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The endometrial microbiota composition may be associated with implantation success. However, a ‘core’ composition has not yet been defined. This exploratory study analysed the endometrial microbiota by 16S rRNA sequencing (V1–V2 region) of 141 infertile women whose first IVF/ICSI cycle failed and compared the microbiota profiles of women with and without a live birth within 12 months of follow-up, and by infertility cause and type. Lactobacillus was the most abundant genus in the majority of samples. Women with a live birth compared to those without had significantly higher Lactobacillus crispatus relative abundance (RA) (p = 0.029), and a smaller proportion of them had ≤ 10% L. crispatus RA (42.1% and 70.4%, respectively; p = 0.015). A smaller proportion of women in the male factor infertility group had ≤ 10% L. crispatus RA compared to women in the unexplained and other infertility causes groups combined (p = 0.030). Women with primary infertility compared to secondary infertility had significantly higher L. crispatus RA (p = 0.004); lower proportions of them had ≤ 10% L. crispatus RA (p = 0.009) and > 10% Gardnerella vaginalis RA (p = 0.019). In conclusion, IVF/ICSI success may be associated with L. crispatus RA and secondary infertility with endometrial dysbiosis, more often than primary infertility. These hypotheses should be tested in rigorous well-powered longitudinal studies.

Intracytoplasmic Sperm Injection (ICSI) using frozen/thawed sperm is a common procedure to obtain embryos from fertile or subfertile mares and stallions. Stallion-associated factors that impact the efficiency of ICSI have been studied less than those associated with the mare. Three experiments were conducted: Experiment 1: the effect of freezing extender composition and cryoprotectant; Experiment 2: the effect of sperm exposure to seminal plasma prior to freezing (ejaculated vs. epididymal sperm; two-freeze/thaw cycles each); and Experiment 3: the effect of sperm morphologic feature used for fertilization (normal vs. cytoplasmic droplet vs. bent tail); on the blastocyst rate after ICSI. In Experiment 1, stallion sperm was cryopreserved using commercially available extenders containing: a) 2% egg-yolk + milk + 4% glycerol (MFR5); b) 2% egg-yolk + milk + 2% glycerol + 3% methyl formamide (CMMFR5); c) 20% egg-yolk + 4.75% glycerol (LE); or d) 20% egg-yolk + 2% glycerol + 3% methyl formamide (CMLE). Sperm from each of the treatment groups were used for Piezo-driven ICSI on in vitro-matured equine oocytes (n = 321). Extender CMLE resulted in a lower cleavage rate (35%) than the other treatment groups (MFR5: 74%, CMMFR5: 62%, LE: 68%; P 0.05). Extender MFR5 yielded a higher blastocyst rate per injected oocyte (21/82 [26%]) than the Groups LE (8/77 [10%]), CMLE (4/80 [5%]) or CMMFR5 (4/82 [5%]; P 0.05). Extender MFR5 also yielded a higher blastocyst rate per cleaved oocyte (34%) than Groups LE, CMLE or CMMFR5 (15%, 14%, 8%; respectively P 0.05). In Experiment 2, ejaculated (EJ) and epididymal (EPD) sperm from a fertile stallion which was initially cryopreserved in the CMLE extender, was thawed and re-cryopreserved in MFR5 extender for use in ICSI. Sperm from both groups (EJ vs. EPD) were used for ICSI on in vitro matured oocytes (n = 127). Differences were not detected for cleavage rate (EJ: 36/63 [57%] vs. EPD: 49/64 [77%]), blastocyst rate per injected oocyte (EJ: 11/63 [17%] vs. EPD: 11/64 [17%]), or blastocyst rate per cleaved oocyte (EJ: 31% vs. EPD: 22%) between treatment groups (P 0.05). In Experiment 3, morphologically normal sperm (N), or sperm with proximal droplets (PD) or bent tails (BT), were obtained from a single fertile stallion and were used for ICSI on in vitro matured oocytes (n = 75). No differences were detected among treatment groups for cleavage rate (N: 19/25 [77%] vs. PD: 20/25 [88%] vs. BT: 18/25 [72%]), blastocyst rate per injected oocyte (N: 6/25 [24%] vs. PD: 5/25 [20%] vs. BT: 2/25 [8%]), and blastocyst rate per cleaved oocyte (N: 32% vs. PD: 23% vs. BT: 11%; P 0.05). In conclusion, the current study indicates that freezing extender composition used for stallion sperm cryopreservation has an impact on the developmental competence of in vitro-matured equine oocytes after ICSI and in vitro culture. Furthermore, we were unable to detect differences on cleavage and blastocyst rates when performing ICSI when using: 1) ejaculated or epididymal sperm; or 2) sperm with different morphologic features. The results from the current study provide additional insight regarding stallion-related factors that should be considered when performing ICSI in horses.

OBJECTIVE: Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing IVF in a modified natural cycle (MNC-IVF)? STUDY DESIGN: This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. All predicted poor responders (Poseidon groups 3 and 4) who underwent MNC-IVF in our center were included. Mild ovarian stimulation (rFSH/uFSH/hp-hMG) was started when a follicle with a mean diameter of 12-14 mm was observed on ultrasound scan; GnRH antagonist was added from the next day onwards. Mature oocytes were inseminated using ICSI. RESULTS: In total 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.28 (0.26) ng/ml, respectively. The daily dose of gonadotropins was either

RESEARCH QUESTION: Is seminal oxidation-reduction potential (ORP) clinically relevant to reproductive outcome? DESIGN: Prospective observational study including a total of 144 couples who had an intracytoplasmic sperm injection (ICSI) cycle between June 2018 and December 2020. The study included patients undergoing fresh ICSI cycles with autologous gametes. Cycles that had day 3 embryo transfers and cryopreservation cycles were excluded. There was no restriction on patients with severe male infertility; couples with unexplained infertility and unexplained male infertility were included, those with azoospermia were excluded. Semen analysis, seminal ORP as determined by means of the MiOXSYS system, sperm DNA fragmentation (SDF) and reproductive outcomes (fertilization, blastocyst development, clinical pregnancy and live birth) were determined. RESULTS: Seminal ORP was significantly negatively correlated with fertilization rate (r = -0.267; P = 0.0012), blastocyst development rate (r = -0.432; P < 0.0001), implantation/clinical pregnancy (r = -0.305; P = 0.0003) and live birth (r = -0.366; P < 0.0001). Receiver operating characteristic curve analysis showed significant predictive power for ORP for fertilization (≥80%; area under the curve [AUC] 0.652; P = 0.0012), blastocyst development rate (≥60%; AUC 0.794; P < 0.0001), implantation/clinical pregnancy (AUC 0.680; P = 0.0002) and live birth (AUC 0.728; P < 0.0001). Comparable results were obtained for SDF (fertilization: AUC 0.678; blastocyst development: AUC 0.777; implantation/clinical pregnancy: AUC 0.665; live birth: AUC 0.723). Normal sperm morphology showed the lowest predictive power for all reproductive outcome parameters. With male age as confounding factor, ORP (cut-off value of 0.51 mV/106 sperm/ml) has significant (P < 0.04667) effects on odds ratios for all reproductive outcome parameters. Multivariate logistic regression to investigate potential seminal and female confounding factors revealed that seminal ORP significantly (P < 0.0039; P < 0.0130) affects reproductive outcome. CONCLUSION: Seminal ORP is relevant for good fertilization, blastocyst development, implantation, clinical pregnancy and live birth.

The objective of this study was to evaluate the association between caffeine and alcohol consumption and in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcomes.The protocol was registered in the PROSPERO database on May 23, 2021 (registration number: CRD42021256649), and updated on August 4, 2022. Two researchers performed a literature search in the PubMed, Embase, and MEDLINE databases for articles published before July 15, 2022 independently. Studies investigating the association between caffeine and alcohol consumption and IVF/ICSI outcomes were included, and studies reporting the consumption amount were analyzed using a one-stage robust error meta-regression-based method to explore potential dose-response relation. Funnel plot was used to assess publication bias if more than 10 studies were included.Twelve studies on caffeine consumption and 14 studies on alcohol consumption were included in the systematic review, of which seven and nine were eligible for the meta-analysis. These studies included 26 922 women and/or their spouses who underwent IVF/ICSI treatment. Women's and men's caffeine consumption was not significantly associated with the pregnancy rate (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.85-1.12; OR 0.93, 95% CI 0.75-1.14; respectively) and the live birth rate (OR 0.98, 95% CI 0.89-1.08; OR 0.98, 95% CI 0.86-1.12; respectively) of IVF/ICSI. Maternal alcohol consumption was negatively associated with pregnancy after IVF/ICSI treatment (OR 0.83, 95% CI 0.69-1.01). Paternal alcohol consumption was negatively associated with partner's live birth after IVF/ICSI treatment (OR 0.88, 95% CI 0.79-0.99). Compared with abstainers, the chance of achieving a pregnancy after IVF/ICSI treatment decreased by 7% for women who consumed 84 g alcohol per week (OR 0.93, 95% CI 0.90-0.98), and the chance of partners achieving a live birth decreased by 9% for men who consumed 84 g alcohol per week (OR 0.91, 95% CI 0.88-0.94).There was no association between caffeine consumption and pregnancy or live birth rate of IVF/ICSI. Women's alcohol consumption was associated with decreased pregnancy rate after IVF/ICSI treatment when weekly consumption was greater than 84 g. Men's alcohol consumption was associated with decreased live birth rate after IVF/ICSI treatment when weekly consumption was greater than 84 g.

