Serum copper assessment in patients with polycystic ovary syndrome and tubal infertility: A retrospective 5-year study.

The association between serum copper and polycystic ovary syndrome (PCOS) lacks definitive conclusions, and the intricate interactions with in vitro fertilization (IVF) cycle characteristics in infertility remain insufficiently explored. This retrospective study included 560 patients with tubal infertility (no-PCOS) and 266 patients with PCOS undergoing IVF at the Affiliated Suzhou Hospital of Nanjing Medical University from January 2018 to December 2022. Patients' basic characteristics, hormonal and metabolic parameters, essential trace elements, and IVF cycle characteristics were measured and analyzed. The results revealed a significantly elevated serum copper level in the PCOS group compared to the control group [17.27 (15.54, 19.67) vs 15.4 (13.87, 17.35), µmol/L; p < .001]. Spearman correlation analyses revealed a significant positive correlation between serum copper concentration and body mass index (BMI), fasting glucose (FG), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL) in the no-PCOS group. Additionally, a notable negative correlation with high-density lipoprotein (HDL) was observed (r = -.184, p < .001). Within the PCOS group, serum copper concentration correlated significantly with BMI (r = .198, p = .004) and TG (r = .214, p = .002). The linear trend analysis indicated no significant relationship between serum copper concentration and ovarian response as well as preimplantation outcomes in both groups after adjusting for confounding factors. Our study provided evidence of elevated serum copper concentration in PCOS patients, closely associated with lipid metabolism but showing no correlation with IVF outcomes. These findings provide valuable real-world data, enriching our nuanced understanding of the role of copper in female fertility.

Variants in NLRP2 and ZFP36L2, non-core components of the human subcortical maternal complex, cause female infertility with embryonic development arrest.

The subcortical maternal complex (SCMC), which is vital in oocyte maturation and embryogenesis, consists of core proteins (NLRP5, TLE6, OOEP), non-core proteins (PADI6, KHDC3L, NLRP2, NLRP7), and other unknown proteins that are encoded by maternal effect genes. Some variants of SCMC genes have been linked to female infertility characterized by embryonic development arrest. However, so far, the candidate non-core SCMC components associated with embryonic development need further exploration and the pathogenic variants that have been identified are still limited. In this study, we discovered two novel variants [p.(Ala131Val) and p.(Met326Val)] of NLRP2 in patients with primary infertility displaying embryonic development arrest from large families. In vitro studies using 293T cells and mouse oocytes, respectively, showed that these variants significantly decreased protein expression and caused the phenotype of embryonic development arrest. Additionally, we combined the 'DevOmics' database with the whole exome sequence data of our cohort and screened out a new candidate non-core SCMC gene ZFP36L2. Its variants [p.(Ala241Pro) and p.(Pro291dup)] were found to be responsible for embryonic development arrest. Co-immunoprecipitation experiments in 293T cells, used to demonstrate the interaction between proteins, verified that ZFP36L2 is one of the human SCMC components, and microinjection of ZFP36L2 complementary RNA variants into mouse oocytes affected embryonic development. Furthermore, the ZFP36L2 variants were associated with disrupted stability of its target mRNAs, which resulted in aberrant H3K4me3 and H3K9me3 levels. These disruptions decreased oocyte quality and further developmental potential. Overall, this is the first report of ZFP36L2 as a non-core component of the human SCMC and we found four novel pathogenic variants in the NLRP2 and ZFP36L2 genes in 4 of 161 patients that caused human embryonic development arrest. These findings contribute to the genetic diagnosis of female infertility and provide new insights into the physiological function of SCMC in female reproduction.

Assisted reproductive technology and neurodevelopment in children at 1 year of age: a longitudinal birth cohort study.

