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Background: Frozen embryo transfer (FET) has become a widely employed assisted reproductive technology technique. There have historically been concerns regarding the long-term metabolic safety of FET technology in offspring due to pregnancy-induced hypertension and large for gestational age, both of which are well-recognized factors for metabolic dysfunction of children. Therefore, we aimed to compare the metabolic profiles of children born after frozen versus fresh embryo transfer at 2 to 5 years of age. Methods and findings: This was a prospective cohort study. Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a birth cohort of offspring born from assisted reproductive technology at the Institute of Women, Children and Reproductive Health, Shandong University, China. We included 4,246 singletons born after FET (n = 2,181) and fresh embryo transfer (n = 2,065) enrolled between 2008 and 2019 and assessed the glucose and lipid variables until the age of 2 to 5 years. During a mean follow-up of 3.6 years, no significant differences were observed in fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance Index, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol levels between offspring conceived by fresh and frozen embryo transfer in the crude model and adjusted model (adjusted for parental age, parental body mass index, parental education level, paternal smoking, parity, offspring age and sex). These results remained consistent across subgroup analyses considering offspring age, the stage of embryo transfer, and the mode of fertilization. Results from sensitivity analysis on children matched for age within the cohort remains the same. The main limitation of our study is the young age of the offspring. Conclusions: In this study, the impact of FET on glucose and lipid profiles during early childhood was comparable to fresh embryo transfer. Long-term studies are needed to evaluate the metabolic health of offspring born after FET. Wei Zhou and co-workers explore the impact of fresh Versus frozen embryo transfer on the metabolic profiles of children in China. Author summary: Why was this study done?: Frozen embryo transfer (FET) is a commonly used assisted reproductive technology technique. Concerns have existed about the long-term metabolism of FET for offspring due to increased risk of well-recognized factors for metabolic dysfunction, including pregnancy-induced hypertension, macrosomia, large for gestational age, and elevated birth weight. Limited studies have reported on the metabolic profiles of children born after FET, leaving the potential long-term metabolic safety of FET unclear. What did the researchers do and find?: Using data from the "Assisted Reproductive Technology borned KIDs (ARTKID)," a prospective birth cohort at a Chinese single reproductive center, 4,246 singletons of "ARTKID" cohort at 2 to 5 years of age born after either FET (n = 2,181) or fresh embryo transfer (n = 2,065) were included. The average duration of follow-up across the study was 3.6 years. Assessments included fasting blood glucose, insulin, total cholesterol, triglycerides, low- and high-density lipoprotein cholesterol. The study found no significant differences in various metabolic parameters between children born after frozen versus fresh embryo transfer, even after adjusting for potential confounders, including parental age, body mass index, and other factors [adjusted mean difference (95% CI): fasting blood glucose, −0.01(−0.03, 0.02); total cholesterol, 0(−0.05, 0.04)]. What do these findings mean?: FET does not have a significant adverse impact on glucose and lipid profiles during early childhood. These data provide valuable evidence on the safety of FET when counselling couples undergoing assisted reproductive technology treatment. The main limitations are the young age of the offspring, as they may not fully manifest comprehensive metabolic phenotypic changes at this stage, necessitating longer follow-up studies for a more thorough understanding. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there any methylome alteration in women with PCOS who were diagnosed using the new international evidence-based guidelines? SUMMARY ANSWER A total of 264 differentially methylated probes (DMPs) and 53 differentially methylated regions (DMRs) were identified in patients with PCOS and healthy controls. WHAT IS KNOWN ALREADY PCOS is a common endocrine disorder among women of reproductive age and polycystic ovarian morphology (PCOM) is one of the main features of the disease. Owing to the availability of more sensitive ultrasound machines, the traditional diagnosis of PCOM according to the Rotterdam criteria (≥12 antral follicles per ovary) is currently debated as there is a risk of overdiagnosis. The new international evidence-based guidelines set the threshold for PCOM as ≥20 antral follicles per ovary when using endovaginal ultrasound transducers with a frequency bandwidth that includes 8 MHz. However, current DNA methylation studies in PCOS are still based on the Rotterdam criteria. This study aimed to explore aberrant DNA methylation in patients diagnosed with PCOS according to the new evidence-based guidelines. STUDY DESIGN, SIZE, DURATION This cross-sectional case–control study included 34 PCOS cases diagnosed using new international evidence-based guidelines and 36 controls. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 70 women, including 34 PCOS cases and 36 controls, were recruited. DNA extracted from whole blood samples of participants were profiled using array technology. Data quality control, preprocessing, annotation, and statistical analyses were performed. Least absolute shrinkage and selection operator (LASSO) regression were used to build a PCOS diagnosis model with DNA methylation sites. MAIN RESULTS AND THE ROLE OF CHANCE We identified 264 DMPs between PCOS cases and controls, which were mainly located in intergenic regions or gene bodies of the genome, CpG open sea sites, and heterochromatin of functional elements. Pathway enrichment analysis showed that DMPs were significantly enriched in biological processes involved in triglyceride regulation. Three of these DMPs overlapped with the PCOS susceptibility genes thyroid adenoma-associated protein (THADA), aminopeptidase O (AOPEP), and tripartite motif family-like protein 2 (TRIML2). Fifty-three DMRs were identified and their annotated genes were largely enriched in allograft rejection, thyroid hormone production, and peripheral downstream signaling effects. Two DMRs were closely related to the PCOS susceptibility genes, potassium voltage-gated channel subfamily A member 4 (KCNA4) and farnesyl-diphosphate farnesyltransferase 1 (FDFT1). Finally, based on LASSO regression, we built a methylation marker model with high accuracy for PCOS diagnosis (AUC=0.952). LIMITATIONS, REASONS FOR CAUTION The study cohort was single-center and the sample size was relatively limited. Further analyses with a larger number of participants are required. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to identify DNA methylation alterations in women with PCOS diagnosed using the new international evidence-based guideline, and it provided new molecular insight into the application of the new guidelines. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China (2021YFC2700400), Basic Science Center Program of NSFC (31988101), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), National Natural Science Foundation of China (32370916, 82071606, 82101707, 82192874, and 31871509), Shandong Provincial Key Research and Development Program (2020ZLYS02), Taishan Scholars Program of Shandong Province (ts20190988), and Fundamental Research Funds of Shandong University. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Was polycystic ovary syndrome (PCOS), which impairs fertility and adheres to the evolutionary paradox, subject to evolutionary selection during ancestral times and did rapidly diminish in prevalence? SUMMARY ANSWER This study strengthened the hypothesis that positive selection of genetic variants occurred and may account for the high prevalence of PCOS observed today. WHAT IS KNOWN ALREADY PCOS is a complex endocrine disorder characterized by both reproductive and metabolic disturbances. As a heritable disease that impairs fertility, PCOS should diminish rapidly in prevalence; however, it is the most common cause of female subfertility globally. Few scientific genetic studies have attempted to provide evidence for the positive selection of gene variants underlying PCOS. STUDY DESIGN, SIZE, DURATION We performed an evolutionary analysis of 2,504 individuals from 14 populations of the 1000 Genomes Project. PARTICIPANTS/MATERIALS, SETTING, METHODS We tested the signature of positive selection for 37 single-nucleotide polymorphisms (SNPs) associated with PCOS in previous genome-wide association studies using six parameters of positive selection. MAIN RESULTS AND THE ROLE OF CHANCE Analyzing the evolutionary indices together, there was obvious positive selection at the PCOS-related SNPs loci, especially within the original evolution window of humans, demonstrated by significant Tajima's D values. Compared to the genome background, six of the 37 SNPs in or close to five genes (DENN domain-containing protein 1A: DENND1A , chromosome 9 open reading frame 3: AOPEP , aminopeptidase O: THADA , diacylglycerol kinase iota: DGKI , and netrin receptor UNC5C: UNC5C) showed significant evidence of positive selection, among which DENND1A , AOPEP , and THADA represent the set of most established susceptibility genes for PCOS. LIMITATIONS, REASONS FOR CAUTION First, only well-documented SNPs were selected from well-designed experiments. Second, it is difficult to determine which hypothesis of PCOS evolution is at play. After considering the most significant functions of these genes, we found that they had a wide variety of functions with no obvious association between them. WIDER IMPLICATIONS OF THE FINDINGS Our findings provide additional evidence for the positive evolution of PCOS. Our analyses require confirmation in a larger study with more evolutionary indicators and larger data range. Further research to identify the roles of the DENND1A , AOPEP , THADA , DGKI , and UNC5C genes is also necessary. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China (2021YFC2700400 and 2021YFC2700701), Basic Science Center Program of NSFC (31988101), CAMS Innovation Fund for Medical Sciences (2021-I2M-5-001), National Natural Science Foundation of China (82192874, 31871509, and 82071606), Shandong Provincial Key Research and Development Program (2020ZLYS02), Taishan Scholars Program of Shandong Province (ts20190988), and Fundamental Research Funds of Shandong University. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11–12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): −2.6%; 95% CI: −9.0% to 3.8%, P- value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: −6.4%; 95% CI: −12.6% to −0.1%, P -value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE May 2018. DATE OF FIRST PATIENT'S ENROLMENT November 2018. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Can whole exome sequencing (WES) followed by trio bioinformatics analysis identify novel pathogenic genetic causes of first trimester euploid miscarriage? SUMMARY ANSWER We identified genetic variants in six candidate genes that indicated plausible underlying causes of first-trimester euploid miscarriage. WHAT IS KNOWN ALREADY Previous studies have identified several monogenic causes of Mendelian inheritance in euploid miscarriages. However, most of these studies are without trio analyses and lack cellular and animal models to validate the functional effect of putative pathogenic variants. STUDY DESIGN, SIZE, DURATION Eight unexplained recurrent miscarriage (URM) couples and corresponding euploid miscarriages were included in our study for whole genome sequencing (WGS) and WES followed by trio bioinformatics analysis. Knock-in mice with Rry2 and Plxnb2 variants and immortalized human trophoblasts were utilized for functional study. Additional 113 unexplained miscarriages were included to identify the mutation prevalence of specific genes by multiplex PCR. PARTICIPANTS/MATERIALS, SETTING, METHODS Whole blood from URM couples and their <13 weeks gestation miscarriage products were both collected for WES, and all variants in selected genes were verified by Sanger sequencing. Different stage C57BL/6J wild-type mouse embryos were collected for immunofluorescence. Ryr2N1552S/+ , Ryr2R137W/+ , Plxnb2D1577E/+ , and Plxnb2R465Q/+ point mutation mice were generated and backcrossed. Matrigel-coated transwell invasion assays and wound-healing assays were performed using HTR-8/SVneo cells transfected with PLXNB2 small-interfering RNA and negative control. Multiplex PCR was performed focusing on RYR2 and PLXNB2. MAIN RESULTS AND THE ROLE OF CHANCE Six novel candidate genes, including ATP2A2 , NAP1L1 , RYR2 , NRK , PLXNB2 , and SSPO , were identified. Immunofluorescence staining showed that ATP2A2, NAP1L1, RyR2, and PLXNB2 were widely expressed from the zygote to the blastocyst stage in mouse embryos. Although compound heterozygous mice with Rry2 and Plxnb2 variants did not show embryonic lethality, the number of pups per litter was significantly reduced when backcrossing Ryr2N1552S/+ ♂ with Ryr2R137W/+ ♀ or Plxnb2D1577E/+ ♂ with Plxnb2R465Q/+ ♀ (P  < 0.05), which were in accordance with the sequencing results of Family 2 and Family 3, and the proportion of Ryr2N1552S/+ offspring was significantly lower when Ryr2N1552S/+ female mice were backcrossed with Ryr2R137W/+ male mice (P  < 0.05). Moreover, siRNA-mediated PLXNB2 knockdown inhibited the migratory and invasive abilities of immortalized human trophoblasts. Besides, additional 10 variants of RYR2 and PLXNB2 were detected in 113 unexplained euploid miscarriages by multiplex PCR. LIMITATIONS, REASONS FOR CAUTION The relatively small number of samples is a limitation of our study which may result in the identification of variants in unique candidate genes with no definitive although plausible causal effect. Larger cohorts are needed to replicate these findings and additional functional research is needed to confirm the pathogenic effects of these variants. Moreover, the sequencing coverage restricted the detection of low-level parental mosaic variants. WIDER IMPLICATIONS OF THE FINDINGS For first-trimester euploid miscarriage, variants in unique genes may be underlying genetic etiologies and WES on trio could be an ideal model to identify potential genetic causes, which could facilitate individualized precise diagnostic and therapeutic regimens in the future. STUDY FUNDING/COMPETING INTERESTS This study was supported by grants from the National Key Research and Development Program of China (2021YFC2700604), National Natural Science Foundation of China (31900492, 82101784, 82171648), Basic Science Center Program of the National Natural Science Foundation of China (31988101), Key Research and Development Program of Shandong Province (2021LCZX02), Natural Science Foundation of Shandong Province (ZR2020QH051), Natural Science Foundation of Jiangsu Province (BK20200223), Taishan Scholars Program for Young Experts of Shandong Province (tsqn201812154) and Young Scholars Program of Shandong University. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Purpose: To study the associations between fetal fraction at the first trimester and subsequent adverse pregnancy outcomes (APOs) in IVF singleton pregnancies with single embryo transfer from frozen cycles. Methods: This is a single-center retrospective cohort study on IVF singleton pregnancies with single embryo transfer from frozen cycles. A total of 8457 women were collected between March 2015 and September 2018 from the Center for Reproductive Medicine, Shandong University, China. Participants underwent cell-free DNA (cfDNA) sequencing at 11–13 weeks' gestation. Multivariable logistic regressions were performed with the risk of APOs based on various predictor variables. Results: A total of 8457 women were included in the analysis of which 1563 (18.48%) women developed one or more APOs. The hypertensive disorders of pregnancy (HDP) (N = 515), gestational diabetes mellitus (GDM) (N = 684), preterm birth (PTB) (N = 567), and low birth weight (LBW) (N = 306) groups had lower fetal fraction compared with the no pregnancy complication (NPC) group (all p values < 0.05). Based on the multivariable logistic regression results, the optimal cutoff values of fetal fraction were 9.30%, 12.54%, 9.10%, 12.65%, and 13.83% for at least one APO, HDP, GDM, PTB, and LBW, respectively. After adjustment for potential maternal confounders, women in the low fetal fraction (LFF) group had a higher risk for the APOs compared with high fetal fraction (HFF) group. Conclusions: The fetal fraction in HDP, GDM, PTB, and LBW groups were lower than NPC group in IVF singleton pregnancies with single embryo transfer from frozen cycles in China. [ABSTRACT FROM AUTHOR]

