Assisted Reproductive Technology Failure Research Articles

Sperm DNA fragmentation and infertility: a narrative review.

The purpose of this narrative review is to provide a practical understanding of sperm DNA fragmentation (SDF) in the management of male infertility. A search for systematic reviews and meta-analyses (SRMA) on SDF between April 1st, 2018 and April 1st, 2023 was performed using PubMed and articles were selected as per their relevance to the topic. Guidelines from major societies were also reviewed. Three clinical cases are reported and discussed. The search initially identified 80 articles. We selected 13 SRMAs based on their relevance to the topic. Of the 13 SRMAs, 7 evaluated the effect of SDF on assisted reproductive technology (ART) outcomes and recurrent pregnancy loss, 3 studied the effect of varicocele repair on SDF, and 3 evaluated the role of SDF involving lifestyle and environmental health factors including body mass index and male factor treatment strategies. Evidence suggests that increased SDF has a negative impact on natural pregnancy and ART outcomes. SDF testing may be particularly important in the infertility evaluation of men with varicoceles, idiopathic or unexplained infertility, recurrent pregnancy loss, or previous ART failure. Further studies are needed on SDF testing and the implications it can have on male factor infertility and pregnancy outcomes as well as its implementation in the setting of ART.

The relevance of prothrombotic genetic variants in women who experienced pregnancy loss or embryo implantation failure: A retrospective analysis of 1922 cases.

The aim of our study was that to assess the allelic and genotype frequencies of nine prothrombotic gene variants in patients with a history of pregnancy loss and recurrent pregnancy loss (RPL). Women who underwent assisted reproductive technology (ART) with ongoing pregnancy and those with recurrent implantation failure (RIF) were also included. Nine prothrombotic gene variants were evaluated: factor V Leiden (FVL), factor V, H1299R variant (FVR2), factor II (FII) G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, beta-fibrinogen -455G>A, factor XIII (FXIII) V34L, human platelet antigen-1 (HPA-1) L33P variants, and plasminogen activator inhibitor-1 (PAI-1) 4G/5G. The following study groups were assessed: (1) women who experienced one (n = 334) or two (n = 264) episodes of pregnancy loss; (2) 468 women who experienced RPL; (3) 214 women who underwent ART followed by ongoing pregnancies; and (4) 282 women who experienced RIF after ART, that is, three or more consecutive implantation failures following high-quality embryo transfers to the uterus with an appropriate endometrium. As control group, 430 subjects from the general population were enrolled. FVL, the -455G>A variant of beta-fibrinogen, and PAI-1 4G were associated with a higher risk of developing RPL compared with the general population. Furthermore, FVL, FVR2, FII G20210A and MTHFR C677T conferred a significantly higher risk of RIF in women who performed ART compared with the general population. No statistical differences between the general population and other study groups were observed. Specific prothrombotic genetic variants are more frequently expressed in women with RPL and RIF, supporting their role in the development of polimicrothrombosis and impairing the invasion during embryo implantation.

Large-scale analysis of de novo mutations identifies risk genes for female infertility characterized by oocyte and early embryo defects

BackgroundOocyte maturation arrest and early embryonic arrest are important reproductive phenotypes resulting in female infertility and cause the recurrent failure of assisted reproductive technology (ART). However, the genetic etiologies of these female infertility-related phenotypes are poorly understood. Previous studies have mainly focused on inherited mutations based on large pedigrees or consanguineous patients. However, the role of de novo mutations (DNMs) in these phenotypes remains to be elucidated.ResultsTo decipher the role of DNMs in ART failure and female infertility with oocyte and embryo defects, we explore the landscape of DNMs in 473 infertile parent–child trios and identify a set of 481 confident DNMs distributed in 474 genes. Gene ontology analysis reveals that the identified genes with DNMs are enriched in signaling pathways associated with female reproductive processes such as meiosis, embryonic development, and reproductive structure development. We perform functional assays on the effects of DNMs in a representative gene Tubulin Alpha 4a (TUBA4A), which shows the most significant enrichment of DNMs in the infertile parent–child trios. DNMs in TUBA4A disrupt the normal assembly of the microtubule network in HeLa cells, and microinjection of DNM TUBA4A cRNAs causes abnormalities in mouse oocyte maturation or embryo development, suggesting the pathogenic role of these DNMs in TUBA4A.ConclusionsOur findings suggest novel genetic insights that DNMs contribute to female infertility with oocyte and embryo defects. This study also provides potential genetic markers and facilitates the genetic diagnosis of recurrent ART failure and female infertility.

Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial

BackgroundGranulocyte colony-stimulating factor (G-CSF) administration increased ovarian preantral follicles and anti-Müllerian hormone (AMH) in animal models with diminished ovarian reserve. We investigated whether G-CSF priming before treatment with assisted reproductive technology (ART) improved embryo development and pregnancy rate while increasing serum AMH in patients with poor ovarian reserve.MethodsIn this prospective randomized open-label controlled trial, 100 patients 20 to 42 years old with AMH below 2 ng/mL were randomized to priming or control groups (50 patients each). None had over 1 ART failure, day-3 follicle-stimulating hormone (FSH) above 30 IU/L, uterine anomalies, or a partner with azoospermia. All patients initially underwent conventional infertility treatment for 2 consecutive cycles in which the priming group but not controls received a subcutaneous G-CSF priming injection during the early luteal phase. Each group then underwent 1 cycle of in vitro fertilization/intracytoplasmic sperm injection and fresh embryo transfer (IVF/ICSI-fresh ET), followed by cryopreserved ET if needed until live birth or embryo depletion. AMH was measured before and after priming.ResultsFertilization rate, embryonic development, and implantation rate by fresh ET were significantly improved by priming. Clinical and ongoing pregnancy rates by IVF/ICSI-fresh ET were significantly higher with priming (30% and 26% in 47 ART patients; 3 delivered with conventional treatment) than in controls (12% and 10% in 49 ART patients; 1 dropped out). With priming, significantly more patients achieved cryopreservation of redundant blastocysts. The cumulative live birth rate was 32% in 50 patients with priming, significantly higher than 14% in 49 controls (relative risk, 2.8; 95% confidence interval, 1.04–7.7). Infants derived from priming had no congenital anomalies, while infant weights, birth weeks, and Apgar scores were similar between groups. Among 4 variables (age, day-3 FSH, AMH, and priming), logistic regression significantly associated age and priming with cumulative live birth. Priming significantly increased serum AMH. No adverse effects of priming were observed.ConclusionG-CSF priming improved embryonic development and pregnancy rate during ART treatment and increased AMH in patients with poor ovarian reserve. Enhanced preantral follicle growth likely was responsible.Trial registrationUMIN registration in Japan (UMIN000013956) on May 14, 2014. https://www.umin.ac.jp/ctr/index.htm.

Efficacy of Platelet-Rich Plasma in Women with a History of Embryo Transfer Failure: A Systematic Review and Meta-Analysis with Trial Sequential Analysis

Assisted reproductive technology (ART) is used to enhance pregnancy in infertile women. In this technique, the eggs are removed from the ovary and fertilized and injected with sperm to make embryos. Unfortunately, embryo implantation failures still occur in many of these women. Platelet-rich plasma (PRP) therapies use a patient's own platelets to promote tissue healing and growth, including endometrium. The growth factors provided by the platelets play a criterial role on the regenerative ability of PRP. In the last years, PRP treatments have been gaining a lot of popularity to treat women with repeated ART failures. In this study, we collected and summarized all information published in the scientific literature to assess the evidence of the PRP effect on pregnancy. We only considered randomized controlled trials (RCT), a type of study designed to be unbiased and considered at the highest level of evidence. Our analysis indicates that PRP therapies might be an effective treatment in cases of poor responsiveness to conventional ART. However, additional studies (well-designed) are necessary to confirm this beneficial effect of PRP.

P-185 The migration speed of nucleolar precursor bodies in pronuclei affects in vitro fertilization-derived human embryo ploidy status

