Reassuring data concerning follow-up data of children born after preimplantation genetic diagnosis Preimplantation genetic diagnosis (PGD) was initially developed to prevent the risk of transmitting genetic diseases to the offspring of the carrier or affected couples. Later, the same procedure was also applied as preimplantation genetic testing for aneuploidies (PGT-A), with the aim of avoiding the transfer of abnormal embryos. The subsequent spread of PGD/PGT-A technology in infertility centers worldwide generated an intense scientific debate about its safety. Children born after assisted reproductive technology (ART), in fact, have been reported to be at higher risk of adverse perinatal outcomes compared with those conceived naturally (1–3).
Epigenetic alterations of the first trimester placenta: insight into preoccupying concerns in assisted reproductive technology Our concerns for the possibility of epigenetic alterations of the developing embryo are recent preoccupations. Yet, the concept of ‘epigenetics’ actually dates to 1942. Conrad H. Waddington first coined the term of epigenetics for describing the interactions existing between the genes and their environment (i.e. between the genotype and phenotype) (1). The concept of epigenetics covers all issues related to the interactions existing between the innate and the acquired. Discovering the realm of epigenetics has therefore indicated that all is not genetics, but the integrity of the individual also depends upon the control of gene expression.
Limits of current male fertility testing In the current approach to male fertility testing, basic semen analysis has limitations as a predictor of fertility status, and the technology is fraught with variability. Nonetheless, it remains the cornerstone of the evaluation of the male infertility, and we recommend adherence to most recent World Health Organization guidelines. Although the current sperm function tests (bioassays) have important drawbacks, they are still valuable as research tools. Sperm quality assays with analysis of sperm DNA fragmentation need further investigation before they can be recommended for routine clinical use.
What are the cost considerations for preimplantation genetic testing for aneuploidy? The study by Somigliana et al. (1) addresses an important and timely clinical question: Is preimplantation genetic testing for aneuploidies (PGT-A) a cost-effective adjunct in IVF? We appreciate the continued study into this aspect of IVF patient care and counseling, which is rapidly expanding in utilization and yet remains controversial. The authors conclude that PGT-A can be cost-effective in specific settings and populations, namely with increasing female age and the number of available blastocysts (1).
In pursuit of middle ground: understanding the bone benefits of hormonal contraception in women with anorexia nervosa In the report entitled “Oral contraceptives partially protect from bone loss in young women with anorexia nervosa” (1), Maïmoun et al. analyzed cross-sectional data obtained from enrolling young women living in Southern France to address a clinically discrete and important question about the relationship between bone mineralization and the condition of anorexia nervosa. The main outcome measure was areal bone mineral density as determined by Hologic QDR-4500A dual-energy X-ray absorptiometry of whole body, lumbar spine, radius, and left femur.
Phthalates and other endocrine-disrupting chemicals: the 21st century's plague for reproductive health Reproductive health is affected by exposures to environmental contaminants during critical periods of human development. These periods include preconception, conception, pregnancy, child and adolescent development, and adult life. Furthermore, environmental contaminants may influence the reproductive health status of the exposed individual's offspring.
Registered reports: prospective peer review emphasizes science over spin Scientific studies are typically considered for publication after they are completed and the results are available. Consequently, the decision to publish is based not only on the importance of the research question and the quality of the methods used, but also on the novelty and statistical significance of the authors' findings. This in turn creates perverse incentives for researchers to seek surprising, positive results, and to prioritize creative interpretation of data over accurate discovery.
Introduction Semen analysis remains the initial laboratory evaluation for infertile men. The limitations of the standard semen analysis along with past attempts to improve the analysis of sperm are reviewed. Advances in genetic testing will lead to fewer diagnoses of idiopathic male infertility, and improvements in picking the best sperm offer hope of improved assisted reproduction outcomes. The development of simplified testing has opened up the availability of tests performed in settings without advanced laboratory facilities as well as by patients in their own homes.
Rapid progression in our understanding of extracellular vesicles and male infertility Spermatogenesis is a complex process requiring the proper functioning of thousands of genes combined with the correct balance of hormones, temperature, and other environmental factors. Sperm isolated from the testicle, however, are generally immotile and immature—incapable of fertilizing an egg on their own, although they can be used for intracytoplasmic sperm injection. Sperm mature during transit through the epididymis, where morphologic, chemical, and other changes occur, giving them capacity for fertilization.
Good outcomes in small babies, and the elephant in the room As reproductive care specialists, we are charged with the difficult task of counseling our patients regarding the risks of fertility treatments. A number of factors complicate this process for us: not only do we discuss risks to the patients themselves, but we also address the possible complications that they or their future offspring could experience. We must communicate to them the subtleties of absolute vs. relative risks, as well as differences in perceived outcomes when various control groups are used.
Poor sleep and delayed time to pregnancy: a wake-up call for physicians and researchers? Other disciplines are increasingly recognizing poor sleep health as a risk factor for a host of adverse health outcomes, including obesity, type 2 diabetes, cardiovascular disease, depression, and all-cause mortality (1). Even within the context of reproductive epidemiology, disrupted sleep patterns have been linked to a higher risk of adverse pregnancy outcomes, such as gestational diabetes (2), stillbirth, preterm birth, and low birth weight (3). Therefore, it is not entirely surprising that new evidence is emerging that sleep disturbances may be associated with impaired fertility in women.
Chromosome arrangement disturbances: another piece of the polycystic ovarian syndrome puzzle The article by Li et al. (1) is adding interesting genetic findings to the otherwise vast literature concerning polycystic ovarian syndrome (PCOS). PCOS is a highly complex endocrine disorder, comprising hyperandrogenemia, insulin resistance, menstrual irregularities, and polycystic ovaries. Uncovering the cause and hence developing good treatments rather than managing symptoms is complicated by the multifactorial origin of the disease. Inflammation possibly influenced by the gut microbiome has recently been suggested as one of the driving forces behind the disease.
