embryo transfer were >57% across all the age groups and similar to those of the controls in the same age groups. CONCLUSION(S): Patients who obtained only aneuploid embryos during their initial IVF cycle retained favorable prognosis in their second cycle, with outcomes comparable with the national age-based standards. Younger women and those who had more embryos available for biopsy had the highest chance of success. These women should receive age-appropriate counseling and should not be discouraged from a second IVF attempt based on the results of their first cycle.

B-cell lymphoma 6 expression is not associated with live birth in a normal responder in vitro fertilization population.

OBJECTIVE: To determine whether increased endometrial B-cell lymphoma 6 (BCL6) expression is associated with live birth in a normal responder in vitro fertilization (IVF) population. DESIGN: Case-control study. SETTING: University-affiliated infertility center. PATIENT(S): Two groups of women undergoing IVF with preimplantation genetic testing for aneuploidy followed by warmed, single, euploid embryo transfer. Group 1 consisted of women who failed to achieve live birth, and group 2 consisted of women who achieved live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometrial BCL6 expression measured by immunohistochemistry in endometrial tissue samples. Overexpression was defined by mean HSCORE with a cutoff of positivity of >1.4, as previously described in the literature. RESULT(S): Twenty-seven patients who achieved live birth and 23 patients who failed to achieve live birth were included. B-cell lymphoma 6 expression/HSCORE and live birth rate were not associated (Odds ratio [OR], 0.78 [0.24-2.55]). Using a cutoff of >1.4 for positivity, 8 of 23 samples were positive for BCL6 in the no live birth group, whereas 7 of 27 were positive in the live birth group. There was no significant association between BCL6 positivity and live birth (OR, 0.66 [0.19-2.21]). CONCLUSION(S): The proportion of patients with BCL6 positivity did not significantly differ between those who achieved live birth and those who did not. In the population of patients at our center, who compromise of women who respond normally to IVF stimulation, BCL6 overexpression was not associated with IVF success. Physicians implementing BCL6 testing as a diagnostic tool for clinical decision making should counsel patients that results may have limited utility in predicting IVF outcomes in this population.

Individual culture leads to decreased blastocyst formation but does not affect pregnancy outcomes in the setting of a single, vitrified-warmed euploid blastocyst transfer.

PURPOSE: To evaluate embryology and pregnancy outcomes following individual and group embryo culture in the setting of contemporary laboratory practices and freeze-all cycles. METHODS: Patients underwent ovarian stimulation followed by intracytoplasmic sperm injection (ICSI). Embryos proceeded through individual culture and then underwent preimplantation genetic testing for aneuploidy (PGT-A) via trophectoderm biopsy. In a subsequent cycle, participants underwent single embryo transfer of a vitrified-warmed, euploid embryo. Outcomes were compared to controls undergoing group culture during the same time frame. The Mann-Whitney U test and logistic regression models were utilized. RESULTS: Outcomes were assessed for 144 patients whose embryos underwent individual culture and 449 controls whose embryos underwent group culture. There were no significant differences in fertilization rates between groups (81.7% for individual culture vs. 84.1% for group culture, p = 0.22). However, individual culture was associated with a decreased rate of blastocyst formation compared to group culture (43.5% vs. 48.5%, p < 0.01). Following single, vitrified-warmed euploid blastocyst transfer, there were no significant differences between individual culture and group culture, respectively, in rates of positive ßhCG (81.9% vs. 81.5%, p = 0.91), sustained implantation (63.9% vs. 65.0%, p = 0.80), biochemical miscarriage (16.7% vs. 12.3%, p = 0.18), or clinical miscarriage (1.4% vs. 4.2%, p = 0.13). CONCLUSION: While individual culture appears to negatively impact the rate of usable blastocyst formation compared to group culture, there were no significant differences in pregnancy outcomes following transfer of a single, vitrified-warmed euploid blastocyst.

Noninvasive prenatal testing in women undergoing in vitro fertilization with preimplantation genetic testing.