Objective: This study was conducted in order to investigate whether non-assisted hatching trophectoderm (TE) biopsy increases the risks of adverse perinatal outcomes in livebirths following elective single cryopreserved-thawed blastocyst transfer. Patients and Methods: A total of 5,412 cycles from 4,908 women who achieved singleton livebirths between 2013 and 2019 were included in this retrospective cohort study. All embryos in this study were fertilized by intracytoplasmic sperm injection (ICSI) and cryopreserved through vitrification. The main intervention is to open the zona pellucida (ZP) of day 5/6 blastocyst immediately for biopsy without pre-assisted hatching. The main outcome measures are the common maternal and neonatal outcomes, including hypertensive disorders of pregnancy (HDPs), gestational diabetes mellitus (GDM), abnormal placentation, abnormalities in umbilical cord and amniotic fluid, preterm birth, cesarean section, low birth weight, postpartum hemorrhage, and prolonged hospital stay (both mothers and infants). The generalized estimation equation (GEE) was used to control the effects of repeated measurements. The non-conditional logistic regression model was used to examine the associations between embryo biopsy status and each adverse perinatal event. Given that the selection bias and changes in learning curve might affect the results, we selected 1,086 similar (matching tolerance = 0.01) cycles from the ICSI group via propensity score matching (PSM) for second comparisons and adjustment (conditional logistic regression). Results: After adjusting for confounders, we confirmed that the non-assisted hatching protocol did not increase the risks of most adverse maternal and neonatal outcomes. Despite this, there were increased risks of GDM (aOR: 1.522, 95% CI: 1.141–2.031) and umbilical cord abnormalities (aOR: 11.539, 95% CI: 1.199–111.067) in the biopsy group. In the second comparisons after PSM, GDM incidence in the biopsy group was still higher (7.26% vs. 5.16%, P = 0.042), yet all measurement outcomes were equally likely to occur in both groups after the second adjustment. Conclusions: The non-assisted hatching TE biopsy does not increase the risks of most adverse perinatal outcomes. However, there is a higher GDM incidence in the biopsy group, and this association warrants further study. Considering its safety and simplicity, the non-assisted hatching protocol has the potential to become the preferred option for TE biopsy, especially in busy clinics and IVF laboratories. [ABSTRACT FROM AUTHOR]