Inflammation and uterine fibrosis: the possible role of chronic endometritis Uterine fibrosis, which can lead to the complete obliteration of the uterine cavity or Asherman syndrome, is a dreadful condition that harms fecundity and against which we are poorly armed. Classically, uterine fibrosis is a complication encountered after uterine surgical procedures. The risk of uterine fibrosis is particularly high after uterine procedures performed in relation to pregnancy. These notably include manual or instrumental revision of the uterine cavity at the time of delivery, curettage after termination of pregnancy (induced or spontaneous), and procedures undertaken for removing retained products of conception.
Home testing for male factor infertility: a review of current options Male factor infertility contributes to about 50% of the incidence of infertility in couples. Semen analysis is key to the diagnosis of the reproductive potential of a male subject. In current practice, men must attend a clinic or other hospital facility to have their semen analyzed. However, many men are not comfortable with this process, which they often find embarrassing and expensive. To solve these problems, many devices for home analysis of semen samples have been developed and commercialized.
Uterine artery occlusion at myomectomy To demonstrate three approaches to uterine artery occlusion at time of myomectomy as a blood-sparing intraoperative technique.
Reducing radiation using quality improvement methodoloy and careful use of fluoroscopy during hysterosalpingogram Hysterosalpingogram (HSG) is a common radiologic technique used to evaluate the anatomy of the female genital tract, particularly structural uterine or tubal abnormalities that may contribute to infertility. There is unavoidable radiation exposure to both the ovaries of the patient as well as to the staff performing the HSG. Though typical radiation use is low, any radiation exposure increases the risk of malignancy, organ damage, and genetic defects in the offspring of the exposed persons. A literature review indicated that reduction in radiation exposure was possible in our practice through simple quality improvement initiatives.
RNA-SEQ reveals cumulative changes in gene expression following blastocyst vitrification and biopsy Epidemiologic studies suggest a difference in neonatal outcomes between babies born following fresh and frozen embryo transfer [1,2]. It is unclear whether this is due to the superovulated environment or the vitrification process. Cryopreservation involves highly concentrated cryoprotectants, which are potentially toxic to embryos [3]. Trophectoderm biopsy for preimplantation genetic testing (PGT) is an additional manipulation that may affect embryonic development. The combination of these two interventions occurs frequently in IVF clinics.
Clinical pregnancy outcomes of fresh versus frozen blastocyst transfers by body mass index More than 1/3 of reproductive-age females in the United States are obese.[1] When compared to normal-weight women, obese women are more likely to be infertile and less likely to achieve clinical pregnancy with IVF, possibly due to a negative association between obesity and endometrial receptivity.[2-4]
Evaluation for germline mosaicism in sperm donors following diagnosis of dominant disorders in donor-conceived offspring Autosomal dominant (AD) disorders are considered to be the result of de novo pathogenic variants when both biological parents are negative for symptoms of that condition. The risk of recurrence for that couple is often quoted to be “low” or “less than 1%”, due to the rare occurrence of germline mosaicism [1]. Guidance regarding management of possible gonadal mosaicism remains limited despite its implications for reproductive planning in sibling pregnancies.
It’s not too late to start! Random start late follicular stimulation for donor IVF Increased use of “freeze-all” cycles in which the endometrium does not have to be synchronized with the ovaries, has opened the door for random start stimulation. Most random start research has focused on luteal phase gonadotropin starts in oncology fertility preservation cases with few studies focused on oocyte donors.1,2,3,4
When more is better: AMH and blastocyst quality Anti-müllerian hormone (AMH) is a well-established marker for ovarian reserve, as it is secreted by the surrounding granulosa cells of each oocyte. Parameters for normal AMH in reproductive-aged women are thought to be between 1 and 3 ng/mL. Elevated plasma and intrafollicular fluid levels of AMH is observed in patients with polycystic ovary syndrome (PCOS). AMH greater than 5 ng/mL is often consistent with PCOS and thought to play a role in follicular arrest resulting in the classic presentation of polycystic ovaries.
A retrospective study on the use of dose-dependent letrozole to decrease cancer recurrence and adverse events in patients undergoing ovarian stimulation Cure rates for cancers in young women and men have never been higher, but treatment commonly comes at the cost of their fertility [1,2]. Assisted reproductive technologies can be employed for the banking of gametes and embryos; however are associated with supraphysiologic sex hormone levels, which in the case of breast cancer presents the theoretical risks of disease progression [1,3]. In order to minimize the risk of ovarian stimulation, anti-estrogen medications like letrozole have been used as an adjuvant to exogenous gonadotropins to minimize serum estradiol levels [3,4].
Attitudes towards posthumous reproduction in patients undergoing embryo or gamete cryopreservation In a recent Ethics Committee Opinion, the ASRM addresses the importance of consenting patients on disposition of gametes or embryos prior to undergoing retrieval [1]. Despite the potential legal and ethical dilemmas that can arise if disposition is not expressly stated, this is not a requirement at all fertility centers. Previous studies have evaluated the attitudes of both the general population and couples seeking fertility counseling, however these were mostly focused on posthumous gamete retrieval, not the use of previously cryopreserved gametes or embryos after death of an intimate partner [2,3].
Risk of ovarian torsion in patients with ovarian hyperstimulation syndrome Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproductive technology (ART) for which hospital admission is required in severe cases to prevent life-threatening complications or for treatment of ovarian torsion. In OHSS, high ovarian volumes increase the risk of torsion, however population-based data evaluating incidence and complications of OHSS-related ovarian torsion are lacking.