Abstract Study question Does the migration speed of nucleolar precursor bodies (NPBs) in male and female pronuclei (mPN and fPN) affect in vitro fertilization (IVF)-derived embryo ploidy status? Summary answer The NPB migration speed in mPN impacts the IVF-derived human embryo ploidy status and this indicator could be an attractive marker for noninvasive embryo selection. What is known already NPBs are not considered as simple nucleolar components transmitted from an oocyte to an embryo, and they could participate in genome remodeling during embryo development. NPBs are essential only shortly after fertilization, suggesting that they may actively participate in centromeric chromatin establishment. A previous study demonstrated that NPBs migrated faster in intracytoplasmic sperm injection-derived zygotes having the potential to develop into a blastocyst and eventually into a baby (Inoue et al., 2021). However, the relationship between NPB migration speed and IVF-derived embryo ploidy status is unclear. Study design, size, duration The relationship between the NPB migration speed and embryo ploidy status was retrospectively analyzed in patients with recurrent assisted reproductive technology failure (euploid n =18; aneuploid n =19; and total = 219 NPBs). Archived time-lapse videos (images were recorded every 5 min; Geri+) from incubation after IVF were retrieved after the patients were identified for the study, and the NPB migration speed was analyzed. The retrospective analyses were performed with the patient’s identities masked. Participants/materials, setting, methods mPN and fPN were identified by appearance location in a zygote (fPN appearance is just below the polar bodies). The mPN, fPN, and 2–3 NPBs/PN central coordinates were measured by Kinovea (motion capture software). Their central coordinates were confirmed/revised every image and were decided. The migration distance of NPBs between two sequential images was calculated as the standard of the central PN coordinates. Thereafter, the migration speed of NPBs was calculated. Main results and the role of chance Both NPB speeds were significantly faster in the euploid than in the aneuploid groups (mPN: 4.08±0.61 vs. 3.54±0.54 µm/h, P =0.003, power [1-β]: 0.999, fPN: 4.03±0.89 vs. 3.26±0.45 µm/h, P <0.003, 1-β: 0.987). The NPB speed in mPN was correlated with that in fPN (rs =0.523, P =0.001). The ploidy status was related to the NPB speeds in mPN and fPN (P <0.05) in univariate logistic analysis including male/female ages, ICM/TE grades, and 29 morphokinetic parameters. The factors associated with ploidy status were the NPB speed in mPN (odds ratio [OR], 10.2; 95% confidence interval [CI], 1.90–54.90; P =0.007) and female age (OR, 0.8; 95%CI, 0.64–0.98; P =0.03) in multivariate logistic analysis. The cutoff value for the NPB speeds in mPN and fPN were 3.65 μm/h (specificity, 73.7%; sensitivity, 77.8%; AUC, 0.78; 95%CI, 0.62–0.93) and 3.77 μm/h (specificity, 89.5%; sensitivity, 66.7%; AUC, 0.78; 95%CI, 0.62–0.94). When the zygotes were categorized by their cutoff values, the euploid rate in zygotes with NPB speeds greater than the cutoff value was significantly higher than that in zygotes with the speeds less than the cutoff value (mPN = 73.7% vs. 22.2% [P =0.003]; fPN = 85.7% vs. 26.1% [P <0.001]). Limitations, reasons for caution The NPB migration in the z-axis direction could not be analyzed. NPB tracking could not be performed when NPBs were large in number or drastically moved. Our findings should help in elucidating the relationship, although they did not completely explain the relationship between NPB migration and embryo development. Wider implications of the findings The migration speed of NPBs impacts human embryo ploidy status. NPB migration speed may add clinical value for embryo selection, which may be associated with live birth, and consequently, the time of the live birth could be shorter. The indicator could be an attractive marker for noninvasive embryo selection. Trial registration number Not applicable

Trapa bispinosa Roxb. extract lowers advanced glycation end-products and increases live births in older patients with assisted reproductive technology: a randomized controlled trial

BackgroundAdvanced glycation end-products (AGE), which accumulate with insulin resistance and aging, impair folliculogenesis and may decrease endometrial receptivity. Hishi (Trapa bispinosa Roxb.) extract, a safe herbal medicine, strongly inhibits AGE formation in vitro. We determined whether Hishi lowers AGE and increases live births in older assisted reproductive technology (ART) patients.MethodsThis prospective randomized open-label controlled trial included 64 patients 38 to 42 years old undergoing ART with or without Hishi extract between June 11, 2015 and July 12, 2019. None had over 2 ART failures, diabetes, uterine anomalies, or exhausted ovarian reserve. After allocation, the Hishi group received Hishi extract (100 mg/day) until late pregnancy or failure. The control group received no extract. Both groups underwent 1 cycle of conventional infertility treatment; 1 long-protocol cycle of ovarian stimulation, oocyte retrieval, in vitro fertilization/intracytoplasmic sperm injection, and fresh embryo transfer (ET); and, if needed, cryopreserved ET until live birth or embryo depletion. Serum AGE were measured before and during ART, as were AGE in follicular fluid (FF).ResultsCumulative live birth rate among 32 Hishi patients was 47%, significantly higher than 16% among 31 controls (p<0.01; RR, 4.6; 95% CI, 1.4 – 15.0; 1 control dropped out). Live birth rate per ET, including fresh and cryopreserved, was significantly higher with Hishi (28% in 47 ET vs. 10% in 49 ET; p<0.05; RR, 3.4; 95% CI, 1.1-10.4). Among variables including age, day-3 FSH, anti-Müllerian hormone, and Hishi, logistic regression identified only Hishi as significantly associated with increased cumulative live birth (p<0.05; OR, 5.1; 95% CI, 1.4 - 18.3). Hishi significantly enhanced oocyte developmental potential, improved endometrial receptivity in natural cycles, and decreased AGE in serum and FF. Larger serum AGE decreases with Hishi were associated with more oocytes becoming day-2 embryos.ConclusionsHishi decreased AGE in serum and FF and improved oocyte developmental potential and endometrial receptivity, increasing live births in older patients. Treatment of infertility by AGE reduction represents a new addition to infertility treatment. Therapeutic trials of Hishi for other AGE-associated diseases might be considered.Trial registrationUMIN registration in Japan (UMIN000017758) on June 1, 2015. https://www.umin.ac.jp/ctr/index.htm

MP31-06 MICRODISSECTION TESTICULAR SPERM EXTRACTION IS AN EFFECTIVE CHOICE TO OPTIMIZE FERTILITY OUTCOMES IN SEVERE OLIGOZOOSPERMIC PATIENTS WHO HAD PRIOR ONE OR MORE ASSISTED REPRODUCTIVE TECHNOLOGY FAILURE

