The GnRH Antagonist Protocol is Associated with a Higher Embryo Aneuploidy Rate Than the GnRH Agonist Long Protocol in Chinese Women

Background: Studies in oocytes have suggested increased aneuploidy rates after ovulation induction in mammals and humans. Conversely, some studies have shown that ovarian stimulation does not significantly increase the embryo aneuploidy rate in humans compared with an unstimulated cycle. In addition, the potential effect of the gonadotropin-releasing hormone (GnRH) antagonist (GnRH-ant) protocol and GnRH agonist (GnRH-a) long protocol on embryo aneuploidy remains unknown.Methods: This is the retrospective cohort study from university-affiliated fertility center. In total, 578 early miscarriage patients who conceived through IVF/intracytoplasmic sperm injection (ICSI) after receiving the gonadotropin-releasing hormone (GnRH) antagonist (GnRH-ant) protocol or the GnRH agonist (GnRH-a) long protocol were analyzed to compare the aneuploidy rates in early aborted tissues. In addition, a total of 466 preimplantation genetic testing for aneuploidy (PGT-A) cycles undergoing GnRH-ant protocol or GnRH-a long protocol were also analyzed to compare the aneuploidy rates in embryo.Results: For early miscarriage patients who conceived through IVF/ICSI, compared to the GnRH-a long protocol group, the GnRH-ant protocol group had a significantly higher rate of aneuploidy in early aborted tissues (48.70% vs. 64.52%), and increased aneuploidy was associated with a significantly higher incidence of trisomy 13, 18, and 21 (p<0.01). Regarding PGT-A cycles, compared to the GnRH-a long protocol group, the rate of embryo aneuploidy was also significantly higher in the GnRH-ant protocol group (48.01% vs. 58%). After stratification and multiple linear regression, the GnRH-ant regimen remained significantly associated with an increased risk of aneuploidy in early aborted tissues and embryos [OR (95% CI) 1.767 (1.174, 2.661), OR (95% CI) 1.465 (1.020, 2.102)]. Furthermore, the embryo aneuploidy rate in the GnRH-ant protocol group was significantly higher than that in the GnRH-a long protocol group but only in young and normal ovarian responders [OR (95% CI) 3.54 (1.48, 8.46)].Conclusions: The GnRH-ant protocol is associated with a higher aneuploidy rate in early aborted tissues and embryos than the GnRH-a long protocol in Chinese women. A multicenter, randomized controlled trial would be the optimal strategy to confirm these results.

Dysregulated Autophagy Leads to Oxidative Stress and Aberrant Expression of ABC Transporters in Women with Early Miscarriage

Early miscarriage (EMC) is a devastating obstetrical complication. ATP-binding cassette (ABC) transporters mediate cholesterol transfer across the placenta and enhance cell survival by effluxing substrates from target cells in the presence of stressors. Recent evidence reports an intricate interplay between autophagy and ABC transporters. We hypothesized that dysregulated autophagy and oxidative stress (OS) in the placenta leads to abnormal expression of membrane transporters contributing to poor pregnancy survival in EMC. We determined mRNA and protein expression of autophagy genes (Beclin-1/Bcl-2/LC3I/LC3II/p62) and ABC transporters (ABCA1/ABCG1/ABCG2) in placentae from EMC patients (n = 20), term controls (n = 19), first trimester (n = 6), and term controls (n = 5) controls. Oxidative/antioxidant status and biomarkers of oxidative damage were evaluated in maternal serum and placentae from EMC and healthy controls. In EMC, placental expression of LC3II/LC3I as well as of the key autophagy regulatory proteins Beclin-1 and Bcl-2 were reduced, whereas p62 was increased. Both in the serum and placentae of EMC patients, total OS was elevated reflected by increased oxidative damage markers (8-OHdG/malondialdehyde/carbonyl formation) accompanied by diminished levels of total antioxidant status, catalase, and total glutathione. Furthermore, we found reduced ABCG1 and increased ABCG2 expression. These findings suggest that a decreased autophagy status triggers Bcl-2-dependent OS leading to macromolecule damage in EMC placentae. The decreased expression of ABCG1 contributes to reduced cholesterol export to the growing fetus. Increasing ABCG2 expression could represent a protective feedback mechanism under inhibited autophagy conditions. In conclusion, dysregulated autophagy combined with increased oxidative toxicity and aberrant expression of placental ABC transporters affects materno-fetal health in EMC.

Hormone replacement therapy may increase the risk of early miscarriage during frozen embryo transfer cycles in patients with a history of cesarean section: a retrospective cohort study

Objective: To investigate the efficacies of three cycle regimens in women receiving FET with a history of CS: natural cycle (NC) treatment, hormone replacement therapy (HRT) and treatment with gonadotropin-releasing hormone agonist (GnRH-a) + HRT). Design: Retrospective cohort study. Setting: University-affiliated center. Population: Patients (N = 6,159) with a history of CS who fulfilled the inclusion criteria were enrolled in the study from January 2014 to December 2019. Methods: Reproductive outcomes of patients in the NC (n = 4,306) versus HRT (n = 1,007) versus GnRH-a + HRT groups (n = 846) were compared. Main Outcome Measure: The main outcome measure was the live birth rate per embryo transfer (ET). Results: The unadjusted odds of the miscarriage rate of singleton pregnancies were also significantly higher in the HRT-group compared with the NC-group (25.5% versus 20.4%, respectively). After adjusting for possible confounding factors, the early miscarriage rate and the miscarriage rate of singleton pregnancies remained significantly higher in the HRT-group than the NC-group. The clinical pregnancy rates in the NC-, HRT- and GnRH-a + HRT-groups of women with a history of CS was 48.8%, 48% and 47.1%, respectively, and the live birth rates were 37%, 34.1% and 35.7%, respectively. Conclusion(s): In women undergoing FET with a history of CS, HRT for endometrial preparation was associated with a higher early miscarriage rate, albeit after statistical adjustment for confounding factors. Funding: The National Science Foundation of China (81501328). Key Words: Caesarean section, endometrial preparation, frozen embryo transfer, miscarriage