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It is estimated that infertility affects 8–12% of couples globally, with a male factor being a primary or contributing cause in approximately 50% of couples. Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. Many health conditions can affect male fertility, which underscores the need for a thorough evaluation of patients to identify treatable or reversible lifestyle factors or medical conditions. Although semen analysis remains the cornerstone for evaluating male infertility, advanced diagnostic tests to investigate sperm quality and function have been developed to improve diagnosis and management. The use of assisted reproductive techniques has also substantially improved the ability of couples with infertility to have biological children. This Seminar aims to provide a comprehensive overview of the assessment and management of men with infertility, along with current controversies and future endeavours.

Background Assisted Reproductive Technology (ART) has undergone considerable changes over the last decade, with consequences on ART outcomes in different regions of the world being unknown. Methods We conducted a systematic review of published national and regional ART registry data to assess how changes in clinical practice between 2004 and 2013 have impacted outcomes in Australia and New Zealand, Canada, Continental Europe, the United Kingdom (U.K.), Japan, Latin America, and the United States (U.S.). The data reflect 7,079,145 total ART cycles utilizing both fresh and previously cryopreserved embryos from autologous oocytes that resulted in 1,454,724 live births. This review focused on the following measures: ART cycle volume, use of cryopreserved embryos, single embryo transfer (SET), live birth rates in fresh and frozen-thawed cycles, and perinatal outcomes in recent years. Results SETs and utilization of frozen-thawed embryos increased worldwide over the study period. In 2012 SET utilization in all ART cycles was highest in Japan and Australia/New Zealand (82.6% and 76.3% respectively) and lowest in Latin America (16.0%). While gradual improvements in live birth rates were observed in most regions, some demonstrated declines. By 2012–2013, fresh cycle live birth rates were highest in the U.S. (29%) and lowest in Japan (5%). In Japan, the observed decline in fresh cycle live birth rate coincided with transition to minimal stimulation protocols, transfer of frozen-thawed rather than fresh embryos, and implementation of an SET policy. Similarly, implementation of an SET policy in parts of Canada was followed by a decline in fresh cycle live birth rate. Increasing live birth rates in frozen-thawed embryo cycles, seen all over the world, partially compensated for declines in fresh ART cycles. During 2012–2013 Australia/New Zealand and Japan reported the lowest multiple delivery rates of 5.6 and 4% respectively while the US had the highest of 27%. In recent years, preterm delivery rates in all regions ranged between 9.0 to 16.6% for singletons, 53.9 to 67.3% for twins, and 91.4 to 100% for triplets and higher order multiples. Inconsistencies in the way perinatal outcome data are presented by various registries, made comparison between regions difficult. Conclusions ART practices are characterized by outcome differences between regions. International consensus on the definition of ART success, which accounts for perinatal outcomes, may help to standardize worldwide ART practice and improve outcomes. Trial registration PROSPERO ( CRD42016033011 )

PurposeThe aim of this review is to gather the available research focusing on female genital tract (FGT) microbiome. Research question focuses in decipher which is the role of FGT microbiota in eubiosis, assisted reproduction techniques (ARTs), and gynaecological disorders, and how microbiome could be utilised to improve reproduction outcomes and to treat fertility issues.MethodsPubMed was searched for articles in English from January 2004 to April 2021 for “genital tract microbiota and reproduction”, “endometrial microbiome”, “microbiome and reproduction” and “microbiota and infertility”. Manual search of the references within the resulting articles was performed.ResultsCurrent knowledge confirms predominance of Lactobacillus species, both in vagina and endometrium, whereas higher variability of species is both found in fallopian tubes and ovaries. Microbial signature linked to different disorders such endometriosis, bacterial vaginosis, and gynaecological cancers are described. Broadly, low variability of species and Lactobacillus abundance within the FGT is associated with better reproductive and ART outcomes.ConclusionFurther research regarding FGT microbiome configuration needs to be done in order to establish a more precise link between microbiota and eubiosis or dysbiosis. Detection of bacterial species related with poor reproductive outcomes, infertility or gynaecological diseases could shape new tools for their diagnosis and treatment, as well as resources to assess the pregnancy prognosis based on endometrial microbiota. Data available suggest future research protocols should be standardised, and it needs to include the interplay among microbiome, virome and mycobiome, and the effect of antibiotics or probiotics on the microbiome shifts.