You have accessJournal of UrologyInfertility: Therapy (MP31)1 Sep 2021MP31-06 MICRODISSECTION TESTICULAR SPERM EXTRACTION IS AN EFFECTIVE CHOICE TO OPTIMIZE FERTILITY OUTCOMES IN SEVERE OLIGOZOOSPERMIC PATIENTS WHO HAD PRIOR ONE OR MORE ASSISTED REPRODUCTIVE TECHNOLOGY FAILURE Cheng-Han Tsai, Wei-Jen Chen, I-Shen Huang, Yi-Hsiu Huang, and William J. Huang Cheng-Han TsaiCheng-Han Tsai More articles by this author , Wei-Jen ChenWei-Jen Chen More articles by this author , I-Shen HuangI-Shen Huang More articles by this author , Yi-Hsiu HuangYi-Hsiu Huang More articles by this author , and William J. HuangWilliam J. Huang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002035.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aim of this study is to assess the fertility outcomes of intracytoplasmic sperm injection (ICSI) using testicular sperm retrieved by either conventional or microdissection testicular sperm extraction (cTESE or mTESE) in oligozoospermic men who failed to conceive their wives in prior assisted reproductive technology (ART) attempts using ejaculated sperm. METHODS: We retrospectively reviewed the charts of 32 oligozoospermic men who had failed one or more in vitro fertilization (IVF) or ICSI cycles using ejaculated sperm. They were categorized into 3 subgroups according to the sperm concentration: 5-20, 1-5 and <1 million/mL respectively. cTESE was done for all 3 groups. Nine patients in group <1 million/mL failed in the cTESE cycle and proceeded to mTESE. The sperm isolated were all used for ICSI. RESULTS: For these 32 patients, mean age was 38.9±5.4 years. Sperm retrieval rate was 100% in both groups. The female partners showed no difference in all groups. The overall fertilization rate per ICSI cycle was 64.8% and pregnancy rate was 46.9%. For patients underwent cTESE, the pregnancy rates were 75%, 18.2% and 15.4% for the group 5-20, 1-5 and <1 million/mL respectively. In 9 patients of <1 million/mL group, sperm retrieval was done by mTESE and the pregnancy rate was 55.6% (p=0.047, compared to cTESE in the <1 million/mL group). There was no complication occurred after testicular sperm extraction. CONCLUSIONS: Testicular sperm retrieval for ICSI is safe and results in much better pregnancy rates in oligozoospermic men who had prior one or more ART failure using ejaculated sperm. Furthermore, mTESE may be considered an effective choice to optimize ICSI outcomes in severe oligozoospermic patients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e557-e557 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cheng-Han Tsai More articles by this author Wei-Jen Chen More articles by this author I-Shen Huang More articles by this author Yi-Hsiu Huang More articles by this author William J. Huang More articles by this author Expand All Advertisement Loading ...

Two novel mutations in PADI6 and TLE6 genes cause female infertility due to arrest in embryonic development

PurposeThis study aims to identify genetic causes of female infertility associated with recurrent failure of assisted reproductive technology (ART) characterized by embryonic developmental arrest.MethodsWe recruited infertile patients from two consanguineous families from the Reproductive Medicine Center of Guizhou Provincial People’s Hospital. Peripheral blood was collected for genomic DNA extraction. Two affected individuals and their family members were performed with whole-exome sequencing and Sanger validation in order to identify possible causative genes. For further analyzing the effect of splicing mutation on mRNA integrity in vivo, TLE6 cDNA from the peripheral blood lymphocyte of the affected individual was sequenced. In addition, the possible impact of the pathogenic mutation on the structure and function of the protein were also assessed.ResultsTwo novel homozygous mutations in the peptidylarginine deiminase type VI (PADI6) and the transducin-like enhancer of split 6 (TLE6) genes were identified in the two families. One patient carried the frameshift deletion mutation c.831_832del:p.S278Pfs*59 of the PADI6 gene and the other patient carried the splicing mutation c.1245-2 A>G of the TLE6 gene. The analysis of the mRNA from the proband’s peripheral blood leukocytes confirmed aberrant splicing.ConclusionsOur findings expand the mutational spectrum of PADI6 and TLE6 associated with embryonic developmental arrest and deepen our understanding of the genetic causes of infertility with recurrent ART failure.

Preimplantation Genetic Screening and The Success Rate of In Vitro Fertilization: A Three-Years Study on Iranian Population.