STUDY QUESTION Does mental health and behaviour differ between those conceived with and those conceived without ART? SUMMARY ANSWER Our study observed less externalizing behaviour (delinquent/aggressive), and more parent-reported internalizing behaviour, as well as more (clinical) depression at age 14 years, in adolescents conceived after ART compared to their non-ART counterparts. WHAT IS KNOWN ALREADY Health outcomes of ART-conceived offspring may differ from those conceived without ART, and previous studies have reported differences in behaviour and mental health, particularly in childhood. STUDY DESIGN, SIZE, DURATION The Growing Up Healthy Study (GUHS) is a prospective cohort study, investigating the long-term health of offspring conceived after ART (aged 14, 17 and 20 years), in the two operational fertility clinics in Western Australia 1991–2001 (n = 303). Their long-term health outcomes were compared to those of offspring conceived without ART from the Raine Study Generation 2 (Gen2) born 1989–1991 (n = 2868). Both cohorts are representative of the local adolescent population. PARTICIPANTS/MATERIALS, SETTING, METHODS Mental health parameters and behaviour were assessed at ages 14 and 17 years, through the parent completed ‘Child Behaviour Checklist’ (CBCL; ART versus non-ART: age 14 years: N = 150 versus N = 1781, age 17 years: N = 160 versus N = 1351), and the adolescent completed equivalent ‘Youth Self-Report’ (YSR; age 14 years: by N = 151 versus N = 1557, age 17 years: N = 161 and N = 1232). Both tools generate a T-score (standardized for age and sex) for internalizing (withdrawn, somatic complaints, anxious/depressed), externalizing (delinquent/aggressive behaviour) and total behaviour. Adolescents also completed the ‘Beck Depression Inventory for Youth’ (BDI-Y; age 14 years: N = 151 versus N = 1563, age 17 years: N = 161 versus N = 1219). Higher scores indicate poorer mental health and behaviour on all the above tools. Parent-reported doctor-diagnosed conditions (anxiety, behavioural problems, attention problems and depression) were also univariately compared between the cohorts. In addition, univariate comparisons were conducted between the GUHS adolescents and Gen2 adolescents born to subfertile parents (time to pregnancy >12 months), as well as between offspring born to subfertile versus fertile parents within the Gen2 cohort. A subgroup analysis excluding offspring born preterm ( MAIN RESULTS AND THE ROLE OF CHANCE At both 14 and 17 years of age, ART versus non-ART-conceived adolescents reported lower mean T-scores for externalizing problems (age 14 years: 49 versus 51, P = 0.045, age 17 years: 49 versus 52, P LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is the time difference between the GUHS and Gen2 assessments. Even though we have adjusted for covariates, additional socio-economic and lifestyle factors affecting behaviour and mental well-being could have changed. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI), owing to the low number of ICSI cycles at the time of study. Fertility sub-analyses need to be replicated in larger cohorts to increase power, potentially using siblingship designs. Lastly, selection bias may be present. WIDER IMPLICATIONS OF THE FINDINGS The reported lower prevalence of externalizing behaviour (delinquent/aggressive), and higher prevalence of internalizing behaviour, as well as more (clinical) depression at age 14 years, in ART versus non-ART-conceived adolescents, is in line with some previous studies, mostly conducted in childhood. It is reassuring that differences in the rates of depression were not observed at age 17 years, however, these findings require replication. As the use of ART is common, and mental health disorders are increasing, knowledge about a potential association is important for parents and healthcare providers alike. STUDY FUNDING/COMPETING INTEREST(S) This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. TRIAL REGISTRATION NUMBER N/A.

SummaryThe follicle-stimulating hormone (FSH) and its receptor regulate the quantity and quality of spermatozoa production. Several studies have analyzed the effect of single nucleotide polymorphisms (SNPs) in exon 10 of the FSH receptor (FSHR) on basic semen parameters without yet reaching a firm consensus. The aim of this study was to evaluate the effect of p.Thr307Ala and p.Asn680Ser polymorphisms in exon 10 of the FSHR gene, in infertile men, on intracytoplasmic sperm injection (ICSI) outcomes. This study was conducted between March 2019 and February 2020 on infertile couples undergoing ICSI at Al Hadi Laboratory and Medical Center, Lebanon. Couples with severe infertility factors that may impair gametogenesis/embryogenesis (e.g. advanced maternal age, premature ovarian failure, underwent gonadotoxic treatments, etc.) were excluded from the study. Semen and blood samples were collected from infertile men on the day of oocyte collection. Infertile men (n = 173) were screened for FSHR variants using polymerase chain reaction-restriction fragment length polymorphism. Moreover, fertilization rates, embryo quality, and pregnancy outcomes were evaluated. Higher sperm concentrations were found in the p.Thr307Ala group than the p.Thr307Thr (P < 0.01) and p.Ala307Ala (P < 0.05) groups. Furthermore, fertilization rate was significantly lower in the p.Ala307Ala genotype than in the p.Thr307Thr genotype (P < 0.05). We showed that FSHR variants in infertile men undergoing ICSI could affect sperm concentration, motility, and fertilization rates. Therefore, it will be important to confirm these results in further studies using a larger sample size.

To assess whether there is an association between extended in vitro culture based on embryo developmental stage at transfer and pre-malignant gestational trophoblastic disease (GTD) risk of molar pregnancy during assisted reproduction.A retrospective study was carried out using Human Fertilization and Embryology Authority (HFEA) anonymized register from 1999 to 2016. A total of 540,376 cycles were eligible to be included in the study after excluding any kind of donor treatment or surrogacy, frozen embryo transfers, and cycles with incomplete data. Subgroup analysis was carried out in subjects with primary infertility aiming to exclude an increased risk in those with a previous GTD. Multivariate logistic regression analysis was used to adjust for possible confounders, and the effect of day of embryo transfer in IVF (in vitro fertilization)/ICSI (intracytoplasmic sperm injection) treatment on a molar pregnancy GTD outcome was analyzed.The prevalence of a molar pregnancy GTD among the study population was 3.4/10,000 livebirths (53/156,683) with a higher risk in the over 40 age category. No significant difference of pre-malignant GTD incidence was seen between IVF and ICSI (0.01% vs 0.009% respectively). No association was seen with GTD based on type/cause of infertility or number of embryos transferred. Crude (1.06; 95% CI 0.852-1.31) and adjusted (1.07; 95% CI (0.857-1.32) odds ratios were calculated to see an association between day of embryo transfer and the occurrence of a GTD. There was no association between day of embryo transfer and molar GTD risk after adjusting for age and secondary infertility.No significant association between pre-malignant molar gestational trophoblastic disease and extended in vitro embryo culture was found after analyzing 540,376 cycles of IVF and ICSI.

There is a paucity of literature on the impact of bariatric surgery on artificial reproductive technology (ART) outcomes. This topic should be examined, given that most bariatric surgery candidates are of reproductive age and those with obesity are significantly more likely to experience poor fertility outcomes. This systematic review aimed to determine if bariatric surgery impacts ART outcomes and if effects vary between females and males.MEDLINE, EMBASE, SCOPUS, and the Cochrane Central Register of Controlled Trials were searched for English studies published between January 1978 and May 2021.Studies with participants who had received bariatric surgery and subsequently underwent ART (i.e., in vitro fertilization or intracytoplasmic sperm injection) were eligible for inclusion. Screening, data abstraction, and risk of bias assessment were conducted independently and in duplicate.Of the 279 articles screened for eligibility, 25 were sought for full text review, and 7 were included for analysis. Four studies (57%) examined ART interventions in females, while 3 (43%) examined interventions in males. Data on cumulative live birth rate (CLBR) was extracted for all 7 studies (N = 169). There were 50 live births with CLBRs ranging from 0.0% to 80.0%. Data on female secondary outcomes were varied. Data on male secondary outcomes were contradictory: 1 study indicated improved sperm parameters following bariatric surgery, while 2 showed decreased parameters, with certain participants seeing improvements after several months.Bariatric surgery prior to ART may have an impact on CLBRs; however, high-quality research is needed to delineate the direct effects of bariatric surgery on ART outcomes. Various sex-specific outcomes should be considered prior to recommending ART after bariatric surgery. Future research should determine the optimal type of bariatric surgery and timing of ART following bariatric surgery.

To discuss existing literature and current use of intravaginal culture (IVC) as an option for patients seeking fertility therapies.IVC is the combination of oocytes and sperm with culture media in a sealed device that is placed vaginally and left in place while fertilization and early embryo development occurs. Studies show that IVC is safe, well-tolerated, and has similar outcomes in patients as compared to standard in vitro fertilization techniques (conventional insemination and/or intracytoplasmic sperm injection). The new device, INVOcell, while recommended by the FDA for minimal stimulation and up to 72 h of culture and seven oocytes, has been used successfully with more oocytes and for 5 days (until blastocyst stage for transfer) in many centers. Live birth rates and neonatal outcomes are reassuring.Infertility is a common disease and the vast majority of patients globally will not seek care. IVC may improve access to care, lower costs, provide an alternative for patients who have ethical or religious concerns, and be an increasingly utilized option for those seeking ART therapies. It may also ease workflow burdens in labs where space, equipment, or highly trained lab staff are scarce. More data is warranted to track cumulative outcomes and optimize the ideal patient candidate, but it is a viable alternative in the armamentarium of fertility therapies.

The purpose of this study was to investigate the effect of intracytoplasmic sperm injection (ICSI) on the normal fertilization rate of oocytes and the clinical pregnancy rate of cycles in male infertility. Eighty cases of male infertility patients attending our hospital from March 2020 to March 2021 were selected and divided into observation group and control group using the random number table method, with 40 cases in each group. The control group was treated with in vitro fertilization (IVF), and the observation group was treated with ICSI. The normal fertilization rate of oocytes and the clinical pregnancy rate of the cycle were compared between the two groups, and the adverse pregnancy outcome and obstetric and perinatal complications were compared between the two groups The rate of normal fertilization and clinical pregnancy in the cycle was higher in the observation group ( P P > 0.05) when comparing adverse pregnancy outcomes between the two groups. The difference was not statistically significant ( P > 0.05) when comparing obstetrics (5.41%, 10.34%) and perinatal complications (8.33%, 14.81%) between the two groups. ICSI in male infertility is significantly effective in improving the rate of normal oocyte fertilization and the clinical pregnancy rate of the cycle. It also has a low impact on adverse pregnancy outcomes and obstetric and perinatal complications and has a high safety profile.

