Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency.

Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated1. Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated. Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote4, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.

Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor. METHODS: We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed. FINDINGS: Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83-1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group. INTERPRETATION: In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.

Sex-Specific Alterations in Placental Proteomics Induced by Intrauterine Hyperglycemia.

Gestational diabetes mellitus (GDM) with intrauterine hyperglycemia induces a series of changes in the placenta, which have adverse effects on both the mother and the fetus. The aim of this study was to investigate the changes in the placenta in GDM and its gender differences. In this study, we established an intrauterine hyperglycemia model using ICR mice. We collected placental specimens from mice before birth for histological observation, along with tandem mass tag (TMT)-labeled proteomic analysis, which was stratified by sex. When the analysis was not segregated by sex, the GDM group showed 208 upregulated and 225 downregulated proteins in the placenta, primarily within the extracellular matrix and mitochondria. Altered biological processes included cholesterol metabolism and oxidative stress responses. After stratification by sex, the male subgroup showed a heightened tendency for immune-related pathway alterations, whereas the female subgroup manifested changes in branched-chain amino acid metabolism. Our study suggests that the observed sex differences in placental protein expression may explain the differential impact of GDM on offspring.

Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.

BACKGROUND: Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. METHODS: Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. RESULTS: Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. CONCLUSIONS: Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.

Characterization of a novel adipose tissue located between abdominal lymph nodes and cervix/prostate in mice.

Perigonadal adipose tissue is a homogeneous white adipose tissue (WAT) in adult male mice without any brown adipose tissue (BAT). However, there are congenital differences in the gonads between male and female mice. Whether heterogeneity existed in perigonadal adipose tissues (ATs) in female mice remains unknown. This study reported a perigonadal brown-like AT located between abdominal lymph nodes and the uterine cervix in female mice, termed lymph node-cervical adipose tissue (LNCAT). Its counterpart, lymph node-prostatic adipose tissue (LNPAT), exhibited white phenotype in adult virgin male mice. When exposed to cold, LNCAT/LNPAT increased uncoupling protein 1 (UCP1) expression via activation of tyrosine hydroxylase (TH), in which abdominal lymph nodes were involved. Interestingly, the UCP1 expression in LNCAT/LNPAT varied under different reproductive stages. The UCP1 expression in LNCAT was upregulated at early pregnancy, declined at midlate pregnancy, and reverted in weaning dams. Mating behavior stimulated LNPAT browning in male mice. We found that androgen but not estrogen or progesterone inhibited UCP1 expression in LNCAT. Androgen administration reversed the castration-induced LNPAT browning. Our results identified a perigonadal brown-like AT in female mice and characterized its UCP1 expression patterns under various conditions.NEW & NOTEWORTHY A novel perigonadal brown-like AT (LNCAT) of female mice was identified. Abdominal lymph nodes were involved in cold-induced browning in this newly discovered adipose tissue. The UCP1 expression in LNCAT/LNPAT was also related to ages, sexes, and reproductive stages, in which androgen acted as an inhibitor role.

Advanced paternal age exacerbates neuroinflammation in offspring via m6A modification-mediated intergenerational inheritance.

BACKGROUND: The trend of postponing childbearing age is prevalent worldwide. Advanced paternal age (APA) is associated with adverse pregnancy outcomes and offspring health. However, the underlying mechanism by which paternal aging affects the risk of offspring neuropsychiatric disorders is unclear. Our study aims to explore the behavioral phenotypes and the pathologic epigenetic alterations of APA offspring inherited from aging sperm. METHODS: Behavioral tests, ELISA assay, immunofluorescence and western blotting were performed on offspring mice. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA immunoprecipitation sequencing (RIP-seq) were used to investigate the modified N6-methyladenosine (m6A) profiles of paternal sperm and offspring hippocampus. Intervention of gene expression by lentivirus and adeno-associated virus in both vivo and vitro examined the potential therapeutic targets of intergenerational inherited neuroinflammation. RESULTS: In our study, APA offspring exhibit cognitive impairment and autism-like behavior. An increase in neuroinflammation in APA offspring is associated with microglial overactivation, which manifests as abnormal morphology and augmented engulfment. MeRIP-seq of F0 sperm and F1 hippocampus reveal that Nr4a2 is hypermethylated with decreased expression in APA offspring involving in synaptic plasticity and microglial function. In addition, Ythdc1, an m6A reader protein, is markedly elevated in aging sperm and remains elevated in adult hippocampus of APA group. Enhanced Ythdc1 recognizes and suppresses the hypermethylated Nr4a2, thereby contributing to the abnormal phenotype in offspring. The overexpression of Ythdc1 triggers microglial activation in vitro and its suppression in the hippocampus of APA progeny alleviates behavioral aberrations and attenuates neuroinflammation. CONCLUSION: Our study provides additional evidence of the abnormal behavioral phenotypes of APA offspring and reveals potential epigenetic inheritance signatures and targeted genes for future research.