In vitro fertilization (IVF) is one of the most efficient approaches within the context of assisted reproductive technology (ART) to treat infertility. High pregnancy rates have become the major index of successful IVF in clinical studies. It is not clear yet which factors are certainly responsible for IVF success, as various outcomes were obtained in different IVF centers with different settings. In this study, we aimed to address controversies in the interpretation of promising results of IVF with respect to preimplantation genetic screening (PGS). In this retrospective case series study, we built a dataset containing data from 213 IVF patient candidates for PGS (654 embryos) with blastomere biopsy at day 3 and trophectoderm biopsy in day 5, referred to Royan Institute, Tehran, Iran from 2015 to 2018. Next, the data were analyzed to find influential factors affecting success rate of ART cycles. Data analyses showed that regardless of PGS indications (ART failures, recurrent miscarriage, chromosomal abnormalities, etc.), the pregnancy rate is influenced by maternal and embryonic factors such as the age of mother as well as quantity and quality of transferred embryos. Furthermore, genotyping of embryos using array comparative genomic hybridization (aCGH) depicted the highest rate of chromosomal aberrations for chromosomes 1, 16 and 19 while the lowest frequency for chromosomes 11 and 17. Similarly, we detected 463 genetically abnormal embryos by aCGH, among which only 41.9% could be detected by classical fluorescent in situ hybridization (FISH) method. This study not only highlighted the advantages of aCGH over the FISH method in detection of chromosomal abnormalities, but also emphasized the importance of genetic abnormality as an indication for determination of IVF success rate.

Curative effect of assisted reproduction technology by Traditional Chinese Medicine multi-channel interventional therapy on 95 cases of in vitro fertilization and embryo transfer failure

ObjectiveTo evaluate the curative effect of Traditional Chinese Medicine (TCM) multi-channel interventional therapy on women with Assisted Reproductive Technology (ART) failure, to compare the curative effect of the dual therapy and triple therapy on women with ART Failure, and to choose the best TCM interventional therapeutic plan. MethodsThe 95 cases with ART Failure from West China second University Hospital of Sichuan University meeting the inclusion criteria were randomly divided into three groups:dual therapy group (31 cases), triple therapy group (33 cases) and control group (31 cases). According to the intervene treatment of in vitro Fertilization and Embryo Transfer (IVF-ET) long cycle scheme, the control group wait naturally for 3 months before IVF-ET. The dual therapy group take TCM prescription E of cultivating emotion and assisting reproduction and auricular acupoint therapy for 3 months before IVF-ET, then Western Medicine treatment progestin supporting as well as auricular application and Antai Recipe after IVF-ET transplantation. The triple therapy group take TCM prescription E of cultivated emotion and assisted reproduction, auricular acupoint therapy and retention enema of TCM, and combination treatment the same as dual therapy group after transplantation. The natural pregnancy number, the period condition of secondary IVF-ET and the improvement of the kidney deficiency, liver depression and blood stasis syndrome among those three groups were compared. ResultsIt was showed from analysis in 95 cases with ART failure that the number of natural pregnancy was as followings: 3 patients from the dual therapy group, 10 patients from the triple therapy group, and no patient from the control group. The comparison among three groups have statistical significance (P < 0.05). The treatment group is superior to the control group, while the triple therapy is superior to the dual therapy. The comparison of the condition of the fertility rate, clinical pregnancy rate, biochemical pregnancy rate and early abortion rate during the period of secondary IVF-ET between pre-therapy and post-treatment of both the dual therapy group and the triple therapy group have statistical significance (P < 0.05). The comparison of the improvement of the kidney deficiency, liver depression and blood stasis syndrome between pre-therapy and post-treatment of both the dual therapy group and the triple therapy group have statistical significance (P < 0.05). The comparison between three groups after treatment have statistical significance (P < 0.05). ConclusionTCM multi-channel interventional therapy can increase the natural pregnancy rate of patients with ART Failure (the triple therapy is superior to the dual therapy); it can increase the fertility rate, clinical pregnancy rate, and decrease the early abortion rate during the period of secondary IVF-ET; it can improve syndromes of kidney deficiency, liver depression and blood stasis.

Assisted reproductive technology treatments and quality of life: a longitudinal study among subfertile women and men.

Quality of life (QoL) may represent a comprehensive indicator for the assessment of the psychological impact of complex clinical conditions, such as infertility. Infertile women have a worse QoL compared to both infertile men and non-infertile controls. However, the initial phases of infertility treatments have been frequently investigated using cross-sectional study designs. This prospective longitudinal study aimed at assessing the health-related QoL change across different phases of assisted reproductive technology (ART) treatments in subfertile women and men. Eighty-five subfertile women and men undergoing ART cycles were assessed at the beginning of the ovarian stimulation, during oocyte retrieval before discharging, and around 14days after the embryo transfer. QoL was assessed through the Short Form 36. Irrespective of the cause of infertility, work status, and age, QoL levels decreased from the first to the third assessment, and women scored significantly lower than men to each QoL indicator. Additionally, a higher number of previous ART failures had a negative impact on QoL, irrespective of gender and the phase of treatment. ART outcome marginally affected women's QoL across time. Infertile women have a worse QoL throughout all phases of ARTs compared to men, and this difference increases in infertile patients with more than one previous ART failure.