Study Question: Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring?Summary Answer: Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life.What Is Known Already: Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms.Study Design, Size, Duration: The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies.Participants/materials, Setting, Methods: The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples.Main Results and the Role Of Chance: In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-β) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-β levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-β levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-β (P = 0.008) levels than the homozygous CC group.Limitations, Reasons For Caution: Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out.Wider Implications Of the Findings: The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects.Study Funding/competing Interest(s): This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Are meiotic segregation patterns of reciprocal translocations affected by the combined effect of chromosome type and carrier's sex?Summary Answer: Interaction of an acrocentric chromosome (Acr-ch) involved in the translocation and sex of the carrier influences the proportion of alternate segregation for normal or balanced chromosome contents during meiotic segregation in autosomal reciprocal translocations.What Is Known Already: Carriers of reciprocal translocations are at a significantly increased risk of fertility problems due to the generation of unbalanced gametes in meiotic segregation of a quadrivalent. Previous studies have reported that meiotic segregation patterns of a quadrivalent can be affected by factors such as a carrier's sex and age and the chromosome type. However, the reported proportion of alternate segregation does not differ significantly, except in one study, and whether combined effects between these factors exist is unclear.Study Design, Size, Duration: A retrospective study of array comparative genomic hybridization (aCGH) outcome data from patients with autosomal reciprocal translocations was conducted to analyse meiotic segregation patterns and blastocyst euploidy rates. We enroled 473 couples whose embryos were tested between January 2013 and September 2016.Participants/materials, Setting, Methods: Meiotic segregation patterns of 2101 blastocysts from 243 female carriers, including 76 cases with translocations involving Acr-ch, and 230 male carriers, including 88 cases with translocations involving Acr-ch, were analysed according to chromosome type, carrier's sex and age.Main Results and the Role Of Chance: In cases with translocations involving the Acr-ch subgroup, the proportion of alternate segregation (53.9 vs 33.4%, P < 0.0001) was significantly higher in male carriers than in female carriers, with the proportion of 3:1 segregation (6.8 vs 16.3%, P < 0.0001) being significantly lower. The proportions of alternate segregation were similar between sexes in cases with translocations not involving the Acr-ch subgroup. Meanwhile, in the female carrier subgroup, the proportion of alternate segregation (33.4 vs 45.2%, P < 0.001) was significantly lower and the proportion of 3:1 segregation (16.3 vs 8.2%, P < 0.001) was significantly higher in cases with translocations involving Acr-ch than in those not. In the male carrier subgroup, the proportion of alternate segregation (53.9 vs 46.9%, P = 0.031) was higher and the proportion of adjacent-1 segregation (27.1 vs 37.3%, P < 0.001) was significantly lower in cases with translocations involving Acr-ch than in those not. Carrier's age did not affect the meiotic segregation patterns. However the euploidy rates were significantly lower in couples with advanced compared to young maternal age respectively.Limitations, Reasons For Caution: Mosaic embryos were not identified using aCGH in this study. Patients with complex chromosome rearrangements and translocations involving sex chromosomes were excluded. Interchromosomal effect was not analysed.Wider Implications Of the Findings: The findings of this study provide detailed information for genetic counselling of couples with autosomal reciprocal translocations on their chances of producing euploid gametes.Study Funding/competing Interest(s): This research was supported by the National Key Research and Development Program of China (2016YFC1000202); the National Natural Science Foundation of China (81671522); the Natural Science Foundation of Shandong Province in China (ZR2016HP09); and the Innovative Foundation of Reproductive Hospital Affiliated to Shandong University (20171114, 20171111). No competing interests are declared.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: Multiple pregnancies are one of the major safety concerns of in vitro fertilization (IVF) due to the increased risk of maternal and neonatal complications. Single embryo transfer is the most effective way to reduce the risk of multiple pregnancies. Selection of the embryo and optimization of the implantation environment are crucial to retain the success rate when the number of transferred embryos is diminished. Fresh embryo transfer with supra-physiological levels of hormones has been suggested to have an adverse effect on implantation. Elective frozen embryo transfer has been suggested to result in a higher rate of live birth than fresh embryo transfer. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy and safety between frozen and fresh single blastocyst transfers.Methods/design: We are conducting a randomized controlled trial in women aged 20-35 undergoing their first cycle of IVF with or without intracytoplasmic sperm injection. After ovarian stimulation with a gonadotropin-releasing hormone antagonist protocol, women who obtain four or more embryos on day 3 of the embryo culture are randomized into two parallel groups: a single fresh blastocyst transfer group and a single frozen blastocyst transfer group (all blastocysts vitrified and a deferred frozen blastocyst transfer). The primary outcome is singleton live birth.Discussion: The results of this study will provide evidence for the efficacy and safety of the strategy of elective frozen single blastocyst transfer in women with a good prognosis.Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IOR-14005405 . Registered on 30 Oct 2014. [ABSTRACT FROM AUTHOR]