PURPOSE OF REVIEW: To discuss the utilization, performance, and interpretation of noninvasive prenatal testing (NIPT) results in women achieving pregnancy through in vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A). RECENT FINDINGS: Although PGT-A is a highly accurate method for the selection of euploid embryos the possibility for error still exists. Many women pursue NIPT after conception via IVF with or without PGT-A, whereas some forgo prenatal screening all together. Recent evidence suggests that the prevalence of a positive NIPT following PGT-A is low, and the positive predictive value is altered in this population. SUMMARY: NIPT is a valuable prenatal screening tool that should be offered to pregnant women regardless of prior PGT. In women who conceive following IVF and PGT-A through the transfer of euploid embryos, positive test results should be interpreted with caution.

Role of the sperm, oocyte, and embryo in recurrent pregnancy loss.

Disorders affecting the sperm, oocyte, or embryo may cause a significant fraction of spontaneous miscarriages and cases of recurrent pregnancy loss (RPL). Altered chromosomal integrity of sperm and oocytes, which is highly dependent of the age of the mother, represents a major cause of miscarriage and in turn RPL. Avoiding transfers of abnormal embryos is possible with preimplantation genetic testing for aneuploidies. Chromosomal anomalies may also be caused by structural rearrangements of one or several chromosomes in either parents, a finding encountered in 12% of couples with RPL, including in those who have had one or several healthy babies. More than 40% of these chromosomal rearrangements are identifiable on regular karyotypes. When abnormal findings are made, preimplantation genetic testing for monogenic disorders allows selection of disease-free embryos. Finally, asymmetric inactivation of the X chromosome has been found more commonly in women with RPL, but no specific treatment is currently available.

Immunologic causes and thrombophilia in recurrent pregnancy loss.

Certain miscarriages result from immunologic factors, but there is no clear identification of the precise causes of recurrent pregnancy loss (RPL). Miscarriages and RPL can arise from a disruption of maternal-fetal immune homeostasis. Remodeling of the maternal uterine spiral arteries is one of the key steps for normal growth and development of the fetus. An adequate oxygen supply is necessary for correct placentation, and it is accomplished by proper vascular changes. The development of fetal tissues creates a potential immunologic problem since the fetus can express paternal antigens and, in some cases, antigens of a gamete donor. The maternal immune system actively responds to fetal antigens, and dysregulation of this crosstalk could partly explain pregnancy complications such as miscarriages and RPL. RPL resulting from thrombophilia is primarily due to acquired thrombophilia, and therefore screening and treatment should be focused on antiphospholipid antibody syndrome.

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.

OBJECTIVE: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance. DESIGN: Prospective cohort study. SETTING: Academic-affiliated private practice. PATIENTS: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018. INTERVENTIONS: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied. MAIN OUTCOME MEASURES: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antimüllerian hormone (AMH) level, peak estradiol (E2) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed. RESULTS: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study. CONCLUSION: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.

Interpretation of noninvasive prenatal testing results following in vitro fertilization and preimplantation genetic testing for aneuploidy.

BACKGROUND: The positive predictive value of noninvasive prenatal testing is approximately 69% in the general population. However, positive predictive value is dependent on the prevalence of the disease in the population being tested. Patients who undergo in vitro fertilization with preimplantation genetic testing for aneuploidy and transfer a euploid embryo are presumably a lower risk population than the general population. OBJECTIVE: In this study, we explored the positive predictive value of noninvasive prenatal testing in women undergoing in vitro fertilization with preimplantation genetic testing for aneuploidy and subsequent transfer of a euploid embryo. STUDY DESIGN: This study was a retrospective cohort study. All patients who underwent in vitro fertilization with preimplantation genetic testing for aneuploidy followed by transfer of a single euploid embryo between 2014 and 2019 at a university-affiliated fertility center were contacted. Noninvasive prenatal testing results were reviewed and those with positive noninvasive prenatal testing were identified. Results of any subsequent prenatal or postnatal diagnostic testing were used to classify each positive noninvasive prenatal testing as a true positive or a false positive. The prevalence and positive predictive value of positive noninvasive prenatal testing was calculated. RESULTS: A total of 1139 patients that underwent noninvasive prenatal testing after transfer of a euploid embryo were identified, 8 of which had positive noninvasive prenatal testing screens. Although 6 of these patients had subsequent definitive prenatal diagnostic testing that revealed a euploid karyotype concordant with their preimplantation genetic testing for aneuploidy results, 1 patient opted out of diagnostic testing and later delivered a normal baby. Of note, 1 patient who had noninvasive prenatal testing positive for Turner syndrome underwent amniocentesis, which confirmed Turner mosaicism (45,X karyotype in 80% of cells). Therefore, the positive predictive value of noninvasive prenatal testing in this patient cohort was 12.5%. CONCLUSION: Clinicians and patients should recognize that patients undergoing transfer of a euploid embryo are at a relatively lower risk for fetal aneuploidy than the general population, and the positive predictive value of noninvasive prenatal testing is lower in this setting.