BACKGROUND: With remarkable advancements in assisted reproductive technology (ART), the number of ART-conceived children continues to increase. Despite increased research investigating the outcomes of ART children, evidence on neurodevelopment remains controversial. OBJECTIVE: The aim of this study was to investigate the association between ART use and neurodevelopment in children at 1 year of age and to determine whether the characteristics of parental infertility and specific ART procedures affect neurodevelopment in children. STUDY DESIGN: The Jiangsu Birth Cohort enrolled couples who received ART treatment and who conceived spontaneously (2014-2020) in Jiangsu Province, China. In this study, we included 3531 pregnancies with 3840 cohort children who completed neurodevelopment assessment at 1 year of age, including 1906 infants conceived by ART (including 621 twins). Poisson regressions were fitted to estimate unadjusted and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for ART use with neurodevelopmental outcomes (cognition, receptive communication, expressive communication, fine motor, and gross motor) in children. RESULTS: Among singletons, ART use was associated with a 24% to 34% decrease in the risk for noncompetent development in 3 domains (cognition, adjusted RR, 0.66; 95% CI, 0.53-0.82; receptive communication, 0.76; 0.64-0.91; expressive communication, 0.69; 0.51-0.93) after adjustment for conventional covariates. However, an inverse association was observed in the gross motor domain, with ART singletons having a greater risk of being noncompetent in gross motor development than their non-ART counterparts (adjusted RR, 1.41; 95% CI, 1.11-1.79). Compared with singletons, twins resulting from ART treatment demonstrated compromised neurodevelopment in several domains. Furthermore, we continued to observe that the transfer of 'poor' quality embryos was associated with greater risks for noncompetent development in receptive communication (adjusted RR, 1.50; 95% CI, 1.05-2.14) and gross motor domains (1.55; 1.02-2.36) among ART singletons. CONCLUSION: These results generally provide reassuring evidence among singletons born after ART in the cognition, communication, and fine motor domains, but drawn attention to their gross motor development. The quality of transferred embryos in ART treatment might be associated with offspring neurodevelopment; however, the potential associations warrant further validation in independent studies, and the clinical significance needs careful interpretation.

Analysis of Preimplantation and Clinical Outcomes of Two Cases by Oxford Nanopore Sequencing.

It is challenging to distinguish embryos with a balanced translocation karyotype from a normal karyotype by existing conventional genetic testing methods. However, in germ-cell gamete generation, chromosome exchange and separation through cell meiosis form a different proportion of unbalanced gametes. Adverse birth events may occur, such as repeated miscarriages and fetal birth defects. In this study, the exact breakpoints of structural variation (SV) from two balanced translocation carrier families by using Nanopore long reads sequencing technology were obtained, and haplotype analysis and Sanger verified the accuracy of the detection results, confirming the application value of the Nanopore sequencing technology in the detection of balanced translocation before embryo implantation. Nanopore long-read sequencing was performed to find the precise breakpoint of chromosome-balanced translocation carriers. The breakpoints were subsequently verified by designing primers across the breakpoints and Sanger sequencing. Haplotype linkage analysis of SNPs which can be linked by a read block of families around the breakpoint regions was followed. After frozen (-thawed) embryo transfer (FET), prenatal cytogenetic analysis of amniotic fluid cells confirmed the predicted karyotypes from the transferred embryos. The presence of breakpoints was detected in three embryos of patient 1. No breakpoints were detected in either embryo of patient 2. One balanced translocated embryo from patient 1 and one normal euploid embryo from patient 2 were transplanted back into the patients, and amniotic fluid cells were analyzed for the karyotype of fetuses. The results were entirely consistent with the fetal karyotype. And through late follow-up, both patients successfully had a live birth fetus. The breakpoint location of the balanced chromosome translocation can be accurately found by Nanopore sequencing. The haplotype of carriers can be successfully constructed by Nanopore and sanger sequencing confirmed that the results were accurate. This is very advantageous for preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) detection in the families without proband.

Identification and interruption of inheritance of familial cryptic translocations: A case report.

