Probability of Pregnancy With Mono vs Multiple Folliculogenesis in Women With Unexplained Infertility.

Context: Ovarian stimulation (OS) increases pregnancy rates but can cause multiple folliculogenesis and multiple pregnancy. Objective: To determine whether the probability of pregnancy differs in OS cycles with mono- vs multifolliculogenesis in women with unexplained infertility (UI). Design: Secondary analysis of a multicenter, randomized controlled trial: Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation with 3 treatment arms: gonadotropins, clomiphene, or letrozole, combined with intrauterine insemination. Women were categorized as having either 1 or ≥ 2 mature follicles (≥ 16 mm). Relative risk (RR) and 95% CIs for clinical pregnancy and live birth by number of follicles were estimated using generalized linear models adjusted for age, body mass index, years of infertility, and history of prior live birth. Setting: 12 US-based clinical sites. Participants: Normally cycling women aged 18 to 40 years with a normal uterine cavity and at least 1 patent fallopian tube. Male partners with ≥ 5 million total motile sperm. Interventions: Gonadotropins, clomiphene, or letrozole with insemination. Main Outcome Measures: Clinical pregnancy rates (CPR) and live birth rates (LBR). Results: A single mature follicle > 16 mm resulted in lower CPR (RR, 0.70; 95% CI, 0.54-0.90) and LBR (RR, 0.67; 95% CI, 0.51-0.89) compared with ≥ 2 mature follicles. When stratified by treatment modality, no association of follicle number with CPR or LBR was observed for letrozole or clomiphene, but women using gonadotropins had lower CPR and LBR with monofolliculogenesis. Conclusion: In couples undergoing gonadotropin treatment for UI, monofolliculogenesis following OS is related to a lower rate of live birth.

A review of the pathophysiology of recurrent implantation failure.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

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.

Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.

OBJECTIVE: To study the true prevalence of recurrent implantation failure. DESIGN: Retrospective cohort study. SETTING: A private assisted reproductive technology center. PATIENT(S): Women (n = 4,429) with anatomically normal uterus who underwent up to three consecutive frozen euploid single embryo transfers (FE-SETs) were included in the study. Cycles with donor eggs or gestational carriers were excluded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences of outcomes between first, second, and third FE-SET and a Kaplan-Meier curve as used to analyze cumulative implantation rate. RESULT(S): The mean age of the patients included in the study was of 35.4 years. The sustained implantation rates of the first, second, and third FE-SET were 69.9%, 59.8%, and 60.3% per transfer, respectively. The cumulative sustained implantation rate after up to three consecutive FE-SET was 95.2%. The live birth rates after the first, second, and third FE-SET were 64.8%, 54.4%, and 54.1% per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6%. The miscarriage rate after observing a positive heartbeat was not different between the first (7.2%), second (8.8%), and third (12.7%) FE-SET. CONCLUSION(S): Our findings suggest that true recurrent implantation failure is rare. For those patients with the ability to make euploid blastocysts, <5% would fail to achieve a clinical pregnancy with three embryos transferred. It remains to be further investigated whether this threshold identifies a truly recalcitrant group or simply a statistical certainty based on random variation.

Male Infertility and the Future of In Vitro Fertilization.

The male contribution to infertility has traditionally been overlooked, or at best oversimplified. In recent years efforts have been made to optimize diagnostic and therapeutic techniques to maximize fertility outcomes. A renewed focus on the male partner has resulted in an increased understanding of both genetic and epigenetic changes within the male germline. Furthermore, single-nucleotide polymorphisms, copy-number variants, DNA damage, sperm cryopreservation, obesity, and paternal age have recently been recognized as important factors that play a role in male fertility. Developing a deeper knowledge of these issues could potentially lead to improved success with assisted reproductive technology.

Embryo's Natural Motion (enMotion): a paired randomized controlled trial evaluating a dynamic embryo culture system.