STUDY QUESTION Does ovarian stimulation with the addition of tamoxifen or letrozole affect the number of cumulus-oocyte complexes (COCs) retrieved compared to standard ovarian stimulation in women with breast cancer who undergo fertility preservation? SUMMARY ANSWER Alternative ovarian stimulation protocols with tamoxifen or letrozole did not affect the number of COCs retrieved at follicle aspiration in women with breast cancer. WHAT IS KNOWN ALREADY Alternative ovarian stimulation protocols have been introduced for women with breast cancer who opt for fertility preservation by means of banking of oocytes or embryos. How these ovarian stimulation protocols compare to standard ovarian stimulation in terms of COC yield is unknown. STUDY DESIGN, SIZE, DURATION This multicentre, open-label randomized controlled superiority trial was carried out in 10 hospitals in the Netherlands and 1 hospital in Belgium between January 2014 and December 2018. We randomly assigned women with breast cancer, aged 18–43 years, who opted for banking of oocytes or embryos to one of three study arms; ovarian stimulation plus tamoxifen, ovarian stimulation plus letrozole or standard ovarian stimulation. Standard ovarian stimulation included GnRH antagonist, recombinant FSH and GnRH agonist trigger. Randomization was performed with a web-based system in a 1:1:1 ratio, stratified for oral contraception usage at start of ovarian stimulation, positive estrogen receptor (ER) status and positive lymph nodes. Patients and caregivers were not blinded to the assigned treatment. The primary outcome was number of COCs retrieved at follicle aspiration. PARTICIPANTS/MATERIALS, SETTING, METHODS During the study period, 162 women were randomly assigned to one of three interventions. Fifty-four underwent ovarian stimulation plus tamoxifen, 53 ovarian stimulation plus letrozole and 55 standard ovarian stimulation. Analysis was according to intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE No differences among groups were observed in the mean (±SD) number of COCs retrieved: 12.5 (10.4) after ovarian stimulation plus tamoxifen, 14.2 (9.4) after ovarian stimulation plus letrozole and 13.6 (11.6) after standard ovarian stimulation (mean difference −1.13, 95% CI −5.70 to 3.43 for tamoxifen versus standard ovarian stimulation and 0.58, 95% CI −4.03 to 5.20 for letrozole versus standard ovarian stimulation). After adjusting for oral contraception usage at the start of ovarian stimulation, positive ER status and positive lymph nodes, the mean difference was −1.11 (95% CI −5.58 to 3.35) after ovarian stimulation plus tamoxifen versus standard ovarian stimulation and 0.30 (95% CI −4.19 to 4.78) after ovarian stimulation plus letrozole versus standard ovarian stimulation. There were also no differences in the number of oocytes or embryos banked. There was one serious adverse event after standard ovarian stimulation: one woman was admitted to the hospital because of ovarian hyperstimulation syndrome. LIMITATIONS, REASONS FOR CAUTION The available literature on which we based our hypothesis, power analysis and sample size calculation was scarce and studies were of low quality. Our study did not have sufficient power to perform subgroup analysis on follicular, luteal or random start of ovarian stimulation. WIDER IMPLICATIONS OF THE FINDINGS Our study showed that adding tamoxifen or letrozole to a standard ovarian stimulation protocol in women with breast cancer does not impact the effectiveness of fertility preservation and paves the way for high-quality long-term follow-up on breast cancer treatment outcomes and women’s future pregnancy outcomes. Our study also highlights the need for high-quality studies for all women opting for fertility preservation, as alternative ovarian stimulation protocols have been introduced to clinical practice without proper evidence. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a grant (2011.WO23.C129) of ‘Stichting Pink Ribbon’, a breast cancer fundraising charity organization in the Netherlands. M.G., C.B.L. and R.S. declared that the Center for Reproductive Medicine, Amsterdam UMC (location VUMC) has received unconditional research and educational grants from Guerbet, Merck and Ferring, not related to the presented work. C.B.L. declared a speakers fee for Inmed and Yingming. S.C.L. reports grants and non-financial support from Agendia, grants, non-financial support and other from AstraZeneca, grants from Eurocept-pharmaceuticals, grants and non-financial support from Genentech/Roche and Novartis, grants from Pfizer, grants and non-financial support from Tesaro and Immunomedics, other from Cergentis, IBM, Bayer, and Daiichi-Sankyo, outside the submitted work; In addition, S.C.L. has a patent UN23A01/P-EP pending that is unrelated to the present work. J.M.J.S. reported payments and travel grants from Merck and Ferring. C.C.M.B. reports her role as unpaid president of the National guideline committee on Fertility Preservation in women with cancer. K.F. received unrestricted grants from Merck Serono, Good Life and Ferring not related to present work. K.F. declared paid lectures for Ferring. D.S. declared former employment from Merck Sharp & Dohme (MSD). K.F. declared paid lectures for Ferring. D.S. reports grants from MSD, Gedeon Richter and Ferring paid to his institution; consulting fee payments from MSD and Merck Serono paid to his institution; speaker honoraria from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono paid to his institution. D.S. has also received travel and meeting support from MSD, Gedeon Richter, Ferring Pharmaceuticals and Merck Serono. No payments are related to present work. TRIAL REGISTRATION NUMBER NTR4108. TRIAL REGISTRATION DATE 6 August 2013. DATE OF FIRST PATIENT’S ENROLMENT 30 January 2014.

Two decades have passed since the discovery of phospholipase C zeta (PLCZ1) as the sperm oocyte-activating factor. At present, there is a general consensus that PLCZ1 is responsible for triggering the calcium (Ca2+) oscillations necessary to start the oocyte activation process in mammals. One proof is that abnormal, reduced, or absent PLCZ1 in human spermatozoa leads to fertilization failure (FF) after intracytoplasmic sperm injection (ICSI). ICSI is the most effective assisted reproduction technique and enables overcoming almost all male infertility conditions. Despite fertilization rates of up to 80%, FF does occur in 1–3% of ICSI cycles, which leaves these patients with few options for obtaining genetically related offspring. Assisted oocyte activation (AOA) using Ca+2 ionophores has emerged as a useful treatment option for these patients. While AOA has been proven very beneficial for the treatment of sperm-related FF, some cases of female-related FF cannot be overcome by AOA. Therefore, the development of appropriate diagnostic tests that predict the prognosis of AOA treatment would be advantageous to improve the clinical management of these patients and shorten the time to pregnancy. The aim of this review is to provide an up-to-date overview of the genetic causes of FF after ICSI and to discuss the advantages and disadvantages of using PLCZ1 as a diagnostic marker or therapeutic molecule in comparison with currently available diagnostic tests and treatments.

Any abnormality of the uterine cavity can result in reduced endometrial receptivity, which negatively affects embryo implantation and leads to lower clinical pregnancy rates. The effects of improved uterine cavity environment on in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)-embryo transfer (ET) treatment outcome are unclear. This study aimed to investigate the impact of improved uterine cavity abnormalities on the pregnancy outcomes of infertile patients undergoing IVF/ICSI-ET.Retrospective study.Single-center.Women with infertility who underwent fresh cycles of IVF/ICSI-ET.We retrospectively analyzed the clinical data of 31 057 cycles of women with infertility undergoing IVF/ICSI-ET with hysteroscopy and treated at the First Affiliated Hospital of Zhengzhou University Reproductive Medicine Center from August 2009 to May 2018. According to the previous condition of their uterine cavity, patients were divided into the normal uterine cavity, single uterine cavity abnormality, and complex uterine cavity abnormality groups. Differences in general conditions and pregnancy-assisted outcomes were compared among the groups, which were screened according to propensity score matching.In 3005 cycles after propensity score matching screening, there were no statistically significant differences in the implantation and clinical pregnancy rates of patients with successfully treated uterine cavity abnormalities and lesions (p.05). The miscarriage rate was significantly higher in the complex uterine cavity abnormality group than in the normal (p = .001) and single uterine cavity abnormality groups (p = .002). Logistic regression analysis showed that the female partner's age (adjusted odds ratio, 1.12; 95% confidence interval, 1.05-1.19; p = .001) and history of intrauterine adhesions (adjusted odds ratio, 1.44; 95% confidence interval, 1.12-1.85; p = .005) were independent risk factors for miscarriage.The age of the female partner and history of intrauterine adhesions increased the miscarriage rate in patients undergoing IVF/ICSI-ET.

Objectives To compare growth trajectories from second trimester to birth of standardized unified estimated fetal weight (EFW) or birthweight (BW) measurements in IVF/ICSI pregnancies obtained after thawed versus fresh blastocyst transfers (BT). Methods Prospective longitudinal cohort study performed in the Fetal Medicine and Obstetric Departments of San Raffaele Hospital in Milan, from 2016 to 2020. Singleton viable gestations conceived by autologous IVF/ICSI conceptions from fresh or thawed BT with BW measurements and ultrasound standard fetal biometry performed at 19-36 weeks by doctors blinded to the employment of cryopreservation. Twins, significant pre-gestational diseases, miscarriages, abnormalities and other types of medically assisted reproduction techniques were excluded. EFW and BW Z-scores and their trajectories were analyzed with general linear model (GLM) and logistic regression (LR) with a unified modelling methodology based upon the Fetal Medicine Foundation fetal and neonatal population weight charts and adjusting for major confounders. Differences between prenatal EFW and postnatal BW centiles were assessed and compared with contingency tables, X2 test and convension of prenatal to postnatal centiles. Results 631 IVF/ICSI pregnancies were considered (fresh BT n=263; thawed BT n=368) with a total of 1795 EFW observations (fresh BT n=715; thawed BT n=1080; median: 3 per patient). EFW and BW small for gestational age (SGA) 90 centile were significantly more frequent in thawed vs fresh BT group (p=0.042 and p=0.003). GLM showed significantly decreasing EFW Z-scores with advancing gestational age (GA) assuming equal effect of GA in both study groups (no significant interaction GA and x group was found). Both smoothed mean EFW Z-scores from 19 weeks to term and smoothed mean BW Z-scores were significantly greater in thawed vs fresh BT (EFW Z-scores: 0.70±1.29 vs. 0.28±1.43; p 90 centile was significantly greater in frozen (p 90th and >97th centile were nearly doubled in thawed vs. fresh (p Conclusions Robust novel unified prenatal-postnatal modelling in IVF/ICSI pregnancies after thawed or fresh BT from 19 weeks to birth showed non-divergent growth trajectories with greater EFW and BW Z-scores in frozen vs. fresh BT. Mean EFW Z-scores in both IVF/ICSI groups were greater as expected for natural conception up to 32 weeks in fresh BT and 35 weeks in thawed BT, with maximum effect at mid-trimester, decreasing with advancing gestation. Mean BW Z-scores were negative in both groups, with lower values in premature fetuses and increasing with advancing gestation. IVF/ICSI conceptions from thawed as compared to fresh BT present increased rate of LGA and reduced rate of SGA both prenatally or postnatally. The proportion of SGA fesuses across gestation increases rapidly in fresh and smoothly in thawed, whereas that of LGA fetuses decreases rapidly in thawed vs smoothly in fresh. Prediction models of SGA-LGA may be improved considering: 1. mode of conception with use of blastocyst cryopreservation; 2.unified prenatal-postnatal curves; 3. greater efficiency of prenatal prediction of SGA for fresh and for LGA in thawed. This article is protected by copyright. All rights reserved.