Background Numerous studies have demonstrated substantial differences in assisted reproductive technology outcomes between black non-Hispanic and white non-Hispanic women. We sought to determine if disparities in assisted reproductive technology outcomes between cycles from black non-Hispanic and white non-Hispanic women have changed and to identify factors that may have influenced change and determine racial differences in cumulative live birth rates. Methods This is a retrospective cohort study of the SARTCORS database outcomes for 2014–2016 compared with those previously reported in 2004–2006 and 1999/2000. Patient demographics, etiology of infertility, and cycle outcomes were compared between black non-hispanic and white non-hispanic patients. Categorical values were compared using Chi-squared testing. Continuous variables were compared using t-test. Multiple logistic regression was used to assess confounders. Results We analyzed 122,721 autologous, fresh, non-donor embryo cycles from 2014 to 2016 of which 13,717 cycles from black and 109,004 cycles from white women. The proportion of cycles from black women increased from 6.5 to 8.4%. Cycles from black women were almost 3 times more likely to have tubal and/or uterine factor and body mass index ≥30 kg/m 2 . Multivariate logistic regression demonstrated that black women had a lower live birth rate (OR 0.71; P  < 0.001) and a lower cumulative live birth rate for their initial cycle (OR 0.64; P  < 0.001) independent of age, parity, body mass index, etiology of infertility, ovarian reserve, cycle cancellation, past spontaneous abortions, use of intra-cytoplasmic sperm injection or number of embryos transferred. A lower proportion of cycles in black women were represented among non-mandated states ( P  < 0.001) and cycles in black women were associated with higher clinical live birth rates in mandated states ( P  = 0.006). Conclusions Disparities in assisted reproductive technology outcomes in the US have persisted for black women over the last 15 years. Limited access to state mandated insurance may be contributory. Race has continued to be an independent prognostic factor for live birth and cumulative live birth rate from assisted reproductive technology in the US.

Background Online interest could serve as critical sentinel indicators for monitoring assisted reproductive technology (ART) demands, detecting regions with access inequities, and identifying shortcomings in policy frameworks; however, global online interest of ART has not been assessed. The study aims to investigate the spatiotemporal evolution of online interest in ART globally. Methods The study follows retrospective observational design. Data were derived from Google Trends and Relative Search Volume (RSV) data across 230 countries and regions were collected. After quality control, data from 59, 76, 69, and 61 countries and regions were included for different search terms (“Assisted reproductive technology,” “In vitro fertilization,” “Intracytoplasmic sperm injection,” and “Preimplantation genetic diagnosis,” respectively). Weekly percentage changes (WPCs) and annual percentage changes (APCs) were used to quantify the temporal variations in online interest. Results Globally, public online interest in ART demonstrated a distinct seasonal fluctuation, peaking during months 3–5 and 9–11, while declining in months 6–8 and 12 − 2. The global online interest showed a significant downward trend (APC = -11.22%, 95% Confidence Interval [CI]: -18.44 to -8.61) from 2004 to 2011, followed by a gradual increase from 2011 to 2016 (APC = 1.76%, 95% CI: -7.64 to 11.99). Interest then rapidly increased from 2016 to 2019 (APC = 27.24%, 95% CI: 12.48 to 35.20), before continuing to decline after 2020 (APC = -6.54%, 95% CI: -12.52 to -3.05) with predictions indicating further decreases by 2030. Overall, Europe exhibited relatively higher online interest, while Africa and Oceania showed lower levels. In Europe, France (RSV = 76), Italy (RSV = 66), and Spain (RSV = 32) had notable interest in ART. Whereas, in Oceania and Africa, Australia (RSV = 8), New Zealand (RSV = 6), Tunisia (RSV = 16), Algeria (RSV = 16), and Nigeria (RSV = 10) showed lower levels of interest. Israel, Réunion (France), and France ranked as the top three countries or regions with the highest online interest in ART worldwide. Conclusions Global online interest in ART shows significant variation across countries and regions, with a decline after 2020. To address these trends, ART resources and services should be allocated effectively based on seasonal and regional demand. Government action is needed to raise social awareness and improve the accessibility and utilization of ART.