BACKGROUND: Cryptic translocations can be identified via genetic analysis of aborted tissues or malformed infants, but it is difficult to deduce the parental origins of the translocations. In the absence of such information, it is not easy to distinguish translocations from normal embryos during pre-implantation genetic testing, that seeks to block familial transmission of translocations. METHODS: Here, we present a new method that detects cryptic translocations and blocks familial transmission thereof. Whole-genome, low-coverage mate-pair sequencing (WGLMPS) revealed chromosome breakpoint sequences, and preimplantation genetic haplotyping (PGH) was then used to discard embryos with cryptic translocations. RESULTS: Cryptic translocations were found in all four families, and familial transmission was successfully blocked in one family. CONCLUSION: Whole-genome, low-coverage mate-pair sequencing combined with preimplantation genetic haplotyping methods powerfully and practically identify cryptic translocations and block familial transmissions.

Homozygous variants in CDC23 cause female infertility characterized by oocyte maturation defects.

Oocyte maturation defects are major phenotypes resulting in female infertility. Although many genetic factors have been found to be responsible for these phenotypes, the underlying pathogenic genes and variants remain to be identified. The anaphase promoting complex or cyclosome (APC/C) is known to be essential in the metaphase-to-anaphase transition. In this study, we identified two homozygous missense variants (c.986A > G, p.Y329C and c.988C > T, p.R330C) in CDC23 that are responsible for female infertility characterized by oocyte maturation defects in three infertile individuals. CDC23 (cell division cycle 23) is one of the core subunits of the APC/C. In vitro experiments showed that the variant c.986A > G (p.Y329C) led to a decrease in CDC23 protein level and the variant c.988C > T (p.R330C) changed the localization of CDC23 in HeLa cells and mouse oocytes. In vivo studies showed that Cdc23Y329C/Y329C mice successfully mimicked the patients' phenotype by causing low expression of CDC23 and APC4 and the accumulation of securin and cyclin B1 in oocytes. AZ3146 treatment was able to rescue the phenotype. Taken together, our findings reveal the important roles of CDC23 in human oocyte maturation and provide a new genetic marker for female infertility.

Meningitis caused by oral anaerobes detected using mNGS tool: a case report and review of literature.

BACKGROUND: Bacterial meningitis is a central nervous system (CNS) infection disease of the meninges and brain parenchyma caused by the bacteria. Few cases of meningitis related to oral anaerobes have been reported in the literature. Here, we report a case of meningitis in a middle-aged woman, caused by oral anaerobes. CASE PRESENTATION: A 58-year-old woman was admitted to hospital with fever, headache for 21 days and left limb weakness for 2 days. The blood cell counts (11.73 × 109/L), neutrophil counts (9.22 × 109/L) and high-sensitivity C-reactive protein levels (> 5.00 mg/L) were elevated. The brain computerized tomography (CT) scanning indicated the new right thalamus infarct. The brain cranial-enhanced magnetic resonance imaging (MRI) showed the right lateral paraventricular and right thalamic infarct, and abnormal signal in occipital horns of bilateral lateral ventricles were increased. In addition, the brain enhanced nuclear magnetic resonance (NMR) scanning suggested that meninges were thickened and enhanced at the base of the brain, with meningitis changes. The neck CT angiography (CTA) revealed arteriosclerotic changes. The metagenomic next-generation sequencing (mNGS) revealed Eubacterium brachy, Porphyromonas gingivalis, Fusobacterium nucleatum and Torque teno virus in her cerebrospinal fluid (CSF). The patient was diagnosed with purulent meningitis caused by infection of oral anaerobes, and treated with mannitol, ceftriaxone and vancomycin. Her symptoms alleviated. Subsequently, she was transferred to the infectious department and treated with ceftriaxone plus metronidazole (anti-anaerobes) and mannitol (reduce intracranial pressure). Her symptoms improved and currently received rehabilitation treatment. CONCLUSION: We herein report a rare case involving meningitis caused by infection of oral anaerobes. The mNGS can accurately detect the pathogens of infectious diseases.

Programmed frozen embryo transfer cycles are associated with a higher risk of abnormal placental development: a retrospective cohort study of singleton live births.

