Young women with poor ovarian response exhibit epigenetic age acceleration based on evaluation of white blood cells using a DNA methylation-derived age prediction model.

STUDY QUESTION: Is poor ovarian response associated with a change in predicted age based on a DNA methylation-derived age prediction model (the Horvath algorithm) in white blood cells (WBCs) or cumulus cells (CCs)? SUMMARY ANSWER: In young women, poor ovarian response is associated with epigenetic age acceleration within WBC samples but is not associated with age-related changes in CC. WHAT IS KNOWN ALREADY: The majority of human tissues follow predictable patterns of methylation which can be assessed throughout a person's lifetime. DNA methylation patterns may serve as informative biomarkers of aging within various tissues. Horvath's 'epigenetic clock', which is a DNA methylation-derived age prediction model, accurately predicts a subject's true chronologic age when applied to WBC but not to CC. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out involving 175 women undergoing ovarian stimulation between February 2017 and December 2018. Women were grouped according to a poor (≤5 oocytes retrieved) or good (>5 oocytes) response to ovarian stimulation. Those with polycystic ovary syndrome (PCOS) (n = 35) were placed in the good responder group. PARTICIPANTS/MATERIALS, SETTING, METHODS: DNA methylation patterns from WBC and CC were assessed for infertile patients undergoing ovarian stimulation at a university-affiliated private practice. DNA was isolated from peripheral blood samples and CC. Bisulfite conversion was then performed and a DNA methylation array was utilized to measure DNA methylation levels throughout the genome. Likelihood ratio tests were utilized to assess the relationship between predicted age, chronologic age and ovarian response. MAIN RESULTS AND THE ROLE OF CHANCE: The Horvath-predicted age for WBC samples was consistent with patients' chronologic age. However, predicted age from analysis of CC was younger than chronologic age. In subgroup analysis of women less than 38 years of age, poor ovarian response was associated with an accelerated predicted age in WBC (P = 0.017). Poor ovarian response did not affect the Horvath-predicted age based on CC samples (P = 0.502). No alternative methylation-based calculation was identified to be predictive of age for CC. LIMITATIONS, REASONS FOR CAUTION: To date, analyses of CC have failed to identify epigenetic changes that are predictive of the aging process within the ovary. Despite the poor predictive nature of both the Horvath model and the novel methylation-based age prediction model described here, it is possible that our efforts failed to identify appropriate sites which would result in a successful age-prediction model derived from the CC epigenome. Additionally, lower DNA input for CC samples compared to WBC samples was a methodological limitation. We acknowledge that a universally accepted definition of poor ovarian response is lacking. Furthermore, women with PCOS were included and therefore the group of good responders in the current study may not represent a population with entirely normal methylation profiles. WIDER IMPLICATIONS OF THE FINDINGS: The process of ovarian and CC aging continues to be poorly understood. Women who demonstrate poor ovarian response to stimulation represent a common clinical challenge, so clarifying the exact biological changes that occur within the ovary over time is a worthwhile endeavor. The data from CC support a view that hormonally responsive tissues may possess distinct epigenetic aging patterns when compared with other tissue types. Future studies may be able to determine whether alternative DNA methylation sites can accurately predict chronologic age or ovarian response to stimulation from CC samples. Going forward, associations between epigenetic age acceleration and reproductive and general health consequences must also be clearly defined. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for the study and there are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Three-dimensional ultrasound diagnosis of T-shaped uterus is associated with adverse pregnancy outcomes after embryo transfer.