OBJECTIVE: To determine if a dynamic embryo culture system affects the reproductive potential of human embryos resulting from in vitro fertilization (IVF). DESIGN: Paired randomized controlled trial (RCT). SETTING: IVF center. PATIENT(S): IVF patients with normal ovarian reserve eligible for two-embryo transfer. INTERVENTION: IVF care was routine until fertilization was confirmed. Two-pronuclear embryos (2PNs) were then randomized: One-half of each patient's 2PNs were cultured in dynamic culture and one-half in static culture. Preimplantation genetic testing for embryonic aneuploidy was used to control for aneuploidy and allow for DNA fingerprinting. The best euploid blastocyst from each culture system was selected and patients underwent a frozen two-embryo transfer. If a singleton gestation resulted, DNA-fingerprinting was used to determine which of the two blastocysts implanted. The dynamic platform used was the NSSB-300 (Nepagene). MAIN OUTCOME MEASURE(S): The primary outcome was the proportion of usable blastocysts obtained. The secondary outcome was sustained implantation rate (SIR). RESULT(S): One hundred participants completed oocyte retrieval and blastocyst vitrification for frozen-thawed embryo transfer; 609 dynamic 2PNs and 615 static 2PNs were followed; and 304 blastocysts developed in dynamic culture and 333 blastocysts developed in static culture. In the paired analysis, the rate of usable blastulation was similar between dynamic and static culture (58.3% vs. 57.1%). In addition, there was no difference in the rate of aneuploidy (20.0% vs. 33.3%) or SIR (67.1% vs. 63.1%) between groups. CONCLUSION(S): In this paired RCT, dynamic culture did not improve usable blastulation rate or SIR. CLINICAL TRIAL REGISTRATION NUMBER: NCT02467725.

Sperm Mitochondrial DNA Copy Number Is Not a Predictor of Intracytoplasmic Sperm Injection (ICSI) Cycle Outcomes.

This study is to determine if sperm mitochondrial DNA copy number (mtDNA CN) is associated with fertilization, blastulation, blastocyst euploidy, and live birth rates in in vitro fertilization (IVF) with ICSI cycles. This is a cohort study conducted on stored sperm samples which were collected prospectively and used to create blastocysts transferred in a couple's first ICSI transfer cycle between 2007 and 2013 at a single large infertility center. Samples from ICSI cycles utilizing surgical or cryopreserved sperm or day 3 embryo biopsy were excluded. The primary outcome was live birth rate. Secondary outcomes included fertilization, usable blastocyst development, and blastocyst euploidy rates. Unique sperm samples used to create transferred embryos were identified. Mitochondrial DNA CN was evaluated using TaqMan® quantitative real-time polymerase chain reaction (qPCR) assays normalized to a nuclear control for relative quantitation. Linear regression and mixed effects logistic regression used were appropriate. A total of 2062 unique sperm samples used to create transferred embryos were included. Lower relative sperm mtDNA content was associated with increased pre-wash sperm motility (p < 0.001). No significant association was identified between sperm mtDNA CN and fertilization (p = 0.40), usable blastocyst development (p = 0.36), blastocyst euploid (p = 0.10), and live birth rates (p = 0.42) while adjusting for sperm pre-wash motility and maternal age. Sperm mtDNA CN is not prognostic of fertilization, usable blastocyst development, euploidy and live birth rates in an infertile population undergoing IVF with ICSI.

Impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer with ejaculated sperm: retrospective cohort study.