In order to study the impact of procedures of IVF/ICSI technology on sex ratio in China, we conducted this multi-center retrospective study including 121,247 babies born to 93,895 women in China. There were 62,700 male babies and 58,477 female babies, making the sex ratio being 51.8% (Male: Female  = 107∶100). In univariate logistic regression analysis, sex ratio was imbalance toward females of 50.3% when ICSI was preformed compared to 47.7% when IVF was used (P<0.01). The sex ratio in IVF/ICSI babies was significantly higher toward males in transfers of blastocyst (54.9%) and thawed embryo (52.4%) when compared with transfers of cleavage stage embryo (51.4%) and fresh embryo (51.5%), respectively. Multiple delivery was not associated with sex ratio. However, in multivariable logistic regression analysis after controlling for related factors, only ICSI (adjusted OR = 0.90, 95%CI: 0.88–0.93; P<0.01) and blastocyst transfer (adjusted OR = 1.14, 95% CI: 1.09–1.20; P<0.01) were associated with sex ratio in IVF/ICSI babies. In conclusion, the live birth sex ratio in IVF/ICSI babies was influenced by the use of ICSI, which may decrease the percentage of male offspring, or the use of blastocyst transfer, which may increase the percentage of male offspring. [ABSTRACT FROM AUTHOR]

