L. Kroener

The effect of timing of embryonic progression on chromosomal abnormality

OBJECTIVE To evaluate the relationship between aneuploidy and timing of blastocyst formation. DESIGN Historical cohort study. SETTING Private IVF clinic. PATIENT(S) Ninety-four couples undergoing IVF treatment in combination with chromosomal screening of embryos. The mean maternal age was 39.2 years and average number of embryos per patient 5.3. INTERVENTION(S) A total of 530 embryos were biopsied on day 3 and underwent chromosome screening with microarray-based comparative genomic hybridization. MAIN OUTCOME MEASURE(S) Effect of day of embryo blastulation and morphologic grade on aneuploidy rate. RESULT(S) Day 5 morulas that progressed to blastocysts on day 6 were significantly less likely to be aneuploid (79.8%) than day 5 morulas that did not progress to blastocysts (92.9%). However, there was no significant difference in aneuploidy rates when embryos that became blastocysts on day 5 were directly compared with embryos that became blastocysts on day 6. CONCLUSION(S) Delayed blastulation is not associated with increased aneuploidy rates, but absence of blastulation is associated with increased aneuploidy. Therefore, we conclude that when choosing a morula for transfer on day 5, there may be a benefit in waiting an extra day for the possibility of blastulation to occur.

Predisposing Factors to Abnormal First Trimester Placentation and the Impact on Fetal Outcomes

Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal and fetal tissues. The resulting intrauterine environment plays an important role in fetal programming and the future health of the fetus, and is impacted by multiple genetic and epigenetic factors. Abnormalities in placentation and spiral artery invasion can lead to ischemia, placental disease, and adverse obstetrical outcomes including preeclampsia, intrauterine growth restriction, and placental abruption. Although first trimester placentation is affected by multiple factors, preconception environmental influences such as mode of conception, including assisted reproductive technologies which result in fertilization in vitro and intrauterine influences due to sex differences, are emerging as potential significant factors impacting first trimester placentation.

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation.

ABSTRACT Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments.

Background: Assisted reproductive technologies are associated with altered methylation in term placenta. However, it is unclear whether methylation patterns are the result of fertility treatments or intrauterine environment. Thus, we set out to determine whether there are differences in the first-trimester placenta that may be altered by the underlying fertility treatments. Genome-wide DNA methylation analyses from chorionic villus sampling (CVS) from matched singleton pregnancies conceived using in vitro fertilization (IVF), non-IVF fertility treatment (NIFT), or those conceived spontaneously were performed using Illumina Infinium HumanMethylation450 BeadChip from 15 matched CVS samples. Nanofluidic quantitative polymerase chain reaction (qPCR) of differently methylated genes was performed in a confirmatory cohort of 23 IVF conceptions and 24 NIFT conceptions. Results: Global methylation was similar among the IVF, NIFT, and spontaneous conceptions. However, differential methylation from IVF and NIFT pregnancies was present at 34 CpG sites, which was significantly different. Of those, 14 corresponded to known genes, with methylation changes detected at multiple loci in 3 genes, anaphase-promoting complex subunit 2 (ANAPC2), C-X-C motif chemokine ligand 14 (CXCL14), and regulating synaptic membrane exocytosis 1 (RIMS1). Nanofluidic qPCR of differentially methylated genes identified pre T-cell antigen receptor alpha (PTCRA) to be significantly downregulated in IVF versus NIFT conceptions. Conclusion: Although global methylation patterns are similar, there are differences in methylation of specific genes in IVF compared to NIFT conceptions, leading to altered gene expression. PTCRA was differentially methylated and downregulated in IVF conceptions, warranting further investigation. It remains to be determined whether these changes affect placentation and whether it is due to the more profound underlying infertility requiring IVF, yet these data provide unique insight into the first-trimester placental epigenome.

Use of fertility medications and cancer risk: a review and update

Purpose of review There is increasing use of fertility medications for ovulation induction and ovarian stimulation for in-vitro fertilization in the treatment of female infertility. In this review, recent literature regarding the association between fertility medication and cancer risk is reviewed. Recent findings Several important publications have recently addressed the relationship between use of fertility medications and cancer risk. There are methodological limitations to many of these studies, including unique challenges in studying rare cancers that often develop several years after the time of fertility medication exposure. Although infertility per se is a risk factor for some female cancers, including breast, endometrial and ovarian cancer, most studies do not show a significant risk of these cancers with the use of fertility medications. Some studies, however, have shown a possible increased relative risk of borderline ovarian cancer, although the increased absolute risk is small without a clear causal relationship. Summary The collective data regarding the risk of developing cancer from use of fertility medications are reassuring, although several methodological issues in these studies limit definitive conclusions.

Analysis of Reported Adverse Events with Uterine Artery Embolization for Leiomyomas

STUDY OBJECTIVE To analyze and investigate reports associated with uterine artery embolization used for treatment of myomas using this database. DESIGN A retrospective review of the Manufacturer and User Facility Device Experience (MAUDE) database for events related to uterine artery embolization (Canadian Task Force Classification III). SETTING The MAUDE database was accessed online. PATIENTS Patients with myomas undergoing uterine artery embolization. INTERVENTIONS The MAUDE database was accessed online and searched for events related to uterine artery embolization reported between 1998 and 2018. These reports were reviewed and analyzed, reported events were categorized, and other relevant information was collected and tabulated. MEASUREMENTS AND MAIN RESULTS A total of 193 reports published during the study period were identified. Pain was the most frequently reported event (68 events; 35.2%), followed by vaginal discharge (45 events; 23.3%), operational misfire (37 events; 19.2%), and fever or infectious complications (36 events; 18.7%). A surgical procedure was required in 27 events (14.0%), with hysterectomy reported in 7.8% of the events. Death following this procedure was mentioned in 5 events (2.6%). CONCLUSION The MAUDE database may be useful for clinicians using a Food and Drug Administration-approved medical device to identify the occurrence of adverse events and complications. A variety of adverse events associated with the use of uterine artery embolization were reported to the MAUDE database related to its use in the treatment of uterine myomas. We encourage physicians to review the MAUDE database when using medical devices, because this is an important tool to assess uncommon but major problems that could be associated with a medical device.