Prevalence of Inherited and Acquired Thrombophilia in Females Post Multiple Assisted Reproductive Technology (ART) Attempts

Introduction: A link between thrombophilia and female infertility has been previously reported and the role of thrombophilia in multiple ART failures has been debated. Most meta-analyses of existing studies yield inconclusive and contradictory results that no antithrombotic therapy could, to-date, be indicated in thrombophilia patients with ART failure(s) without clinical thrombosis. As analysis of a large cohort is therefore warranted, we embarked on this study to identify the true prevalence of thrombophilia in a large number of women who presented for infertility and recurrent ART failures evaluation to detect the true prevalence of thrombophilia.Methods: This is an IRB-approved retrospective cohort analysis of Egyptian women with 3 or more ART attempts referred to our center NSA-Diagnostic Laboratories from 1/1/2009 to 1/1/2015. Females with known venous thromboembolism (VTE) prior to infertility evaluation were excluded. Aspirin use and results of thrombophilia testing were collected on all patients. Thrombophilia testing included Factor V Leiden mutation (FVL), prothrombin gene mutation, Plasminogen Activator Inhibitor-1 (PAI-1), Factor XIII level, b-Fib, HPA, ACE, ApoB, ApoE, anticardiolipin IgG and IgM (ACLG, ACLM respectively), Protein C deficiency, Protein S deficiency, antithrombin (AT), lupus anticoagulant (LA), CD16, CD56, methylenetetrahydrofolate reductase (MTHFR) A or C, and homocysteine level. Thrombophilia was categorized into simple and complex reflecting 1 and >1 homozygous mutations detected, respectively. Demographic characteristics and the prevalence of the different mutations were analyzed. Statistical analysis was performed using SPSS software version 20.0.Results: Inclusion criteria and all data were available in 2585 female subjects. Age range was 21-43. While all subjects had at least one or more mutation(s) of any kind, 305 subjects (11.8%) did not have any homozygous mutations. Simple thrombophilia (one homozygous mutation) was found in 894 patients (34.6%). Complex thrombophilia (more than one homozygous mutation) with 2, 3, 4, and 5 concomitant abnormalities was encountered: in 35.8%, 13.5%, 3.9% and 0.4%, respectively. Prevalence of homozygous and heterozygous mutations was as follows: FVL (2.9%; 21.9%), prothrombin gene mutation (0.1%; 4.0%), PAI (17.4%; 67.5%), factor XIII (1.2%; 23.7%), b-Fib (39.2%; 2.7%), HPA (10%; 30%), ACE (49.6%; 49.2%), ApoB (0.1%; 0%), ApoE (62.7%; 21.3%). ACLG was positive in 1.2%, ACLM in 3.6%, Protein C deficiency in 0.4%, Protein S deficiency in 0.2%, AT in 1.0%, LA in 1.8%, CD16 in 0.1%, CD56 in 1.1% and hyperhomocysteinemia in 0.7%. Heterozygous and homozygous MTHFR A (45.1%; 9.8%), MTHFR C (35.3%; 7.7%) mutations were noted. When compared to historical controls in the literature, similar prevalence was found for Protein C/S deficiencies, higher prevalence for FVL and Prothrombin gene mutation, and a lower prevalence for hyperhomocysteinemia in our cohort. No VTE was reported in subjects from the time of testing until data collection and follow up. Prophylactic anticoagulation with low molecular weight heparin and low dose aspirin in subjects were noted. All subjects with successful pregnancies post identification of thrombophilia were prescribed prophylactic anticoagulation with low molecular weight heparin through pregnancy and for 6 weeks postpartum. Low dose aspirin and first trimester steroids were also used. Analysis of full term pregnancy as an outcome is underway.Discussion: Thrombophilia prevalence in infertile Egyptian women presenting to our center with multiple failed ART attempts is higher for certain mutations than reported in the literature. Our cohort is unique in that women did not have a history of clinically evident VTE and had a higher prevalence of complex homozygous mutations. Our study has implications on the evaluation of female patients with infertility and helps set up the stage for future prospective and interventional trials using antithrombotic therapy. DisclosuresNo relevant conflicts of interest to declare.

Investigating Infertility-Related Stress and Adoption in Iranian Infertile Females with Assisted Reproductive Technology Failure

Background: Using Assisted Reproductive Technologies (ART) is a stressful experience marked by lengthy and invasive medical procedures, high financial cost and relatively low success rate. Adoption is considered as one of the infertility treatment methods that can have great impact on healing emotional problems of infertile couples and can improve their relationship. Objectives: The current study aimed to investigate infertility-related stress and adoption in Iranian Infertile females with a history of ART failure, during year 2015. Methods: This was a cross sectional study in which 30 Iranian infertile females, 30 to 45 years old, with primary infertility of five years or more, and history of ART failure, were investigated. Data collection instruments included the questionnaire of infertility and demographic factors, fertility problem inventory (FPI) and adoption questionnaire. The data were analyzed by SPSS V22, using descriptive statistics and Pearson test to assess possible correlations. Results: The mean of the total score of infertility stress of the participants was 186.1 ± 29.46 (moderate to high). All participants showed some level of infertility stress. The mean score of adoption was 38.4 ± 3.73 (moderate acceptance), 53.33% of which showed moderate acceptance. There was no relationship between infertility stress and adoption (correlation = - 0.13, P = 0.48). Conclusions: Infertile females with a history of unsuccessful ART had a high level of infertility stress and moderate acceptance of adoption. We must pay more attention to psychological aspects of infertility and failure of treatment. There is an obvious need to increase society awareness about adoption and promote “adoption” as a sensible choice to form a family.

