Embryo Transfer Strategies for Women with Recurrent Implantation Failure During the Frozen-thawed Embryo Transfer Cycles:Sequential Embryo Transfer or Double-blastocyst Transfer?

Objective Both sequential embryo transfer(SeET)and double-blastocyst transfer(DBT)can serve as embryo transfer strategies for women with recurrent implantation failure(RIF).This study aims to compare the effects of SeET and DBT on pregnancy outcomes.Methods Totally,261 frozen-thawed embryo transfer cycles of 243 RIF women were included in this multicenter retrospective analysis.According to different embryo quality and transfer strategies,they were divided into four groups:group A,good-quality SeET(GQ-SeET,n=38 cycles);group B,poor-quality or mixed-quality SeET(PQ/MQ-SeET,n=31 cycles);group C,good-quality DBT(GQ-DBT,n=121 cycles);and group D,poor-quality or mixed-quality DBT(PQ/MQ-DBT,n=71 cycles).The main outcome,clinical pregnancy rate,was compared,and the generalized estimating equation(GEE)model was used to correct potential confounders that might impact pregnancy outcomes.Results GQ-DBT achieved a significantly higher clinical pregnancy rate(aOR 2.588,95%CI 1.267–5.284,P=0.009)and live birth rate(aOR 3.082,95%CI 1.482–6.412,P=0.003)than PQ/MQ-DBT.Similarly,the clinical pregnancy rate was significantly higher in GQ-SeET than in PQ/MQ-SeET(aOR 4.047,95%CI 1.218–13.450,P=0.023).The pregnancy outcomes of GQ-SeET were not significantly different from those of GQ-DBT,and the same results were found between PQ/MQ-SeET and PQ/MQ-DBT.Conclusion SeET relative to DBT did not seem to improve pregnancy outcomes for RIF patients if the embryo quality was comparable between the two groups.Better clinical pregnancy outcomes could be obtained by transferring good-quality embryos,no matter whether in SeET or DBT.Embryo quality plays a more important role in pregnancy outcomes for RIF patients.

Cause analysis and reoperation effect of failure and recurrence after epiblepharon correction in children

BACKGROUND In children, it is common to see failure and recurrence in the correction ofepiblepharon and to have reoperation due to obvious irritation symptoms andcorneal injury.AIM To explore the causes of failure and recurrence after epiblepharon correction inchildren, to remove accurately redundant epiblepharon and orbicularis oculimuscle in patients via the cilia-everting suture technique combined with lidmargin splitting in some patients due to inverted lashes in the medial part of theeyelid, and to observe the therapeutic effect.METHODS From 2015 to 2019, in the Outpatient Department of Ophthalmology of BeijingTongren Hospital, 22 children (40 eyes) with epiblepharon, aged 5-12 years, weretreated due to correction failure and recurrence. Fourteen patients (28 eyes)underwent the full-thickness everting suture technique, and eight patients (16eyes) underwent incisional surgery. They were treated by reviewing the previoussurgical methods and observing epiblepharon, eyelash direction, and cornealinjury. During reoperation, a subciliary incision was made 1 mm below theinferior lash line. Incisional surgery for the lower eyelid was used to removeaccurately redundant epiblepharon and part of the pretarsal orbicularis muscle.Subcutaneous tissue and the orbicularis muscle of the upper skin-muscle flapwere anchored to the anterior fascia of the tarsal plate by rotational sutures. Lidmargin splitting was used only for patients who had seriously inverted lasheslocated in the medial part of the eyelid. All patients were followed for 6-12 moafter reoperation to observe the lower eyelid position, skin incision, eyelash direction, corneal damage, and recurrence.RESULTS After reoperation, all the patients were corrected. Photophobia, rubbing the eye,winking, and tearing disappeared. There was no lower eyelid entropion,ectropion, or retraction. There was no obvious sunken scar or lower eyelid crease.The eyelashes were far away from the cornea, and when the patients lookeddown, the eyelashes on the lower eyelid did not contact the cornea or conjunctiva.The corneal injuries were repaired. Follow-up observation for 6 mo showed norecurrence of epiblepharon.CONCLUSION The type of suture method, the failure to remove accurately redundant skin andorbicularis muscle, the lack of cilia rotational suture use, and excessive reversegrowth of eyelashes are the main causes of failure and recurrence afterepiblepharon correction in children.