Background The use of preimplantation genetic testing for aneuploidy (PGT-A) allows for the selection of euploid embryos and has been thought to improve outcomes in ART, particularly in women ≥ 35 years old. However, little is known regarding PGT-A utilization among minority women in the United States (US). The objective of this study was to determine the trend of utilization of PGT-A in the US among minority women. Methods We conducted a retrospective cohort study using the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) database. We included initial autologous ART cycles performed between 2014 and 2020. We assessed the rate of PGT-A utilization by race/ethnicity. Results This study included 150,604 PGT-A and 287,979 non-PGT-A initial autologous cycles. The overall trend of PGT-A utilization, regardless of race/ethnicity, increased from 11.5 to 49.0% ( p  < 0.001) over seven years. Of all ART cycles, 33% of White women used PGT-A, in comparison to 24% of Black women, 31% of Hispanic women, and 44% of Asian women ( p  < 0.001). Multiple Logistic Regression (MLR) determined race/ethnicity as an independent predictor of PGT-A utilization when adjusting for age, BMI, and AMH ( p  < 0.001). Compared to White women, MLR showed that Black and Hispanic women were 35% and 16% less likely to use PGT-A (aOR = 0.65, 95% CI 0.63–0.67, and aOR = 0.86, 95% CI 0.84–0.88, respectively, p  < 0.001). In contrast, Asian women were 41% (aOR = 1.41, 95% CI 1.39–1.44) more likely to use PGT-A ( p  < 0.001). Overall, regardless of race/ethnicity, women 35 and older were 71% (aOR = 1.71, 95% CI 1.69–1.74) more likely to use PGT-A compared to women younger than 35 ( p  < 0.001). Conclusion Despite a significant increase in overall PGT-A utilization in the US over 7 years, utilization has been consistently less in ART cycles for Black and Hispanic women, in comparison to White women. This is in marked contrast to an increase in PGT-A utilization in cycles for Asian women.

The use of intracytoplasmic sperm injection has increased substantially worldwide, primarily in couples with non-male factor infertility. However, there is a paucity of evidence from randomised trials supporting this approach compared with conventional in-vitro fertilisation (IVF). We aimed to investigate whether intracytoplasmic sperm injection would result in a higher livebirth rate compared with conventional IVF. This open-label, multicentre, randomised trial was done at two IVF centres in Ho Chi Minh City, Vietnam (IVFMD, My Duc Hospital and IVFAS, An Sinh Hospital). Eligible couples were aged at least 18 years and the male partner's sperm count and motility (progressive motility) were normal based on WHO 2010 criteria. Couples had to have undergone two or fewer previous conventional IVF or intracytoplasmic sperm injection attempts, have used an antagonist protocol for ovarian stimulation, and agree to have two or fewer embryos transferred. Couples were randomly assigned (1:1) to undergo either intracytoplasmic sperm injection or conventional IVF, using block randomisation with variable block size of 2, 4, or 8 and a telephone-based central randomisation method. The computer-generated randomisation list was prepared by an independent statistician who had no other involvement in the study. Embryologists and couples were not masked to study groups because of the type of interventions and differences in hospital fees, but clinicians performing embryo transfer were unaware of study group allocation. The primary outcome was livebirth after the first embryo transfer from the initiated cycle. Analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03428919. Between March 16, 2018, and Aug 12, 2019, we randomly assigned 1064 couples to intracytoplasmic sperm injection (n=532) or conventional IVF (n=532). Livebirth after the first embryo transfer from the initiated cycle occurred in 184 (35%) of 532 couples randomly assigned to intracytoplasmic sperm injection and in 166 (31%) of 532 couples randomly assigned to conventional IVF (absolute difference 3·4%, 95% CI −2·4 to 9·2; risk ratio [RR] 1·11, 95% CI 0·93 to 1·32; p=0·27). 29 (5%) couples in the intracytoplasmic sperm injection group and 34 (6%) couples in the conventional IVF group had fertilisation failure (absolute difference −0·9%, −4·0 to 2·1, RR 0·85, 95% CI 0·53 to 1·38; p=0·60). In couples with infertility in whom the male partner has a normal total sperm count and motility, intracytoplasmic sperm injection did not improve the livebirth rate compared with conventional IVF. Our results challenge the value of the routine use of intracytoplasmic sperm injection in assisted reproduction techniques for this population. My Duc Hospital and Merck Sharp and Dohme.