A study to compare the birth outcomes of infants conceived by intravaginal culture using the invocellTM device and conventional in vitro fertilization in traditional incubators Intravaginal culture of oocytes (INVO) was first described by Ranoux et al in 1988 with the goal of developing a simplified alternative to conventional in vitro fertilization.1 The device is a gas-permeable closed vessel that contains culture medium but uses the vagina to maintain a stable temperature and pH. This creates an environment conducive to fertilization without the need for a gas incubator and costs associated with it.3 Several studies have demonstrated the efficacy of the INVO procedure, with clinical pregnancy rates between 20-59%.
Oncofertility: does ovarian response to hormonal stimulation change with a cancer diagnosis? It is predicted that by 2030 the number of new cancer cases per year will rise to 23.6 million. As the number of cancer patients rises, so does the number of survivors whose quality of life is impacted by infertility. While the use of follicular stimulating hormone (FSH) and luteinizing hormone (LH) has not proven to be harmful to female cancer patients, cancer treatment itself may be gonadotoxic. Therefore, patients facing a cancer diagnosis can preserve future fertility through embryo or oocyte cryopreservation.
Duration of controlled ovarian stimulation is associated with decrease in follicular fluid proinflammatory Th1 cytokines Ovarian follicular maturation and subsequent ovulation involves a complex relationship between the inflammatory and endocrine systems. The presence of various cytokines can influence the surrounding environment to promote protective or pathologic immune responses.[1] Physiologic processes of the reproductive system involve well-orchestrated changes to the cytokine profile. For example, the maternal immune system preferentially mounts Th2 responses and downregulates proinflammatory Th1 cytokines to protect the growing conceptus during a pregnancy, while upregulating Th1 cytokines for fetal expulsion near the time of delivery.[2] Several factors may influence cytokine expression in vivo.
Hysterosalpingography may not be Reliable in the Diagnosis of Hydrosalpinx in Infertile Patients Hysterosalpingography (HSG) is commonly performed in the evaluation of the infertile couple to assess the uterine cavity and fallopian tubes. It has been well established that the presence of a hydrosalpinx negatively impacts pregnancy outcomes in in-vitro fertilization (IVF) cycles, and that salpingectomy of a fallopian tube effected by hydrosalpinx dramatically improves IVF pregnancy outcomes. HSG is a primary diagnostic tool in the evaluation of tubal disease but its ability to correctly diagnose a clinically significant hydrosalpinx in IVF patients is poorly understood.
Humidity level during culture does not affect mouse embryo development Embryo culture is routinely performed with or without added humidification to the incubation chamber. For example, time-lapse incubators typically lack added humidification, to maintain optical clarity and minimize the risk of contamination proliferation. Regardless of humidification, an oil overlay is commonly used to cover the culture medium to reduce the rate of evaporation. It has, however, been shown that even with an oil overlay the osmolality changes more in an incubator with ambient humidity than in an incubator with added humidity (Swain 2016, Carpenter 2018, Holmes 2018, Yoshimura 2018).
Are obstetrical outcomes after IVF with PGT-A more strongly correlated with embryo grading prior to biopsy or day of thaw for embryo transfer? The relationship between obstetrical outcomes and embryo grading after in vitro fertilization (IVF) has been extensively analyzed independently of pre-implantation genetic testing for aneuploidy (PGT-A). The capacity to assess for aneuploidy with PGT has enhanced embryo selection, increased the rate of implantation per embryo transfer (ET), and decreased the overall rate of miscarriage. However, this technology does not predict with certainty which embryos will result in a pregnancy and healthy live birth, or pregnancy loss.
A machine learning approach to predict blastocyst formation in vitro Despite decades of experience with in vitro fertilization, there is still significant uncertainty in predicting patient outcomes. Standard operating procedures for clinical decision-making rely on few variables analyzed independently of each other. While the predictive power of a single variable, such as age, is clinically useful, a more sophisticated and personalized approach could improve the quality of patient care.
Random start luteal phase stimulation for donor IVF: a useful tool in the rei clinician’s armamentarium Conventional gonadotropin stimulation begins in the early follicular phase of the menstrual cycle to allow appropriate synchronization of the follicular cohort and endometrium for fresh embryo transfer. As clinical experience accumulates with planned freeze-all and unsynchronized donor cycles, novel stimulation strategies have emerged such as luteal phase stimulation (LPS). Previous studies have supported the viability of LPS with comparable oocyte maturity and fertilization rates.1,2,3
Evaluating the use of natural cycle endometrial receptivity array prior to embryo transfer The endometrial receptivity array (ERATM) is a tool designed to improve implantation by pinpointing a patient’s specific window of implantation by profiling the patterned genetic expression of proteins in the endometrium. Nearly all published studies evaluating the use of ERA are in medicated cycles (1-6) while there is a paucity of data evaluating the use of natural cycle ERA (NC-ERA) prior to natural cycle frozen embryo transfer (NC-FET).
Knowledge of long term health sequelae among women with polycystic ovary syndrome Polycystic ovary syndrome (PCOS) is one the most common hormonal disorders among women of reproductive age, with an estimated prevalence of 5-10%. PCOS is associated with long-term health risks including infertility, insulin resistance, diabetes, metabolic syndrome, cardiovascular disease, obstructive sleep apnea, endometrial carcinoma, depression and anxiety. Despite an increase in medical literature regarding the association of PCOS with long term health sequelae, there are few published studies that assess the patient's understanding and awareness of these risks.