Summary Objective The aim of this study was to describe the endocrine and metabolic characteristics of Chinese women with polycystic ovarian syndrome (PCOS) according to different phenotypes, including menstrual cycle pattern and body mass index (BMI). Design Retrospective study. Patient(s) A total of 3539 patients with PCOS and 590 controls were recruited from the Centre for Reproductive Medicine. Patients with PCOS were divided into three groups according to the characteristics of the menstrual cycle (amenorrhoea, oligomenorrhea and eumenorrhea) and the BMI (<25 kg/m2; 25 ≤ and ≤ 30 kg/m2; and BMI > 30 kg/m2). Measurements Waist circumference, hip circumference, weight, height, Ferriman-Gallwey score, and endocrine and metabolic variables were measured. Results The serum testosterone, luteinizing hormone (LH) and oral glucose tolerance test 2 h-glucose levels were increased in the amenorrhoea group ( P < 0·05). The triglycerides (TG) and low-density lipoprotein-cholesterol (LDL) levels were the highest in the amenorrhoea group ( P < 0·05). The same trend existed in total cholesterol and non- high-density lipoprotein-cholesterol (HDL) levels, although there was no statistical significance ( P > 0·05). Subjects with a BMI<25 kg/m2 had higher values of follicle stimulating hormone (FSH), LH, LH/FSH and prolactin ( P < 0·001) than the other two groups. The levels of TG, LDL and non-HDL and the indices of glucose and insulin metabolism increased with the change in BMI ( P < 0·001). Conclusions The amenorrhoea group had severe endocrine and metabolic abnormalities, which appeared to be related to latent long-term complications and higher morbidity. The degree of dysbolism was positively associated with the change in BMI. [ABSTRACT FROM AUTHOR]

Background: Extreme ambient temperature has been linked to decline in males' semen quality. Although the temperature–semen quality association has been examined in certain cities of South China, how the effect size of the extreme temperature may lag over critical windows in spermatogenesis and whether the strength of association may vary in North China have yet been adequately explored. Objectives: To quantify the association between air temperature and semen quality, and identify critical exposure windows in a Northern Peninsular Province, China. Materials and methods: Data on semen quality in 2014−2019 were collected from the Human Sperm Bank of Institute of Women, Children and Reproductive Health, Shandong University, China. Daily meteorological data (0.01°×0.01°) were assigned to each subject's residential address. The linear mixed‐effect model combined with the distributed lag nonlinear model was used to estimate the effect of ambient temperature over critical spermatogenesis windows. Results: The temperature–semen quality association was inverted V‐shaped, with the maximum lag being 0–45 days before ejaculation and the threshold being 9.2°C. Progressively and total motile sperm number, and total sperm number declined more substantially than other semen quality parameters. Semen quality was more sensitive to cold exposure during the epididymal storage period than the sperm motility development period. By contrast, semen quality was insensitive to heat exposure during both critical spermatogenesis windows. Impairment of certain semen quality parameters was more obvious for males with higher educational attainment and those aged over 35 years. Discussion and conclusion: Exposure to non‐optimal temperature is associated with decreased semen quality in North China, with the epididymal storage and sperm motility development periods more sensitive to cold exposure than heat. Older males and those with higher educations may need particular awareness. [ABSTRACT FROM AUTHOR]

In China, our research personnel and projects are mainly funded by the central government, provincial government, and nongovernmental foundations. Occasionally, we do some multicenter clinical research under the solicitation of pharmaceutical companies. [ABSTRACT FROM AUTHOR]