Intrauterine hyperglycemia induces SIRT3-mediated mitochondrial dysfunction: the fetal origin pathogenesis of precocious osteoarthritis.

OBJECTIVE: Diabetes and other metabolic and inflammatory comorbidities are highly associated with osteoarthritis (OA). However, whether early-life hyperglycemia exposure affects susceptibility to long-term OA is still unknown. The purpose of this study was to explore the fetal origins of OA and provide insights into early-life safeguarding for individual health. METHOD: This study utilized streptozotocin to induce intrauterine hyperglycemia and performed destabilization of the medial meniscus surgery on the knee joints of the offspring mice to induce accelerated OA. Cartilage degeneration-related markers, as well as the expression levels of mitochondrial respiratory chain complexes and mitophagy genes in the adult offspring mice, were investigated. In vitro, mitochondrial function and mitophagy of chondrocyte C28/I2 cells stimulated under high glucose conditions were also evaluated. The methylation levels of the sirt3 gene promoter region in the articular cartilage of intrauterine hyperglycemia-exposed offspring mice were further analyzed. RESULTS: In this study, we found that the intrauterine hyperglycemic environment could lead to an increase in individual susceptibility to OA in late adulthood, mainly due to persistently low levels of Sirt3 expression. Downregulation of Sirt3 causes impaired mitophagy in chondrocytes and abnormal mitochondrial respiratory function due to a failure to clear aged and damaged mitochondria in a timely manner. Overexpressing Sirt3 at the cellular level or using Sirt3 agonists like Honokiol in mouse models can partially rescue mitophagy disorders caused by the hyperglycemic environment and thus alleviate the progression of OA. CONCLUSION: Our study revealed a significantly increased susceptibility to OA in the gestational diabetes mellitus offspring, which is partly attributed to exposure to adverse factors in utero and ultimately to the onset of disease via epigenetic modulation.

Safety of embryo cryopreservation: insights from mid-term placental transcriptional changes.

BACKGROUND: In recent years, with benefits from the continuous improvement of clinical technology and the advantage of fertility preservation, the application of embryo cryopreservation has been growing rapidly worldwide. However, amidst this growth, concerns about its safety persist. Numerous studies have highlighted the elevated risk of perinatal complications linked to frozen embryo transfer (FET), such as large for gestational age (LGA) and hypertensive disorders during pregnancy. Thus, it is imperative to explore the potential risk of embryo cryopreservation and its related mechanisms. METHODS: Given the strict ethical constraints on clinical samples, we employed mouse models in this study. Three experimental groups were established: the naturally conceived (NC) group, the fresh embryo transfer (Fresh-ET) group, and the FET group. Blastocyst formation rates and implantation rates were calculated post-embryo cryopreservation. The impact of FET on fetal growth was evaluated upon fetal and placental weight. Placental RNA-seq was conducted, encompassing comprehensive analyses of various comparisons (Fresh-ET vs. NC, FET vs. NC, and FET vs. Fresh-ET). RESULTS: Reduced rates of blastocyst formation and implantation were observed post-embryo cryopreservation. Fresh-ET resulted in a significant decrease in fetal weight compared to NC group, whereas FET reversed this decline. RNA-seq analysis indicated that the majority of the expression changes in FET were inherited from Fresh-ET, and alterations solely attributed to embryo cryopreservation were moderate. Unexpectedly, certain genes that showed alterations in Fresh-ET tended to be restored in FET. Further analysis suggested that this regression may underlie the improvement of fetal growth restriction in FET. The expression of imprinted genes was disrupted in both FET and Fresh-ET groups. CONCLUSION: Based on our experimental data on mouse models, the impact of embryo cryopreservation is less pronounced than other in vitro manipulations in Fresh-ET. However, the impairment of the embryonic developmental potential and the gene alterations in placenta still suggested it to be a risky operation.

A morphological study of symptomatic uterine niche using three-dimensional models from thin-slice magnetic resonance imaging.

RESEARCH QUESTION: Is there a correlation between various morphological parameters of the uterine niche and post-menstrual spotting using three-dimensional models from thin-slice (1 mm) magnetic resonance imaging (MRI)? DESIGN: This study retrospectively identified women diagnosed with a symptomatic niche by thin-slice MRI between December 2019 and December 2021. Univariable and multivariable linear regression models assessed the correlations between morphological parameters and the duration post-menstrual spotting. Morphological differences of the niche formed by one versus two Caesarean sections were analysed by univariable and multivariable logistic analysis. RESULTS: A total of 205 women diagnosed with symptomatic niche were included in the study. The niche among most women with post-menstrual spotting was ellipsoidal, with width greater than length greater than depth, from which niche volume was estimated based on manual measurements (volume = 0.520 × length × width × depth). Manually calculated niche length (ß = 0.257, 95% confidence interval [CI] 0.040-0.473, P = 0.020) and radiomically assessed minor axis length (ß = 0.329, 95% CI 0.009-0.795, P = 0.045) both positively correlated with the duration of post-menstrual spotting, whereas the distance between the niche and external os (ß = -0.120, 95% CI -0.202 to -0.038, P = 0.004) was inversely correlated. Women with two Cesarean sections reported more days of post-menstrual spotting (8.76 ± 3.54 versus 6.68 ± 3.90 days, P < 0.001) and had increased niche length diameter (adjusted odds ratio [aOR] 1.304, 95% CI 1.190-1.429) and a smaller surface-area-to-volume ratio (aOR 0.296, 95% CI 0.129-0.680). CONCLUSIONS: Niche-associated post-menstrual spotting correlates with the length diameter of the niche and the distance between the niche and external os. Niches in women after two Caesarean sections tend to be longer in length diameter and more spherical.

Association between frozen embryo transfer and childhood allergy: a retrospective cohort study.

RESEARCH QUESTION: Does frozen embryo transfer (FET) increase the risk of allergic diseases in offspring? DESIGN: This study followed up 653 singleton children: 166 born through FET and 487 born through natural conception. Demographic characteristics, perinatal information and allergic diseases of children and their parents were collected through clinical medical systems and questionnaires. Among these 653 children, allergen-specific immunoglobulin E (IgE) testing was performed using peripheral blood samples collected from 207 children: 145 in the FET group and 62 in the natural conception group. The prevalence of allergic diseases and positive rates of allergen-specific IgE testing were compared between the two groups with adjustments for confounding factors. RESULTS: The prevalence of food allergy was significantly higher in children born through FET compared with children born through natural conception (adjusted OR = 3.154, 95% CI 1.895-5.250; P < 0.001). In addition, positive rates of food allergen sensitization were higher in children in the FET group compared with children in the natural conception group (adjusted OR = 5.769, 95% CI 2.859-11.751, P < 0.001). Children in the FET group had a higher positive sensitization rate to at least one allergen compared with children in the natural conception group (adjusted OR = 3.127, 95% CI 1.640-5.961, P < 0.001). No association was observed between FET and other allergic diseases, including asthma (P = 0.136), atopic dermatitis (P = 0.130) and allergic rhinitis (P = 0.922). Allergen sensitization IgE testing indicated no differences between the two groups in terms of positive sensitization rates of other common allergens, including animal and insect allergens (P = 0.627), inhaled outdoor allergens (P = 0.915) and inhaled outdoor allergens (P = 0.544). CONCLUSION: This study suggests that children born through FET have increased risk of developing food allergy in early childhood.

Association of maternal mild hypothyroidism in the first and third trimesters with obstetric and perinatal outcomes: a prospective cohort study.

BACKGROUND: Mild hypothyroidism, including subclinical hypothyroidism and isolated maternal hypothyroxinemia, is fairly common in pregnant women, but its impact on pregnancy outcomes is less clear, especially mild hypothyroidism in late pregnancy. OBJECTIVE: To evaluate the impact of subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first and third trimesters, respectively, on obstetric and perinatal outcomes. STUDY DESIGN: This large prospective study was conducted at the International Peace Maternity and Child Health Hospital in Shanghai; 52,027 pregnant women who underwent the first-trimester antenatal screening at International Peace Maternity and Child Health Hospital were consecutively enrolled from January 2013 to December 2016. To evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the first trimester on pregnancy outcomes, participants were divided into 3 groups according to thyroid function in the first trimester: first-trimester euthyroidism group (n=33,130), first-trimester subclinical hypothyroidism group (n=884), and first-trimester isolated maternal hypothyroxinemia group (n=846). Then, to evaluate the impact of maternal subclinical hypothyroidism and isolated maternal hypothyroxinemia in the third trimester on pregnancy outcomes, the first-trimester euthyroidism group was subdivided into 3 groups according to thyroid function in the third trimester: third-trimester euthyroidism group (n=30,776), third-trimester subclinical hypothyroidism group (n=562), and third-trimester isolated maternal hypothyroxinemia group (n=578). Obstetric and perinatal outcomes, including preterm birth, preeclampsia, gestational hypertension, gestational diabetes mellitus, large for gestational age, small for gestational age, macrosomia, cesarean delivery, and fetal demise were measured and compared between those in either subclinical hypothyroidism/isolated maternal hypothyroxinemia group and euthyroid group. Binary logistic regression was used to assess the association of subclinical hypothyroidism or isolated maternal hypothyroxinemia with these outcomes. RESULTS: Thirty-four thousand eight hundred sixty pregnant women who had first (weeks 8-14) and third trimester (weeks 30-35) thyrotropin and free thyroxine concentrations available were included in the final analysis. Maternal subclinical hypothyroidism in the first trimester was linked to a lower risk of gestational diabetes mellitus (adjusted odds ratio 0.64, 95% confidence interval 0.50-0.82) compared with the euthyroid group. However, third-trimester subclinical hypothyroidism is associated with heightened rates of preterm birth (adjusted odds ratio 1.56, 95% confidence interval 1.10-2.20), preeclampsia (adjusted odds ratio 2.23, 95% confidence interval 1.44-3.45), and fetal demise (adjusted odds ratio 7.00, 95% confidence interval 2.07-23.66) compared with the euthyroid group. Isolated maternal hypothyroxinemia in the first trimester increased risks of preeclampsia (adjusted odds ratio 2.14, 95% confidence interval 1.53-3.02), gestational diabetes mellitus (adjusted odds ratio 1.45, 95% confidence interval 1.21-1.73), large for gestational age (adjusted odds ratio 1.64, 95% confidence interval 1.41-1.91), macrosomia (adjusted odds ratio 1.85, 95% confidence interval 1.49-2.31), and cesarean delivery (adjusted odds ratio 1.35, 95% confidence interval 1.06-1.74), while isolated maternal hypothyroxinemia in the third trimester increased risks of preeclampsia (adjusted odds ratio 2.85, 95% confidence interval 1.97-4.12), large for gestational age (adjusted odds ratio 1.49, 95% confidence interval 1.23-1.81), and macrosomia (adjusted odds ratio 1.60, 95% confidence interval 1.20-2.13) compared with the euthyroid group. CONCLUSION: This study indicates that while first-trimester subclinical hypothyroidism did not elevate the risk for adverse pregnancy outcomes, third-trimester subclinical hypothyroidism was linked to several adverse pregnancy outcomes. Isolated maternal hypothyroxinemia in the first and third trimesters was associated with adverse pregnancy outcomes, yet the impact varied by trimester. These results suggest the timing of mild hypothyroidism in pregnancy may be pivotal in determining its effects on adverse pregnancy outcomes and underscore the importance of trimester-specific evaluations of thyroid function.

Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations.

BACKGROUND: De novo mutations (DNMs) are linked with many severe early-onset disorders ranging from rare congenital malformation to intellectual disability. Conventionally, DNMs are considered to have an estimated recurrence rate of 1%. Recently, studies have revealed a higher prevalence of parental mosaicism, leading to a greater recurrence risk, resulting in a second child harbouring the same DNM as a previous child. METHODS: In this study, we included 10 families with DNMs leading to adverse pregnancy outcomes. DNA was extracted from tissue samples, including parental peripheral blood, parental saliva and paternal sperm. High-throughput sequencing was used to screen for parental mosaicism with a depth of more than 5000× on average and a variant allele fraction (VAF) detection limit of 0.5%. RESULTS: The presence of mosaicism was detected in sperms in two families, with VAFs of 2.8% and 2.5%, respectively. Both families have a history of multiple adverse pregnancies and DNMs shared by siblings. Preimplantation genetic testing (PGT) and prenatal diagnosis were performed in one family, thereby preventing the reoccurrence of DNMs. CONCLUSION: This study is the first to report the successful implementation of PGT for monogenic/single gene defects in the parental mosaicism family. Our study suggests that mosaic detection of paternal sperm is warranted in families with recurrent DNMs leading to adverse pregnancy outcomes, and PGT can effectively block the transmission of the pathogenic mutation.