The association between ovarian reserve and luteal phase deficiency Luteal phase deficiency (LPD) is attributable to insufficient progesterone production from the corpus luteum and failure to maintain normal secretory endometrium. LPD has been associated with infertility, recurrent pregnancy loss, and irregular menstrual bleeding [1,2]. Clinical signs of a LPD include a short luteal phase or luteal bleeding [3,4]. Given that corpus luteum function may decrease with declining ovarian reserve, we hypothesize that diminished ovarian reserve (DOR) is associated with LPD.
Arginase II and nitric oxide synthase uncoupling – a culprit for oocyte quality deterioration in older patients? Utilizing nitric oxide (NO) selective electrode, recently we have shown that the intraoocyte NO concentration of oocytes obtained from young are significantly higher than those from old animals. NO supplementation of old and young oocytes not only resulted in sustained the ability of oocytes to undergo normal fertilization and development, but also prevented the onset of apoptosis in the embryos created from aged oocytes. NO is generated enzymatically by three distinct isoforms of NO synthase (NOS): neuronal, inducible, and endothelial.
Women’s health providers’ perspectives on preimplantation genetic testing Preimplantation Genetic Testing (PGT) is a commonly used procedure to screen for genetic abnormalities in an embryo prior to transfer. Patients with medical indications for PGT may be identified and counseled by OB/GYN providers, gynecologic oncologists, or infertility specialists. The attitudes of women’s health providers among these specialties regarding PGT has not been well characterized.
Agonist or antagonist? comparison of IVF protocols by body mass index category in patients with unexplained infertility Obese women undergoing assisted reproductive technologies have decreased pregnancy and live birth rates. However, studies have conflicting views on the ideal protocol for these patients. Previous analysis demonstrated higher clinical pregnancy rates (CPR) and live birth rates (LBR) for agonist cycles over antagonist cycles. This study examined whether this association persisted in patients with suspected equivalent ovarian reserve by analyzing those with unexplained infertility.
Self-administered questionnaire to screen for polycystic ovarian syndrome Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy affecting reproductive aged women. However, it is often underdiagnosed. Given the long-term health risks associated with PCOS, such as infertility, diabetes, and endometrial cancer, it is important to optimize accurate diagnosis. A self-reported questionnaire that identifies women who should undergo clinical screening for PCOS could reduce the number of women who go undiagnosed and untreated and would also facilitate research on risk factors for this condition.
Relationship between omega-3 and omega-6 serum free fatty acids and ovarian reserve Fatty acids are necessary substrates for early reproductive processes including oocyte maturation and embryo implantation. Numerous studies have investigated the impact of free fatty acids (FFAs), particularly n-3 and n-6, on chronic disease states and general health outcomes. An elevated ratio of n-6:n-3 has been linked to inflammatory conditions and adverse pregnancy outcomes in overweight and obese women. Evidence is lacking regarding the effect of FFAs and the n-6:n-3 ratio on ovarian reserve in a reproductive age population of women.
The impact of antimullerian hormone and maternal age on cycle outcome following a frozen transfer of a single euploid embryo Antimullerian hormone (AMH) is one of the clinical markers for diminished ovarian reserve (DOR) and data suggests that AMH levels better correlate with the number of antral follicles than other measures. Whether there is an association between AMH levels cycle outcome is not clear especially when a patient has a euploid embryo available for frozen embryo transfer (FET).
Utilization and knowledge of oncofertility preservation services: a single institution experience For women diagnosed with cancer, treatment may require removal of reproductive organs and/or administration of gonadotoxic chemotherapy/radiation. One of the major determinants of quality of life in reproductive aged survivors is fertility status. With advancements in treatment options, conservation of reproductive function is possible for many patients1. In a retrospective review by McCray et al2, only 80% of women aged 40 years or younger diagnosed with breast cancer had discussions regarding fertility with their physicians.
PGT-A outcomes in high and low responding donors: a comparison study At present, it is unknown whether ovarian response among oocyte donors is associated with embryonic aneuploidy. Controlled ovarian stimulation in in-vitro fertilization may impart variations in theca and granulosa cell functions that may affect oocyte quality1. As more recipient couples utilize preimplantation genetic testing for aneuploidy (PGT-A), the impact of oocyte stimulation on embryonic aneuploidy warrants further investigation. Previous studies showed that moderate ovarian stimulation in infertile patients does not significantly increase the rate of chromosomally abnormal embryos2, 3.
Preimplantation genetic testing for aneuploidy (PGT-A) in donor oocyte single blastocyst transfer cycles: is there benefit? The use of PGT-A in donor oocyte cycles is increasing, however, its clinical benefit in these cycles is still unclear. A wide range of euploidy rates in blastocyst biopsies from donor oocyte cycles have been shown, from 39.5% to 82.5%1. Furthermore, implantation rates in women 40-43 years of age have been shown to be higher in PGT-A tested euploid embryos compared with unscreened embryos2, albeit with autologous oocytes. While these factors might make PGT-A appealing in donor oocyte cycles when average oocyte donor age is significantly younger than average recipient age, little is known about the impact of trophectoderm biopsy on implantation3.
Why do euploid embryos fail to implant? One of the most difficult patient discussions involves explaining why a euploid embryo transfer fails to result in pregnancy. One possibility involves embryo quality e.g. mosaicism or an abnormality affecting energy. The second possibility involves endometrial receptivity. Early studies suggested that ultrasound assessment of endometrial thickness at the end of the estrogen phase could determine a receptive endometrium for frozen embryo transfer (FET). A recent study of > 20,000 FET cycles demonstrated that pregnancy rates decreased significantly for each millimeter increment below 7mm.