A possible role of PM 2.5 components on ovarian reserve has not been adequately unexplored. To evaluate the association between PM 2.5 components and women' ovarian reserve over critical exposure periods in northern China, where the level of air pollution is among the nation's highest. We included 15,102 women with serum anti-Müllerian hormone (AMH) measurements from the Center for Reproductive Medicine of Shandong University during 2015–2019. Concentrations of PM 2.5 and its five major components (0.1° × 0.1°), including sulfate, nitrate, ammonium, organic matter, and black carbon, were assigned to each residential address. Multivariable linear mixed effect models combined with constituent-residual models were performed to estimate the effect sizes of essential components over six short- to long-term exposure periods. The strength of association was stronger during the process from primary to small antral follicle compared with other longer windows. For every interquartile range increase in PM 2.5 mass was associated with − 8.7% (95%CI: −12.3%, −4.9%) change in AMH and the effect size was greatest for sulfate. Women with the lower level of attained education and those living inland were more susceptible compared with other population subgroups. Exposure to specific components of air pollution during critical exposure windows is associated with a decline in ovarian reserve. These data add to the growing body of evidence that environmental factors have adverse effects on reproductive health, particularly for vulnerable population subgroups. [Display omitted] • Short-term exposure to ambient PM 2.5 mass and its five major components was associated with decreased ovarian reserve. • SO 4 2- was identified as having the strongest adversed effects on ovarian reserve. • Lower educated women or those living inland were more vulnerable to PM 2.5 mass and its components than others. [ABSTRACT FROM AUTHOR]

The prevalence of infertility in couples actively trying to conceive is 25%. What is the consultation-seeking behaviour, diagnosis and related treatment in infertile couples across China? Large cross-sectional population-based study in 2010–2011, in which 25,270 couples from eight provinces/municipalities in China were approached by a multistage stratified cluster sampling strategy. Among the 2680 couples reporting infertility, 1246 infertile couples consulted a fertility doctor. Age of the couple, man's body mass index and women's educational level were found to be associated with consultation behaviour. After the fertility work-up, diagnoses were tubal infertility (n = 353, 28.3%), unexplained infertility (n = 311, 25.0%), male infertility (n = 234, 18.8%), ovulatory disorder (n = 194, 15.6%) and endometriosis (n = 34, 2.7%), while 8.6% (n = 107) were not classified. Most couples received non-assisted reproductive technology (ART) fertility treatment (n = 906, 89.3%), with a proportion using traditional Chinese medicine (TCM) (n = 298, 29.4%). Intrauterine insemination (n = 62, 6.1%) and IVF/intracytoplasmic sperm injection (n = 57, 5.6%) were less frequent. Medical treatment and outcomes among five subtypes of infertility were also reported: about 30% of couples with unexplained infertility (n = 94, 30.3%) or male infertility (n = 67, 29.0%) used TCM to treat infertility. Apart from patients with endometriosis, of whom 20.6% (n = 7) received ART, patients with other infertility subtypes rarely received ART. For subsequent fertility outcome, 94% of them did not achieve a pregnancy. The prevalence of infertility in China is high, but the uptake of treatment is relatively low. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of frozen embryo transfer on maternal and neonatal complications of singleton and twin pregnancies compared with fresh embryo transfer in women with polycystic ovary syndrome (PCOS).Design: A secondary analysis of a multicenter, randomized, controlled trial comparing live birth after frozen vs. fresh embryo transfer (FreFro-PCOS).Setting: Reproductive medicine centers.Patient(s): A total of 1,508 patients with a diagnosis of PCOS who were undergoing IVF were enrolled.Intervention(s): On day of oocyte retrieval, eligible patients were randomized to the fresh or frozen embryo transfer groups. Up to two embryos were transferred in both groups. All pregnancies were followed up until delivery.Main Outcome Measure(s): Gestational diabetes mellitus, pre-eclampsia, preterm birth, small for gestational age, and large for gestational age.Result(s): The risks of gestational diabetes mellitus, preterm birth, and small for gestational age were comparable between the frozen and fresh embryo transfer groups in both singleton and twin births. However, singleton infants born after frozen embryo transfer were more likely to be large for gestational age (25.2% vs. 17.5%; relative risk 1.44, 95% confidence interval 1.01-2.07, P=.044) than those born after fresh embryo transfer. Twin pregnancy after frozen embryo transfer had a higher risk of pre-eclampsia (12.0% vs. 2.8%; relative risk 4.31, 95% confidence interval 1.27-14.58, P=.009) than those after fresh embryo transfer.Conclusion(s): In women with PCOS, frozen embryo transfer resulted in an increased risk of large for gestational age in singleton pregnancy and a higher risk of pre-eclampsia in twin pregnancy.Clinical Trial Registration Number: NCT01841528. [ABSTRACT FROM AUTHOR]

Objective: To detect ZP (zona pellucida) gene (ZP1-ZP4) mutations in patients with oocyte anomalies.Design: Case-control genetic study.Setting: University-based reproductive medicine center.Patient(s): A total of 92 infertile patients with repeated cycles of oocyte maturation arrest (group I, n = 49) or oocyte morphologic defect (group II, n = 43) as well as 373 healthy controls.Intervention(s): Genomic DNA extracted from peripheral blood and coding regions of ZP genes amplified by polymerase chain reaction and sequenced by a DNA analyzer.Main Outcome Measure(s): Variant prediction of ZP genes with software.Result(s): In group I with oocyte maturation arrest, no novel variants were found. In group II with oocyte morphologic defects, four novel variants, two in the ZP1 gene [c.247T>C (p.W83R) and c.1413G>A (p.W471X)] and two in the ZP2 gene [c.1599G>T (p.R533S) and c.1696T>C (p.C566R)] were detected in 4 of 43 patients (approximately 9%) but were absent from the controls. Protein alignments showed that the four variants were highly conserved among different species, and all four variants were predicted to be deleterious by gene software predictions.Conclusion(s): ZP gene variants may account for patients with oocyte morphologic abnormalities but not for those with oocyte maturation arrest. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the common variant rs2305957 spanning PLK4 (Polo-like kinase 4) confers risk to embryo development in Northern Chinese Han (CHN) women.Design: Genetic association study.Setting: University hospital.Patient(s): A total of 2,015 infertile women who underwent in vitro fertilization (IVF), 530 women with early recurrent miscarriage (ERM), and 600 fertile control women in the CHN population.Intervention(s): Genotyping of rs2305957 was performed by means of high-resolution melting analysis.Main Outcome Measure(s): Blastocyst formation, implantation, early miscarriage, and live birth rates in infertile women; genotype distribution at rs2305957 in ERM case and control subjects.Result(s): In the first cohort of this study, infertile women with AA genotype had a lower blastocyst formation rate than those with AG or GG genotype. No significant differences were observed in implantation rate, early miscarriage rate, or live birth rate among AA, AG, and GG subgroups. In the second cohort, common variant rs2305957 was related to ERM. Genotype frequency differences were also significant in both additive model and dominant model.Conclusion(s): Common variant rs2305957 is associated with blastocyst formation and ERM in CHN women. Further investigations of PLK4 gene during embryo development could be worthwhile. [ABSTRACT FROM AUTHOR]