Long-term health risk of offspring born from assisted reproductive technologies.

Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.

[Expert consensus on the clinical application strategy of NIPT2.0, a new-generation non-invasive prenatal screening technology].

The new-generation non-invasive prenatal screening technology (NIPT2.0) is a new method successfully realized in recent years based on high-throughput sequencing to synchronously and accurately detect fetal chromosomal aneuploidies, microdeletion/microduplication syndromes and dominantly inherited monogenic disorders. NIPT2.0 can circumvent the shortcomings of previous non-invasive prenatal screening techniques (NIPT and NIPT Plus) including incapability to detect fetal monogenic disorders, insufficient accuracy of detection and low positive predictive values for certain chromosomal abnormalities (in particular trisomy 13, sex chromosomal abnormalities, and small-segment microdeletions and microduplication syndromes). How to apply NIPT2.0 reasonably and normatively to maximize its clinical value has become an issue which requires clarification. The Reproductive Health Branch of the Chinese Maternal and Child Health Care Association and the Genetic Diagnosis Branch of the Genetics Society of China have organized experts to fully discuss and jointly drafted this consensus, which has put forwards suggestions over the clinical application strategy for NIPT2.0, including the scope of application, target disease, pre-test consultation, clinical application pathway, post-test genetic counseling and intervention, quality control and limitations, for the reference by peers, with a view to standardize its application and provide better clinical service.

Effects of exposure to multiple metallic elements in the first trimester of pregnancy on the risk of preterm birth.

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 µg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB.

[Reproductive Health-Oriented Development in Assisted Reproductive Technologies]. / ä»¥ç”Ÿæ®–å¥åº·ä¸ºå¯¼å‘çš„è¾ åŠ©ç”Ÿæ®–æŠ€æœ¯å‘å±•.

Assisted reproductive technologies (ARTs) are core components of the field of reproductive medicine, encompassing multiple pivotal stages of early development from gamete maturation and fertilization to embryo development. Against the backdrop of a deteriorating trend of global decline in fertility rates, patients with infertility problems increasingly turn to ARTs to realize their dreams of parenthood. However, concomitant with this trend is a growing apprehension regarding the potential adverse effects of ARTs. Herein, we endeavor to discuss several common ARTs procedures utilized in clinical settings and the relevant cutting-edge advancements. The ARTs discussed in the article include in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), biphasic in vitro maturation (biphasic IVM), frozen embryo transfer (FET), preimplantation genetic testing (PGT), non-invasive PGT (niPGT), etc. In addition, we reevaluated their roles within the broader context of assisted reproduction aimed at promoting reproductive health. Additionally, we will delve into the impact of ARTs on the reproductive health of the offspring. By prioritizing the reproductive well-being of both patients and their offspring, the ongoing development and improvement of ARTs to enhance their efficacy and safety will contribute significantly to the advancement of human reproductive health.

Chinese experts' consensus guideline on preimplantation genetic testing of monogenic disorders.

Recent developments in molecular biological technologies and genetic diagnostic methods, accompanying with updates of relevant terminologies, have enabled the improvements of new strategies of preimplantation genetic testing for monogenic (single gene) disorders (PGT-M) to prevent the transmission of inherited diseases. However, there has been much in the way of published consensus on PGT-M. To properly regulate the application of PGT-M, Chinese experts in reproductive medicine and genetics have jointly developed this consensus statement. The consensus includes indications for patient selection, genetic and reproductive counseling, informed consent, diagnostic strategies, report generation, interpretation of results and patient follow-ups. This consensus statement serves to assist in establishment of evidence-based clinical and laboratory practices for PGT-M.

Effects of Particulate Matter on the Risk of Gestational Hypertensive Disorders and Their Progression.