RESEARCH QUESTION: Is T-shaped uterine cavity morphology associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst? DESIGN: In this secondary analysis of a prospective cohort study, 648 patients with three-dimensional ultrasound (3D-US) data obtained on the day before embryo transfer were categorized into three groups according to uterine cavity morphology: normal (n = 472), intermediate (n = 166) and T-shaped (n = 10). Quantitative uterine cavity dimensions were used to evaluate uterine cavity morphology. Pregnancy outcomes, including live birth, clinical miscarriage and ectopic pregnancy, were compared among the groups. RESULTS: The prevalence of a T-shaped uterus in this cohort was 1.5%. Uterine cavity morphology was strongly associated with the ratio of interostial distance and isthmic diameter (P < 0.01). Live birth rates were 66.5% for normal, 65.7% for intermediate and 40.0% for T-shaped cavity morphology. Women with a T-shaped uterus had an increased risk of clinical miscarriage (40.0% versus 7.0% for normal and 9.0% for intermediate cavity morphology, P < 0.01) and ectopic pregnancy (10.0% versus 1.1% for normal and 1.9% for intermediate cavity morphology, P = 0.05). When evaluating interostial distance and isthmic diameter ratio to determine pregnancy outcomes, a cut-off value of 2 was noted to have weak predictive value for live birth, but not clinical miscarriage or ectopic pregnancy. CONCLUSIONS: T-shaped uterine cavity morphology is associated with adverse pregnancy outcomes after transfer of a single thawed euploid blastocyst. Given the low prevalence of this condition, quantifying the magnitude of risk will require a larger cohort of patients.

Relation between plasma phospholipid oleic acid and risk of heart failure.

BACKGROUND AND AIMS: Although the association between monounsaturated fatty acids (MUFA) and risk factors for heart failure (HF) has been reported, it is unclear whether oleic acid, the predominant MUFA in olive oil, plays a role in the development of HF. Consequently, we sought to examine the relation of plasma phospholipid oleic acid with HF in a male cohort. In a secondary analysis, we examined the relation of the ratio of plasma monounsaturated-to-saturated fatty acids (MUFA: SFA) with HF. METHODS: This prospective nested case-control study was based on 788 incident HF cases and 788 controls from the Physicians' Health Study. Plasma phospholipid fatty acids were measured using gas chromatography and incident HF was self-reported via annual follow-up questionnaires and validated in a subsample using medical records. RESULTS: The mean age was 58.7 years at blood collection. In a conditional logistic regression, multivariable adjusted-odds ratios (95% confidence interval) for HF across consecutive quartiles of oleic acid were 1.0 (reference), 1.10 (0.79-1.54), 1.02 (0.72-1.44), and 1.05 (0.72-1.54). For MUFA:SFA ratio, corresponding odds ratios (95% CI) for HF were 1.0 (ref), 1.12 (0.80-1.58), 1.19 (0.84-1.68), and 0.97 (0.66-1.42). CONCLUSIONS: Our data do not lend support to an association between plasma phospholipid oleic acid or MUFA: SFA ratio and the risk of HF. These results warrant confirmation in the general population including women and other ethnic groups.

The dilemma of aneuploidy screening on low responders.

PURPOSE OF REVIEW: Preimplantation genetic testing for aneuploidy (PGT-A) has been demonstrated to improve implantation and pregnancy rates and decrease miscarriage rates over standard morphology-based embryo selection. However, there are limited data on its efficacy in patients with diminished ovarian reserve or a poor response to stimulation who may have fewer embryos to select amongst. RECENT FINDINGS: Early findings demonstrate that PGT-A reduces the miscarriage rate and decreases the time to delivery in poor responders. These studies highlight the importance of designing trials that compare outcomes over multiple cycles as the benefit of PGT-A in this patient population lies in eliminating the time lost to futile transfers of aneuploid embryos. Furthermore, recent studies have demonstrated that a catch-all category of 'poor responder' may need to be reevaluated as different subpopulations of patients with low response exhibit different clinical characteristics. SUMMARY: More information is needed on characterizing the physiology of ovarian aging across multiple phenotypes of diminished ovarian reserve and establishing the predictive value of aneuploid results across multiple PGT-A platforms. However, initial data suggests benefit of PGT-A in poor responders.

Levels of trophectoderm mitochondrial DNA do not predict the reproductive potential of sibling embryos.