To compare efficacy of Intra Cytoplasmic Sperm Injection (ICSI) with conventional in vitro fertilization (IVF) on treatment outcome in women undergoing in vitro fertilization with donor sperm.We examined retrospectively the outcome data from 203 patients undergoing fresh cycles of conventional IVF (cIVF) or ICSI and an additional 77 frozen-thawed embryo transfer (FET) cycles during 2003-2014, all using donor sperm. Fertilization, cleavage, pregnancy and live birth rates and number of high-quality embryos were compared between cIVF and ICSI.Altogether 185 women underwent 479 transfer cycles of fresh embryos (237 cIVF vs. 224 ICSI and 18 "rescue ICSI" cycles). In addition, 77 FET cycles were compared (24 cIVF vs. 53 ICSI cycles). No differences were found between cIVF and ICSI in fertilization, cleavage, pregnancy and live birth rates (92.6% vs 92.2%, 73.4% vs 72.4%, 25.3% vs 27.2% and 13.1% vs 14.7%, respectively). Pregnancy and life birth rates remained similar even when FET cycles were included (25.8% vs 26.2% and 13.1% vs 13.7%, respectively). The use of ICSI was associated with lower rates of high-quality embryos (52.7% vs. 63.3%, P 0.0001). A multivariate logistic regression analysis found that patients' age, number of transferred embryos and smoking were independently associated with the chance to conceive. Patient age correlated inversely with fertilization rate (r = - 0.13, P 0.006).Non-smokers were more likely to become pregnant (OR = 2.23, P 0.012).Our results show that ICSI does not bypass the age-related decrease in oocyte quality in patients using donor sperm for IVF. Use of ICSI was associated with lower rates of high-quality embryos. The findings imply that ICSI should not be the primary method of insemination in patients undergoing IVF with donor sperm.

Male factors are implicated as the cause of roughly half of cases of infertility, and the presence of antisperm antibodies (ASA) may be responsible for some of these. Their presence is associated with a reduction in natural conception and live birth and impacts the success of assisted reproductive technologies. Interpretation of the data regarding ASAs and fertility is complicated by a lack of standardization in testing methodology and test thresholds and a lack of data on their prevalence in the healthy fertile population. Although their pathogenesis remains elusive, and many cases are idiopathic, a disruption in the immunologic blood-testis barrier (BTB) appears to contribute to the formation of ASA. As delineation of the specific antigen targets of ASA advances, it has been recognized that they may affect almost all aspects of sperm function, and ASA against different targets likely have specific mechanisms of impairing fertility. Intracytoplasmic sperm injection (ICSI) appears to be the most reliable method by which to overcome fertility impairment due to ASA, achieving similar outcomes to ASA-negative patients with regard to fertilization rates, embryonic development, clinical pregnancy rates, and live birth rates. The lack of consistency in testing for and reporting ASA remains a substantial barrier to achieving clarity in describing their role in infertility and the optimal management approach, and future research should use a unified approach to the detection and description of ASA. Determination of the specific antigens targeted by ASA, and their function and clinical relevance, would contribute to improving the understanding of ASA-mediated impacts on fertility and tailoring treatment appropriately to achieve the best outcomes for patients.

PURPOSE: Ovarian hyperstimulation syndrome (OHSS) represents a rare but dangerous condition associated with controlled ovarian stimulation (COS) in IVF/ICSI. Over the last decades, many strategies have been introduced into clinical practice with the objective of preventing this potentially life-threatening condition. Among these, the freeze-all policy has gained great popularity, thanks to improvements in vitrification. Nevertheless, not all clinics have adequate skills in vitrification procedures and patients may be dissatisfied with a longer time to pregnancy. METHODS: This study is a systematic review and network meta-analysis of randomized controlled trials comparing different strategies of ovarian stimulation in IVF/ICSI cycles (freeze-all policy, algorithm-based individualization of the starting dose, experience-based individualization of the starting dose, standard dose) in terms of reduction of OHSS, in normal responders. RESULTS: The results indicate that only the algorithm-based individualization of the starting gonadotropin dose reduces OHSS similarly to the freeze-all strategy. CONCLUSION: Albeit in the era of the freeze-all policy, the personalization of the starting gonadotropin dose obtained by the use of algorithms should be pursued as a valid and safe option for IVF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-022-02503-2.

PURPOSE: To investigate the potential genetic cause in a primary infertility patient with multiple morphological abnormalities of sperm flagella (MMAF). METHODS: The patient’s sperm was observed by light and electron microscopy. Whole-exome sequencing (WES) was carried out to identify candidate genes. Then, the mutation found by WES was verified by Sanger sequencing. The proteins interacting with ARMC2 were revealed by co-immunoprecipitation (co-IP) and mass spectrometry. Intracytoplasmic sperm injection (ICSI) was carried out to achieve successful pregnancy. RESULTS: Typical MMAF phenotype (absent, short, coiled, bent irregular flagella) was shown in the patient’s sperm. A novel homozygous mutation in ARMC2 (c.1264C > T) was identified. The proteins interacting with ARMC2 we found were CEP78, PGAM5, RHOA, FXR1, and SKIV2L2. The ICSI therapy was successful, and boy-girl twins were given birth. CONCLUSION: We found a novel mutation in ARMC2 which led to MMAF and male infertility. This is the first report of ICSI outcome of patient harboring ARMC2 mutation. The interacting proteins indicated that ARMC2 might be involved in multiple processes of spermatogenesis.

STUDY QUESTION Does processing of spermatozoa for IVF with ICSI by a microfluidic sperm separation device improve embryo quality compared with density-gradient centrifugation? SUMMARY ANSWER Patients randomized to microfluidic sperm preparation had similar cleavage- and blastocyst-stage embryo quality and clinical and ongoing pregnancy rates to those who underwent standard sperm processing for IVF with ICSI. WHAT IS KNOWN ALREADY Microfluidic sperm preparation can isolate spermatozoa for clinical use with minimal DNA fragmentation but with unclear impact on clinical outcomes. STUDY DESIGN, SIZE, DURATION A prospective randomized controlled trial of 386 patients planning IVF from June 2017 through September 2021 was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and ninety-two patients were allocated to sperm processing with a microfluidic sperm separation device for ICSI, while 194 patients were allocated to clinical standard density-gradient centrifugation (control) at an academic medical centre. MAIN RESULTS AND THE ROLE OF CHANCE In an intention to treat analysis, there were no differences in high-quality cleavage-stage embryo fraction [66.0 (25.8)% control versus 68.0 (30.3) microfluidic sperm preparation, P = 0.541, absolute difference −2.0, 95% CI (−8.5, 4.5)], or high-quality blastocyst fraction [37.4 (25.4) control versus 37.4 (26.2) microfluidic sperm preparation, P = 0.985, absolute difference −0.6 95% CI (−6, 5.9)] between groups. There were no differences in the clinical pregnancy or ongoing pregnancy rates between groups. LIMITATIONS, REASONS FOR CAUTION The population studied was inclusive and did not attempt to isolate male factor infertility cases or patients with a history of elevated sperm DNA fragmentation. WIDER IMPLICATIONS OF THE FINDINGS Microfluidic sperm separation performs similarly to density-gradient centrifugation in sperm preparation for IVF in an unselected population. STUDY FUNDING/COMPETING INTEREST(S) No external funding to declare. M.P.R. is a member of the Clinical Advisory Board for ZyMōt® Fertility, Inc. TRIAL REGISTRATION NUMBER NCT03085433. TRIAL REGISTRATION DATE 21 March 2017. DATE OF FIRST PATIENT’S ENROLLMENT 16 June 2017.

This study aims to examine the capacity of anti-Müllerian hormone (AMH) to predict cumulative live birth rate (CLBR) following IVF/ICSI within 36 months since start of treatment.This is a cohort study of women seeking IVF/ICSI fertility treatment in a private Australian IVF clinic in a single calendar year. Live births were monitored over three years following start date of IVF/ICSI. The impact of serum AMH level on the CLBR was assessed using Cox's proportional hazard models, and its incremental values in the prediction of CLBR were evaluated.The CLBRs were significantly higher in women with AMH levels in the highest (44.5 pmol/L; 87.0%, 95% CI 79.2% - 95.1%) and in the middle two quartiles (between 11.5 and 44.5 pmol/L; 81.0%, 95% CI 74.2% - 87.6%), compared with AMH levels below the 25th percentile (≤11.5 pmol/L; 63.2%, 95% CI 53.2% - 74.5%). Approximately half of the women with AMH in the lowest quartile conceived a live birth within 12 months of starting IVF compared with two-thirds of the women in the upper three quartiles. After adjusting for confounders, AMH remained a significant, albeit slight predictor of CLBR with a fall of 3 pmol/L equating to an 1% decrease in CLBR. The AMH's added values into the prediction of live birth were slight, indicated by a net reclassification improvement of 13.8%. The value is lower than that of maternal age (35.1%).Serum AMH level was a significant slight predictor of CLBR following IVF/ICSI. AMH should not be used to exclude women from IVF/ICSI however, women with low AMH should be counselled on the likelihood of taking longer to achieve a live birth than individuals with normal AMH levels.

To quantify the effect of unilateral oophorectomy (UO) on the rates of live birth and pregnancy in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).Systematic review and meta-analysis.Search of databases of published articles.The final analytical cohort encompassed 1,057 IVF/ICSI cycles in women with previous UO and 45,813 IVF/ICSI cycles in control women. Eighteen studies were identified by database searches of MEDLINE, Embase, Web of Science, and cited references. The review encompassed studies published up to June 1, 2021.UO prior to IVF/ICSI.The primary outcomes were the rates of live birth and pregnancy following IVF/ICSI. The secondary outcomes included the amount of gonadotropins administered for ovarian stimulation and the number of retrieved oocytes.The studies were rated from medium to high quality (from 5 to 8) according to the Newcastle-Ottawa Quality Assessment Scale. All studies were observational, with inherent bias, and heterogeneity was high. The primary outcome of live birth had a significantly lower odds ratio (OR) in women with previous UO compared with controls (OR = 0.72, 95% confidence interval [CI] 0.57 to 0.91, z = -2.72). The OR for pregnancy rate per initiated treatment cycle was also significantly lower in women with previous UO compared with controls (OR = 0.70, 95% CI 0.57 to 0.86, z = -3.35). Additionally, the dose of administered gonadotropins was significantly higher and the number of retrieved oocytes was significantly lower in women with UO.The meta-analysis showed a significant detrimental effect of UO on the rates of live birth and pregnancy. The analysis further supports previous data showing a decreased sensitivity to gonadotropins and a lower number of recovered oocytes in women with previous UO.PROSPERO 2020, CRD42020160313.