Lack of evidence exists on whether air pollution exposure may affect ovarian reserve, especially for Chinese women. To explore the association between exposure to various air pollutants and anti-Müllerian hormone (AMH), a predictor of ovarian reserve, over different exposure windows in Shandong Province, China. We enrolled 18,878 women who had AMH measurements in the Center for Reproductive Medicine, Shandong University during 2010–2019. Daily average concentrations of ambient particulate matter with diameters ≤1 μm/2.5 μm/10 μm (PM 1 , PM 2.5 , and PM 10), nitrogen dioxide (NO 2) and ozone (O 3) were developed at a spatial resolution of 0.01° × 0.01°, and assigned to the residential addresses. Three exposure windows were considered, i.e., the process from primary to small antral follicle stage (W1), from primary to secondary follicle stage (W2), and from secondary to small antral follicle stage (W3). The air pollution-AMH association was fitted using the multivariable linear mixed effect model with adjustment for potential confounders. Stratified analyses were performed by age group, overweight status, residential region, and educational level. The level of AMH changed by −8.8% (95% confidence interval (CI): −12.1%, −5.3%), −2.1% (95% CI: −3.5%, −0.6%), −1.9% (95% CI: −3.3%, −0.5%), and −4.5% (95% CI: −7.1%, −1.9%) per 10 μg/m3 increase in PM 1 , PM 2.5 , PM 10 , and NO 2 , respectively, during W1. The effect estimates were significant during W2 for PM 1 , PM 2.5 and NO 2 while minimal association was observed in W3. Greater vulnerability for certain air pollutants were observed for women who lived in inland areas and were less educated. We found that ovarian reserve was negatively associated with air pollution exposure for women, particularly from the primary to secondary follicle stage. The effect estimate increased by the reduction in the diameter of PMs, which also varied across population sub-groups. • Exposure to elevated air pollutants was associated with ovarian reserve impairment. • The crucial exposure period is from the primary to secondary follicle stage. • The effect estimates increased by the reduction in the size of particulate matter. • Greater vulnerability for pollutants for women lived in inland area and less educated. [ABSTRACT FROM AUTHOR]

Exonuclease 1 (EXO1) is required for both DNA repair and meiosis. Inactivation of EXO1 gene in mice leads to infertility. This study aimed to investigate whether variants in the EXO1 gene contribute to human premature ovarian failure (POF). The coding region of EXO1 was sequenced in 186 Han Chinese patients with non-syndromic POF. No plausible mutation was detected. The results suggest that mutations in the coding region of EXO1 may not be responsible for POF in Han Chinese women. [ABSTRACT FROM AUTHOR]

Objective: The melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese.Study Design: In total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested.Results: An association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018).Conclusion: This study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS. [ABSTRACT FROM AUTHOR]

• Each increase of 10 μg/m3 in PM 2.5 was associated with decreased fecundity by 11%. • It was also associated with an 20% increased likelihood of infertility. • The association might explain the increased infertility rates in polluted areas. Whether exposure to airborne particulate matter less than 2.5 μm (PM 2.5) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM 2.5 exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population. We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant's 1-year, 3-year, and 5-year average PM 2.5 exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 μg/m3 change of PM 2.5. We also estimated the odds ratio (OR) of infertility per 10 μg/m3 change of PM 2.5 , using logistic regression models. Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2–10 months). The median PM 2.5 exposure was 56.8 μg/m3, with a wide range of 9.2–93.5 μg/m3. In Cox regression models, each increase of 10 μg/m3 in the 1-year average PM 2.5 exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval [CI]: 0.86–0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13–1.27). PM 2.5 exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM 2.5 pollution. [ABSTRACT FROM AUTHOR]

This first large-scale report of birth defects in 15,405 offspring conceived by assisted reproductive technologies in China found infants born after IVF alone to have a birth defect frequency comparable to that in the general Chinese population; rates were nonsignificantly higher in infants conceived with use of intracytoplasmic sperm injection compared with those conceived after IVF alone. [Copyright &y& Elsevier]