Study question: What is the predictive value of trophectoderm mitochondrial DNA (mtDNA) quantity for blastocyst reproductive potential? Summary answer: This study demonstrates that, within a given cohort, mtDNA quantitation does not distinguish between embryos that implant and embryos that do not implant after double embryo transfer (DET). What is already known: An association between implantation failure and increased quantities of mtDNA has been observed in two studies but not in a third. Study design, size and duration: A total of 187 patients (nine who received donor oocytes) with DET of one male and one female euploid blastocyst were included in this retrospective study, with 69 singleton deliveries providing the primary dataset to evaluate the predictive value of mtDNA for reproductive potential between January 2010 and July 2016. Participants/materials, setting and method: MtDNA was quantified in cell lines to validate the quantitative PCR assay on limited quantities of starting material and then applied to 374 blastocyst biopsies. Pregnancies resulting in a singleton outcome were analyzed and newborn gender was utilized as a means to identify the implanted embryo. MtDNA quantity was then compared between implanted and non-implanted embryos in order to define the predictive value of mtDNA content for reproductive potential in this subset of patients. Main results and the role of chance: An initial comparison of mtDNA levels between all successful and unsuccessful embryos revealed no significant differences. In order to control for patient-specific variables, gender was subsequently used to identify the implanted embryo in DETs resulting in a singleton (n = 69). No systematic difference in relative mtDNA quantity was detected between implanted and non-implanted embryos. Limitations, reasons for caution: This study was conducted at a single center and did not evaluate the entire cohort of embryos from each patient to evaluate cohort specific variation in mtDNA quantity. Although the largest of its kind so far, the sample size of DETs leading to a singleton was relatively small. Wider implications of the findings: These data highlight the importance of control over patient-specific variables when evaluating candidate biomarkers of reproductive potential. All current available data suggest that mtDNA quantification needs further study before its clinical use to augment embryo selection. Study funding/competing interests: The authors have no potential conflict of interest to declare. No external funding was obtained for this study. Trial registration number: Not applicable.

Oxygen tension in embryo culture: does a shift to 2% O2 in extended culture represent the most physiologic system?

There has been much debate regarding the optimal oxygen tension in clinical embryo culture. The majority of the literature to date has compared 5% oxygen to atmospheric levels (20-21%). While the majority of modern IVF labs have accepted the superiority of 5% oxygen tension, a new debate has emerged regarding whether a further reduction after day 3 of development represents the most physiologic system. This new avenue of research is based on the premise that oxygen tension is in fact lower in the uterus than in the oviduct and that the embryo crosses the uterotubal junction sometime on day 3. While data are currently limited, recent experience with ultra-low oxygen (2%) after day 3 of development suggests that the optimal oxygen tension in embryo culture may depend on the stage of development. This review article will consider the current state of the literature and discuss ongoing efforts at studying ultra-low oxygen tension in extended culture.

FMR1 gene CGG repeat variation within the normal range is not predictive of ovarian response in IVF cycles.

The relationship between FMR1 CGG premutation status and decreased ovarian responsiveness is well established. The association between FMR1 CGG repeat number in the currently defined normal range (less than 45 repeats) and ovarian reserve, however, is controversial. This retrospective study examined whether variation in CGG repeat number in the normal range was associated with markers of ovarian response in IVF cycles. The first IVF cycle of 3006 patients with FMR1 CGG repeat analysis was examined. Only patients carrying two alleles with less than 45 CGG repeats were included for analysis. The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Patients were also separated into biallelic genotype groups, based on the recently proposed narrower "new normal" range of 26-34 CGG repeats. A linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield. The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups. No difference was found in the rate of cycle cancellation for poor response. Despite increasing use, FMR1 CGG repeats in the normal range cannot be used as a predictor of ovarian response to gonadotrophin stimulation.

Deliveries from trophectoderm biopsied, fresh and vitrified blastocysts derived from polar body biopsied, vitrified oocytes.