Embryonal mitochondrial DNA: relationship to embryo quality and transfer outcomes.

PURPOSE: The aim was to study the association between embryonal mitochondrial DNA (mtDNA) content and embryo quality and implantation outcomes. METHODS: A retrospective chart review was performed with data collected from a private IVF center database. The study population included female infertility patients with ages ranging from 31 to 38 years old, and the main outcome measures were embryo quality and transfer outcomes. RESULTS: From a total of 1510 blastocyst biopsies, the majority of embryos consisted of grade 1 (High), followed by grade 2 (mid), and grade 3 (poor). Embryos with higher mtDNA content were found to be of poorer quality (grade 3) relative to grades 1 and 2 (P = 0.003). Using a logistic model, mtDNA best predicted lowest and highest grades, but not mid-grade embryos. There was no correlation between mtDNA content and the subjects' age (R2 = 0.0018). In an analysis of only euploid embryos (N = 717), there was no longer an association between mtDNA content and embryo quality (P = 0.834). There was no difference in mtDNA content between groups of embryos that did and did not implant (P = 0.53). There was also no association noted between mtDNA content and ongoing pregnancy. Compared to day 6, day 5 blastocysts contain significantly higher amounts of mtDNA (P = 0.0005), lower rates of aneuploidy (P < 0.001), and were more likely to be high-quality blastocysts (grade 1) (P < 0.001). CONCLUSION: Although the mtDNA content shows some association to the morphologic grade of an embryo, this association does not persist in an analysis of only euploid embryos. Mitochondrial DNA content also does not appear to be associated with implantation or ongoing pregnancy. Day 5 blastocysts have significantly higher mtDNA content compared to day 6 blastocysts.

Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision.

Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman's management decisions.

Medicolegal Review: Essure Lawsuits and Legal Strategies Adverse to Gynecologists.

The minimally invasive Essure procedure for hysteroscopic sterilization is an ongoing target for litigation. Although efficacious, this device has been scrutinized by the US Food and Drug Administration (FDA) owing to alleged complications. Patients affected by these potential complications are filing lawsuits against Bayer, the manufacturer of Essure. Many of these lawsuits have been barred by preemption, a legal doctrine that limits what can be required of a product by state lawsuits once the FDA approves it; however, in the lawsuits that have been allowed to proceed, the manufacturer has used a legal strategy termed the "learned intermediary doctrine" in an effort to shift blame to the gynecologist to absolve itself of liability. The learned intermediary only requires that a manufacturer inform the gynecologist of the risks associated with the device, and the gynecologist, in turn, must notify the patients through adequate informed consent. To incorporate the necessary components of informed consent, a gynecologist should include what a reasonable practitioner would consider pertinent to the discussion, as well as what a prudent patient would want to know to make a treatment decision. This disclosure entails explaining the risks, benefits, and alternatives, which should be clearly documented in the medical records. Understanding the importance of proper documentation and the legal strategies used in suits will help gynecologists lessen liability exposure when using a medical device, such as Essure, that is being targeted for litigation.