Effect of heparin on recurrent IVF-ET failure patients

Objective:To elucidate the possible role of unfractionated heparin in patients with failed repeated in in vitro fertilization and embryo transfer(IVF-ET)and thrombophilia.Methods:This case control study evaluated the efficacy of the unfractionated heparin in increasing the pregnancy and implantation ratio in women with recurrent IVF-ET failures.Eighty-six women received in vitro fertilization/intracytoplasmic sperm injection(IVF/ICSI)with a record of three or more previous IVF-ET failures.Participants were randomly distributed into two groups.Group A(n=43)received unfractionated heparin 5000 IU twice daily,and group B(n=43)did not take any antithrombotic drugs.Coagulation abnormalities such as factor桋Leiden(FVL)mutation,methylene tetra hydro folate reductase(MTHFR)mutation and prothrombin mutation(F栻)were evaluated.Age,body mass index,basal follicular stimulating hormone,basal estradiol,duration of infertility,and number of IVF-ET failures were compared between two groups.Results:45.0%and 17.4%of women were pregnant with and without MTHFR and prothrombin mutation,respectively,when they received unfractionated heparin treatment.The implantation rate was more in group A(12.5%)than group B(4.3%)and differences in the fertilization rate of the two groups were observed(27.7%vs.35.9%).The clinical pregnancy rate per cycle was remarkably more in group A(30.2%)than group B(14.0%).Conclusions:Heparin is a safe and valuable treatment for patients with repeated IVF-ET failures.The clinical pregnancy and implantation rates are higher in the heparin-treated group in contrast with the control group.

Immediate Effect of Electro-acupuncture on Endometrial Blood Flow in Patients with Recurrent Implantation Failure:A Randomized Controlled Trial

Objective To investigate the immediate effects of electro-acupuncture(EA)on endometrial blood flow among recurrent implantation failure(RIF)patients.Methods Eighty RIF patients,enrolled from March 2022 to December 2022,were randomly allocated into either the EA group(40 cases)or the waiting-list(WL)group(40 cases)by using a random number table.The EA group underwent acupuncture at points of Shenting(GV 24),Baihui(GV 4),Benshen(GB 13),bilateral Zigong(EX-CA 1),Huangshu(KI 16),Sanyinjiao(SP 6)and Xuehai(SP10),and electric acupuncture apparatus was connected to EX-CA 1,KI 16,SP 6,and SP 10 with disperse-dense waves at 4/20 Hz frequencies for 30 min after transvaginal ultrasound,while the WL group received no intervention.The primary outcome measured was the endometrial volume blood flow.The secondary outcomes included the bilateral uterine artery index,endometrial volume,endometrial blood flow type,vascular distribution index(VI^(MV))for endometrial and ovary,clinical pregnancy rate,and embryo implantation rate.Results In the EA group,there was a notable decrease in the bilateral pulsatility index and a significant improvement in the endometrial blood flow type post-EA(P<0.05).Both the endometrial blood flow type and VI^(MV) for the endometrium and right ovary were markedly higher in the EA group compared to the WL group post-treatment(P<0.05).Conversely,no significant disparities were observed in vascular index,flow index,vascular blood flow index,uterine arterial blood flow indices,endometrial volume,clinical pregnancy rate and embryo implantation rate between the two groups after treatment(P>0.05).Besides,no adverse events related to EA were observed.Conclusions EA can promptly ameliorate VI^(MV) for the endometrial and right ovary,and endometrial blood flow type.Future randomized controlled trials are warranted to investigate the long-term effects of EA on blood flow of RIF patients and its implications for pregnancy outcomes.(Trial registration No.ChiCTR2200057377).

Macrophage polarization disorder in the endometrial immune microenvironment may contribute to recurrent implantation failure

Objective:To investigate the role and mechanisms by which macrophages(MΦ)contribute to the immune environment of the endometrium in cases of recurrent implantation failure(RIF).Methods:Endometrial transcriptome data from women with and without RIF(control group)were collected.The CIBERSORT software was used to determine the abundance of immune cells within the endometrial tissue based on expression profiles.Weighted gene co-expression network analysis was used to identify crucial regulatory genes and pathways.Results:Application of CIBERSORT confirmed significant infiltration of macrophages in the RIF group.SOX6,TTC21A,KLHL31,NFIA,TNNT1,TPM1,CPVL,FUS,PEX5,and SLC43A3 were all closely correlated with M2 and M0 macrophages.Metascape and DisNor analyses revealed that these genes contribute to the regulation of macrophage polarization via the Wnt signaling pathway.Conclusion:This study identified dysregulation of macrophage polarization within the immune microenvironment of the endometrium in patients with RIF.A comprehensive analysis was conducted to investigate the potential mechanisms underlying this disorder.Dysregulation of macrophage polarization in the endometrium of patients with RIF is strongly associated with the Wnt signaling pathway.