This longitudinal study reports preliminary findings of six patients who underwent first polar body biopsy followed by oocyte vitrification. All oocytes were warmed, inseminated by intracytoplasmic sperm injection and cultured to blastocyst. All suitable blastocysts underwent trophectoderm biopsy for aneuploidy screening, and supernumerary blastocysts were vitrified. Euploid blastocysts were transferred either fresh or in a subsequent programmed cycle. Of the 91 metaphase II oocytes, 30 had euploid first polar bodies. Development to blastocyst was more likely in oocytes with a euploid first polar body (66.7% versus 24.6%; P < 0.001). Nineteen euploid blastocysts were produced: 10 from oocytes with a euploid first polar body and nine from oocytes with an aneuploid first polar body. Five out of six patients (83%) had a live birth or ongoing pregnancy at the time of analysis. Eleven euploid blastocysts have been transferred and seven implanted (64%). Although the chromosomal status of the first polar body was poorly predictive of embryonic ploidy, an association was found between chromosomal status of the first polar body and development to blastocyst. Further study is required to characterize these relationships, but proof of concept is provided that twice biopsied, twice cryopreserved oocytes and embryos can lead to viable pregnancies.

Identification and expression of GnRH2 and GnRH3 in the black sea bass (Centropristis striata), a hermaphroditic teleost.

We cloned two cDNAs for two gonadotropin-releasing hormones, GnRH2 (chicken GnRH-II) and GnRH3 (salmon GnRH), respectively, from the black sea bass (Centropristis striata). Black sea bass are protogynous hermaphroditic teleosts that change from females to males between 2 and 5 years of age. Similar to other GnRH precursors, the precursors of black sea bass GnRH2 and GnRH23 consisted of a signal peptide, decapeptide, a downstream processing site, and a GnRH-associated peptide. Our analyses failed to identify GnRH1. GnRH3 precursor transcript was more widely distributed in a variety of tissues compared with GnRH2. Further examination of GnRH expression and gonadal histology was done in black sea bass from three different size groups: small (11.4-44.1 g), medium (179.4-352.2 g) and large (393.8-607.3 g). Interestingly, GnRH3 expression occurred only in the pituitaries of males in the small and medium groups compared with expression of GnRH2. Future functional studies of the sea bass GnRHs will be valuable in elucidating the potential underlying neuroendocrine mechanisms of black sea bass reproduction and may ultimately contribute to management advances in this commercially important fish.

Acute mitral regurgitation and cardiogenic shock: Reverse takotsubo cardiomyopathy or acute coronary syndrome?

Reverse takotsubo cardiomyopathy (rTCM) is characterized by basal ballooning and accounts for approximately 1% of all TCM. To our knowledge, there have been no reports describing rTCM complicated by acute, severe, transient mitral regurgitation (MR). A 75-year-old woman with a medical history of hypertension, dyslipidemia, and anxiety presented to the hospital with 2 days of substernal chest pain, dyspnea, and nausea. Initial troponin was 0.203 ng/mL, and electrocardiography showed sinus tachycardia at 121 bpm, with inferior and anterolateral ST segment depressions. Transthoracic echocardiogram (TTE) found an ejection fraction of 30%, apical hyperkinesis, severe hypokinesis of the basal to mid segments of the left ventricle (LV), and a severe central MR jet. Cardiac angiography demonstrated non-obstructive coronary artery disease, and elevated left ventricular end diastolic pressures. Left ventriculography showed a hyperdynamic apex and severe basal hypokinesis. The patient was treated medically, clinical status improved, and was discharged on day 3. TTE four weeks later, showed an ejection fraction of 60-65%, mild MR, and normal LV function. rTCM is the rarest variant of TCM. Basal and mid-myocardial stunning can cause severe secondary MR leading to acute congestive heart failure, mimicking acute coronary syndrome with acute MR. rTCM with rapidly reversible severe MR has not previously been described. .

A comparison of the relative efficiency of ICSI and extended culture with epididymal sperm versus testicular sperm in patients with obstructive azoospermia.