The survival, biopsy, ploidy and pregnancy rates of previously vitrified blastocysts subjected to warming/biopsy/revitrification for PGT-A analysis Although PGT-A with Next Generation Sequencing (NGS) is becoming the standard of care, there are a large number of blastocysts that were frozen prior to having embryo biopsy and genetic analysis. As a result, there are an increasing number of patients requesting genetic information of their previously undiagnosed frozen blastocysts. It is important to understand how these embryos perform following warming (thaw), biopsy and revitrification (refreeze) for PGT-A analysis; and their ability to initiate pregnancies following re-warming.
Examining the effects of temperature on embryo growth Debate exists about the ideal temperature for embryo culture. The temperature of the female reproductive tract may be different than the commonly used human core body temperature of 37 degrees Celsius (°C).
Why do gestational carriers fail? Recent IUD may be culprit Employing a gestational carrier (GC) has become an increasingly common and safe way for intended parents to have a biological child. GCs are expected to have an optimal environment for embryo transfer given they have had successful past pregnancies. However, the odds of cancellation for GC cycles and women undergoing IVF treatment show no significant difference 1. An unsuccessful GC cycle is devastating, representing both a psychological and financial burden for the intended parents. Endometrial lining measuring under 7 mm are a major cause for cancellation or suboptimal embryo transfers.
Transfer of a single genetically screened embryo in women >43 results in significantly higher pregnancy rates and lower pregnancy loss rates than transfer of multiple unscreened embryos Traditionally, women of advanced age underwent in vitro fertilization (IVF) cycles with replacement of multiple unscreened fresh embryos to optimize the chance of per-cycle success. Unfortunately, results were variable, with failed cycles, miscarriages, and multiple gestations bein a common outcome. Preimplantation genetic testing for aneuploidy (PGT-A) with elective single euploid frozen embryo transfer (FET) has emerged as a progressive treatment strategy to improve implantation rates, decrease pregnancy loss rates, and promote healthy singleton pregnancies for both mother and baby.
Is the rate of embryo development after IVF correlated with chromosomal sex; an analysis of 10,523 embryos observed under time lapse microscopy and after PGT-A evaluation The capacity to assess for chromosomal abnormalities with pre-implantation genetic testing for aneuploidy (PGT-A) has enhanced embryo selection, increased the rate of implantation per embryo transfer (ET), and decreased the overall rate of miscarriage. For patients who are unlikely to have an embryo survive to blastocyst ET/PGT-A, our institution routinely performs fresh ET after in vitro fertilization (IVF). Cleavage stage embryos are selected for ET based on morphology. We have previously studied the correlation of day 3 embryo morphology with aneuploidy and obstetrical outcomes.
Carrier screening: should evaluating more genes be the standard of care? Carrier screening utilization varies widely among clinicians including obstetricians (ObGyns), genetic counselors (GCs), maternal fetal medicine specialists (MFMs) and reproductive endocrinologists (REIs).1,2 ACOG currently recommends screening for cystic fibrosis (CF) and spinal muscular atrophy (SMA), regardless of ethnicity. Ethnicity-based screening for hemoglobinopathies and Jewish genetic disorders is also recommended. ACOG acknowledges that expanded carrier screening (ECS) has many benefits however advises that expanded panels should only include disorders that are well-understood, severe, and have a carrier frequency of 1/100 or greater.
Utilization and outcomes of ovarian conservation at the time of hysterectomy for cervical cancer Cervical cancer predominately affects young women, in whom ovarian conservation (OC) has significant long-term benefits for cardiovascular and bone health and provides the opportunity for fertility preservation. In early-stage disease, risk of metastasis to the ovary or metachronous ovarian malignancy is low, thus OC is reasonable without compromising survival. No guidelines exist for OC in young women with cervical cancer, and trends and outcomes of OC in this population have been understudied.
Removing obstacles from the modern infertility patient’s journey: patient dropout is low in an employer sponsored high-touch program Patients facing reproductive challenges are commonly faced with a myriad of physical, emotional and financial obstacles. Approximately 50% of infertile couples never seek out fertility care,1 and treatment discontinuation rates range from 7.7% to 89%.2,3 Treatment costs can be a significant barrier to accessing care, especially for patients who self-pay. Even for insured patients, dropout rates tend to be high, ranging from 46% to 58%.4 Studies suggest that high levels of psychological stress also play a role in patient dropout.
A national population-based survey of maternal hypertension in women who received infertility treatment Infertility affects approximately 11% of couples in the United States (1). Infertility treatment has been linked to hypertensive disorders of pregnancy including pre-eclampsia, a leading cause of maternal and fetal morbidity worldwide (2, 3). Infertility status and infertility treatment may function independently as risk factors for hypertensive disorders of pregnancy (3). Most of this risk may be due to the higher frequency of multifetal gestation; however, risk remains increased even in singleton gestations for those undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI; 4,5).
Type of frozen transfer in relation to euploid miscarriage outcomes The literature on in-vitro fertilization (IVF) outcomes with different frozen embryo transfer protocols is limited, particularly with euploid embryos. In particular, miscarriage rate after euploid embryo transfer in this context has rarely been studied.
Use of repeat-dose GnRH agonist, hCG, and co-trigger for final follicular maturation have similar rates oocyte maturity Use of GnRH agonists with or without hCG for final follicular maturation has become increasingly common in high responders as well as in patients with normal ovarian reserve. However, studies investigating the effect of trigger type on IVF outcomes have been inconsistent and the majority studies have looked at patients triggered with single-dose rather than repeat-dose GnRH. (1-3)
Pregnancy outcomes with frozen-thawed single euploid blastocyst transfer following IVF cycles using HCG versus GNRH agonist trigger for final oocyte maturation It is now well known that GnRH agonist (GnRHa) when used to trigger final oocyte maturation results in early luteolysis and consequently luteal phase dysfunction in fresh autologous IVF cycles. However, with the use of adjuvant low dose hCG, pregnancy outcomes are favorable and comparable to after hCG trigger(1). This suggests that GnRHa trigger does not impact oocyte or embryo quality. Furthermore, previous studies have shown comparable live birth rates after frozen-thawed embryo transfer (FET) cycles utilizing embryos obtained from cycles triggered previously with GnRHa versus hCG (2).