Abstract The increasing prevalence of metabolic diseases places a substantial burden on human health throughout the world. It is believed that predisposition to metabolic disease starts early in life, a period of great susceptibility to epigenetic reprogramming due to environmental insults. Assisted reproductive technologies (ART), i.e., treatments for infertility, may affect embryo development, resulting in multiple adverse health outcomes in postnatal life. The most frequently observed alteration in ART pregnancies is impaired placental nutrient transfer. Moreover, consequent intrauterine growth restriction and low birth weight followed by catch-up growth can all predict future obesity, insulin resistance, and chronic metabolic diseases. In this review, we have focused on evidence of adverse metabolic alterations associated with ART, which can contribute to the development of chronic adult-onset diseases, such as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Due to high phenotypic plasticity, ART pregnancies can produce both offspring with adverse health outcomes, as well as healthy individuals. We further discuss the sex-specific and age-dependent metabolic alterations reflected in ART offspring, and how the degree of interference of a given ART procedure (from mild to more severe manipulation of the egg) affects the occurrence and degree of offspring alterations. Over the last few years, studies have reported signs of cardiometabolic alterations in ART offspring that are detectable at a young age but that do not appear to constitute a high risk of disease and morbidity per se. These abnormal phenotypes could be early indicators of the development of chronic diseases, including metabolic syndrome, in adulthood. The early detection of metabolic alterations could contribute to preventing the onset of disease in adulthood. Such early interventions may counteract the risk factors and improve the long-term health of the individual.

Background Placenta accreta spectrum (PAS) is a life-threating complication in the field of obstetrics. Sometimes we face with unexpected PAS cases which is potentially higher maternal mortality and morbidity compared with expected cases. The present study was conducted to examine the prevalence of PAS and to elucidate its risk factors using a large Japanese birth cohort study. Methods We reviewed the results of a nationwide prospective birth cohort study in Japan, and identified 90,554 participants treated from 2011 to 2014 in 15 regional centers. Multiple regression models were created to identify the risk factors for PAS. These data were obtained from self-reported questionnaires or patient medical records. Results This analysis consisted of 202 cases of PAS (18 with placenta previa and 184 without placenta previa) and 90,352 cases without PAS. The multiple logistic regression analysis showed that placenta previa (adjusted odds ratio [aOR]: 12.86, 95% confidence interval [CI] 7.70–21.45, P  < 0.001), assisted reproductive technology-related pregnancies (aOR: 6.78, 95% CI 4.54–10.14, P  < 0.001), smoking during pregnancy (aOR: 1.95, 95% CI 1.15–3.31, P  = 0.013), more than two previous cesarean sections (aOR: 2.51, 95% CI 1.35–4.67, P  = 0.004), and uterine anomalies (aOR: 3.97, 95% CI 1.24–12.68, P  = 0.020) increased the risk of PAS. Conclusion In general population, placenta previa, assisted reproductive technology-related pregnancy, smoking during pregnancy, repeated cesarean sections, and uterine anomalies were risk factors for PAS in the Japanese population.

Recent decades have seen declining total fertility rates (TFR) globally, alongside increased use of assisted reproductive technology (ART). However, TFR includes ART births and excludes induced abortions, complicating assessments of population fecundity. Here, we examine trends in cohort total fertility rates (cTFR), induced abortions, and ART use through a nationwide cohort study of 1,648,971 pregnancies, including abortions, among Danish women aged 15–45 years born between 1958 and 1999. A new index, the Comprehensive Unassisted Pregnancy Rate (live births and induced abortions, excluding ART births), was developed. Our findings reveal a decline in unassisted pregnancy rates for women born after 1961, with an accelerated decline for those born after 1970. In contrast, cTFR increased for women born between 1958 and 1970 before decreasing, driven by trends in induced abortions and ART births. These differences highlight a disconnect between cTFR and fecundity measures. The declining unassisted pregnancy rates, reduced abortions, and increased ART demand raise concerns about population fecundity. Understanding these trends’ biological and socioeconomic drivers requires large-scale, transdisciplinary studies of representative populations. Our results emphasize the need for alternative measures, like the Comprehensive Unassisted Pregnancy Rate, to assess reproductive health and fertility trends accurately.