Introduction: Abnormal placental development can lead to adverse outcomes for both mother and fetus. The effect of different types of endometrium preparation regimens of frozen-thawed cycles on the placental development features associated with the perinatal outcomes remains unclear. Hence, we conducted a retrospective cohort study to assess the impact of specific endometrial preparation regimens on placenta-mediated pregnancy complications in singleton live births. Methods: A retrospective cohort study was conducted evaluating data of all singleton live births both conceived naturally or by in vitro fertilization (IVF) therapy from 2018 to 2020 at our hospital. Two exposed groups of frozen-thawed embryo transfer (FET) were created by the endometrium preparation regimen as the modified natural cycles (mNC) and the programmed cycles. The nonexposed group was the singleton pregnancies conceived naturally. The obstetrical and perinatal outcomes were compared among the three groups using multivariate analysis to adjust the results for determinants potentially associated with the abnormal placental development. Results: A total of 2186 pregnant women with singleton live births were included in our final analysis and were divided into three groups as naturally conceived group (n=1334), mNC-FETs group (n=217) and programmed-FETs group(n=635). After adjusting for maternal age and parity, no significant difference was observed on the risk of placental disorders between mNC-FET cycles and natural conceived pregnancies (aOR 1.16; 95%CI 1.31-7.01), while programmed-FET cycles were associated with a higher occurrence of placental disorders (aOR 5.36; 95%CI 3.63-8.05). Using the mNC-FET group as a reference and adjusting for confounders such as maternal age, parity, endometrial thickness, and number of embryos transferred, we found that the main manifestation of abnormal placentation in programmed FET cycles was abnormal placental attachment, including placental adhesion and placenta increta (aOR 2.50, 95%CI 1.36-4.90). The dysfunction of placentation in programmed-FET cycles was independently associated with the type of infertility, the total dose of Femostone and thinner endometrium. Additionally, placental disorders in the programmed-FET group were associated with higher rate of preeclampsia, postpartum hemorrhage and Cesarean section. Conclusion: Our retrospective study revealed that the programmed-FET has a substantial impact on placental development, resulting in a higher incidence of preeclampsia, postpartum hemorrhage and Cesarean section. These findings have significant implications on clinical decision-making.

NLRP7 participates in the human subcortical maternal complex and its variants cause female infertility characterized by early embryo arrest.

Successful human reproduction requires normal oocyte maturation, fertilization, and early embryo development. Early embryo arrest is a common phenomenon leading to female infertility, but the genetic basis is largely unknown. NLR family pyrin domain-containing 7 (NLRP7) is a member of the NLRP subfamily. Previous studies have shown that variants of NLRP7 are one of the crucial causes of female recurrent hydatidiform mole, but whether NLRP7 variants can directly affect early embryo development is unclear. We performed whole-exome sequencing in patients who experienced early embryo arrest, and five heterozygous variants (c.251G > A, c.1258G > A, c.1441G > A, c. 2227G > A, c.2323C > T) of NLRP7 were identified in affected individuals. Plasmids of NLRP7 and subcortical maternal complex components were overexpressed in 293 T cells, and Co-IP experiments showed that NLRP7 interacted with NLRP5, TLE6, PADI6, NLRP2, KHDC3L, OOEP, and ZBED3. Injecting complementary RNAs in mouse oocytes and early embryos showed that NLRP7 variants influenced the oocyte quality and some of the variants significantly affected early embryo development. These findings contribute to our understanding of the role of NLRP7 in human early embryo development and provide a new genetic marker for clinical early embryo arrest patients. KEY MESSAGES: Five heterozygous variants of NLRP7 (c.1441G > A; 2227G > A; c.251G > A; c.1258G > A; c.2323C > T) were identified in five infertile patients who experienced early embryo arrest. NLRP7 is a component of human subcortical maternal complex. NLRP7 variants lead to poor quality of oocytes and early embryo development arrest. This study provides a new genetic marker for clinical early embryo arrest patients.

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

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

Serum anti-Müllerian hormone levels are associated with perinatal outcomes in women undergoing IVF/ICSI: A multicenter retrospective cohort study.