This is a retrospective cohort study comparing blastocyst transfer outcomes following intracytoplasmic sperm injection utilizing epididymal versus testicular sperm for men with obstructive azoospermia. All cases at a single center between 2012 and 2016 were included. Operative approach was selected at the surgeon's discretion and included microepididymal sperm aspiration or testicular sperm extraction. Blastocyst culture was exclusively utilized prior to transfer. The primary outcome was live birth rate. Secondary outcomes included fertilization rate, blastulation rate, euploidy rate, and implantation rate. A mixed effects model was performed. Seventy-six microepididymal sperm aspiration cases and 93 testicular sperm extraction cases were analyzed. The live birth rate was equivalent (48.6% vs 50.5%, P = 0.77). However, on mixed effects model, epididymal sperm resulted in a greater likelihood of fertilization (adjusted OR: 1.37, 95% CI: 1.05-1.81, P = 0.02) and produced a higher blastulation rate (adjusted OR: 1.41, 95% CI: 1.1-1.85, P = 0.01). As a result, the epididymal sperm group had more supernumerary blastocysts available (4.3 vs 3, P < 0.05). The euploidy rate was no different. Pregnancy rates were no different through the first transfer cycle. However, intracytoplasmic sperm injection following microepididymal sperm aspiration resulted in a greater number of usable blastocysts per patient. Thus, the true benefit of epididymal sperm may only be demonstrated via a comparison of cumulative pregnancy rates after multiple transfers from one cohort.

Academic pursuits in board-certified reproductive endocrinologists.

OBJECTIVE: To determine research interests of reproductive endocrinology and infertility (REI) physicians and assess their academic productivity. DESIGN: A questionnaire composed by the Society for REI (SREI) board members was e-mailed to members. PubMed was queried to quantify peer-reviewed publications. SETTING: An internal SREI questionnaire to members and online publication search. PATIENT(S): Not applicable. INTERVENTION(S): Questions involving research being performed, funding, relevance to fellow thesis, and important areas of future research. Publications were ascertained in the past 3 years, past 10 years, and total publications for SREI members. MAIN OUTCOME MEASURE(S): Question responses and number of peer-reviewed publications. RESULT(S): Most respondents currently conduct research, which was predominantly clinical. One-third have current research funding and two-thirds were ever funded. One-third had a National Institutes of Health grant and about half were principal investigators. Two-thirds had a basic science fellow thesis and 44% of respondents perform research related to their fellowship thesis. Important research areas included infertility outcomes, implantation, preimplantation genetic testing, and genetics. In the past 3 years, SREI members published 3,408 peer-reviewed articles (mean ± standard deviation [SD], 4.4 ± 9.0). In the past 10 years, SREI members had 10,162 peer-reviewed publications (mean±SD, 13.0 ± 24.3). When all publications were considered, SREI members published 24,088 peer-reviewed articles (mean±SD, 30.9 ± 53.0). CONCLUSION(S): The REI fellows have learned to construct scientific articles, which will help them to better interpret the literature in the care of patients. The SREI members continue to pursue scientific investigation, commonly related to their fellowship thesis. Respondents support SREI funding research; the success of which should be judged by publications. Overall, SREI members have demonstrated significant academic productivity and published about 1,000 articles/year for the past 10 years, affirming the importance of research training.

Assisted Reproductive Technology and Origins of Disease: The Clinical Realities and Implications.

The majority of offspring born following assisted reproductive technology (ART) achieve equivalent development milestones and demonstrate comparable health as spontaneously conceived children. Yet, multiple studies have suggested offspring conceived with ART have slightly increased risk of metabolic derangements, cardiovascular disease, and malignancy. However, the associations observed in these studies often inadequately control for a variety of confounding variables, such as multiple gestation, premature birth, and low birth weight. Furthermore, many studies fail to account for the increased risk of many of these pathologies in the offspring of subfertile women in general. Lastly, the absolute risk of most of the ailments studied is extremely low. In nearly all examples, the number of women who would need to be treated to observe one additional diagnosis is substantially high. When compared with the number of couples who would have remained childless due to severe male factor infertility or would have been exposed to the risk of passing on a severe monogenic disorder, the general increased risks to ART-exposed children is very small.

Knowledge gaps in male infertility: a reproductive endocrinology and infertility perspective.

Reproductive research has moved forward at a remarkable pace. Some of these advances are the result of a separation between male and female specialties, allowing focused study in specific areas of the field. However, the different training programs between male and female fertility specialists has created an environment in which some discoveries are not put in the greater context of clinical care. At times, interventions have been measured against surrogate markers of outcome that may not impact the most meaningful outcome for patients-the delivery of a healthy neonate. For example, medical and surgical interventions that use changes in semen parameters may have a limited impact on the likelihood of achieving a live birth due to the limitations inherent in the semen analysis for predicting outcomes. Other commonly used tests, such as sperm DNA fragmentation assays provide promising biological plausibility to account for subfertility of some male partners. However, until well defined thresholds for predicting outcomes in different treatment scenarios are available, changes in sperm DNA fragmentation testing is not an adequate outcome for measuring the utility of interventions. The biggest limitation for these tests remains their analysis of bulk semen. Tests allowing interrogation of the reproductive competence of a given sperm, while allowing that sperm to be used in assisted reproductive technology procedures remain elusive. Progress toward reaching this end (whether by hyaluronic acid binding, IMSI, or Ramen spectroscopy) is underway, but much remains to be learned. Achieving testing and capture of individual sperm would better facilitate studies that measure the most meaningful outcome for patients and providers-the delivery of a healthy baby.

DNA methylation-based age prediction and telomere length in white blood cells and cumulus cells of infertile women with normal or poor response to ovarian stimulation.

An algorithm assessing the methylation levels of 353 informative CpG sites in the human genome permits accurate prediction of the chronologic age of a subject. Interestingly, when there is discrepancy between the predicted age and chronologic age (age acceleration or "AgeAccel"), patients are at risk for morbidity and mortality. Identification of infertile patients at risk for accelerated reproductive senescence may permit preventative action. This study aimed to assess the accuracy of the "epigenetic clock" concept in reproductive age women undergoing fertility treatment by applying the age prediction algorithm in peripheral (white blood cells [WBCs]) and follicular somatic cells (cumulus cells [CCs]), and to identify whether women with premature reproductive aging (diminished ovarian reserve) were at risk of AgeAccel in their age prediction. Results indicated that the epigenetic algorithm accurately predicts age when applied to WBCs but not to CCs. The age prediction of CCs was substantially younger than chronologic age regardless of the patient's age or response to stimulation. In addition, telomeres of CCs were significantly longer than that of WBCs. Our findings suggest that CCs do not demonstrate changes in methylome-predicted age or telomere-length in association with increasing female age or ovarian response to stimulation.

Celiac disease is not more prevalent in patients undergoing in vitro fertilization and does not affect reproductive outcomes with or without treatment: a large prospective cohort study.

OBJECTIVE: To study the prevalence of celiac disease in the infertile population undergoing in vitro fertilization (IVF) and assess outcomes. DESIGN: Prospective cohort study. SETTING: A single infertility center from January 2016 to March 2017. PATIENT(S): Women 18-45 years of age participating in IVF. INTERVENTION(S): Patients had serum tissue transglutaminase (tTG) and endomysial (EMA) IgA testing to screen for celiac disease and completed a 10-question "yes or no" survey to assess their medical history, previous testing, dietary habits, and pertinent symptoms. MAIN OUTCOME MEASURE(S): IVF cycle outcomes were compared between seronegative and seropositive patients. RESULT(S): Of 1,000 patients enrolled, 995 completed serologic screening and 968 underwent oocyte retrieval. Eighteen patients screened positive for both tTG and EMA (1.8%) and 10 additional patients (1.0%) screened positive for one of the two antibodies. The number of mature oocytes retrieved, fertilization rates, and blastulation rates were equivalent between seronegative and seropositive patients. There were 987 patients who completed the questionnaire (98.7%), and 84 reported being gluten free (8.5%). Those who reported being gluten free were no more likely to be antibody positive than the general population. Furthermore, a low-gluten diet was not associated with markers of ovarian reserve, oocytes retrieved, fertilization, blastulation, sustained implantation and pregnancy loss rates. CONCLUSION(S): The prevalence of seropositive celiac disease was consistent with that of the general population (2.8%). Patients who were seropositive for celiac disease-related antibodies had outcomes equivalent to seronegative patients, and patients with a gluten-free diet did not have improved outcomes.

Preimplantation genetic testing for aneuploidy is cost-effective, shortens treatment time, and reduces the risk of failed embryo transfer and clinical miscarriage.