The value of assessing subfertile males with oligozoospermia is controversial due to prevailing notions that therapies are limited and ICSI may provide the couple with a baby without the need to explain the nature or cause of underlying male infertility. This article highlights that indiscriminately offering ICSI to oligozoospermic men is not free of potential adverse effects and does not grant subfertile men the best fertility pathway. Recent data support associations between oligozoospermia and poor male reproductive health, DNA and epigenetic damage in spermatozoa, and possible adverse health consequences to offspring. Many conditions affecting the testicles are capable of causing oligozoospermia (varicocele, genital infections, congenital and genetic defects testicular torsion/trauma, chronic diseases, inadequate lifestyle, occupational/environmental exposure to toxicants, drugs, cancer and related treatments, acute febrile illness, endocrine disorders, and iatrogenic damage to the genitourinary system). If oligozoospermia is detected, therapeutic interventions can improve sperm quantity/quality and the overall male health, ultimately resulting in better pregnancy outcomes even when ICSI is used. Fertility clinics are urged to engage male infertility specialists in diagnosing and treating oligozoospermia as a matter of best clinical practice. A well-conducted male infertility evaluation represents a unique opportunity to identify relevant medical and infertility conditions, many of which may be treated or alleviated. The andrological assessment may also help guide the optimal application of ICSI. The final goals are to positively impact the overall patient health, the couple's pregnancy prospects, and the offspring's well-being.

To compare assisted reproductive technology (ART) outcomes and preimplantation embryo development between underweight and normal-weight women.This retrospective cohort study included 26 underweight women (body mass index [BMI] 18.50 kg/mThe mean ± standard deviation age of the underweight and normal-weight women was similar (31.6 ± 4.17 vs 32.4 ± 3.59 years;Underweight status has no adverse impacts on the outcomes of IVF/ICSI with either fresh or frozen ET or on preimplantation embryo development and quality.

BACKGROUND: Studies have suggested that controlled ovarian hyperstimulation adversely affects endometrial receptivity due to advanced endometrial maturation. This adverse effect is mainly attributed to supraphysiological levels of both estrogen and progesterone identified in stimulated cycles. There is a paucity of published data investigating the very early luteal steroid profile following hCG trigger. AIM OF THE STUDY: This prospective, observational study was undertaken to determine the increase in serum progesterone levels after human chorionic gonadotrophin (hCG) trigger in stimulated IVF/ICSI cycles. MATERIALS AND METHODS: This proof-of-concept study included 11 patients requiring ovarian stimulation for IVF/ICSI and who planned to avail of pre-implantation genetic screening with embryo vitrification of their biopsied embryos at blastocyst stage. For each study participant, five additional blood samples were drawn at the following specific times in the stimulation cycle, on the morning (10.00–12.00) of the assigned day to induce final oocyte maturation with hCG trigger, immediately prior to administration of hCG for final oocyte maturation, 1 h, 2 h, and 36 h post hCG trigger. A prediction model, the Gompertz curve, was used to determine serum progesterone levels at intervals between the 2 h post hCG trigger sample and the day of oocyte retrieval. RESULTS: Statistically significant increases in serum progesterone levels were identified following hCG administration as early as 1 h following trigger (P4 0.57 ng/ml, p

Purpose To evaluate the efficacy and safety of short-term insemination and early-rescue intracytoplasmic sperm injection (ICSI), an approach that rescued oocytes with unclear second polar body 6 h after initial insemination by ICSI (early R-ICSI) to avoid total or near-total fertilization failure in conventional in vitro fertilization (IVF). Methods We performed a retrospective study in 16,769 patients (short-term IVF, n = 12,094; ICSI, n = 3452; early R-ICSI, n = 1223) who received IVF/ICSI treatment in our hospital from January 2009 to October 2018. Fertilization and clinical outcomes were compared among those three groups. Results When considering the R-ICSI embryos in the early R-ICSI group independently, the rates of fertilization and day-3 cleaved embryos in 2PN oocytes were comparable, the rates of fertilization (2PN) and high-quality embryos were lower, whereas the multi-PN fertilization rate (3.27%) was significantly higher than the ICSI group (1.26%). The difference of clinical pregnancy rate between the part of transferred R-ICSI embryos (40.81%) and the ICSI group (44.73%) remained nonsignificant. Furthermore, the rate of congenital birth defects in the early R-ICSI group (0.99%) was not significantly different from those in the short-term IVF (0.76%) and ICSI groups (1.07%). Conclusion Despite the multi-PN fertilization rate, our study highlights early R-ICSI as a safe and effective alternative in assisted reproduction to decrease complete IVF fertilization failure and reduce ICSI utilization. Additional large amount and long-term follow-up studies are needed to further validate the use of early R-ICSI.

To assess the effect of adenomyosis, endometriosis and combined adenomyosis and endometriosis, diagnosed on MRI, on IVF/ICSI outcomes versus male subfertility controls.This single-centre matched retrospective cohort study was carried out at Catharina Hospital in Eindhoven, The Netherlands. The study group consisted of infertile women undergoing their first, fresh embryo transfer during IVF/ICSI, with adenomyosis only (N = 36), endometriosis only (N = 61), and combined adenomyosis and endometriosis (N = 93) based on MRI. The control group consisted of IVF/ICSI patients undergoing treatment due to male subfertility (N = 889). 1:2 case-control matching based on age during IVF/ICSI, parity and number of embryos transferred was performed. Odds ratios were calculated for biochemical pregnancy, ongoing pregnancy and live birth rate versus matched male subfertility controls, and were corrected for embryo quality.Only the combined adenomyosis and endometriosis group showed a significantly reduced OR for biochemical pregnancy (p = 0.004, OR 0.453 (95% CI :(0.284-0.791)), ongoing pregnancy (p = 0.001, OR 0.302 (95% CI: (0.167-0.608)) and live birth (p = 0.001, OR 0.309 (95% CI: (0.168-0.644)) compared to matched male subfertility controls.The lower (ongoing) pregnancy and live birth rates in the combined adenomyosis and endometriosis women can be attributed to more severe disease in these women, ultimately resulting in increased chances for failed implantation and miscarriage. This highlights the importance of screening for adenomyosis in endometriosis patients, and identifies these women target for additional (hormonal) treatment prior to IVF/ICSI.

What are the pregnancy outcomes of IVF vitrified-warmed embryo transfer (IVF-FET) carried out in a clinical setting located at an altitude of 3650 m in Tibet, China?A retrospective analysis of 238 infertility couples (n = 344 treatment cycles) who underwent FET treatment at the Xizang Fukang Hospital, Tibet. The overall clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate and ectopic pregnancy rate were statistically analysed. Women were categorized into two groups based on age: 35 years or younger (n = 265 cycles) and over 35 years (n = 79 cycles). The general characteristics and pregnancy outcomes were compared between the two groups.The clinical pregnancy rate, implantation rate, live birth rate, miscarriage rate, and ectopic pregnancy rate of the 344 FET cycles were 43.02%, 30.90%, 35.17%, 18.24% and 1.35%, respectively. The clinical pregnancy rate (46.04% versus 32.91%), implantation rate (33.92% versus 21.01%) and live birth rate (38.11% versus 25.32%) in the group aged 35 years or younger were significantly greater than those in the group aged over 35 years (P = 0.039, P = 0.004, P = 0.037). The miscarriage rate (17.21% versus 23.08%) and ectopic pregnancy rate (0.82% versus 3.85%) were not significantly different in the two groups.A live birth rate of 35.17% can be achieved with IVF-FET in high-altitude areas (3650 m above sea level). Maternal age is still an important determinant of clinical pregnancy rate, implantation rate, and live birth rate of infertile patients in high-altitude areas.

OBJECTIVES: To explore the prevalence of poor sleep quality in couples undergoing fertility treatment and study possible associations.PARTICIPANTS: 163 women and 132 partners receiving in vitro (IVF) or intracytoplasmic sperm injection (ICSI) fertility treatment.SETTING: Three public Danish fertility clinics.DESIGN AND MEASUREMENTS: Participants completed the Pittsburgh Sleep Quality Index (PSQI) at three time-points as part of a larger RCT. Additional data from patient records and questionnaires were included to evaluate possible associations with treatment protocol type, psychological distress, and pregnancy outcome.RESULTS: Mean PSQI global scores before treatment were 8.1 (standard deviation = 2.3), with 91% of participants having PSQI scores > 5, indicating poor sleep quality. Scores did not differ between women and their partners and did not change during treatment. Statistically significant associations were found between sleep quality and depressive symptoms and state anxiety (p < .001). No difference in PSQI scores was found between protocol types. While there was a trend towards higher clinical pregnancy rates among women with good sleep quality (PSQI ≤ 5 = 72.7%, PSQI 6-10 = 52.6% and PSQI ≥ 11 = 42.3%), the differences did not reach statistical significance (p = .10-.21).CONCLUSIONS: Poor sleep quality is a prevalent problem among couples undergoing fertility treatment and is associated with psychological distress and possibly with pregnancy outcomes. Success rates after fertility treatment remain moderate, and poor sleep quality, a potentially modifiable factor, could be relevant to screen for and treat among couples undergoing fertility treatment. The high prevalence of poor sleep quality calls for further investigation.