Introduction: Anti-Müllerian hormone (AMH) level has long been considered as a serum biomarker of ovarian reserve clinically, while emerging data suggest that serum AMH level may also predict pregnancy outcomes. However, whether pregestational serum AMH levels are related to perinatal outcomes among women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles is unknown. Objective: To explore the association between different AMH levels and perinatal outcomes in women with live births in IVF/ICSI. Methods: This multicenter retrospective cohort study was conducted among three different provinces in China, from January 2014 to October 2019. A total of 13,763 IVF/ICSI cycles with 5657 live-delivery pregnant women and 6797 newborns were recruited. Participants were categorized into three groups according to the <25th (low), 25 to 75th (average), and >75th (high) percentile of serum AMH concentration. Perinatal outcomes were compared among groups. Subgroup analyses were conducted based on the number of live births. Results: Among women with singleton deliveries, low and high AMH levels increased the risk of intrahepatic cholestasis of pregnancy (ICP) (aOR1 = 6.02, 95%CI: 2.10-17.22; aOR2 = 3.65, 95%CI:1.32-10.08) and decreased the risk of macrosomia (aOR1 = 0.65, 95%CI:0.48-0.89; aOR2 = 0.72, 95%CI:0.57-0.96), while low AMH reduced the risk of large for gestational age (LGA, aOR=0.74, 95%CI:0.59-0.93) and premature rupture of membrane (PROM, aOR=0.50, 95%CI:0.31-0.79)compared with the average AMH group. In women with multiple deliveries, high AMH levels increased the risks of gestational diabetes mellitus (GDM, aOR=2.40, 95%CI:1.48-3.91) and pregnancy-induced hypertension (PIH, aOR=2.26, 95%CI:1.20-4.22) compared with the average AMH group, while low AMH levels increased the risk of ICP (aOR=14.83, 95%CI:1.92-54.30). However, there was no evidence of differences in preterm birth, congenital anomaly, and other perinatal outcomes among the three groups in both singleton and multiple deliveries. Conclusions: Abnormal AMH levels increased the risk of ICP regardless of the number of live births for women undergoing IVF/ICSI, while high AMH levels increased the risks of GDM and PIH in multiple deliveries. However, serum AMH levels were not associated with adverse neonatal outcomes in IVF/ICSI. The underlying mechanism warrants further investigation.

Loss of SUN1 function in spermatocytes disrupts the attachment of telomeres to the nuclear envelope and contributes to non-obstructive azoospermia in humans.

One of the most severe forms of infertility in humans, caused by gametogenic failure, is non-obstructive azoospermia (NOA). Approximately, 20-30% of men with NOA may have single-gene mutations or other genetic variables that cause this disease. While a range of single-gene mutations associated with infertility has been identified in prior whole-exome sequencing (WES) studies, current insight into the precise genetic etiology of impaired human gametogenesis remains limited. In this paper, we described a proband with NOA who experienced hereditary infertility. WES analyses identified a homozygous variant in the SUN1 (Sad1 and UNC84 domain containing 1) gene [c. 663C > A: p.Tyr221X] that segregated with infertility. SUN1 encodes a LINC complex component essential for telomeric attachment and chromosomal movement. Spermatocytes with the observed mutations were incapable of repairing double-strand DNA breaks or undergoing meiosis. This loss of SUN1 functionality contributes to significant reductions in KASH5 levels within impaired chromosomal telomere attachment to the inner nuclear membrane. Overall, our results identify a potential genetic driver of NOA pathogenesis and provide fresh insight into the role of the SUN1 protein as a regulator of prophase I progression in the context of human meiosis.

Clinical detection, diagnosis and treatment of morphological abnormalities of sperm flagella: A review of literature.

Sperm carries male genetic information, and flagella help move the sperm to reach oocytes. When the ultrastructure of the flagella is abnormal, the sperm is unable to reach the oocyte and achieve insemination. Multiple morphological abnormalities of sperm flagella (MMAF) is a relatively rare idiopathic condition that is mainly characterized by multiple defects in sperm flagella. In the last decade, with the development of high-throughput DNA sequencing approaches, many genes have been revealed to be related to MMAF. However, the differences in sperm phenotypes and reproductive outcomes in many cases are attributed to different pathogenic genes or different pathogenic mutations in the same gene. Here, we will review information about the various phenotypes resulting from different pathogenic genes, including sperm ultrastructure and encoding proteins with their location and functions as well as assisted reproductive technology (ART) outcomes. We will share our clinical detection and diagnosis experience to provide additional clinical views and broaden the understanding of this disease.

Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest.

PURPOSE: The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test. METHODS: Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes. RESULTS: A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes. CONCLUSION: By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.

Improved pregnancy outcomes from mosaic embryos with lower mtDNA content: a single-center retrospective study.

RESEARCH QUESTION: The purpose of this study is to investigate whether the mitochondrial DNA (mtDNA) content can reflect the state of mosaic embryos. DESIGN: The study included 1669 blastocysts derived from 394 PGT-A cycles between January 2018 and December 2020, in which preimplantation genetic testing for aneuploidy was performed and mtDNA content was determined. The standard deviation (SD) of whole genomic sequencing data was calculated for quality control. mtDNA content was measured as the proportion of mtDNA to genomic DNA. 1558 blastocysts with SD values less than 4.0 and mtDNA values less than 0.4% were selected for statistical analysis. RESULTS: The mtDNA content of the PGT mosaic group was significantly higher than that of the PGT normal group (P < 0.001). Twenty-six mosaic embryos were transferred, and the results were as follows: 2 out of 26 had undergone a spontaneous miscarriage, 15 were not pregnant, and 9 resulted in a live birth. There were significant differences in the mtDNA content between the miscarriage/non-pregnancy group and the live birth group (**P < 0.01; ***P < 0.001). There was no mosaic embryo with more than 0.157% mtDNA content found in the live birth group. CONCLUSIONS: This study demonstrates that mtDNA analysis has the ability to identify mosaic embryos with high developmental potential. It can be a valuable supplementary index for the selection of mosaic embryos for transfer. Larger studies with a greater sample size will further our understanding of the relationships between metabolic activity and mosaicism.

Associations between antenatal corticosteroid exposure and neurodevelopment in infants.

BACKGROUND: It has been well recognized that antenatal administration of dexamethasone to pregnant women at risk of preterm delivery may markedly accelerate fetal maturation and reduce the risk of adverse perinatal outcomes in their preterm infants, particularly for births before 34 weeks of gestation. Since 2015, antenatal corticosteroid administration has been extended beyond 34 weeks of gestation by clinical guidelines, as it might have beneficial effects on fetal maturation and perinatal outcomes. However, concerns regarding the potential influence of antenatal corticosteroid treatment on offspring neurodevelopment have been raised. OBJECTIVE: This study aimed to investigate whether maternal antenatal corticosteroid administration was associated with neurodevelopment in infants at 1 year of age. STUDY DESIGN: In this prospective and longitudinal birth cohort study, women were followed up throughout gestation, and their infants underwent a Bayley Scales of Infant and Toddler Development, Third Edition, screening test at 1 year of age between December 2018 and September 2020. Finally, 1609 pregnant women and 1759 infants were included in the current study. Using a generalized linear mixed model, we examined the association between antenatal corticosteroid exposure and infant neurodevelopment in cognitive, receptive communication, expressive communication, fine motor, and gross motor functions. RESULTS: Of the 1759 infants eligible for this study, 1453 (82.6%) were singletons. A total of 710 infants were exposed to antenatal corticosteroids, among whom 415 were dexamethasone exposed and 483 were prednisone exposed. Dexamethasone was prescribed most often in late pregnancy, whereas prednisone was often used before 8 weeks of gestation among women who conceived through assisted reproductive technology. Compared with those who had no exposure, antenatal corticosteroid exposure was associated with an increased risk of infants being noncompetent in the cognitive development domain after adjusting for conventional risk factors (adjusted risk ratio, 1.53; 95% confidence interval, 1.08-2.18; P=.017). For medication-specific exposure, those exposed vs not exposed to antenatal dexamethasone were 1.62-fold (95% confidence interval, 1.10-2.38; P=.014) more likely to be noncompetent in the cognitive development domain at 1 year. The association did not vary markedly between preterm and term infants, singletons and twins, or assisted reproductive technology-conceived and spontaneously conceived infants (all P>.05 for heterogeneity). In contrast, a null association was observed for the risk of being noncompetent in any domain of neurodevelopment with antenatal prednisone exposure at early pregnancy. CONCLUSION: Here, antenatal corticosteroid, particularly dexamethasone exposure, was markedly associated with an increased risk of infants being noncompetent in the cognitive development domain at 1 year of age. These findings may provide new information when weighing the benefits and potential risks of maternal antenatal corticosteroid administration.