Operational and performance qualification of 35 liter cryostorage dewar tanks by weight measurement-fluid level correlations As surveyed anonymously in a recent Webinar (1), potentially catastrophic cryogenic storage tanks failures have historically occurred at a higher rate than we would care to admit. Due to reputation and financial liability concerns, such events are often judicially silenced in litigation settlements. However, the highly publicized cryogenic failure events reported worldwide in early 2018 placed the entire ART community on high alert that liquid nitrogen (LN2) storage tank failures are real. The latter wake-up call has reminded all of us that a strict and comprehensive quality management (QM) plan is warranted (2) to avert serious liability.
Deep learning-enabled blastocyst prediction system for cleavage stage embryo selection Current morphological grading methods rely on descriptive parameters to rank cleavage-stage embryos for transfer. The limited measurements and overall subjective nature of these parameters likely contribute to the low positive predictive value (PPV: 0.3-0.4) reported in the literature for identifying cleavage-stage embryos that will develop into blastocysts. Advancements in the field of artificial intelligence (AI) and convolutional neural networks (CNN) have enabled for pattern recognition in images with unprecedented accuracy.
Preliminary application of convolutional neural network to improve the efficiency of finding rare spermatozoa in micro-tese samples The most severe form of male infertility, non-obstructive azoospermia (NOA), is a lack of sperm in the ejaculate with very little to no sperm production in the seminiferous tubules. Non-obstructive azoospermia accounts for 10% of male infertility cases because the sperm are rare in NOA patients, identification and collection of these cells are inefficient, costly, and time consuming. The field of artificial intelligence (AI) provides opportunities for many needs in cell biology, but is particularly powerful when considering applications in low cell number analyses/identification.
Intramuscular versus vaginal progesterone: can we expect differences in endometrial receptivity? The Endometrial Receptivity Analysis (ERA) test allows for the molecular diagnosis of a patient’s receptive phase through the transcriptome analysis of 248 genes related to endometrial receptivity. A bioinformatic predictor determines the moment of maximum receptivity, providing the ideal time to perform a personalized embryo transfer (pET). To perform ERA, the patient undergoes a mock embryo transfer cycle and an endometrial biopsy is taken in the moment in which the blastocyst transfer would be performed.
Characterizing ovarian function by karyotype in a cohort of women with turner’s syndrome A majority of women with complete or mosaic Turner Syndrome (TS) undergo accelerated follicular apoptosis and loss of fertility. Unfortunately, due to the heterogeneity of this group, there is no clear data on the prediction of timing of ovarian depletion, making counseling on options and timing of intervention via fertility preservation difficult.
Impact of radiation-induced menopause in young women with gynecological cancer Young women with gynecological cancer such as cervical and endometrial cancers often undergo treatments that induce a menopausal state, either by surgical removal of ovaries or radiation-induced ovarian failure. While surgical menopause has been well studied, radiation-induced menopause has been relatively understudied.
Moderate physical activity is positively associated with ovarian reserve Epidemiologic studies demonstrate that physical activity is associated with female fertility and time to pregnancy, and that this association varies with BMI. Few studies have examined the association between physical activity and ovarian reserve in women with no history of infertility, and we are unaware of any studies that have examined this association in a diverse North American population.
Patients with isolated male factor infertility undergoing therapeutic donor insemination: to superovulate or not? Therapeutic donor insemination (TDI) is an frequently employed fertility treatment for patients with absolute male factor infertility. Among infertile couples, the use of superovulation and IUI is associated with higher live birth rates1. The benefit of empiric superovulation in unpartnered females or same sex female couples without a history or risk factors for infertility has not been evaluated. The increased risk of multiples with oral medication to induce superovulation in this population is not well defined either, but possibly higher than the 4-8% seen in those with unexplained infertility2.
Cystic fibrosis heterozygosity does not impact ovarian reserve or assisted reproductive technology outcomes Cystic fibrosis (CF) carrier status has been hypothesized to modulate female reproductive function, as the CFTR gene has been observed to be in the proximity of several fertility and primary ovarian insufficiency-related genes on chromosome 7 [1]. In mouse-model studies, the CFTR gene has been identified to control HCO3 entry into ovarian and granulosa cells, which consecutively regulates FSH-stimulated estrogen [2] and influences follicular fluid accumulation during oocyte maturation [3]. Previous published research has shown that CFTR mutation heterozygosity does not impact ovarian response and IVF cycle outcome [4], albeit this study was performed prior to the current era of routine preimplantation genetic testing (PGT).
Is there a CGG repeat threshold to predict the risk of occult premature ovarian failure in fragile X premutation carriers? Fragile X premutation carriers are at risk for Fragile X-associated premature ovarian insufficiency (FXPOI).1 CGG repeat ranges have historically been used to assess the possibility of expansion to full mutation in subsequent generations. Recently, CGG repeats have been considered to be a potential marker of diminished ovarian reserve, albeit no common threshold currently exists to predict a patient’s risk for FXPOI.
Minimal ovarian stimulation with intravaginal embryo culture: a low-cost alternative to conventional ART The total cost of medications, cycle monitoring, and embryo culture for conventional ART treatments is cost-prohibitive for many couples nationwide. Our practice has developed a unique Affordable IVFSM (A-IVF) program, incorporating both minimal ovarian stimulation (letrozole followed by gonadotropins) and an intravaginal embryo culture device, to reduce cycle costs and increase access to ART.