OBJECTIVE: To evaluate the impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENTS: Couples undergoing a first in vitro fertilization cycle with fresh ejaculated sperm who used intracytoplasmic sperm injection for fertilization followed by preimplantation genetic testing for aneuploidy and single-embryo transfer of a euploid embryo between January 2012 and December 2018. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Embryology outcomes assessed were fertilization rate, blastulation rate, and euploid rate. Pregnancy outcomes assessed included positive human chorionic gonadotropin rate, delivery rate, biochemical loss rate, and clinical loss rate. RESULTS: A total of 4,058 patients were assessed. After adjusting for female age, increased paternal age in the setting of fresh ejaculated sperm use was associated with decreased blastulation and decreased euploid rate using 40 years as an age cutoff. CONCLUSIONS: In this study, advancing paternal age appears to have a detrimental impact on rates of blastocyst formation and euploid status. However, if a euploid embryo is achieved, older paternal age does not appear to affect negatively pregnancy outcomes.

Consistency in rates of diagnosis of embryonic mosaicism, segmental abnormalities, and "no call" results among experienced embryologists performing preimplantation genetic testing for aneuploidy.

OBJECTIVE: To determine whether differences exist in rates of subchromosomal abnormalities, mosaicism, and "no call" results among embryologists performing and loading trophectoderm biopsies for preimplantation genetic testing for aneuploidy (PGT-A). DESIGN: Retrospective cohort. SETTING: Large infertility center. PATIENTS: All patients undergoing in vitro fertilization with PGT-A. INTERVENTIONS: The NexCCS next generation sequencing platform was used for PGT-A. The χ2 testing assessed differences in rates of primary outcomes between embryologists. Intraclass correlation coefficients evaluated inter-embryologist reliability in rates of abnormal and no call results. Median absolute performance difference (MAPD) scores, which quantify the impact of technical variation on analytical performance, were averaged for individual embryologists. Analysis of variance assessed differences in mean MAPD scores. MAIN OUTCOME MEASURES: Interoperator variability in rates of mosaic, segmental, and no call results. RESULTS: Four embryologists performed 30,899 biopsies and 6 embryologists loaded specimens into designated tubes. Among individuals performing trophectoderm sampling, rates of mosaicism were 4.3% to 6.1%, segmental errors were 9.0% to 10.7%, and inconclusive results were 1.1% to 2.9%. For those loading, the incidence of mosaicism was 4.2% to 5.9%, subchromosomal abnormalities was 9.7% to 10.4%, and no call results was 1.2% to 2.2%. The intraclass correlation coefficient was 0.978 for embryologists performing biopsies and 0.981 for those loading. Differences in mean MAPD scores were within 0.6% and 0.2% of each other for doing biopsies and loading embryologists, respectively. CONCLUSIONS: Rates of mosaicism, segmental, and no call PGT-A results are consistent among experienced embryologists. Due to the large sample size included, differences within 1% of the mean were deemed clinically irrelevant despite statistical significance.

Cumulus cells have longer telomeres than leukocytes in reproductive-age women.

OBJECTIVE: To investigate whether telomere length (TL) in granulosa cells (GC) or cumulus cells (CC) correlates with TL in leukocytes (L). DESIGN: Prospective noninterventional study. SETTING: Private assisted reproductive technology center. PATIENT(S): Thirty-five egg donors were included in the study. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Average relative leukocyte telomere length (LTL), cumulus cell telomere length (CCTL), and granulosa cell telomere length (GCTL) measurements from each study subject. RESULT(S): Participants had a mean age of 25.43 ± 4.57 years, antimüllerian hormone level of 1.90 ± 0.92 ng/mL, antral follicle count of 23.29 ± 5.11, and the mean number of mature oocytes retrieved was 23.29 ± 9.13. No significant association between these variables and GCTL, CCTL, or LTL was found. In addition, no correlation was observed between TL measurements of L vs. CC, L vs. GC, or CC vs. GC. Interestingly, CCTL was significantly higher than LTL (1.54-fold), although no significant differences were found between GCTL vs. CCTL or GCTL vs. LTL. CONCLUSION(S): CC from mature follicles have significantly longer telomeres than L, suggesting that the follicular environment could possess different mechanisms to cope against telomere shortening compared with other somatic tissues. Furthermore, these data do not support the utility of telomere DNA measurement in L as an estimate of TL in follicular cells.