Maternal PM2.5 exposure during gestation and offspring neurodevelopment: Findings from a prospective birth cohort study.

Emerging data have suggested the potential role of prenatal PM2.5 exposure as a neurotoxin for offspring. However, the existing results are equivocal, and no study has examined the effects of complex chemical constituents of the particular matter on offspring neurodevelopment. Therefore, in a prospective birth cohort study conducted in Jiangsu, China, we aimed to investigate the association between prenatal exposure to PM2.5 and the neurodevelopment in infants, and further assess the effects of specific chemical constituents of PM2.5. A total of 1531 children who had available data on daily prenatal PM2.5 exposure and completed assessment on neurodevelopment at 1 year old were enrolled. We used the high-performance machine-learning model to estimate daily PM2.5 exposure concentrations at 1 km × 1 km spatial resolution. The combined geospatial-statistical model was applied to evaluate average concentrations of six chemical constituents [organic matter (OM), black carbon (BC), sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), and soil dust (Dust)]. The neurodevelopment of children was assessed using Bayley-III Screening Test. After adjusting for confounding factors, the risk of non-optimal gross motor development increased by 31 % for every 10 µg/m3 increase in average PM2.5 exposure during gestation (aRR: 1.31; 95 % CI: 1.04, 1.64). Further analysis of PM2.5 constituents showed that prenatally exposed to high SO42- was associated with the risk of non-optimal gross motor development (aRR: 1.40; 95 % CI: 1.08, 1.81). Null associations were observed for the rest four neurodevelopment domains. Collectively, our study suggested that prenatal exposure to PM2.5, particularly with high SO42- concentration, was associated with children's non-optimal gross motor development at 1 year old. The short- and long-term influences of perinatal PM2.5 exposure on children's neurodevelopment warrant further investigation.

Noninvasive embryo evaluation and selection by time-lapse monitoring vs. conventional morphologic assessment in women undergoing in vitro fertilization/intracytoplasmic sperm injection: a single-center randomized controlled study.

OBJECTIVE: To determine whether time-lapse monitoring (TLM) for cleavage-stage embryo selection improves reproductive outcomes in comparison with conventional morphological assessment (CMA) selection. DESIGN: Prospective randomized controlled trial. SETTING: Single academic center. PATIENTS: We randomly assigned 139 women who were undergoing their first in vitro fertilization or intracytoplasmic sperm injection cycle to undergo either fresh embryo transfer or first frozen embryo transfer (FET). Only 1 cleavage-stage embryo was transferred to each participant. INTERVENTIONS: The patients were randomly assigned to either the CMA or the TLM group. In the CMA group, day 2 and day 3 embryos were observed. A good-quality cleavage-stage embryo was selected for transfer or freezing in both groups. MAIN OUTCOME MEASURES: The primary and secondary outcomes were the clinical pregnancy rate (CPR) and the live birth rate (LBR), respectively, after the first embryo transfer (fresh embryo transfer or FET). RESULTS: The CPR and LBR were significantly lower in the TLM group than in the CMA group (CPR: 49.18% vs. 70.42%; relative risk, 0.70; 95% confidence interval [CI], 0.52-0.94; LBR: 45.90% vs. 64.79%; relative risk, 0.71; 95% CI, 0.51-0.98). The CPR with fresh embryo transfer or FET did not significantly differ between the TLM and the CMA groups (fresh embryo transfer: 44.44% vs. 70.0%, relative risk, 0.63, 95% CI, 0.39-1.03; FET: 52.94% vs. 70.73%, relative risk, 0.75, 95% CI, 0.52-1.09). There was a significant difference in the LBR with fresh embryo transfer between the TLM and the CMA groups (40.74% vs. 66.67%; relative risk, 0.61; 95% CI, 0.36-1.03). The LBRs with FET were similar in the TLM and the CMA groups (50.0% vs. 63.41%; relative risk, 0.79; 95% CI, 0.52-1.19). The rates of early spontaneous abortion and ectopic pregnancy did not differ between the TLM and the CMA groups. CONCLUSIONS: Elective single cleavage-stage embryo transfer with TLM-based selection did not have any advantages over CMA when day 2 and day 3 embryo morphology was combined in young women with a good ovarian reserve. Because of these results, we conclude that TLM remains an investigational procedure for in vitro fertilization practice. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1900021981.