Artificial intelligence-enabled system for embryo classification and selection based on image analysis Accurate and consistent classification and identification of top quality embryos from a patient’s cohort remains a significant challenge in the field of embryology due to the subjective nature of the current morphologic grading systems. Machine learning is a powerful tool that can be used to automatically detect patterns in image data which can then be utilized to predict future outcomes and can enable objective decision making.
Insights into the mechanisms by which clomid and E2 regulate WNT signaling in the endometrium Hormonal effects on epithelial cells of the endometrium are often mediated through stromal cell receptors. Endometrium from women undergoing IVF using minimal stimulation with clomiphene citrate (CC) is characterized by marked atrophy of endometrial glands accompanied by relative increases in stromal cells (despite supraphysiologic levels of E2). Although it’s commonly believed that CC exhibits its effects simply as an estrogen receptor antagonist, recent studies indicate that CC differentially affects endometiral cell compartments.
Comparison of testicular sperm aspiration to testicular sperm extraction in men with obstructive azoospermia Obstructive azoospermic men who are unwilling or unable to undergo microsurgical reconstruction are able to have fertility treatment utilizing the advances in sperm retrieval techniques and assisted reproductive technology. The ideal sperm retrieval technique may vary depending on the clinical situation but the goal is to retrieve adequate numbers of high quality sperm for fresh use and/or for cryopreservation [1]. Open and percutaneous sperm retrieval techniques have been well described but there is a paucity of literature describing and comparing these techniques in obstructive azoospermic males.
Oxidative reduction potential and sperm motility remain stable for up to two hours post-semen collection There is an inverse correlation between successful outcomes following intrauterine insemination (IUI) and the time from ejaculation and semen processing. The World Health Organization recommends that male patients produce samples at the laboratory in order to expedite semen analysis (SA), while patients who produce at home are suggested to bring samples to the laboratory within one hour to accurately assess semen quality. There is evidence to suggest that increased time from collection to processing may result in impaired semen quality due to environmental exposures and a surge in reactive oxygen species (ROS) of the spermatozoa.
Differential effects of controlled ovarian stimulation protocols on endometrial histomorphology The use of clomiphene citrate with low dose gonadotropins is an acceptable alternative for patients with expected poor ovarian response. Clomiphene citrate is a selective estrogen receptor modulator with agonist effects on the ovaries and antagonist effects on the endometrium. Although believed to be an antagonist on the endometrium, its effects on endometrial histomorphology are not well documented.
Comparing bhcg values and pregnancy outcomes in intravaginal culture (IVC) to traditional in vitro incubation Since its introduction in the mid 1980s, intravaginal culture (IVC) has been proposed as a viable alternative option for assisted reproduction when compared to traditional IVF (1). IVC has the ability to reduce costs, decrease laboratory manipulation and increase patient involvement in assisted reproduction (2). Compared to traditional IVF laboratories, IVC uses normal physiological diurnal changes for incubation. In addition, studies demonstrate that the percentage of quality blastocysts transferred and live birth rates show no difference between the two groups (3).
Comparing the uterine microbiome in recurrent pregnancy loss to parous fertile controls Classically the uterine cavity was considered a sterile organ and the presence of bacteria indicated pathology. Studies in the last decade have challenged this notion and recent studies suggest the composition of this uterine microbiome is significantly associated with differences in implantation, pregnancy and live birth rates. In infertile patients undergoing IVF, the presence of a non-lactobacillus-dominated microbiota of < 90% has been associated with a significant decrease in implantation (60.7% vs 23.1%), pregnancy (70.6% vs.
Clinical experience utilizing single-nucleotide polymorphism data captured by FAST-SeqS to reduce the transfer of polyploid embryos Our FAST-SeqS NGS aneuploidy screening (PGT-A) platform now analyzes single-nucleotide polymorphisms (SNPs) in addition to long interspersed nucleotide elements (LINE-1s). The SNP enhancements permit the detection of all forms of triploidy (e.g., 69,XXX), other forms of polyploidy (e.g., 92,XXXX), haploidy/whole genome uniparental isodisomy (WG-UPiD), and many instances of single-chromosome UPiD, in addition to whole-chromosome and segmental aneuploidy. FAST-SeqS improvements allow for correct classification of abnormalities potentially misclassified previously, which is essential for decreasing molar pregnancy and miscarriage rates.
Elevated serum progesterone during in vitro fertilization treatment and the risk of ischemic placental disease Elevated progesterone on the day of human chorionic gonadotropin (hCG) administration is associated with lower live birth rates and lower birth weight after fresh embryo transfer in an IVF cycle. While previous research indicates that elevated estradiol during ovarian stimulation increases the risk of preeclampsia and low birth weight, few studies have examined the association between progesterone and risk of adverse pregnancy outcomes.
Parent perspective on childhood developmental milestones after assisted reproductive technology, a national survey Assisted reproductive technology (ART) is an increasingly common mechanism for conception, but parents’ perspectives of newborn development after ART has not been extensively studied. Mixed evidence exists regarding the effect of ART on childhood developmental milestones, as ART itself increases the risk of prematurity and low birth weight, both of which are associated with developmental delay. (1-3) Studies have suggested that ART does not have a negative effect on the physical and mental development of children when compared to naturally conceived offspring (4-5), but how do these parents perceive their child’s development?
Comparing pregnancy outcomes using an endometrial receptivity array (ERA) prior to frozen embryo transfer (FET) with euploid embryos The receptivity of the uterus for implantation is determined by a complex interplay of various maternal and embryonic factors. The window of implantation refers to the time period in which a mid-secretory phase endometrium is primed to accept a blastocyst stage embryo. Recent advances in next generation sequencing have allowed for development of tests which can reliably identify the state of the endometrial lining and test for “endometrial receptivity”, although their clinical applicability in IVF for improving pregnancy rates has not yet been fully investigated.
Polycystic ovary syndrome and the risk of preeclampsia Data suggests that patients with polycystic ovary syndrome (PCOS) are at increased risk of developing preeclampsia; however several studies have failed to find an association between the two. The precise mechanism that links PCOS to preeclampsia remains unknown, although aberrant placental growth may play a role. In addition, many PCOS patients ultimately conceive through assisted reproductive technology, a process that has been independently associated with preeclampsia.
The effect of masculinizing therapies on ART outcomes in female mice Fertility preservation is an important aspect of care for all patients who may have their fertility compromised secondary to disease, medical treatments, or age, including treatments for gender dysphoria. Multiple societies recommend fertility preservation be discussed prior to initiation of treatment for gender dysphoria1-3. Transgender male patients are also presenting to fertility clinics for fertility preservation or treatment after the initiation of therapies such as leuprolide acetate and testosterone therapy.
Karyotype of first miscarriage is prognostic of subsequent pregnancy outcome Fetal chromosomal abnormalities are the most common cause of miscarriage. Genetic testing of products of conception is routinely performed after a second consecutive pregnancy loss [1]. While euploid miscarriage is a negative prognostic indicator in the setting of RPL, it is unknown if sporadic euploid miscarriage is predictive of future pregnancy outcomes [2].
The complexity of conditions for which patients pursue PGT-M: a modern snapshot The first genetic testing on preimplantation embryos (PGT-M) was performed for single gene disorders. Due to the costs and health risks associated with IVF, PGT-M was historically pursued only for the most severe genetic conditions and when there was a known family history. Recent decades have seen an explosion of genetic testing options, including whole exome sequencing and preconception expanded carrier screening, and the landscape of conditions for which PGT-M may be pursued has grown in complexity as a result.
Understanding the role of seminal fluid exosomes within the male reproductive tract Exosomes are small lipid-membrane bound vesicles containing functional biomolecules, such as proteins, lipids, micro-RNA, and DNA. They are released from most cells in the body and are also present in many bodily fluids. Seminal fluid exosomes have been previously isolated, however, little is known about their source and their role in the male reproductive tract1. Exosomes in other tissues have been shown to mediate immunomodulatory functions and even to direct tumor metastasis2. Seminal fluid exosomes have been postulated to act via a similar mechanism during fertilization and implantation, as well as to possibly participate in directing spermatogenesis3.
Single embryo transfer versus double embryo transfer: a cost-effectiveness analysis in a United States military treatment facility In vitro fertilization (IVF) has historically been associated with multiple gestations due to the number of embryos transferred. Due to increased morbidity seen in multiple gestations, the American Society of Reproductive Medicine recommends transfer of blastocysts one at a time (SET) for most patients. While cost-effectiveness models have compared single embryo transfer (SET) to double embryo transfer (DET), few incorporate maternal and neonatal morbidity, and none have been performed in U.S. Military Treatment Facilities.
A workflow for simultaneous DNA copy number and methylome analysis of ICM and TE cells from human blastocysts Preimplantation genetic testing for aneuploidy (PGT-A) has become an integral part of assisted reproduction and is being used to identify genetically competent embryos. Despite implementation of this technology many euploid embryos fail to implant for reasons that remain largely unknown. Analysis of embryonic cells for other markers of embryo competence may provide insight into the cause of such failures. DNA Methylation is an integral component of epigenetic regulation during gamete and embryonic development.
Pilot utilization of convolutional neural networks to improve the efficiency of fertilization checks Fertilization determination currently involves the manual inspection of inseminated oocytes by embryologists. This determination not only entails time outside the incubation environment but also requires significant experience to be accomplished in a timely manner to avoid compromising zygote viability. We report an efficient use of convolutional neural networks (CNN) to distinguish 2 pronuclei (2PN) from 3PN and germinal vesicle (GV). This pilot demonstrates the potential of an application of artificial intelligence technologies (AI) in the IVF lab.
Assessment of freezing different types of surgically acquired sperm: impact on fertilization, blastocyst formation and pregnancy outcomes Development of techniques to acquire sperm surgically has been a revolutionary advancement for ART, allowing for application to a previously excluded population. Cryopreservation of sperm has also been a beneficial advancement, permitting fertility preservation, but also helping address timing issues associated with various steps in ART processes. Combining surgical sperm retrieval and cryopreservation has been instrumental in expanding treatment options. However, cryopreservation can be a stressful process for the cells, potentially impacting quality.
Epigenetic clock measuring age acceleration via DNA methylation levels in blood is associated with decreased oocyte yield Among women, there is significant variability in the age at menopause, the rate of decline in oocyte number, and the ability to reproduce. Various methods have been developed to assess ovarian response; however, limitations exist in their clinical utility. Among these, anti-müllerian hormone (AMH) and antral follicle count (AFC) have been described as the most predictive (1,2). Models that incorporate both of these measurements can even further enhance predictive value by including chronological age (3).
Uterine toxicity following exposure to polychlorinated biphenyl 126 is mediated by the aryl hydrocarbon receptor Polychlorinated biphenyls (PCBs) are persistent organic pollutants which adversely affect reproduction. They are endocrine and immune disrupting chemicals and have been associated with increased risk of miscarriage. The mechanisms underlying these adverse effects are unclear. PCB 126 is a particularly toxic congener and a strong agonist of the aryl hydrocarbon receptor (AhR). It is unclear whether the activation of the AhR and its downstream effects and/or other mechanisms lead to reproductive tissue damage.
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