Association of novel DNAH11 variants with asthenoteratozoospermia lead to male infertility.

BACKGROUND: Bi-allelic variants in DNAH11 have been identified as causative factors in Primary Ciliary Dyskinesia, leading to abnormal respiratory cilia. Nonetheless, the specific impact of these variants on human sperm flagellar and their involvement in male infertility remain largely unknown. METHODS: A collaborative effort involving two Chinese reproductive centers conducted a study with 975 unrelated infertile men. Whole-exome sequencing was employed for variant screening, and Sanger sequencing confirmed the identified variants. Morphological and ultrastructural analyses of sperm were conducted using Scanning Electron Microscopy and Transmission Electron Microscopy. Western Blot Analysis and Immunofluorescence Analysis were utilized to assess protein levels and localization. ICSI was performed to evaluate its efficacy in achieving favorable pregnancy outcomes for individuals with DNAH11 variants. RESULTS: In this study, we identified seven novel variants in the DNAH11 gene in four asthenoteratozoospermia subjects. These variants led the absence of DNAH11 proteins and ultrastructure defects in sperm flagella, particularly affecting the outer dynein arms (ODAs) and adjacent structures. The levels of ODA protein DNAI2 and axoneme related proteins were down regulated, instead of inner dynein arms (IDA) proteins DNAH1 and DNAH6. Two out of four individuals with DNAH11 variants achieved clinical pregnancies through ICSI. The findings confirm the association between male infertility and bi-allelic deleterious variants in DNAH11, resulting in the aberrant assembly of sperm flagella and contributing to asthenoteratozoospermia. Importantly, ICSI emerges as an effective intervention for overcoming reproductive challenges caused by DNAH11 gene variants.

Comparative motility assessment of sperm retrieved from micro-testicular sperm extraction: A single-centre study comparing fresh and frozen-thawed sperm.

INTRODUCTION: Microsurgical testicular sperm extraction (microTESE) is crucial for treating non-obstructive azoospermia (NOA), offering both 'fresh' and 'frozen' options. This study evaluates the impact of fresh versus frozen microTESE on the progression to intra-cytoplasmic sperm injection (ICSI) cycles, focusing on sperm motility. MATERIALS AND METHODS: We conducted a retrospective analysis of microTESE procedures at a major medical centre from 2007 to 2021, excluding cases of obstructive azoospermia and cryptozoospermia. Patients were divided into two groups: fresh microTESE (Group FR) and frozen microTESE (Group FZ). Sperm motility was assessed, and ICSI outcomes were compared between groups. RESULTS: Out of 128 microTESE procedures on 113 NOA patients, 31 were fresh and 97 were frozen. Sperm was found in 67.7% of fresh cases and 45.3% of frozen cases. In fresh cases, 85.7% had motile sperm for ICSI, whereas in frozen cases, 81.8% had motile sperm initially, but only 52.7% retained motility post-thaw. CONCLUSIONS: Our findings indicate a significant drop in motile sperm availability for ICSI in frozen microTESE cases compared to fresh ones. This suggests a potential advantage of fresh microTESE for certain couples, despite the logistical challenges, highlighting the need for careful patient selection and counselling.

Assisted reproductive technologies in Africa: The African Network and Registry for ART, 2020.

RESEARCH QUESTION: What were the utilization, effectiveness and safety of assisted reproductive technology (ART) in Africa during 2020? DESIGN: Cross-sectional, cycle-based and retrospective summary data were collected from voluntarily participating ART centres. RESULTS: During 2020, 37,063 ART procedures were reported by 67 centres in 15 countries. Autologous fresh transfers were predominant at 65.0%, whereas autologous frozen embryo transfers (FET) represented 26.2% and oocyte donation cycles remained less than 10%. Women undergoing autologous fresh embryo transfer had a mean age of 34.9 years and received a mean number of 2.4 embryos per transfer. The clinical pregnancy rate (CPR) per embryo transfer was 37.3% after fresh embryo transfer and 37.8% after frozen embryo transfer. The cumulative CPR per aspiration was 41.9% in autologous cycles. Most ART procedures resulted in a multiple delivery rate above 20%. After autologous ART, multiples were predominantly born preterm (twin and triplet deliveries 59.5% versus singleton 21.9% born before 37 weeks), with a substantially increased perinatal mortality compared with ART singletons (59.0‰ versus 22.2‰). Cycle-based data documented that elective single embryo transfer (eSET) provides the optimal balance of effectiveness (eSET CPR per embryo transfer 36.7%) and safety. CONCLUSION: This fourth report of the African Network and Registry for ART provides real-world evidence of ART utilization, practices and outcomes in Africa, which is relevant to many stakeholders. It critically informs and represents regional ART development based on national, regional and global cooperation.

Artificial oocyte activation improves ICSI outcomes following unexplained fertilization abnormalities.

