Springer Science and Business Media LLC

Adding preimplantation genetic screening to in vitro fertilization has been shown to increase live birth rate in women older than 37. However, preimplantation genetic screening is an expensive procedure. Information on the cost-effectiveness of preimplantation genetic screening can help inform clinical decision making. We constructed a decision analytic model for a hypothetical fresh, autologous in vitro fertilization cycle (with versus without preimplantation genetic screening) for women older than age 37 who had a successful oocyte retrieval and development of at least one blastocyst. The model incorporated probability and cost estimates of relevant clinical events based on data from published literature. Sensitivity analyses were performed to examine the impact of changes in model input parameters. In base-case analysis, IVF-PGS offered a 4.2 percentage point increase in live birth rate for an additional cost of $4509, yielding an incremental cost-effectiveness ratio (ICER) of $105,489 per additional live birth. This ICER was below the expected cost of $145,063 for achieving one live birth with IVF (assuming an average LBR of 13.4% and $19,415 per cycle for this patient population). Sensitivity analysis suggested that ICER improved substantially with decreases in PGS cost and increases in PGS effectiveness. Monte Carlo simulation showed PGS to be cost-effective in 93.9% of iterations at an acceptability cutoff of $145,063. Considering the expected cost of achieving one live birth with IVF, PGS is a cost-effective strategy for women older than 37 undergoing IVF. Additional research on patients’ willingness-to-pay per live birth would further inform our understanding regarding the cost-effectiveness of PGS.

The aim was to assess the correlation of sperm apoptotic transcript levels with cleavage stage embryokinetic and pregnancy outcomes of intracytoplasmic morphologically selected sperm injection (IMSI) and ICSI methods in patients with male factor infertility. Eighty male factor cases were divided into ICSI and IMSI groups. ICSI was done routinely, and for IMSI, sperm was selected at high magnification and injected. On day 3, time-lapse parameters were evaluated, and the best embryos were transferred and followed to delivery. In addition, sperm DNA fragmentation and apoptotic transcript levels were quantified using reverse transcription Q-PCR between the groups. IMSI selected spermatozoa had lower DNA fragmentation and apoptotic transcript levels compared with ICSI (p < 0.0001). Moreover, all cytokinetic variables and cleavage abnormalities were noticeably different between groups (p < 0.0001); the rates of clinical outcomes were higher in the IMSI group. The transcript levels of Caspase 3 showed a moderate negative correlation with s2 and s3 (rs = − 0.57, P = 0.008 and rs = − 0.51, p = 0.021, respectively) in the IMSI group. However, there was no relationship between sperm apoptotic transcript levels and clinical outcomes in two groups. Sperms selected at high magnification showed lower DNA fragmentation and apoptosis genes transcript. Also, better embryo kinetics and clinical outcomes were confirmed in IMSI than ICSI groups. Some time-lapse parameters may be associated with transcript levels of apoptosis genes. Therefore, these noninvasive techniques may be unique in assisting couples with male factor infertility. This trial retrospectively registered on 4 July 2020 (IRCT20180130038561N1).

Endometriosis is recognized as a steroid hormone-dependent disorder. However, controversies exist regarding the status of the steroid hormone receptor expression in endometriotic tissues. The purpose of this study was to determine the ontogeny of cellular changes in the expression of estrogen receptors (ERα, ERβ), G protein-coupled estrogen receptor 1 (GPER1), and progesterone receptors (PRs) in endometriosis using a mouse model. We used the autologous uterine tissue transfer mouse model and studied the mRNA and protein expression of ERα, ERβ, GPER1, and PR in ectopic lesions at 2, 4, and 8 weeks of induction of endometriosis. As compared to endometrium of controls, in the ectopic endometrium, ERα is reduced while ERβ was elevated in stromal cells; however, Gper1 and PR levels are reduced in both stromal and epithelial cells in a time-specific manner. There is a high inter-animal variation in the levels of these receptors in ectopic endometrium as compared to controls; the levels also varied by almost 100-fold within the same lesion resulting in “micro-heterogeneity.” The expression of all these receptors also deferred between two lesions from the same animal. In the endometriotic tissue, there is extensive inter-animal and intra-lesion heterogeneity in the expression of ERα, ERβ, GPER1, and PR. These changes are not due to the influence of the peritoneal environment but appear to be tissue intrinsic. We propose that the variable outcomes in hormonal therapy for endometriosis could be possibly due to heterogeneity in the expression of steroid hormone receptors in the ectopic endometrium.

To determine the pattern of expression of parathyroid hormone-related protein (PTHrP) and its receptor, parathyroid hormone receptor 1 (PTHR1), in mouse embryos in different stages of preimplantation development. Embryos were cultured from the pronuclear zygote stage and harvested as 2-cell, 4-cell and 8-cell embryos, morulae and blastocysts. RT-PCR was carried out on mRNAs of these and of trophoblast outgrowths for detection of PTHrP and PTHR1. Whole mounted embryos intact or stripped of zonae pellucidae were immunofluorescently stained for PTHrP and PTH receptor and observed with confocal microscopy. PTHrP mRNA was present in the pronuclear zygote, not present in 2-cell, 4-cell and uncompacted 8-cell embryos, present in the 8-cell compacting embryo, and not detected in 16-cell morulae or blastocysts. The mRNA was present in trophoblasts growing on fibronectin beds. mRNA for PTHR1 was detected in the pronuclear zygote, then undetected until the compacted 8-cell stage and thereafter. PTH receptor protein was observed in 2-cell embryos, morulae and in the inner cell mass and trophectoderm of blastocysts. PTHrP was observed dispersed in the cytoplasm of 2-cell, 4-cell and uncompacted 8-cell embryos, and in distinct foci near the nuclei of morulae. In blastocysts, PTHrP appeared on the apical surface of only trophoblast cells which had extruded from the zona pellucida. Fully hatched blastocysts expressed the protein on the apical side of all trophoblasts. When morulae were prematurely stripped of their zonae, PTHrP was observed on the embryos’ outer surface. PTHrP protein is expressed throughout early embryo development, and its receptor PTHR1 is expressed from the morula stage. Embryo hatching is associated with translocation of PTHrP to the apical plasma membrane of trophoblasts. PTHrP may thus have autocrine effects on the developing blastocyst.

Intracytoplasmic sperm injection (ICSI) imparts physical stress on the oolemma of the oocyte and remains among the most technically demanding skills to master, with success rates related to experience and expertise. ICSI is also time-consuming and requires workflow management in the laboratory. This study presents a device designed to reduce the pressure on the oocyte during injection and investigates if this improves embryo development in a porcine model. The impact of this device on laboratory workflow was also assessed. Porcine oocytes were matured in vitro and injected with porcine sperm by conventional ICSI (C-ICSI) or with microICSI, an ICSI dish that supports up to 20 oocytes housed individually in microwells created through microfabrication. Data collected included set-up time, time to align the polar body, time to perform the injection, the number of hand adjustments between controllers, and degree of invagination at injection. Developmental parameters measured included cleavage and day 6 blastocyst rates. Blastocysts were differentially stained to assess cell numbers of the inner cell mass and trophectoderm. A pilot study with human donated MII oocytes injected with beads was also performed. A significant increase in porcine blastocyst rate for microICSI compared to C-ICSI was observed, while cleavage rates and blastocyst cell numbers were comparable between treatments. Procedural efficiency of microinjection was significantly improved with microICSI compared to C-ICSI in both species. The microICSI device demonstrated significant developmental and procedural benefits for porcine ICSI. A pilot study suggests human ICSI should benefit equally.

To evaluate the association between the DNA methylation of specific genes and sperm DNA integrity status in human sperm samples. A total of 166 semen samples were evaluated (86 controls and 80 cases with impaired sperm DNA integrity). We detected the methylation status of 257 CpG sites among two imprinted genes (H19 and SNRPN) and four non-imprinted genes related to male infertility (MTHFR, GSTM1, DAZL, and CREM) by using a targeted next-generation sequencing method. Differential methylation was found in 43 CpG sites of the promoters of the six candidate genes. H19, SNRPN, MTHFR, DAZL, GSTM1, and CREM contained 22, 12, 1, 4, 0, and 4 differentially methylated CpG sites (P<0.05), respectively. The imprinting genes were associated with relatively higher rates of differentially methylated CpG sites (28.21% in H19 and 41.38% in SNRPN) than the non-imprinting genes. One CpG site in H19 remained significant after performing strict Bonferroni correction. In this study, we found that different site-specific DNA methylation signatures were correlated with sperm DNA integrity status. Further studies are needed to investigate the specific mechanisms leading to the epigenetic modifications.

To evaluate the risk of prematurity and infant mortality by maternal fertility status, and for in vitro fertilization (IVF) pregnancies, by oocyte source and embryo state combinations. Women in 14 States who had IVF-conceived live births during 2004–13 were linked to their infant’s birth and death certificates; a 10:1 sample of non-IVF births was selected for comparison; those with an indication of infertility treatment on the birth certificate were categorized as subfertile, all others were categorized as fertile. Risks were modeled separately for the fertile/subfertile/IVF (autologous-fresh only) group and for the IVF group by oocyte source-embryo state combinations, using logistic regression, and reported as adjusted odds ratios (AORs) and 95% confidence intervals (CI). The study population included 2,474,195 pregnancies. Placental complications (placenta previa, abruptio placenta, and other excessive bleeding) and prematurity were both increased with pregestational and gestational diabetes and hypertension, among subfertile and IVF groups, and in IVF pregnancies using donor oocytes. Both subfertile and IVF pregnancies were at risk for prematurity and NICU admission; IVF infants were also at risk for small-for-gestation birthweight, and subfertile infants had greater risks for neonatal and infant death. Within the IVF group, pregnancies with donor oocytes and/or thawed embryos were at greater risk of large-for-gestation birthweight, and pregnancies with thawed embryos were at greater risk of neonatal and infant death. Prematurity was associated with placental complications, diabetes and hypertension, subfertility and IVF groups, and in IVF pregnancies, donor oocytes and/or thawed embryos.