Thrombophilia and assisted reproduction technology-any detrimental impact or unnecessary overuse?

The aim of this study is to provide an overview of the studies investigating a possible association between thrombophilia and assisted reproductive technology (ART) outcome. This is a literature review. Congenital thrombophilias (CoT) are reported to be associated with pregnancy loss. However, the association between CoT and early pregnancy loss is weak and does not necessarily support causation. CoT are more likely to be associated with late fetal loss. Even though data pooled from case-control and cohort studies suggest an increased risk of ART failure in women with CoTs, there seems no association when the analysis is confined to better quality cohort studies. The evidence supporting anticoagulation to improve ART outcome in CoT carriers is weak. Likewise, studies on antiphospholipid antibodies (APAs) and ART outcome suffer from multiple methodological limitations and a detrimental impact of APA positivity is controversial. Empirical administration of heparin or low molecular weight heparin to women with recurrent ART failures is supported by weak evidence. Importantly, thrombophilias are likely to increase thrombotic complications after ovarian stimulation for ART. Current evidence does not support routinely testing for or treatment of thrombophilia in the setting of ART nor in couples with implantation failure. A careful personal and family history should be obtained and a risk assessment for thrombotic complications should be made in every woman undergoing ovarian stimulation. If positive, testing for thrombophilia is warranted.

Effects of assisted reproductive technology and of women’s quality of life on depressive symptoms in the early postpartum period: a prospective case-control study

This study explored the influence of both assisted reproductive technology (ART) and reduced quality of life (QoL) during pregnancy on postpartum blues (PPB). Sixty-three sub-fertile patients who conceived through ART and 72 women who naturally conceived were enrolled in this prospective study. At 22nd and 32nd gestational weeks, women completed the Edinburgh Postnatal Depression Scale (EPDS) and the Short-Form 36 (SF-36), to investigate depressive symptoms and QoL, respectively; EPDS was again used at 15 days after birth to assess PPB. At both time points, higher EPDS scores and lower mental well-being scores (SF-36) significantly predicted PPB. The number of previous ART cycles emerged as the strongest predictor, whereas no significant effect was observed for the conceiving method. The results suggest the usefulness of assessing QoL during pregnancy and considering previous ART failures in preventing PPB.

The clinical effectiveness of preimplantation genetic diagnosis for aneuploidy in all 24 chromosomes (PGD-A): systematic review.

Is preimplantation genetic diagnosis for aneuploidy (PGD-A) with analysis of all chromosomes during assisted reproductive technology (ART) clinically and cost effective? The majority of published studies comparing a strategy of PGD-A with morphologically assessed embryos have reported a higher implantation rate per embryo using PGD-A, but insufficient data has been presented to evaluate the clinical and cost-effectiveness of PGD-A in the clinical setting. Aneuploidy is a leading cause of implantation failure, miscarriage and congenital abnormalities in humans, and a significant cause of ART failure. Preclinical evidence of PGD-A indicates that the selection and transfer of euploid embryos during ART should improve clinical outcomes. A systematic review of the literature was performed for full text English language articles using MEDLINE, EMBASE, SCOPUS, Cochrane Library databases, NHS Economic Evaluation Database and EconLit. The Downs and Black scoring checklist was used to assess the quality of studies. Clinical effectiveness was measured in terms of pregnancy, live birth and miscarriage rates. Nineteen articles meeting the inclusion criteria, comprising three RCTs in young and good prognosis patients and 16 observation studies were identified. Five of the observational studies included a control group of patients where embryos were selected based on morphological criteria (matched cohort studies). Of the five studies that included a control group and reported implantation rates, four studies (including two RCTs) demonstrated improved implantation rates in the PGD-A group. Of the eight studies that included a control group, six studies (including two RCTs) reported significantly higher pregnancy rates in the PGD-A group, and in the remaining two studies, equivalent pregnancies rates were reported despite fewer embryos being transferred in the PGD-A group. The three RCTs demonstrated benefit in young and good prognosis patients in terms of clinical pregnancy rates and the use of single embryo transfer. However, studies relating to patients of advanced maternal age, recurrent miscarriage and implantation failure were restricted to matched cohort studies, limiting the ability to draw meaningful conclusions. Relevant studies may have been missed and findings from RCTs currently being undertaken could not be included. Given the uncertain role of PGD-A techniques, high-quality experimental studies using intention-to-treat analysis and cumulative live birth rates including the comparative outcomes from remaining cryopreserved embryos are needed to evaluate the overall role of PGD-A in the clinical setting. It is only in this way that the true contribution of PGD-A to ART can be understood.