RESEARCH QUESTION: Is artificial oocyte activation (AOA) effective for patients with unexplained low or no fertilization following IVF/intracytoplasmic sperm injection (ICSI)? DESIGN: All IVF/ICSI cases resulting in total fertilization failure or fertilization rate ≤25% at Ninewells Assisted Conception Unit, Dundee between January 2014 and December 2021 (n = 231) were reviewed contemporaneously. After exclusion of obvious stimulation, egg, sperm and/or assisted reproductive technology laboratory factors, patients with at least one cycle of IVF/ICSI resulting in apparently unexplained fertilization abnormalities were offered research investigations, including sperm immunocytochemistry for phospholipase C zeta (PLCζ) protein expression. This retrospective case-control cohort study evaluated laboratory and clinical outcomes for 39 couples (15 attended for sperm studies research) that subsequently undertook ICSI-AOA with Ca2+ ionophore. RESULTS: Comparing preceding IVF/ICSI and subsequent ICSI-AOA for each patient, the number of eggs collected was similar; however, ICSI-AOA resulted in a significantly improved fertilization rate (57.2% versus 7.1%; P < 0.0001). The uplift for a subset of 10 patients identified with PLCζ deficiency was 66.3% versus 4.6% (P < 0.0001). Overall, ICSI-AOA resulted in a higher number of fresh embryo transfers (94.6% versus 33.3%; P < 0.0001), a significantly higher clinical pregnancy rate (CPR) and live birth rate (LBR; 18.9% versus 2.6%; P = 0.02), a significant increase in cycles with surplus embryos suitable for cryostorage (43.6% versus 0%; P < 0.0001), and increased cumulative CPR (41.0% versus 2.6%; P < 0.0001) and LBR (38.5% versus 2.6%; P < 0.0001). CONCLUSION: AOA is a powerful tool that can transform clinical outcomes for couples experiencing apparently unexplained fertilization abnormalities. PLCζ assays have the potential to be valuable diagnostic tools to determine patient selection for ICSI-AOA, and research efforts should continue to focus on their development.

ART altered DNA methylation of the imprinted gene H19 in fetal tissue after multifetal pregnancy reduction.

PURPOSE: This study aimed to assess whether assisted reproductive technology alters DNA methylation levels at the H19 promoter and H19 imprinting control element (ICE) in fetal tissues obtained after multifetal pregnancy reduction. METHODS: Fetal tissues from multiple pregnancies were obtained, including fresh and frozen-thawed embryos: nine from conventional in vitro fertilization (c-IVF), four from intracytoplasmic sperm injection (ICSI), ten from cryopreserved IVF embryos (cryo-IVF), and six from cryopreserved ICSI (cryo-ICSI) embryos. Next-generation sequencing-based bisulfite PCR was used to determine the DNA methylation status of three CpG islands (H19-1, H19-2, and H19-3) in the H19 promoter and H19 ICE. The primary outcome was H19-1 DNA methylation status, whereas secondary outcomes assessed H19-2, H19-3, and ICE methylation. RESULTS: The ICSI (ß = -3.189, 95% CI = -5.034 to -1.345, p = 0.0026), cryo-IVF (ß = -2.150, 95% CI = -3.706 to -0.593, p = 0.0129), and cryo-ICSI (ß = -2.238, 95% CI = -3.817 to -0.659, p = 0.0110) groups exhibited significantly lower methylation levels in the primary outcome H19-1 region than the c-IVF group after adjustment. For the secondary outcome H19-2 region, significant decreases were observed in the cryo-IVF (ß = -2.132, 95% CI = -4.071 to -0.192, p = 0.0425) and cryo-ICSI groups (ß = -2.598, 95% CI = -4.566 to -0.630, p = 0.0168). CONCLUSIONS: These findings further indicate that embryo cryopreservation and potentially ICSI can lower the methylation level of the H19 promoter, advocating for careful use of these techniques when necessary.

Maternal Characteristics in Natural and Medically Assisted Reproduction Dizygotic Twin Pregnancies.

Previous studies have shown that mothers of naturally conceived dizygotic (DZ) twins tend to be taller, older, and smoke more than mothers of naturally conceived monozygotic (MZ) twin and mothers of singletons. Here, we investigate whether mothers of naturally conceived DZ twins differ from mothers who conceived their DZ twins after medically assisted reproduction (MAR) in eight maternal traits related to fertility based on observational survey data. We include data from 33,648 mothers from the Netherlands Twin Register (NTR) and 1660 mothers of twins from the Norwegian Mother, Father and Child Cohort Study (MoBA). We contrast mothers of naturally conceived DZ twins with mothers of MAR DZ twins. Next, we further segment the MAR group into mothers who underwent hormonal induction of ovulation but not in vitro fertilization (IVF) and those who IVF twins, comparing them both to each other and against the mothers of naturally conceived DZ twins. Mothers of naturally conceived DZ twins smoke more often, differ in body composition, have a higher maternal age and have more offspring before the twins than mothers of MZ twins. Compared to MAR DZ twin mothers, mothers of naturally conceived DZ twins have fewer miscarriages, lower maternal age and increased height, more offspring and are more often smokers. BMI before the twin pregnancy is similar in both natural and MAR DZ twin mothers. Mothers who received hormonal induction of ovulation (OI) have a lower maternal age, fewer miscarriages, and a higher number of offspring before their twin pregnancy than twin mothers who received IVF and/or intracytoplasmic sperm injection (ICSI) treatments. Our study shows that twin mothers are a heterogenous group and the differences between twin mothers should be taken into account in epidemiological and genetic research that includes twins.