Improved pregnancy outcomes of cyclosporine A on patients with unexplained repeated implantation failure in IVF/ICSI cycles: A retrospective cohort study.

PROBLEM: Repeated implantation failure (RIF) is a daunting obstacle restricting the further improvement of embryo implantation rate (IR) and live birth rate (LBR). The beneficial effect of cyclosporine A (CsA) on reproductive outcomes of unexplained RIF(URIF) was explored after de novo embryo transfer (ET). METHOD OF STUDY: A retrospective cohort study was conducted, comparing pregnancy outcomes of 146 cycles (CsA group, n = 62; control group, n = 84) at the IVF center of Suzhou Municipal Hospital from April 2016 to March 2020. RESULTS: Baseline and transfer cycle characteristics of participants were comparable between groups. Overall, CsA exerted obvious improvement on IR (51.16% vs 31.97%, P = .006), clinical pregnancy rate (CPR) (58.06% vs 38.10%, P = .017), and LBR (48.39% vs 32.14%, P = .047). Especially, CsA showed remarkably enhancement on IR (41.38% vs 14.63%, P = .012), CPR (47.62% vs 17.24%, P = .021) of non-high quality embryos. No difference in obstetric and pediatric complications was observed, and no birth defects were reported under CsA application. CsA was found to be a predictor of clinical pregnancy [fine adjusted OR 2.360, 95 % CI 1.165-4.781; P = .017] and live birth [fine adjusted OR 2.339, 95% CI 1.124-4.867; P = .023] for multivariate logistic regression. Not surprisingly, the number of high quality embryos should also be considered as an independent predictor for clinical pregnancy [fine adjusted OR 1.637,95%CI 1.027-2.609; P = .038] and live birth [fine adjusted OR 1.890, 95% CI 1.165-3.068; P = .010]. CONCLUSION: CsA application in patients with URIF promotes the pregnancy outcomes and does not increase the risk of obstetric and pediatric complications.

Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens.

PURPOSE: Congenital bilateral absence of the vas deferens (CBAVD) is a major cause of obstructive azoospermia and male factor infertility. CBAVD is mainly caused by mutations in the genes encoding CFTR (cystic fibrosis transmembrane conductance regulator) and ADGRG2 (adhesion G protein-coupled receptor G2). This study aimed to describe CFTR and ADGRG2 variations in 46 Chinese CBAVD patients and evaluated sperm retrieval and assisted reproductive technology outcomes. METHODS: The CFTR and ADGRG2 genes were sequenced and analyzed by whole-exome sequencing (WES), and variations were identified by Sanger sequencing. Bioinformatic analysis was performed. We retrospectively reviewed the outcomes of patients undergoing sperm retrieval surgery and intracytoplasmic sperm injection (ICSI). RESULTS: In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found. In addition to the IVS9-5 T allele, there were 27 CFTR variations, of which 4 variations were novel and predicted to be damaging by bioinformatics. Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI. CONCLUSION: There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele. Therefore, WES might be the best detection method, and genetic counseling should be different from that provided to Caucasian populations. After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI.