Does embryo biopsy, independent of vitrification, impact perinatal outcomes? An analysis of perinatal outcomes following preimplantation genetic testing biopsy in fresh and frozen embryo transfer cycles.

Objective: To compare neonatal outcomes in pregnancies resulting from embryos that have undergone preimplantation genetic testing (PGT) biopsy compared with no biopsy in both fresh and frozen embryo transfers (ETs) and determine whether findings are mediated by multiple births. Design: Retrospective cohort study. Setting: Society of Assisted Reproductive Technologies-Clinical Outcomes Reporting System data, 2014-2015. Patients: Autologous in vitro fertilization treatment cycles using fresh or frozen blastocyst ET, with or without PGT biopsy. Interventions: Not applicable. Main Outcome Measures: Large for gestational age (LGA), small for gestational age, and preterm delivery. Secondary outcomes included high birthweight, low birthweight, and clinical pregnancy measures. Outcomes were evaluated using log-binomial regression models with repeated measures. Models were used to estimate the controlled direct effects of biopsy on birth outcomes that were not mediated by multiple gestations. Results: In fresh ET, biopsy was associated with an increase in LGA (relative risk [RR] 1.45, confidence interval [CI] 1.04-2.02) that persisted in the model mediated for multiple gestation (RR 1.36, 95% CI 1.01-1.83) but was not present in an analysis restricted to elective single ET (RR 0.99, 95% CI 0.91-1.09). In frozen ET, there were no differences in any of the primary outcomes after accounting for multiple gestations. Conclusions: In a large multicenter database, there were no differences in neonatal outcomes after PGT biopsy in frozen ET cycles, and an increase in LGA was noted in fresh transfers that persisted even after accounting for multiple gestations but was not present in analysis restricted to elective single ET.

Blastocyst Vitrification and Trophectoderm Biopsy Cumulatively Alter Embryonic Gene Expression in a Mouse Model.

Although embryo vitrification has been used extensively in human assisted reproductive technology (ART) and animal models, epidemiologic evidence and randomized controlled trials suggest differences in pregnancy/perinatal outcomes (birthweight, risk for preterm birth, and pre-eclampsia) between babies born from fresh versus frozen embryo transfers. To address the uncertainty surrounding the effects of laboratory manipulations of embryos on clinical outcomes, we subjected mouse blastocysts to increasing levels of manipulation for transcriptome analysis. Blastocysts were randomly divided into four groups: no manipulation (control), single vitrification/thaw (1 vit), double vitrification/thaw (2 vit), and single vitrification/thaw plus trophectoderm biopsy and again vitrified/thawed (2 vit + bx). Three sets of 15 blastocysts in each group were pooled for RNA sequencing, and differentially expressed genes (DEGs) and pathways were determined by statistical analysis. Blastocysts were also stained for ZO-1 and F-actin to assess cytoskeletal integrity. Freeze/thaw and biopsy manipulation affected multiple biological pathways. The most significant differences were detected in genes related to innate immunity, apoptosis, and mitochondrial function, with the magnitude of change proportional to the extent to manipulation. Significant disruptions were also seen in cytoskeletal staining, with greater disruptions seen with greater of manipulation. Our data suggests that embryo vitrification and biopsy affect embryo gene transcription, with several identified DEGs that may have plausible mechanisms for the clinical outcomes seen in human offspring following ART. Further study is required to determine whether these alterations in gene expression are associated with clinical differences seen in children born from fresh or frozen embryo transfer.

Differential Effects of Progestogens Used for Menopausal Hormone Therapy.

Recommendations regarding menopausal hormone therapy continue to evolve as more studies are completed. Progestogens, indicated for endometrial protection in women on estrogen therapy who have an intact uterus, seem to confer greater health risks than estrogen alone. Thus, it is important for clinicians to be well informed when prescribing these medications. This review focuses on the different types and use of progestogens in women with an intact uterus using systemic menopausal hormone therapy.

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization.

In vitro fertilization (IVF) and embryo cryopreservation have become increasingly common in recent years. As utilization increases, it is important to understand the clinical effects these technologies have on offspring, as well as the mechanisms behind these effects. Many epidemiologic studies have observed that pregnancies following IVF are more likely to be affected by obstetric complications such as pre-eclampsia, preterm birth, and small for gestational age neonates compared with naturally conceived pregnancies. There has been a great deal of research emerging suggesting that these differences are related to the supraphysiologic hormonal environment that results from ovarian superovulation. While pregnancies resulting from frozen embryo transfer are less likely to experience these complications, babies born after frozen transfer are more likely to be large for gestational age. Epigenetic studies point toward differential methylation of genes critical for growth that may be responsible for the increased incidence of larger neonates following transfer of vitrified embryos. Although it does appear that perinatal outcomes are improved by transferring frozen embryos instead of fresh, it would be premature at this time to recommend universal freeze-all protocols in all patients. This article, as part of the "IVF Reviews" special issue of this journal, aims to expound on the issues outlined above.

Alcohol and fertility: how much is too much?

Alcohol use is prevalent in the United States. Given that a substantial portion of the drinking population is of reproductive age, it is not uncommon for couples who are attempting conception, or for women who are already pregnant, to be regularly consuming alcohol. Alcohol use is associated with multiple reproductive risks, including having a child with a Fetal Alcohol Spectrum Disorder, increased risk of fetal loss, and decreased chance of live birth. This review serves to examine the risks of alcohol in the context of reproductive health.

Contraception and conception in Mid-life: a review of the current literature.

In the United States, there are an increasing number of couples who are intentionally delaying child-bearing. As the average age of mothers continues to rise, more and more women are being faced with the difficulties of attempting conception at the various stages leading up to the menopausal transition. Not only do the chances of conception drastically decrease after the age of 40 years, but the probability of fetal loss (both early and late in pregnancy) significantly increases during this period as well. The aims of this review include providing an overview of the natural progression of the menopausal transition, examining the importance of appropriate contraception, and identifying the difficulties that women face when attempting conception during this physiologically dynamic stage of life. Finally, we will discuss the non-contraceptive benefits of contraception in preparation for pregnancy during the mid-life.

Randomized Controlled Trial of Autologous Endometrial Coculture Versus Traditional in Vitro Fertilization.

OBJECTIVE: To determine if autologous endometrial cell coculture improves embryo development and clinical outcomes. STUDY DESIGN: Patients who met the inclusion criteria were randomized to either traditional in vitro fertilization (IVF) (control, n=73) or autologous endometrial cell coculture (AECC) (n=61). All patients underwent endometrial biopsy on cycle day 5­10 post luteinizing hormone surge. A total of 129 patients underwent embryo transfer (69 control, 60 AECC). Clinical outcomes as well as embryonic quality measures were then compared between the 2 groups. RESULTS: The mean age, day 3 follicle-stimulating hormone, number of oocytes collected, and clinical outcomes were similar between the 2 groups. Embryo development was overall similar, with the exception that embryonic grade was significantly better with AECC than with control: 1.5 (0.04) vs. 2.6 (0.03), p<0.0001. There was no difference in implantation, live birth or multiple gestation rates. CONCLUSION: This is one of the largest prospective randomized controlled trials of AECC versus traditional IVF. There was significant improvement in embryo morphology in the coculture group, although clinical outcomes were similar between the groups. Further studies are necessary to achieve enough power to fully delineate the effects of coculture on IVF outcome.

Uterine fibroids associated with infertility.

In recent years, there has been an increasing focus on the contributory role of uterine fibroids to infertility. The prevalence of these tumors increases with age, which becomes significant as more women are delaying childbearing. Therefore, fibroids and infertility frequently occur together. Treatment varies with fibroid location and size. The various methods of treatment include open myomectomy, laparoscopic or robot-assisted myomectomy, medical treatment, uterine artery embolization and magnetic resonance guided focused ultrasound surgery. While there is a general consensus on the treatment of submucosal fibroids, the management of intramural fibroids in the infertility patient remains controversial. This paper aims to review and summarize the current literature in regards to the approach to uterine fibroids in the infertile patient.

Anterior hippocampal and orbitofrontal cortical structural brain abnormalities in association with cognitive deficits in schizophrenia.

OBJECTIVE: Numerous studies have implicated the hippocampus and prefrontal cortex in schizophrenia. However, precisely which subregions of the hippocampus and prefrontal cortex are abnormal remain unknown. Our study goal was to investigate the structure of the anterior hippocampus, posterior hippocampus, dorsolateral prefrontal cortex (DLPFC), and orbitofrontal cortex (OFC) simultaneously in thirty-eight patients with schizophrenia and twenty-nine controls to determine which of these subregions are abnormal in schizophrenia. As an exploratory study goal, we investigated the relation of neurocognition to brain structure in schizophrenia patients. METHOD: We generated detailed structural magnetic resonance imaging data and compared hippocampal and prefrontal subregional structural brain volumes between schizophrenia and control groups. We obtained a neurocognitive test battery in schizophrenia patients and studied the association of abnormal brain structures to neurocognition. RESULTS: Structural brain abnormalities were pinpointed to the left anterior hippocampus and left OFC in schizophrenia patients, which were both significantly reduced in volume. The DLPFC and posterior hippocampus, though numerically decreased in volume, were not significantly decreased. Anterior hippocampal volumes were more strongly associated with OFC volumes in schizophrenia patients compared to controls. By contrast, DLPFC volume was unrelated to anterior or posterior hippocampal volume. Both the anterior hippocampus and OFC were independently related to cognitive abnormalities common in schizophrenia, including indices of verbal, language, and executive functions. The DLPFC and posterior hippocampal volumes were unrelated to cognitive measures. CONCLUSIONS: These findings highlight related abnormalities of the anterior hippocampus and OFC in schizophrenia, which may shed light on the pathophysiology of the disorder.