RESEARCH QUESTION: Does magnetic-activated cell sorting (MACS) for sperm selection increase cumulative live birth rates (CLBR) or improve clinical parameters of reproductive success in couples undergoing intracytoplasmic sperm injection (ICSI) with donor oocytes? DESIGN: Retrospective multicentre observational study including data compiled from unselected couples who underwent ICSI cycles with donated oocytes in 15 Spanish IVIRMA fertility clinics (January 2008 to February 2020). Patients were divided into reference (standard semen processing, n = 40,157) and MACS (additional sperm selection step by MACS, n = 1,240) groups. CLBR were plotted on Kaplan-Meier curves and compared using the Mantel-Cox test. Proportions were compared with a generalized estimating equation model, and results were adjusted to clinically relevant variables. RESULTS: The MACS group showed a 27.1% CLBR after one embryo was transferred and 81.6% after four; the reference group had CLBR of 19.6% and 78.5%, respectively. CLBR in the MACS group was 4.2% after five oocytes were used and 75.5% after 15; for the reference group, CLBR were 7.8% and 78.3%, respectively. Kaplan-Meier curves showed statistically significant differences in CLBR per number of embryos transferred and per number of donated metaphase II oocytes between the two groups (both P

Letrozole reduces serum oestradiol by inhibiting the aromatase enzyme and has growing clinical indications in fertility. The available evidence of letrozole's role in ovarian stimulation for IVF and intracytoplasmic sperm injection (ICSI) and clinical outcomes was assessed. Medline, Cochrane, and ClinicalTrials.gov databases were systematically searched up until August 2021, including 31 studies (n = 16 randomized controlled trials [RCTs]; n = 15 observational studies). Live birth rate (LBR) in poor responders significantly increased by 7% (95% CI, 1% to 13%, P = 0.03) with letrozole co-treatment. Concomitantly, the gonadotrophin consumption was significantly reduced, without decreasing the number of retrieved oocytes. In normal responders, number of oocytes increased with 1.8 oocytes (95% CI 0.35 to 3.27, P = 0.01) with letrozole co-treatment. No significant effect on LBR, clinical pregnancy rate (CPR), or ovarian hyperstimulation syndrome rate was demonstrated. Only two studies reported on high responders and revealed no effect on LBR or CPR. Overall, the endometrium thickness was slightly affected, where as the, miscarriage rate and cancellation rate were unaffected by letrozole co-treatment. None of the included studies reported on neonatal outcomes. The quality of evidence was high or moderate in the RCTs and low in the observational studies. In conclusion, poor responders may benefit from co-treatment with letrozole during ovarian stimulation for IVF, whereas letrozole for normal and high responders requires further investigation with larger, high-quality studies.

Growth hormone, letrozole, and clomiphene citrate do not have US Food and Drug Administration approval for their use in in vitro fertilization (IVF) cycles. However, despite this fact, they often are used to augment the IVF cycle in women considered "low responders." Unfortunately, because of the problems inherent to recruiting women who have undergone several unsuccessful IVF treatment cycles, and their inevitable low live birth rate, studies involving adjuvants for women considered low responders to ovarian stimulation often are underpowered. This is compounded further by the difficulty in recruiting vulnerable women to a study with a placebo arm. Consequently, the evidence base for their use as adjuncts to IVF treatment may be limited, and consequently their use may be empirical rather than evidence based. This short narrative review describes the evidence for these "add-ons" for a patient with a low response to ovarian stimulation. It suggests that a woman with a low ovarian response will derive benefit from using growth hormone; with a reduction in the ovarian stimulation required for oocyte retrieval, collection of a greater number of oocytes, and improvement in the clinical pregnancy rate. Although there currently is insufficient evidence to state categorically that it leads to an increased chance of a live birth. In the same situation, clomiphene citrate and letrozole lead to a reduced requirement for gonadotropins before oocyte retrieval, but with no improvement in live birth rate for their use.

Objective. To explore the intracytoplasmic sperm injection (ICSI) and in vitro fertilization (IVF) method on the clinical outcomes of infertile women with ≤3 eggs retrieved. Study Design. We retrospectively analyzed a cohort of female patients who received IVF/ICSI to assist pregnancy with retrieved eggs ≤3. The general conditions, i.e., two pronuclei (2PN) fertilization rate, abnormal fertilization rate, high-quality embryo rate, cycle cancellation rate, pregnancy rate of fresh embryo transfer, cumulative pregnancy rate, and miscarriage were compared between the two groups. Results. When the number of retrieved eggs was one, the fertilization rate of 2PN was higher and the cycle cancellation rate was lower in the ICSI group than in the IVF group P < 0.05 . The pregnancy rates of fresh embryo transfer, frozen-thawed embryo transfer, and the cumulative pregnancy rate were all higher in the ICSI group than in the IVF group P < 0.05 . When the number of retrieved eggs was two, the pregnancy rate of frozen-thawed embryo transfer and cumulative pregnancy rate in the ICSI group were higher than those in the IVF group P < 0.05 . When the number of retrieved eggs was three, the fertilization rate of 2PN and the pregnancy rate of frozen-thawed embryo transfer were higher in the ICSI group than those in the IVF group (all P < 0.05 ). Conclusions. For patients with one egg retrieved, ICSI fertilization can reduce abnormal fertilization rate and cycle cancellation rate and improve cumulative pregnancy rate significantly enhancing patients’ benefits. However, increasing the number of eggs retrieved decreases the advantages of ICSI fertilization.

In this essay, the bioethical implications of the recent genetic manipulation in human embryos with CRISPR-Cas9 to eliminate the CCR5 gene and the birth of a pair of discordant twin girls are analyzed. The experiment was disseminated via social media. The main bioethical flaws identified include the justification of the model, the informed consent process and the lack of disclosure of evident conflicts of interest. The consequences of the experiment on the life of the twins that were born were not properly evaluated, such as the impact on their autonomy, the alleged benefits to be received and the future risks of harm during their lifetime. Having manipulated the germ cell line, the effects on their future offspring were not considered. This type of actions negatively affects the way society conceives science. Genetic engineering should be reserved to the basic experimental context or as clinical research for the correction of known serious diseases of genetic origin under strict regulatory and bioethical supervision and using a gradualist approach in accordance with the advances of gene editing techniques.En este ensayo se analizan las implicaciones bioéticas de la reciente manipulación genética en embriones humanos con CRISPR-Cas9 para eliminar el gen CCR5 y el nacimiento de dos gemelas discordantes. El experimento se divulgó en medios sociales. Los principales problemas bioéticos identificados son la justificación del modelo, el proceso de consentimiento informado y la falta de declaración de evidentes conflictos de interés. No se evaluaron apropiadamente las consecuencias del experimento sobre la vida de las gemelas nacidas como la afectación a su autonomía, los supuestos beneficios por recibir y los riesgos futuros de daño durante su vida. Habiendo manipulado la línea celular germinal, no se consideraron los efectos sobre su descendencia futura. Este tipo de acciones tiene un impacto negativo en la forma como la sociedad concibe la ciencia. La ingeniería genética debe reservarse al contexto experimental básico o bien como investigación cínica para la corrección de enfermedades conocidas graves de origen genético, bajo estricta supervisión regulatoria y bioética y de manera gradualista de acuerdo con el progreso de las técnicas de edición genética.

Background: We aimed to analyse our clinical results for a particular subgroup of patients with poor ovarian response (POR) in order to clarify if lower number of oocytes is a drawback for proceeding to C-IVFMaterials and methods: In this retrospective study, patient files of all couples (#1733) who underwent oocyte retrieval between January 2017 and December 2019 were reviewed and 191 cases diagnosed with non-male factor infertility in which ≤3 cumulus-oocyte-complexes available for fertilisation were analysed. Exclusion criteria were: woman age>42, patients with a history of previous ART trial, prenatal genetic testing cycles and couples undergoing total cryopreservation for any indication. Three groups were constructed depending on the method of fertilisation and on semen quality as follows: IVF non-male factor (Group 1,n=77); ICSI non-male factor (Group 2, n=65); ICSI male factor- ICSI/MF n=49 according to WHO reference values. Main outcome parameters were: fertilisation rate, implantation rate and live birth rate. Results: Fertilisation rate per collected COC was significantly higher in group 1 compared to the other two groups (85,68%, 72,58%, 73,33% respectively, p=0,004). FR per inseminated oocyte also tended to be higher in group 1 but not reaching a statistically significant level. Both techniques yielded similar implantation rates (20,42%, 28,49%, 23,33% respectively, p=0,407) and live birth rates (26,8%, 30,6%, 31,1% respectively, p=0.643).Conclusions: In the presence of normal semen parameters, low egg number is not an indication to perform ICSI. The choice of fertilisation method should be based primarily on semen quality, in combination with the patient’s previous history regardless of the ovarian reserve.

In sperm processing for IVF/ICSI incubation times differ considerably both between and within assisted reproduction facilities. There is no established consensus on the optimal sperm incubation timings to maximize pregnancy rates, and the few studies addressing this association rely on manual and operator-dependent methods for time recording. The present retrospective cohort study includes 1169 ICSI cycles using fresh semen processed by swim-up. An operator-independent, radiofrequency-based system was used to record sperm incubation times: from sample collection to swim-up (T1, 0.35 ± 0.26); from swim-up to ICSI (T2, 3.30 ± 2.2); and total time from sample collection to ICSI (T, 3.66 ± 2.26). In oocyte donation cycles, we observed a significant negative effect of T1 on fertilization rate (FR; generalized linear modelling regression, coeff. -0.20, p = 0.001); however, after analysing all times by deciles and by adjusted logistic regression, none of the time intervals had a significant effect on pregnancy (biochemical, clinical, and ongoing) and live birth (LB) rates (p 0.05 for all outcomes). In cycles using the patient's oocytes, we observed a negative effect of T2 (ordinal regression, coeff. -0.25, p = 0.011) and T (-0.33, p = 0.005) on the mean morphological score of the embryo cohort. In these cycles, a trend associating longer values of T with higher LB rates was identified (OR = 1.47, p = 0.050), although this difference is likely not clinically significant. In conclusion, while longer sperm incubation in vitro may impact slightly both FRs and embryo morphology after ICSI, no adverse effects were detected on the reproductive outcomes.

Research question Is there an influence of maternal lifestyle factors on the incidence of oocyte dimorphisms and the outcomes of intracytoplasmic sperm injection (ICSI) cycles? Design A total of 752 female patients undergoing ICSI cycle, in a private university-affiliated in vitro fertilization center, from January/2015 to December/2019, were included in this historical cohort study. Prior to start of controlled ovarian stimulation (COS), participants answered a questionnaire regarding cigarette smoking habit, consumption of items such as alcoholic beverages, refined sugar, artificial sweetener, soft drinks, fruits, legumes and vegetables, milk and dairy, and meats, and exercise frequency over the past 6 months. Oocyte morphology was evaluated before ICSI. The influence of maternal lifestyle factors on the incidence of oocyte dimorphisms and ICSI outcomes was evaluated by multivariate general linear models and generalized linear models, adjusted for potential confounders. The main outcome measures were the incidence of oocyte dimorphisms per cycle and clinical outcomes. Results Lifestyle factors and nutritional habits such as cigarette smoking, and the consumptions of alcohol, refined sugar, and artificial sweetener were positively associated with incidence of several oocyte dimorphisms and negatively associated with the response to COS and embryo development. Negative relationships were also observed between those habits and pregnancy outcomes, apart from miscarriage rate, in which positive relationships were observed. Significant negative dose-dependent relationships between those habits and implantation rate were noted. The intake of alcoholic beverages also showed inverse dose-dependent relationships with pregnancy and live-birth rates. Live-birth rate was also negatively associated with cigarette smoking, in a dose-dependent manner. Conclusions Bad maternal habits were associated with reduced oocyte quality and ICSI outcomes. Many of those associations were shown to be dose-dependent.

STUDY QUESTION What is the impact of uterine malformations on reproductive and neonatal outcomes of IVF/ICSI–frozen embryo transfer? SUMMARY ANSWER Unification defective uteri are associated with poorer neonatal outcomes including higher preterm delivery rate and lower birthweight, and septate uteri are associated with worse fertility outcomes including higher miscarriage and lower live birth rates (LBRs). WHAT IS KNOWN ALREADY Several studies have investigated the negative effects of uterine malformations on pregnancy outcomes. However, an all-round and definitive conclusion has not been reached yet owing to the relatively low incidence of the disease and the heterogeneity of study populations, especially among women undergoing ART. STUDY DESIGN, SIZE, DURATION This was a retrospective cohort study including 411 women with congenital uterine anomalies and 14 936 women with a normal uterus who underwent first frozen-thawed embryo transfer cycles of IVF/ICSI from July 2008 to August 2019. We compared reproductive outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductive outcomes of women with uterine malformations were studied through three propensity score-matched comparisons (patients with bicorporeal uterus, septate uterus and hemi-uterus [bicorporeal, septate and hemi-uterus groups, respectively] along with corresponding control groups without uterine malformations). We also compared pregnancy and neonatal outcomes, and performed subgroup analysis addressing didelphus, bicornuate uteri and septate uteri before and after surgery independently. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the matched control group, women with a bicorporeal uterus had a significantly lower LBR (24.4% versus 34.8%, odds ratio (OR) 0.61 [95% CI: 0.37, 1.00], P = 0.048). The incidence of miscarriage and preterm delivery was higher but not statistically significant (29.0% versus 18.1%, OR 1.85 [95% CI: 0.82, 4.19], P = 0.135; 22.6% versus 9.9%, OR 2.64 [95% CI: 1.07, 6.52], P = 0.063, respectively). In addition, the bicorporeal group had a significantly lower gestational age, higher caesarean rate and lower birthweight than bicorporeal control. Women with a septate uterus had comparable clinical pregnancy rates to controls (43.3% versus 49.9%, OR 0.77 [95% CI: 0.57, 1.04], P = 0.091), increased miscarriage rates (23.5% versus 13.0%, OR 2.05 [95% CI: 1.18, 3.58], P = 0.010) and lower LBRs (29.4% versus 42.2%, OR 0.57 [95% CI: 0.41, 0.79], P = 0.001). In both singleton and twins pregnancies, pregnancy and neonatal outcomes were comparable between women with a septate uterus and control. Women with a hemi-uterus had a tendency for lower clinical pregnancy rate (36.8% versus 42.3%, OR 0.80 [95% CI: 0.52, 1.21], P = 0.287) and LBR (29.8% versus 33.1%, OR 0.86 [95% CI: 0.55, 1.34], P = 0.502), compared to women without malformations. The incidences of miscarriage and preterm delivery, respectively, were 16.7% versus 16.6% (OR 1.01 [95% CI: 0.41, 2.47], P = 0.989), and 9.5% versus 11.4% (OR 0.82 [95% CI: 0.27, 2.51], P = 1) in women with a hemi-uterus as compared to control. LIMITATIONS, REASONS FOR CAUTION This was a single-centre, retrospective study in which neonatal data were extracted from parental questionnaires. The information on uteri septum type and surgery methods was poorly presented, with limited detail. In patients with uterine malformations, the number of babies with birth defects and twin pregnancies was relatively small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS Compared to patients with a normal uterus, women with uterine malformation have poorer reproductive outcomes. Pregnant women with a uterine anomaly need to be managed as high-risk pregnancies and followed with appropriate obstetric review. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Ministry of Technology (2018YFC1003000), the Elite Team Project of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JY201801), Shanghai Sailing Program (21YF1423200) and the Fundamental Research Program Funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZZ117). B.W.M. is supported by an NHMRC Investigatorgrant (GNT1176437). B.W.M. reports consultancy (with stock options) for ObsEva. B.W.M. has received research funding from Ferring and Merck. The authors declare no other competing interests. TRIAL REGISTRATION NUMBER N/A.

It has been shown that biotin, a water-soluble vitamin (B7), plays roles in reproductive functions, such as oocyte maturation and embryo development, in experimental animals. On the other hand, little is known about the clinical effects of biotin on human reproduction. In this study, serum and follicular fluid biotin levels were measured in patients who underwent in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), and their associations with reproductive outcomes were evaluated. As a result, biotin was detected in follicular fluid, as well as serum, and the biotin levels of follicular fluid were found to be positively correlated with those of serum. The biotin levels of serum were higher than those of follicular fluid, suggesting that biotin may be taken up into the follicular fluid from the blood. Although serum and follicular fluid biotin levels tended to be higher in pregnant patients than in non-pregnant patients, these data did not show the significant statistical difference. These findings indicate that biotin does not contribute to the maintenance of oocyte quality, and hence, it does not increase fertilization and pregnancy rates. J. Med. Invest. 69 : 65-69, February, 2022.

Objective To examine the cause of monopronucleated zygote (1PN) formation that includes both maternal and paternal genomes. Design Retrospective cohort study. Setting Private fertility clinic. Patient(s) A total of 44 1PN and 726 2-pronuclear zygotes from 702 patients were observed using 2 different time-lapse observation systems. Intervention(s) Previously recorded time lapse data were reviewed to examine the mechanism of 1PN formation. Main Outcome Measure(s) The distance between the position of the second polar body extrusion and the fertilization cone or epicenter/starting position of the cytoplasmic wave was measured, and the consequent data were analyzed. Cytoplasmic waves were confirmed using vector analysis software. Result(s) The cut-off value for the difference in the distance between the position of the second polar body extrusion and the fertilization cone or the epicenter/starting position of the cytoplasmic wave was 17 μm (AUC: 0.987, 95% CI: 0.976–0.999) for the Embryo Scope and 18 μm (AUC: 0.972, 95% CI: 0.955–0.988) for the iBIS time-lapse observation systems. Conclusion(s) In this study, it was found with a high degree of accuracy that a monopronucleus is formed when the fusion of the sperm takes place within 18 μm from the point of the second polar body extrusion. The theoretical chance of 1PN occurrence after in vitro fertilization is 2.7% when the sperm is considered to be fused anywhere in the plasma membrane of an oocyte.

RESEARCH QUESTION Is ovarian response associated with individualized follitropin delta dosing regimen comparable across different ethnic populations? DESIGN Post-hoc analysis of ovarian response in 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) undergoing stimulation with individualized follitropin delta dosing based on serum anti-Mullerian hormone concentration and body weight in two randomized controlled trials conducted in Japan (NCT03228680) and in Europe, North America and South America (NCT01956110). RESULTS On average, Japanese women weighed 10 kg less, which affected the total follitropin delta dose, compared with White women (83.5 ± 28.9 versus 90.2 ± 25.2 µg). At the end of stimulation, serum FSH concentrations were not significantly different between Japanese and White women (median 14.3 versus 14.0 IU/l), whereas serum oestradiol concentrations were significantly higher in Japanese women (median 6517 versus 5298 pmol/l, P < 0.0001). Japanese and White women had a similar number of oocytes retrieved with no significant differences among all women who started stimulation (9.3 ± 5.4 versus 9.5 ± 5.7), potential low responders (7.2 ± 3.7 versus 7.6 ± 4.6) or potential high responders (10.8 ± 5.9 versus 11.0 ± 6.0). At each level of ovarian response, serum oestradiol concentrations were significantly higher in Japanese women (P = 0.024). The incidence of early ovarian hyperstimulation syndrome was significantly higher in Japanese women compared with White women; overall (10.0% versus 2.2%, P = 0.0124) and at similar serum oestradiol concentrations (P = 0.0137). CONCLUSIONS The individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients, but the oestradiol response is higher in Japanese women.

The objective of a study was to assess the ability of the pre-implantation genetic testing of embryos for aneuploidy (PGT-A) and Endometrial receptivity array (ERA)-alone or in combination to improve the clinical outcomes in intracytoplasmic sperm injection (ICSI) cycles in patients with repeated implantation failure (RIF).This was a retrospective study of the 253 cycles with a history of the previous RIF. They were divided into four groups: Group I - frozen embryo transfers without any additional tests or procedures (pure FET),Median age of the entire study group for the females was 35 years. Only Group II (FET + PGT-A) showed statistically significant higher chance in achieving both biochemical (Patients with RIF can benefit from testing for embryo aneuploidy using the PGT-A method, but the ability of the ERA test to improve the clinical outcome in ICSI cycles seems to be rather limited. Although the endometrium cycle is also weakened with age, the contribution of the embryo genetic quality is evidently more important for successful implantation, although in principle both factors reflect the reproductive health.

BACKGROUND Impaired paternal genome expression may cause poor embryonic development after in vitro fertilization (IVF). OBJECTIVE To evaluate the expression of male infertility on embryo morphokinetics using a time-lapse incubator and its impact on IVF cycles. MATERIALS AND METHODS This retrospective cohort study followed patients from January 2017 to August 2019. Patients were divided according to the cause of infertility to male factor (study group) and unexplained infertility (control group) and further subdivided according to the severity of male infertility. RESULTS A cohort of 462 patients who underwent IVF cycles, with a total of 3,252 embryos was evaluated. Intracytoplasmic sperm injection (ICSI) was conducted more often in the study group compared to the control group (94% vs. 47%, p

What is the association between endometrial thickness (EMT) on HCG trigger day and outcomes related to birth weight in fresh IVF and intracytoplasmic sperm injection (ICSI) embryo transfer cycles?A retrospective cohort study of 9273 singleton live births born to women undergoing fresh IVF/ICSI cycles in a single centre between January 2014 and December 2018. Multivariable logistic regression was used to investigate the associations between EMT, low birth weight (LBW) and small for gestational age (SGA). Multivariable-adjusted linear regression models incorporating restricted cubic splines were used to investigate the dose-response relationship between EMT, birth weight and birth weight z-score, respectively. An EMT of 8 mm was set as a reference value.Compared with women with an EMT of 8.0 to14.0 mm the risk of delivering a SGA infant was increased with EMT8.0 mm (adjusted odds ratio [aOR] 1.78, 95% confidence interval [CI] 1.09 to 2.90) and decreased with EMT ≥ 14.0 mm (aOR 0.57, 95% CI 0.35 to 0.93, respectively). Birth weights of infants born to women with an EMT of 8.0 mm compared with women with EMT of 5.0, 6.0, and 7.0 mm were lower by 120 g (95% CI -175 g to -66 g), 80 g (95% CI -116 g to -44 g), and 40 g (95% CI -58 g to -22 g) respectively; infant birth weight z-scores were also decreased by 0.19 (95% CI -0.27 to -0.10), 0.12 (95% CI -0.18 to -0.07) and 0.06 (95% CI -0.09 to -0.03), respectively.A thinner endometrium was associated with lower birth weight and birth weight z-score, and higher risk of SGA. Women with a thin endometrium warrant special attention during pregnancy.

To investigate whether patients with a previous recombinant follicle stimulating hormone (rFSH)-stimulated cycle would have improved outcomes with rFSH + recombinant luteinizing hormone (rLH) stimulation in the following cycle. For the present retrospective case-control study, 228 cycles performed in 114 patients undergoing intracytoplasmic sperm injection (ICSI) between 2015 and 2018 in an in vitro fertilization (IVF) center were evaluated. Controlled ovarian stimulation (COS) was achieved with rFSH (Gonal-f, Serono, Geneva, Switzerland) in the first ICSI cycle (rFSH group), and with rFSH and rLH (Pergoveris, Merck Serono S.p.A, Bari, Italy) in the second cycle (rFSH + rLH group). The ICSI outcomes were compared among the groups. Higher estradiol levels, oocyte yield, day-3 high-quality embryos rate and implantation rate, and a lower miscarriage rate were observed in the rFSH + rLH group compared with the rFSH group. In patients 35 years old, the implantation rate was higher in the rFSH + rLH group compared with the rFSH group. In patients ≥ 35 years old, higher estradiol levels, oocyte yield, day-3 high-quality embryos rate, and implantation rate were observed in the rFSH + rLH group. In patients with ≤ 4 retrieved oocytes, oocyte yield, mature oocytes rate, normal cleavage speed, implantation rate, and miscarriage rate were improved in the rFSH + rLH group. In patients with ≥ 5 retrieved oocytes, higher estradiol levels, oocyte yield, and implantation rate were observed in the rFSH + rLH group. Ovarian stimulation with luteinizing hormone (LH) supplementation results in higher implantation rates, independent of maternal age and response to COS when compared with previous cycles stimulated with rFSH only. Improvements were also observed for ICSI outcomes and miscarriage after stratification by age and retrieved oocytes. Investigar se há algum efeito da suplementação com hormônio luteinizante (LH, na sigla em inglês) no regime com antagonista do hormônio liberador de gonadotropina (GnRH, na sigla em inglês) sobre os resultados dos ciclos consecutivos de injeção intracitoplasmática de espermatozoides (ICSI, na sigla em inglês). MéTODOS: Para o presente estudo retrospectivo de caso-controle, foram avaliados 228 ciclos de microinjeção intracitoplasmática de espermatozoides (ICSI, na sigla em inglês) realizados em 114 pacientes entre 2015 e 2018 em um centro privado de fertilização in vitro (FIV) afiliado a uma universidade. O estímulo ovariano controlado (EOC) foi feito com hormônio folículo- estimulante recombinante (rFSH, na sigla em inglês) (Gonal-f, Serono, Genebra, Suíça) no primeiro ciclo de ICSI (grupo rFSH), e com rFSH e rLH (Pergoveris, Merck Serono S.p.A, Bari, Itália) no segundo ciclo (grupo rFSH + rLH). Os desfechos dos ciclos de ICSI foram comparados entre os grupos. Níveis mais elevados de estradiol, de recuperação oocitária, taxa de embriões de alta qualidade no 3° dia e taxa de implantação, e menor taxa de aborto foram observados no grupo rFSH + rLH. Em pacientes 35 anos, a taxa de implantação foi maior no grupo rFSH + rLH em comparação com o grupo rFSH. Em pacientes com ≥ 35 anos, maiores níveis de estradiol, recuperação oocitária, a taxa de embriões de alta qualidade no 3° dia e a taxa de implantação foram observados no grupo rFSH + rLH. Em pacientes com baixa resposta ao EOC (≤ 4 oócitos recuperados), a recuperação oocitária, a taxa de oócitos maduros, a taxa de velocidade normal de clivagem, a taxa de implantação e a taxa de aborto foram melhoradas no grupo rFSH + rLH. Em pacientes com resposta normal ao EOC (≥ 5 oócitos recuperados), níveis mais elevados de estradiol, recuperação oocitária e taxa de implantação foram observados no grupo rFSH + rLH. CONCLUSãO: A estimulação ovariana com suplementação de LH resultou em taxas de implantação mais altas, independentemente da idade materna e da resposta ao EOC, em comparação com os ciclos anteriores estimulados apenas com rFSH. Melhorias também foram observadas nos resultados da ICSI e na taxa de aborto quando as pacientes foram estratificadas por idade e número de oócitos recuperados.

Research question Are there associations between dyslipidaemia and pregnancy outcomes in the first complete cycle of IVF/intracytoplasmic sperm injection (ICSI)? Design This long-term, retrospective real-world analysis involved 5030 infertile women who underwent a first complete IVF/ICSI cycle between January 2015 and October 2020. They were categorized into dyslipidaemia (n = 1903) and control (n = 3127) groups according to serum lipid concentrations before ovarian stimulation. Propensity score matching and multivariable logistic regression were used to control for confounding variables. Results In the raw cohort, women with dyslipidaemia had a significantly increased late miscarriage rate (P = 0.039), decreased term birth rate (P = 0.002) and decreased live birth rate (P = 0.005) compared with non-dyslipidaemic women. In the propensity score-matched cohort, the term birth rate (P = 0.038) and live birth rate (P = 0.044) were significantly lower in the dyslipidaemia group (n = 1686) than the controls (n = 1686). Multivariable logistic regression indicated that infertile women with dyslipidaemia (P = 0.026) and elevated serum total cholesterol concentrations (total cholesterol ≥5.20 mmol/l; P = 0.028) were significantly less likely to have a live birth. Rates of late miscarriage (P = 0.027), term birth (P = 0.003) and live birth (P = 0.010) differed significantly among women with normal, borderline increased and increased serum lipid concentrations. Compared with controls, women with increased serum lipid concentrations had a significantly higher late miscarriage rate, lower term birth rate and lower live birth rate. Women with increased serum lipid concentrations were significantly less likely than controls to have a live birth. Conclusions Dyslipidaemia, total cholesterol ≥5.20 mmol/l and degrees of elevated serum lipid concentrations are negatively associated with live birth rate in the first complete IVF/ICSI cycle in infertile women.

Based on the inconsistent literature published thus far involving infertile patients, whether intracytoplasmic sperm injection (ICSI) allows overcoming total fertilization failure due to sperm DNA fragmentation is still unclear. Related to this, female factors, which may have a significant impact on assisted reproduction outcomes, can mask male infertility. In this scenario, evaluating ICSI outcomes following cycles using healthy donor gametes could shed light on this realm, as it would avoid the influence of (un)known confounding factors present in infertile individuals. The present work, therefore, aimed to address whether single- and double-stranded sperm DNA fragmentation leads to impaired ICSI outcomes in double gamete donation cycles. The study also compared these double-gamete donation cycles to cycles in which only sperm were donated and oocytes were obtained from infertile patients. Two cohorts were included: (a) the Donor-Donor (DD) cohort, which included 27 semen donor samples used in 49 ICSI cycles with young healthy oocyte donors; and (b) the Donor-Infertile (DI) cohort, which involved 34 semen donor samples used in 57 ICSI cycles with oocytes from patients. Single- and double-stranded sperm DNA breaks were determined with alkaline and neutral Comet assays, respectively; ICSI was conducted following standard protocols and embryos were monitored through time-lapse microscopy. In the DD cohort, the percentage of sperm with high overall DNA damage correlated with fertilization rates (Rs = − 0.666;P P = 0.040). In addition, sperm DNA damage delayed the first embryo division (Rs = 0.421;P = 0.036), and development from the 8-cell to the morula stage (Rs = 0.424;P = 0.034). In contrast, double-stranded DNA breaks had no effect in this cohort. As far as the DI cohort is concerned, while overall sperm DNA damage was not found to be correlated to fertilization or blastocyst rates, pronuclei formation following ICSI was delayed when the incidence of double-stranded DNA breaks was high (Rs = 0.485;P = 0.005). In conclusion, this study, which is the first involving double donation cycles (i.e., a donor-donor cohort), supports that sperm DNA damage has a detrimental impact on fertilization rates after ICSI, and delays embryo development. Moreover, the use of oocytes from infertile individuals is suggested to hide the male-factor effect.

ImportanceIntracytoplasmic sperm injection (ICSI), the most common type of assisted reproductive technology (ART), might damage the sperm or embryo. The implications of male infertility and ICSI for the neurodevelopmental health of offspring remain unknown.ObjectiveTo analyze the risks of neurodevelopmental disorders in offspring of couples with male or female infertility with or without ICSI use.Design, Setting, and ParticipantsThis cohort study was conducted in Taiwan and used information collected from the national population registry data set, national birth data set, and national ART data set for all live singleton births from January 1, 2008, to December 31, 2016. The follow-up period started from the date of birth until the diagnosis of a disorder or December 31, 2018, whichever occurred first. Data were analyzed from July 1, 2021, to August 1, 2022.ExposuresMale or female infertility with or without ICSI.Main Outcomes and MeasuresThe outcome was the incidence of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and developmental delay in offspring with ART conception. Taiwan’s national population registry data set was used to identify ASD, ADHD, and developmental delay diagnosed in outpatient clinic and hospitalization records.ResultsThe study included 1 575 971 singleton births (mean [SD] age, 5.87 [2.60] years; 819 389 boys [52.0%]), of whom 1 568 257 (99.5%) had natural conception, 2111 (0.1%) had ART conception with male infertility, and 5603 (0.4%) had ART conception with female infertility. The risks of ASD (adjusted hazard ratio, 2.49; 95% CI, 1.61-3.84; P P Conclusions and RelevanceResults of this study suggest that male infertility was not associated with an increased risk of neurodevelopmental disorders in offspring. In both male and female infertility groups, ICSI had unfavorable implications for the neurodevelopmental health of offspring in terms of increased risks of ASD and developmental delay.