Integrated bioinformatics analysis to identify key genes and pathways involved in the endometria of patients with recurrent implantation failure undergoing in vitro fertilization and embryo transfer

Objectives: Recurrent implantation failure (RIF) is a challenging clinical problem that occurs in approximately 10% of patients undergoingin vitro fertilization and embryo transfer. Because of the varied criteria for RIF, as well as differences in the time and methods of endometrial biopsy, previous studies have not reached an agreement regarding the key genes and pathways of RIF. In this study, bioinformatic analyses were performed in a homogeneous population with consistent biopsy conditions to explore the molecular mechanisms and identify key RIF-associated genes and pathways in the endometrium.Methods: Seven datasets from the Gene Expression Omnibus database were reviewed in detail, and GSE111974, GSE103465, and GSE26787 were included for further analysis. Common differentially expressed genes (DEGs) were identified using the GEO2R online tool. Gene Ontology and pathway enrichment analyses were performed and a protein–protein interaction (PPI) network was constructed. The RNA and protein expression files of the hub genes were obtained.Results: A total of 402 common DEGs were identified between patients with RIF and controls. The enrichment of these DEGs was mainly associated with tube morphogenesis, vasculature development, and positive regulation of cell migration. Pathway enrichment indicated that pathways involved in cancer, the vascular endothelial growth factor A-vascular endothelial growth factor receptor 2 signaling pathway, and cell cycle pathways were mainly involved. Moreover, a PPI network was constructed, and the three most significant submodules were mainly involved in rRNA processing and the regulation of proteolysis. The following ten DEGs with high degrees of connectivity were identified as hub genes:CDC42,VEGFA,MAP2K1,APP,CYCS,UBE2I,PLEK,LMNA,SMAD2, andATRX.Conclusion: Key genes and pathways identified in this study could improve our understanding of the underlying molecular events in RIF and be used as potential biomarkers and therapeutic targets. Further studies are required to confirm these results and explore the functions of hub genes in the endometrium during the implantation window in patients with RIF.

Sperm DNA fragmentation, recurrent implantation failure and recurrent miscarriage

Evidence is increasing that the integrity of sperm DNA may also be related to implantation failure and recurrent miscarriage （RM）. To investigate this, the sperm DNA fragmentation in partners of 35 women with recurrent implantation failure （RIF） following in vitro fertilization, 16 women diagnosed with RM and seven recent fathers （control） were examined. Sperm were examined pre- and post-density centrifugation by the sperm chromatin dispersion （SCD） test and the terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay. There were no significant differences in the age of either partner or sperm concentration, motility or morphology between three groups. Moreover, there were no obvious differences in sperm DNA fragmentation measured by either test. However, whilst on average sperm DNA fragmentation in all groups was statistically lower in prepared sperm when measured by the SCD test, this was not seen with the results from the TUNEL assay. These results do not support the hypothesis that sperm DNA fragmentation is an important cause of RIF or RM, or that sperm DNA integrity testing has value in such patients. It also highlights significant differences between test methodologies and sperm preparation methods in interpreting the data from sperm DNA fragmentation tests.

Advances in the Treatment of Recurrent Implantation Failure

Recurrent implantation failure(RIF)is a syndrome of complex etiology.Excluding the involvement of embryonic factors,RIF is characterized by women aged≤40 years who fail to achieve clinical pregnancy after at least four high-quality embryos transfer in a minimum of three fresh or frozen cycles.However,current methods in the treatment of RIF are controversial.So far,there are no reports of any criteria or guidelines,and the mechanism of RIF is still not clear.Herein,we summarize the pathogenesis of RIF and highlight recent methods in its treatment,to provide reference for the basic and clinical research on RIF.

A mysterious cause of recurrent acute liver dysfunction for over a decade

Introduction Acute liver failure(ALF)is an uncommon disease in pediatric cases.Etiology includes infections,autoimmune diseases,inborn errors of metabolism,and intoxications.Metabolic disorders account for 25%of resolved cases.However,the etiology remains unknown in half of pediatric ALF[1].The recognition of molecular etiopathogenesis has been facilitated after the common use of next-generation sequencing techniques.Recently,biallelic variants in neuroblastoma-amplified sequence(NBAS),Leucyl-tRNA synthetase 1(LARS1),and RAD50-interacting protein(RINT1)were identified in recurrent ALF(RALF)[2–4].