Associations between particulate matter (PM) and gestational hypertensive disorders (GHDs) are well documented, but there is no evidence on the associations between PM and GHD progression, especially among those with assisted reproductive technology (ART) conceptions. To explore the effects of PM on the risk of GHDs and their progression among pregnant women with natural or ART conception, we enrolled 185,140 pregnant women during 2014-2020 in Shanghai and estimated the associations during different periods using multivariate logistic regression. During the 3 months of preconception, 10 µg/m3 increases in PM concentrations were associated with increased risks of gestational hypertension (GH) (PM2.5: aOR = 1.076, 95% CI: 1.034-1.120; PM10: aOR = 1.042, 95% CI: 1.006-1.079) and preeclampsia (PM2.5: aOR = 1.064, 95% CI: 1.008-1.122; PM10: aOR = 1.048, 95% CI: 1.006-1.092 ) among women with natural conception. Furthermore, for women with ART conceptions who suffered current GHD, 10 µg/m3 increases in PM concentrations in the third trimester elevated the risk of progression (PM2.5: aOR = 1.156, 95% CI: 1.022-1.306 ; PM10: aOR = 1.134, 95% CI: 1.013-1.270). In summary, women with natural conception should avoid preconceptional PM exposure to protect themselves from GH and preeclampsia. For women with ART conceptions suffering from GHD, it is necessary to avoid PM exposure in late pregnancy to prevent the disease from progressing.

Mixed exposure effect of seminal metals on semen quality, mediation of total antioxidant capacity, and moderation of GSTM1/GSTT1 gene deletion in Chinese reproductive-aged men.

BACKGROUND: The effects of metal exposure on semen quality and the role of oxidative damage in this process remain unclear. METHODS: We recruited 825 Chinese male volunteers, and 12 seminal metals (Mn, Cu, Zn, Se, Ni, Cd, Pb, Co, Ag, Ba, Tl, and Fe), the total antioxidant capacity (TAC), and reduced glutathione were measured. Semen parameters and GSTM1/GSTT1-null genotypes were also detected. Bayesian kernel machine regression (BKMR) was applied to evaluate the effect of the mixed exposure to metals on semen parameters. The mediation of TAC and moderation of GSTM1/GSTT1 deletion were analyzed. RESULTS: Most seminal metal concentrations were correlated with each other. The BKMR models revealed a negative association between the semen volume and metal mixture, with Cd (cPIP = 0.60) and Mn (cPIP = 0.10) as the major contributors. Compared to fixing all scaled metals at their median value (50th percentiles), fixing the scaled metals at their 75th percentiles decreased the TAC by 2.17 units (95%CI: -2.60, -1.75). Mediation analysis indicated that Mn decreased the semen volume, with 27.82% of this association mediated by TAC. Both the BKMR and multi-linear models showed that seminal Ni was negatively correlated with sperm concentration, total sperm count, and progressive motility, which was modified by GSTM1/GSTT1. Furthermore, Ni and the total sperm count showed a negative association in GSTT1 and GSTM1 null males (ß[95%CI]: 0.328 [-0.521, -0.136]) but not in males with GSTT1 and/or GSTM1. Although Fe and the sperm concentration and total sperm count were positively correlated, they showed inverse "U" shapes in univariate analysis. CONCLUSION: Exposure to the 12 metals was negatively associated with semen volume, with Cd and Mn as the major contributors. TAC may mediate this process. GSTT1 and GSTM1 can modify the reduction in the total sperm count caused by seminal Ni exposure.

Fetal weight estimation based on deep neural network: a retrospective observational study.

BACKGROUND: Improving the accuracy of estimated fetal weight (EFW) calculation can contribute to decision-making for obstetricians and decrease perinatal complications. This study aimed to develop a deep neural network (DNN) model for EFW based on obstetric electronic health records. METHODS: This study retrospectively analyzed the electronic health records of pregnant women with live births delivery at the obstetrics department of International Peace Maternity & Child Health Hospital between January 2016 and December 2018. The DNN model was evaluated using Hadlock's formula and multiple linear regression. RESULTS: A total of 34824 live births (23922 primiparas) from 49896 pregnant women were analyzed. The root-mean-square error of DNN model was 189.64 g (95% CI 187.95 g-191.16 g), and the mean absolute percentage error was 5.79% (95%CI: 5.70%-5.81%), significantly lower compared to Hadlock's formula (240.36 g and 6.46%, respectively). By combining with previously unreported factors, such as birth weight of prior pregnancies, a concise and effective DNN model was built based on only 10 parameters. Accuracy rate of a new model increased from 76.08% to 83.87%, with root-mean-square error of only 243.80 g. CONCLUSIONS: Proposed DNN model for EFW calculation is more accurate than previous approaches in this area and be adopted for better decision making related to fetal monitoring.