OBJECTIVE: To determine if preimplantation genetic testing for aneuploidy (PGT-A) is cost-effective for patients undergoing in vitro fertilization (IVF). DESIGN: Decision analytic model comparing costs and clinical outcomes of two strategies: IVF with and without PGT-A. SETTING: Genetics laboratory. PATIENTS: Women ≤ 42 years of age undergoing IVF. INTERVENTION(S): Decision analytic model applied to the above patient population utilizing a combination of actual clinical data and assumptions from the literature regarding the outcomes of IVF with and without PGT-A. MAIN OUTCOME MEASURE(S): The primary outcome was cumulative IVF-related costs to achieve a live birth or exhaust the embryo cohort from a single oocyte retrieval. The secondary outcomes were time from retrieval to the embryo transfer resulting in live birth or completion of treatment, cumulative live birth rate, failed embryo transfers, and clinical losses. RESULTS: 8,998 patients from 74 IVF centers were included. For patients with greater than one embryo, the cost differential favored the use of PGT-A, ranging from $931-2411 and depending upon number of embryos screened. As expected, the cumulative live birth rate was equivalent for both groups once all embryos were exhausted. However, PGT-A reduced time in treatment by up to four months. In addition, patients undergoing PGT-A experienced fewer failed embryo transfers and clinical miscarriages. CONCLUSION: For patients with > 1 embryo, IVF with PGT-A reduces healthcare costs, shortens treatment time, and reduces the risk of failed embryo transfer and clinical miscarriage when compared to IVF alone.

Translocations, inversions and other chromosome rearrangements.

Chromosomal rearrangements have long been known to significantly impact fertility and miscarriage risk. Advancements in molecular diagnostics are challenging contemporary clinicians and patients in accurately characterizing the reproductive risk of a given abnormality. Initial attempts at preimplantation genetic diagnosis were limited by the inability to simultaneously evaluate aneuploidy and missed up to 70% of aneuploidy in chromosomes unrelated to the rearrangement. Contemporary platforms are more accurate and less susceptible to technical errors. These techniques also offer the ability to improve outcomes through diagnosis of uniparental disomy and may soon be able to consistently distinguish between normal and balanced translocation karyotypes. Although an accurate projection of the anticipated number of unbalanced embryos is not possible at present, confirmation of normal/balanced status results in high pregnancy rates (PRs) and diagnostic accuracy.

High relative deoxyribonucleic acid content of trophectoderm biopsy adversely affects pregnancy outcomes.

OBJECTIVE: To evaluate the association between relative DNA content of the trophectoderm biopsy and pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Academic-affiliated private practice. PATIENT(S): This study included patients undergoing their first single embryo transfer after trophectoderm biopsy and comprehensive chromosome screening (CCS) at a single center between January 2010 and February 2014. INTERVENTION(S): In phase 1 of the study, a standard curve was developed to estimate the relative DNA content of trophectoderm biopsies. Phase 2 of the study examined reproductive outcomes in patients undergoing single embryo transfer after trophectoderm biopsy and CCS. Samples were divided into quartiles according to their relative DNA content, and clinical outcomes were compared. MAIN OUTCOME MEASURE(S): Chemical pregnancy rate, clinical implantation rate, ongoing pregnancy rate, live birth rate. RESULT(S): The quartile of highest relative DNA content had a significantly lower live birth rate when compared with the other three quartiles (relative risk 0.84, 95% confidence interval 0.75-0.95). There was no difference between the quartiles regarding age, body mass index, ovarian response, or endometrial thickness. Among those patients who had a live birth, there was no difference in hCG levels, gestational age at delivery, or birth weight with respect to biopsy DNA content. CONCLUSION(S): Trophectoderm biopsies with the highest relative DNA content are associated with lower live birth rates after single embryo transfer. Possible explanations for this phenomenon include diminished accuracy of the euploid diagnosis vs. a mechanical impact of the biopsy. Regardless of the cause, the outcomes emphasize the importance of obtaining appropriately sized trophectoderm biopsies for CCS.