Improved cycle outcomes after laparoscopic ovarian diathermy in hyper-responder patients with previous ART failure

Excessive response to ovarian stimulation is common among hyper-responder patients undergoing assisted reproductive technology (ART). Cycle cancellations and severe ovarian hyperstimulation syndrome (OHSS) are all detrimental consequences observed within this cohort and several approaches have been proposed to enhance outcomes. The current study is designed to evaluate whether laparoscopic ovarian diathermy (LOD) improves ART outcomes and pregnancy rates by reducing Anti-mullerian hormone (AMH) levels in a group of patients who had a history of recurrent ART failure and high response. A total of 40 hyper-responder patients with history of previous ART failure were included. Group I consisted of 22 patients that underwent LOD prior to ART. Group II consisted of 18 patients that underwent only ART. Cycle outcomes of groups were compared. Following LOD, significant reduction in AMH levels were detected in group I (4.75 ng/mL to 2.25 ng/mL). Clinical pregnancies were similar among groups (40% versus 27.8% p = 0.65). There was no cycle cancellation in Group I, whereas there were three cycle cancellations observed due to OHSS in Group II. Our results indicate that LOD might offer enhanced fertility outcomes and may reduce the likelihood of cycle cancellations in hyper-responders with previous ART failures.

Cost-effectiveness analysis comparing continuation of assisted reproductive technology with conversion to intrauterine insemination in patients with low follicle numbers

To compare the cost effectiveness of proceeding with oocyte retrieval vs. converting to intrauterine insemination (IUI) in patients with ≤4 mature follicles during assisted reproductive technology (ART) cycles. Probabilistic decision analysis. The cost effectiveness of completing ART cycles in poor responders was compared to that for converting the cycles to IUI. Not applicable. Not applicable. Cost-effectiveness analysis. Cost effectiveness, which was defined as the average direct medical costs per ongoing pregnancy. In patients with 1-3 mature follicles, completing ART was more cost effective if the cost of a single ART cycle was between $10,000 and $25,000. For patients with 4 mature follicles, if an ART cycle cost<$18,025, it was more cost effective to continue with oocyte retrieval than to convert to IUI. In patients with ≤4 mature follicles following ovarian stimulation in ART cycles, it was on average more cost effective to proceed with oocyte retrieval rather than convert to IUI. However, important factors, such as age, prior ART failures, other fertility factors, and medications used in each individual case need to be considered before this analysis model can be adapted by individual practices.

両側卵管水腫に伴うART反復不成功例の治療指針

Objectives: To evaluate the reproductive outcomes of infertile patients who underwent laparoscopic surgery for hydrosalpinx and to propose a guideline for repeated assisted reproductive technology (ART) failures in patients with hydrosalpinx. Design: Retrospective analysis.Setting: The Gynecologic Laparoscopic Surgery Group of Kurashiki Medical Center and IVF Center at the Kurashiki Medical Clinic.Patient(s): The study included 31 infertile patients with bilateral tubal obstruction who were treated from January 2010 to October 2013. Nine of these patients underwent laparoscopic surgery because of repeated pregnancy failures after ART. We suggested the clinical records of patients who immediately conceived after surgery.Intervention(s): Laparoscopic salpingectomy and salpingostomy.Main Outcome Measure(s): Pregnancy after surgery.Result(s): Among the patients with severe hydrosalpinx who underwent salpingectomy, there were 4 patients with a hydrosalpinx diameter > 25 mm and 3 patients with a hydrosalpinx diameter < 25 mm. All the patients undergoing salpingostomy had fallopian tubes that were undetectable on ultrasound scanning (USS). The reason for repeated failure of ART for the patients undergoing salpingectomy was disordered implantation of good-quality embryos, while for the patients undergoing salpingostomy, there was 1 case of disordered implantation of good-quality embryos and 1 case with inadequate embryos. [Case 1] A 35-year-old nulliparous woman had severe hydrosalpinx that was diagnosed as swelling of the oviduct on hysterosalpingography (HSG), vaginal USS, and magnetic resonance imaging (MRI). The patient repeatedly failed to conceive, despite the transfer of high-quality blastcysts. After laparoscopic salpingectomy was performed, successful implantation was achieved with the first blastcyst transfer. [Case 2] A 26-year-old nulliparous woman repeatedly failed to conceive after ART. High-quality blastcysts were not obtained during 3 ART cycles. The patient was diagnosed with mild hydrosalpinx because the fallopian tubes were only visible on HSG but not on USS or MRI. Laparoscopic salpingostomy was performed. The patient conceived spontaneously 2 months after surgery.Conclusion(s): The therapeutic strategies for patients with hydrosalpinx and failure to conceive after repeated ART should be based on both the severity of hydrosalpinx and the type of ART failures.