Effect of sperm DNA fragmentation on the cumulative live birth rate in patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment.

BACKGROUND: Sperm DNA fragmentation testing is a valuable tool for predicting male infertility independent of routine semen analysis. However, it remains unclear whether sperm DNA fragmentation affects in vitro fertilization/intracytoplasmic sperm injection outcomes, especially their live birth rates. This study aimed to investigate the effects of sperm DNA fragmentation on the cumulative live birth rates over 1 year of in vitro fertilization/intracytoplasmic sperm injection treatment. METHODS: This retrospective study included 5050 couples who had undergone in vitro fertilization/intracytoplasmic sperm injection treatment from 2016 to 2022. These patients were divided into four groups according to their sperm DNA fragmentation percentages (group 1: sperm DNA fragmentation ≤10%, group 2: > 10% to ≤20%, group3: > 20% to ≤30%, and group 4: > 30%) determined using the sperm chromatin dispersion assay. Both conservative and optimistic methods were used for estimating cumulative live birth rates, the primary outcome, was defined as an ongoing pregnancy leading to live birth that had arisen from all embryo transfers performed within 1 year following the first ovum pick-up. RESULTS: The conservative and optimistic cumulative live birth rates showed no significant differences between sperm DNA fragmentation groups when total patients or in vitro fertilization patients were analyzed while adjusting for the confounders. However, compared with those in the group with low sperm DNA fragmentation values (≤10%), the conservative cumulative live birth rate was significantly decreased in intracytoplasmic sperm injection patients in the group with sperm DNA fragmentation > 30%, and the optimistic cumulative live birth rates were significantly decreased in intracytoplasmic sperm injection patients in the three groups with high sperm DNA fragmentation values (> 10% to ≤20%, > 20% to ≤30%, > 30%). These results were further confirmed by the analyses of smooth curves generated by generalized additive models. In intracytoplasmic sperm injection patients, the cumulative live birth rates decreased significantly as the sperm DNA fragmentation increased (p = 0.034), and these effects were stronger with the increase in female age. A similar pattern of correlation between sperm DNA fragmentation and cumulative live birth rate was found in in vitro fertilization patients, but the correlation was not significant (p = 0.232). DISCUSSION AND CONCLUSION: Sperm DNA fragmentation has a significant effect on the cumulative probability of achieving a live birth during 1 year of treatment involving intracytoplasmic sperm injection.

Rescue ICSI Improved Cumulative Live Birth Rate for Cycles with Second Polar Body Extrusion Rate <50% in Young Women: Generalized Addictive Model.

OBJECTIVE: To determine the indications for early rescue intracytoplasmic sperm injection (ICSI) application. DESIGN: A retrospective cohort study SUBJECTS: The study included 19,808 patients who underwent conventional in vitro fertilization (IVF) or rescue ICSI for their first cycles between February 2017 and December 2021. EXPOSURE: Rescue ICSI cycles constituted the study group, where oocytes that had not extruded the second polar body 4-6 hours after insemination were rescued by ICSI. The control group consisted of conventional IVF cycles with no interventions to rescue oocytes without the second polar body. Generalized additive models (GAMs) were constructed to describe the relationship between the second polar body extrusion rate and cumulative live birth rate in conventional IVF and rescue ICSI cycles, respectively. The cutoff value of the second polar body extrusion rate guiding rescue ICSI application was determined from the intersection point of GAMs. Maternal age range applicable to rescue ICSI was further analyzed using the same method. Clinical outcomes were compared between conventional IVF and rescue ICSI cycles across different second polar body extrusion rate and maternal age subgroups. MAIN OUTCOME MEASURES: The second polar body extrusion rate and maternal age range for rescue ICSI application, normal fertilization rate, and cumulative live birth rate. RESULTS: GAMs showed that the cutoff value for the second polar body extrusion rate about rescue ICSI application was 50%. When the rate <50%, normal fertilization rate and cumulative live birth rate (63.7% vs. 46.1%, OR: 1.609, 95% CI: 1.276-2.030) were significantly higher in rescue ICSI cycles than conventional IVF cycles. When the rate ≥50%, rescue ICSI cycles had similar normal fertilization rate and cumulative live birth rate compared to conventional IVF cycles. Further analysis on maternal age in cycles with second polar body extrusion rate <50% released that rescue ICSI cycles showed a higher cumulative live birth rate (67.7% vs. 48.3%, OR: 1.732, 95% CI: 1.361-2.202) than conventional IVF cycles for women aged < 38 years. CONCLUSION: IVF cycles with second polar body extrusion rate <50% in women aged < 38 years was applicable to early rescue ICSI.

Livebirth rates are influenced by an interaction between male and female partners' age: analysis of 59 951 fresh IVF/ICSI cycles with and without male infertility.

STUDY QUESTION: Does advanced male partner's age impact live birth rates (LBRs) in IVF treatment when female partner's age is factored in? SUMMARY ANSWER: In fresh IVF cycles LBRs decline with male partner's age ≥40 years when the female partner is aged 35-39 years, irrespective of the presence or absence of male factor; but not when the female partner is <35 years or ≥40 years of age; this decline is not observed in ICSI cycles. WHAT IS KNOWN ALREADY: Advanced paternal age is associated with declining sperm parameters, impaired embryo development, compromised pregnancy outcomes, and abnormalities in the offspring in IVF/ICSI cycles. However, data on the interaction between maternal and paternal age on IVF outcomes are very limited and inconsistent. No significant effect of male partner's age on pregnancy outcomes has been noted in donor oocyte cycles. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of all eligible autologous IVF/ICSI cycles with oocyte retrieval and intended fresh embryo transfer (ET) from the UK's national anonymized registry, published online by the Human Fertilisation and Embryology Authority (HFEA). There were 59 951 cycles that qualified the inclusion criteria in the study period: 1 January 2017 to 31 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples underwent IVF (n = 27 226) or ICSI (n = 32 725) treatment with partner's sperm followed by fresh ET due to unexplained (n = 31 846), tubal (n = 6605), or male infertility (n = 22 905). Treatment cycles with endometriosis (n = 5563), ovulatory disorders (n = 9970), female partner aged >44 years (n = 636), and PGT (n = 280) were excluded. Women were stratified by age in the following groups: <35, 35-39, 40-42, and 43-44 years; male partner's age as <35 (reference group), 35-37, 38-39, 40-42, 43-44, 45-50, 51-55, 55-60, and >55 years as presented by the HFEA. Some age-groups were merged in the analysis to increase the population size. Chi-square test was used to compare binominal data; and multiple logistic regression to find any association between male and female age-groups on live birth adjusting for other confounders that had a significant effect on this outcome. MAIN RESULTS AND THE ROLE OF CHANCE: LBRs per oocyte retrieval as well as per ET were no different across the male partners' age-groups when the female partners were aged <35 years or in 40- to 44-year age-group, whether male-factor infertility was included or excluded and whether it was IVF or ICSI cycle. However, when IVF was the method of insemination in the female partner's age-group of 35-39 years, LBRs per oocyte retrieval dropped significantly from 27.0% in the male age-group of <35 years (reference group) to 22.9% (P = 0.002), 22.0% (P = 0.006), and 18.8% (P = 0.004) in 40-44, 45-50, and >50 years age-group, respectively in population that included male-factor infertility. Likewise, LBR per retrieval declined from 27.6% in 35 years age-group to 23.5% (P = 0.002) and 22.2% (P = 002) in 40-44 years and older groups, respectively in cycles without male infertility. However, there was no impact of male age on LBR in any female partner's age-group when ICSI was performed in either the presence or the absence of male infertility. A similar decline in the LBR per retrieval and per ET was observed in female age-group of 35-39 years in the analyses with IVF and ICSI cycles combined. The inference remained unchanged when only the first treatment cycle was included (per patient analysis) or when single blastocyst transfer cycles were analysed, eliminating the impact of the number and stage of embryo transferred. After adjusting for confounders including male age, female age, number of previous treatment cycles, previous live birth, insemination method (IVF or ICSI), number of embryos transferred, and day (stage) of ET, male partner's age remained significantly associated with LBR in the female age-group of 35-39 years, but not when women were in <35 years or 40- to 44-year age-group, in population including as well as excluding male infertility. Miscarriage rates per single ET trended to rise (non-significantly) in IVF as well as ICSI cycle only when men were over 55 years and female partners aged <40 years, particularly when male infertility was excluded. LIMITATIONS, REASONS FOR CAUTION: Information on ovarian reserve and stimulation protocols was not available. This probably would have had little impact, given the large size of the population studied. The ages of female and male partners were given in groups necessitating taking them as ordinal variable in the regression analysis. Cumulative LBRs could not be determined as the information on subsequent frozen-thawed ET cycles could not be traced and the severity or cause of abnormal semen parameters were not present in the HFEA database. Some age-groups with small number of patients were merged to obtain a reliable result. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest clinical data to support the laboratory evidence of the ability of oocytes from young women to reverse the age-related deterioration of sperm quality. As the ageing oocytes lose this reparatory mechanism, the ageing sperm exert a detrimental effect on the LBR. The message of this study is important in counselling of patients and planning out treatment. Further research on interaction between male and female age will increase our understanding of this matter and help to establish whether ICSI procedure is more appropriate for older male partners even when there is no apparent semen abnormality. STUDY FUNDING/COMPETING INTEREST(S): No funding was required. There is no competing interest. TRIAL REGISTRATION NUMBER: N/A (retrospective analysis).

Effect of Waiting Period on Initial Adverse Vaginal Microbiome Composition in IVF-ICSI Patients.

Background/Objectives: In this observational prospective cohort study, conducted at the Fertility Centre of the University Hospital, Duesseldorf Germany, the spontaneous reversal capacity and the effect of waiting time on an adverse vaginal microbiome profile in subfertile patients were investigated. Methods: Vaginal swabs of 76 patients were obtained before starting a fertility treatment using a commercially available test to perform a microbiome analysis. Patients with a favorable microbiome profile ("medium" or "high profile") according to the manufacturer's algorithm proceeded with the fertility treatment. Patients with an unfavorable microbiome profile ("low profile") postponed their fertility treatment and were sampled up to four times in each successive cycle or until a shift to a more favorable profile was detected. Results: Initially, 54/76 subjects had a high or medium profile and 23/76 had a low profile. Within 3 months, 75% of patients with an initial low profile shifted to a more favorable profile (7/23 dropouts). The presence of Lactobacillus crispatus in the initial sample was associated with a higher likelihood of a spontaneous shift to a more favorable profile. Conclusions: The vaginal microbiome is subject to strong fluctuations. Even an unfavorable microbiome profile can develop into a favorable microbiome profile within a few months without treatment.

Recombinant human luteinizing hormone increases endometrial thickness in women undergoing assisted fertility treatments: a systematic review and meta-analysis.

Introduction: The optimal dosage of recombinant human luteinizing hormone (r-hLH) and its impact on endometrial thickness (EMT) when administered alongside recombinant human follicle-stimulating hormone (r-hFSH) during controlled ovarian stimulation (COS) for in vitro fertilization/intracytoplasmic sperm injection and embryo transfer are uncertain, which formed the aims of this systematic review and meta-analysis. Method: A search was performed in PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, and Wanfang from its inception to 10 July 2023. Twenty-seven Randomized controlled trials comparing r-hFSH/r-hLH co-treatment with r-hFSH alone during in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) were included. Pooled odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data, with their respective 95% confidence intervals (CI), were generated. Meta-analysis employed fixed-effect or random-effect models based on heterogeneity, using Q-test and I2-index calculations. The main outcomes included EMT on trigger day, clinical pregnancy rate (CPR) and live birth rate (LBR). Results: r-hFSH/r-hLH significantly increased EMT on trigger day (MD = 0.27; 95% CI, 0.11-0.42; I2 = 13%), but reduced oocyte number (MD = -0.60; 95% CI, -1.07 to -0.14; I2 = 72%) and high-quality embryos (MD = -0.76; 95% CI, -1.41 to -0.10; I2 = 94%) than r-hFSH alone, more pronounced with the gonadotrophin-releasing hormone agonist long protocol. A subgroup analysis showed r-hLH at 75 IU/day increased CPR (OR = 1.23; 95% CI, 1.02-1.49; I2 = 16%) and EMT on trigger day (MD = 0.40; 95% CI, 0.19-0.61; I2 = 0%). Participants ≥35 years of age exhibited decreased retrieved oocytes (MD = -1.26; 95% CI, -1.78 to -0.74; I2 = 29%), but an increase in EMT on trigger day (MD = 0.26; 95% CI, 0.11-0.42; I2 = 29%). Conclusion: r-hFSH/r-hLH during COS significantly improved EMT compared to r-hFSH alone. An r-hLH dose of 75 IU/day may be considered for optimal pregnancy outcomes, which still require further clinical studies to support this dosing regime. Systematic Review Registration: [www.crd.york.ac.uk/PROSPERO], identifier [CRD42023454584].

Clinical evidence of coenzyme Q10 pretreatment for women with diminished ovarian reserve undergoing IVF/ICSI: a systematic review and meta-analysis.

BACKGROUND: To quantitatively evaluate the effect of coenzyme Q10 (CoQ10) pretreatment on outcomes of IVF or ICSI in women with diminished ovarian reserve (DOR) based on the existing randomized controlled trials (RCTs). METHODS: Nine databases were comprehensively searched from database inception to November 01, 2023, to identify eligible RCTs. Reproductive outcomes of interest consisted of three primary outcomes and six secondary outcomes. The sensitivity analysis was adopted to verify the robustness of pooled results. RESULTS: There were six RCTs in total, which collectively involved 1529 participants with DOR receiving infertility treatment with IVF/ICSI. The review of available evidence suggested that CoQ10 pretreatment was significantly correlated with elevated clinical pregnancy rate (OR = 1.84, 95%CI [1.33, 2.53], p = 0.0002), number of optimal embryos (OR = 0.59, 95%CI [0.21, 0.96], p = 0.002), number of oocytes retrieved (MD = 1.30, 95%CI [1.21, 1.40], p < 0.00001), and E2 levels on the day of hCG (SMD = 0.37, 95%CI [0.07, 0.66], p = 0.01), along with a reduction in cycle cancellation rate (OR = 0.60, 95%CI [0.44, 0.83], p = 0.002), miscarriage rate (OR = 0.38, 95%CI [0.15, 0.98], p = 0.05), total days of Gn applied (MD = -0.89, 95%CI [-1.37, -0.41], p = 0.0003), and total dose of Gn used (MD = -330.44, 95%CI [-373.93, -286.96], p < 0.00001). The sensitivity analysis indicated that our pooled results were robust. CONCLUSIONS: These findings suggested that CoQ10 pretreatment is an effective intervention in improving IVF/ICSI outcomes for women with DOR. Still, this meta-analysis included relatively limited sample sizes with poor descriptions of their methodologies. Rigorously conducted trials are needed in the future.

Untangling the independent effect of endometriosis, adenomyosis, and ART-related factors on maternal, placental, fetal, and neonatal adverse outcomes: results from a systematic review and meta-analysis.

BACKGROUND: Women with endometriosis may constitute a group at a particularly increased risk of pregnancy-related complications. Furthermore, women selected for assisted reproductive technology (ART) are exposed to additional endocrinological and embryological factors that have been associated with adverse pregnancy outcomes. OBJECTIVE AND RATIONALE: This study aimed to investigate the independent effect of endometriosis, adenomyosis, and various ART-related factors on adverse maternal, placental, fetal, and neonatal outcomes. SEARCH METHODS: Published randomized controlled trials, cohort studies, and case-control studies were considered eligible. PubMed, MEDLINE, ClinicalTrials.gov, Embase, and Scopus were systematically searched up to 1 March 2024. This systematic review and meta-analysis was performed in line with the PRISMA and the MOOSE reporting guidelines. To thoroughly investigate the association between endometriosis/adenomyosis and adverse pregnancy outcomes, sub-analyses were conducted, whenever possible, according to: the method of conception (i.e. ART and non-ART conception), the endometriosis stage/phenotype, the coexistence of endometriosis and adenomyosis, any pre-pregnancy surgical treatment of endometriosis, and the form of adenomyosis. The odds ratio (OR) with 95% CI was used as effect measure. The quality of evidence was assessed using the GRADE approach. OUTCOMES: We showed a higher risk of placenta previa in women with endometriosis compared to controls (34 studies, OR 2.84; 95% CI: 2.47, 3.26; I2 = 83%, moderate quality). The association was observed regardless of the method of conception and was particularly strong in the most severe forms of endometriosis (i.e. rASRM stage III-IV endometriosis and deep endometriosis (DE)) (OR 6.61; 95% CI: 2.08, 20.98; I2 = 66% and OR 14.54; 95% CI: 3.67, 57.67; I2 = 54%, respectively). We also showed an association, regardless of the method of conception, between endometriosis and: (i) preterm birth (PTB) (43 studies, OR 1.43; 95% CI: 1.32, 1.56; I2 = 89%, low quality) and (ii) cesarean section (29 studies, OR 1.52; 95% CI: 1.41, 1.63; I2 = 93%, low quality). The most severe forms of endometriosis were strongly associated with PTB. Two outcomes were associated with adenomyosis both in the main analysis and in the sub-analysis that included only ART pregnancies: (i) miscarriage (14 studies, OR 1.83; 95% CI: 1.53, 2.18; I2 = 72%, low quality) and (ii) pre-eclampsia (7 studies, OR 1.70; 95% CI: 1.16, 2.48; I2 = 77%, low quality). Regarding ART-related factors, the following associations were observed in the main analysis and confirmed in all sub-analyses conducted by pooling only risk estimates adjusted for covariates: (i) blastocyst stage embryo transfer (ET) and monozygotic twinning (28 studies, OR 2.05; 95% CI, 1.72, 2.45; I2 = 72%, low quality), (ii) frozen embryo transfer (FET) and (reduced risk of) small for gestational age (21 studies, OR 0.59; 95% CI, 0.57, 0.61; P < 0.00001; I2 = 17%, very low quality) and (increased risk of) large for gestational age (16 studies, OR 1.70; 95% CI, 1.60, 1.80; P < 0.00001; I2 = 55%, very low quality), (iii) artificial cycle (AC)-FET and pre-eclampsia (12 studies, OR 2.14; 95% CI: 1.91-2.39; I2 = 9%, low quality), PTB (21 studies, OR 1.24; 95% CI 1.15, 1.34; P < 0.0001; I2 = 50%, low quality), cesarean section (15 studies, OR 1.59; 95% CI 1.49, 1.70; P < 0.00001; I2 = 67%, very low quality) and post-partum hemorrhage (6 studies, OR 2.43; 95% CI 2.11, 2.81; P < 0.00001; I2 = 15%, very low quality). WIDER IMPLICATIONS: Severe endometriosis (i.e. rASRM stage III-IV endometriosis, DE) constitutes a considerable risk factor for placenta previa and PTB. Herein, we recommend against superimposing on this condition other exposure factors that have a strong association with the same obstetric adverse outcome or with different outcomes which, if coexisting, could determine the onset of an ominous obstetric syndrome. Specifically, we strongly discourage the use of AC regimens for FET in ovulatory women with rASRM stage III-IV endometriosis or DE. We also recommend single ET at the blastocyst stage in this high-risk population. REGISTRATION NUMBER: CRD42023401428.

Endometrial compaction to predict pregnancy outcomes in patients undergoing assisted reproductive technologies: a systematic review and meta-analysis.

STUDY QUESTION: Does endometrial compaction (EC) help predict pregnancy outcomes in those undergoing ART? SUMMARY ANSWER: EC is associated with a significantly higher clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR), but this does not translate to live birth rate (LBR). WHAT IS KNOWN ALREADY: EC describes the progesterone-induced decrease in endometrial thickness, which may be observed following the end of the proliferative phase, prior to embryo transfer. EC is proposed as a non-invasive tool to help predict pregnancy outcome in those undergoing ART, however, published data is conflicting. STUDY DESIGN SIZE DURATION: A literature search was carried out by two independent authors using PubMed, Cochrane Library, MEDLINE, Embase, Science Direct, Scopus, and Web of Science from inception of databases to May 2023. All peer-reviewed studies reporting EC and pregnancy outcomes in patients undergoing IVF/ICSI treatment were included. PARTICIPANTS/MATERIALS SETTING METHODS: The primary outcome is LBR. Secondary outcomes included other pregnancy metrics (positive pregnancy test (PPT), CPR, OPR, miscarriage rate (MR)) and rate of EC. Comparative meta-analyses comparing EC and no EC were conducted for each outcome using a random-effects model if I 2 > 50%. The Mantel-Haenszel method was applied for pooling dichotomous data. Results are presented as odds ratios (OR) with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 4030 screened articles, 21 cohort studies were included in the final analysis (n = 27 857). No significant difference was found between LBR in the EC versus the no EC group (OR 0.95; 95% CI 0.87-1.04). OPR was significantly higher within the EC group (OR 1.61; 95% CI 1.09-2.38), particularly when EC ≥ 15% compared to no EC (OR 3.52; 95% CI 2.36-5.23). CPR was inconsistently defined across the studies, affecting the findings. When defined as a viable intrauterine pregnancy <12 weeks, the EC group had significantly higher CPR than no EC (OR 1.83; 95% CI 1.15-2.92). No significant differences were found between EC and no EC for PPT (OR 1.54; 95% CI 0.97-2.45) or MR (OR 1.06; 95% CI 0.92-1.56). The pooled weighted incidence of EC across all studies was 32% (95% CI 26-38%). LIMITATIONS REASONS FOR CAUTION: Heterogeneity due to differences between reported pregnancy outcomes, definition of EC, method of ultrasound, and cycle protocol may account for the lack of translation between CPR/OPR and LBR findings; thus, all pooled data should be viewed with an element of caution. WIDER IMPLICATIONS OF THE FINDINGS: In this dataset, the significantly higher CPR/OPR with EC does not translate to LBR. Although stratification of women according to EC cannot currently be recommended in clinical practice, a large and well-designed clinical trial to rigorously assess EC as a non-invasive predictor of a successful pregnancy is warranted. We urge for consistent outcome reporting to be mandated for ART trials so that data can be pooled, compared, and concluded on. STUDY FUNDING/COMPETING INTERESTS: H.A. was supported by the Hewitt Fertility Centre. S.G.P. and J.W. were supported by the Liverpool University Hospital NHS Foundation Trust. D.K.H. was supported by a Wellbeing of Women project grant (RG2137) and MRC clinical research training fellowship (MR/V007238/1). N.T. was supported by the National Institute for Health and Care Research. D.K.H. had received honoraria for consultancy for Theramex and has received payment for presentations from Theramex and Gideon Richter. The remaining authors have no conflicts of interest to report. REGISTRATION NUMBER: PROSPERO CRD42022378464.

The fertility outcome of assisted oocyte activation combined with spindle view-assisted intracytoplasmic sperm injection in patients with low fertilization rate.

OBJECTIVE: To examine the possible synergic effect of spindle view-assisted intracytoplasmic sperm injection (SV-ICSI) with assisted oocyte activation (AOA) for low fertilization rate. MATERIALS AND METHODS: A single-center retrospective study from 2019/09-2023/06, a total of 47 patients, autologous IVF cycle, and low fertilization rate history, including control group (SV-ICSI, 33 patients) and intervention group (AOA-SV-ICSI, 14 patients), comparing fertilization rate, blastocyst formation rate, and clinical pregnancy rate. RESULTS: The blastocyst formation rate was significantly higher (p = 0.020) in the AOA-SV-ICSI group than in the SV-ICSI group. The fertilization rate (P = 0.468) and clinical pregnancy rate (p = 0.057) were non-significant between groups. CONCLUSION: The AOA-SV-ICSI group's blastocyst formation rate significantly improved in patients with previous low fertilization rates, which might help them obtain more useable embryos for further embryo implantation.

The risk of asthma in singletons conceived by ART: a retrospective cohort study.

STUDY QUESTION: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? SUMMARY ANSWER: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. WHAT IS KNOWN ALREADY: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. STUDY DESIGN SIZE DURATION: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. PARTICIPANTS/MATERIALS SETTING METHODS: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. MAIN RESULTS AND THE ROLE OF CHANCE: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. LIMITATIONS REASONS FOR CAUTION: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: ChiCTR2300069906.

Comparison of pregnancy outcomes between 4th day morula and 5th day blastocyst after embryo transfer: a retrospective cohort study.

BACKGROUND: This study was designed to evaluate pregnancy outcomes between morulae transferred on day 4 (D4) and blastocysts transferred on day 5 (D5). METHODS: From September 2017 to September 2020, 1963 fresh transfer cycles underwent early follicular phase extra-long protocol for assisted conception in our fertility center were divided into D4 (324 cases) and D5 (1639 cases) groups, and the general situation and other differences of patients in both groups were compared. To compare the differences in pregnancy outcomes, the D4 and D5 groups were further divided into groups A and B based on single and double embryo transfers. Furthermore, the cohort was divided into two groups: those with live births (1116 cases) and those without (847 cases), enabling a deeper evaluation of the effects of D4 or D5 transplantation on assisted reproductive outcomes. RESULTS: In single embryo transfer, there was no significant difference between groups D4A and D5A (P > 0.05). In double embryo transfer, group D4B had a lower newborn birthweight and a larger proportion of low birthweight infants (P < 0.05). The preterm delivery rate, twin delivery rate, cesarean delivery rate, and percentage of low birthweight infants were lower in the D5A group than in the D5B group (P < 0.05). Analysis of factors influencing live birth outcomes further confirmed the absence of a significant difference between D4 and D5 transplantation in achieving live birth (P > 0.05). CONCLUSION: When factors such as working life and hospital holidays are being considered, D4 morula transfer may be a good alternative to D5 blastocyst transfer. Given the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) success rate and risk of twin pregnancy, D4 morula transfer requires an adapted decision between single and double embryo transfer, although a single blastocyst transfer is recommended for the D5 transfer in order to decrease the twin pregnancy rate. In addition, age, endometrial thickness and other factors need to be taken into account to personalize the IVF program and optimize pregnancy outcomes.

Gonadotropin-Releasing Hormone (GnRH) Agonist Protocol Improves Pregnancy Outcomes During In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) Treatment in Young Infertile Women: A Retrospective Study.

Objective The objective of this study was to determine if gonadotropin-releasing hormone agonist (GnRH-a) or gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment in young infertile women improve their pregnancy outcomes. Methodology We retrospectively reviewed the records of 876 young infertile women aged 20-35 years who underwent fresh embryo transfer in IVF/ICSI cycles. The data were collected from their initial visits to the reproductive medicine center of the Second Affiliated Hospital of Zhengzhou University between January 2019 and December 2022. We divided them into two groups according to the controlled ovarian hyperstimulation (COH) protocols: GnRH-a (n = 580) and GnRH-ant (n = 296). The primary outcome assessed in this study was the live birth rate. The secondary observation indicators included the total dose and duration of gonadotropin (Gn), total embryo transfer, day three (D3) embryo transfer, total two pro-nuclei (2PN) cleavage count, number of fertilizations, and implantation rate. Results The live birth rate had no clinical significance (P > 0.05). The total dose and duration of Gn stimulation in the GnRH-ant group were lower than in the GnRH-a group (P  < 0.05). The total embryo transfer, D3 embryo transfer, total cleavage count, total 2PN cleavage count, number of fertilizations, transfer, and mature oocytes in metaphase II (MII) of D3 embryos in the GnRH-a group were higher than those in the GnRH-ant group (P  < 0.05). The clinical pregnancy rate and implantation rate of the GnRH-a group were higher than those of the control group. Conclusions The total embryo transfer, D3 embryo transfer, total cleavage count, total 2PN cleavage count, number of fertilizations, transfer and MII of D3 embryos, clinical pregnancy, and implantation rates were significantly higher in the GnRH-a protocol group. The total dosage of Gn and duration of Gn stimulation were lower in the GnRH-ant group than in the GnRH-a group. These findings provide the basis for the selection of the COH protocol in normal Chinese ovarian response patients undergoing IVF/ICSI.

What sperm parameters effect blastocyst formation and quality during ICSI with severe male infertility.

Sperm-derived genetic material contributes half of the genome to the embryo, hence it's crucial to investigate which sperm parameter influences blastocyst formation in the intracytoplasmic sperm injection (ICSI) cycles with severe male infertility. The retrospective study analyzed 296 ICSI cycles with severe oligoasthenoteratozoospermia (OAT) and 99 ICSI cycles with preimplantation genetic testing for aneuploidy (PGT-A). Following the correlation analysis, data stratifications were performed in the OAT ICSI subgroup. The results showed that the matching blastocyst in the OAT ICSI cycles had inferior sperm parameters. DFI and sperm morphology had an influence on the blastocyst formation rate and the high-quality blastocysts formation rate on Day6, but no significant effect on the blastocyst development on Day 5. The high-quality blastocysts formation rate and ratio of high-quality blastocyst on Day 6 were demonstrably better in the subgroup of the teratozoospermic morphology when DFI was within the normal range. In the case of the normal sperm morphology, no statistically significant difference was found in blastocyst development, although there were numerical differences within different DFI subgroups. It was concluded that the blastocyst quality and development declined with the decreased sperm qualities.