Objective: To study the age-specific distribution of antimüllerian hormone (AMH) and describe the association of AMH with androgenic and metabolic profiles at different ages.Design: Cross-sectional study.Setting: University hospital.Patient(s): A total of 6,763 Chinese women from birth to menopause.Intervention(s): None.Main Outcome Measure(s): Anthropometric parameters (height, weight, and blood pressure), and levels of AMH and testosterone, glucose metabolism, and lipid profiles.Result(s): According to the level of AMH, four age phases were established: childhood (0-10 years), adolescence (11-18 years), reproductive age (19-50 years), and advanced age (≥51 years). During childhood and adolescence, AMH levels increased, reaching a peak at 18 years. A decline occurred thereafter during the reproductive-age period until the age of 50 years, and it remained at a low level above 0 onward. We found that AMH was negatively correlated with testosterone in childhood (r = -0.25), but was positively correlated with testosterone and the free androgen index in adolescence (r = 0.30; r = 0.26, respectively) as well as during the reproductive phases (r = 0.28; r = 0.31, respectively). No correlation was observed between AMH and body mass index, fasting blood glucose, fasting insulin, the homeostasis model assessment, total cholesterol, triglycerides, low-density lipoprotein, or high-density lipoprotein at any phase.Conclusion(s): From birth to 18 years, AMH increases, then it declines thereafter, indicating changes of ovarian maintenance. A positive relationship between androgenic profiles and AMH during adolescence and reproductive years implies a synchronism between androgens and ovarian reserve. [ABSTRACT FROM AUTHOR]

Background: While most research has focused on the association between intracytoplasmic sperm injection (ICSI) and neurodevelopmental disorders in children, relatively little attention has been given to its metabolic effects. Previous studies have reported that low serum lipid levels are associated with mental health problems. Our objective was to analyze the impact of ICSI on metabolic alterations compared to their in vitro fertilization (IVF) counterparts in male offspring, as well as its interaction with paternal overweight/obesity., Methods: We recruited families between January 2006 and December 2017 at the Center for Reproductive Medicine, Shandong University, China. Prospective data of offspring were obtained for body mass index (BMI), blood pressure, glucose, and lipid profile in their 0-11 years old. Linear mixed models were utilized to compute the mean difference and 95% confidence intervals (CI)., Results: A total of 14,196 offspring visits were identified. In offspring aged 4-11 years, ICSI-conceived offspring exhibited significantly lower fasting glucose z-scores, total cholesterol z-scores, and low-density lipoprotein cholesterol (LDL-C) z-scores compared with their IVF counterparts (fasting glucose z-score: adjusted mean difference: - 0.13, 95% CI: - 0.23 to - 0.03; total cholesterol z-score: adjusted mean difference: - 0.13, 95% CI: - 0.23 to - 0.02; LDL-C z-score: adjusted mean difference: - 0.12, 95% CI: - 0.22 to - 0.01). Paternal overweight/obesity significantly influenced the relationship between ICSI and metabolic changes in offspring. In offspring born from fathers with overweight/obesity, ICSI-conceived offspring displayed significantly lower fasting glucose and total cholesterol z-scores than their IVF controls (fasting glucose z-score: adjusted mean difference: - 0.20, 95% CI: - 0.32 to - 0.08; total cholesterol z-score: adjusted mean difference: - 0.15, 95% CI: - 0.27 to - 0.02). In offspring born to fathers with normal weight, ICSI-conceived offspring showed significantly lower systolic blood pressure z-scores compared to those conceived via the IVF procedures (adjusted mean difference: - 0.21, 95% CI: - 0.37 to - 0.05)., Conclusions: The findings of this study suggested that ICSI was associated with altered glucose and lipid profiles compared to their IVF controls, characterized by lower fasting glucose z-scores, total cholesterol z-scores, and LDL-C z-scores. Encouraging fathers to reduce their body weight could potentially improve the metabolic health of their ICSI-conceived children., (© 2024. The Author(s).)

Background: To the best of our knowledge, no study has investigated the potential joint effect of large for gestational age (LGA) and assisted reproductive technology (ART) on the long-term health of children., Methods: This was a prospective cohort study that recruited children whose parents had received ART treatment in the Center for Reproductive Medicine, Shandong Provincial Hospital, affiliated to Shandong University, between January 2006 and December 2017. Linear mixed model was used to compare the main outcomes. The mediation model was used to evaluate the intermediary effect of body mass index (BMI)., Results: 4138 (29.5%) children born LGA and 9910 (70.5%) children born appropriate for gestational age (AGA) were included in the present study. The offspring ranged from 0.4 to 9.9 years. LGAs conceived through ART were shown to have higher BMI, blood pressure, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance values, even after controlling for all covariates. The odds of overweight and insulin resistance are also higher in LGA subjects. After adjusting for all covariates, LGAs conceived through ART had BMI and BMI z-scores that were 0.48 kg/m 2 and 0.34 units greater than those of AGAs, respectively. The effect of LGA on BMI was identified as early as infancy and remained consistently significant throughout pre-puberty., Conclusions: Compared to AGA, LGA children conceived from ART were associated with increased cardiovascular-metabolic events, which appeared as early as infancy and with no recovery by pre-puberty., (© 2024. The Author(s).)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Premature ovarian insufficiency (POI) is one of the key aspects of ovarian infertility. Due to early cession of ovarian function, POI imposes great challenges on the physiological and psychological health of women and becomes a common cause of female infertility. In the worldwide, there has been a special outpouring of concern for about 4 million reproductive-aged women suffering from POI in China. Driven by advances in new technologies and efforts invested by Chinses researchers, understanding about POI has constantly been progressing over the past decade. Here, we comprehensively summarize and review the landmark development and achievements from POI studies in China spanning 2011-2020, which aims to provide key insights from bench to bedside., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Assisted reproductive technology (ART) has been widely used for treatment of infertility and has brought millions of births worldwide. The health of offspring conceived by ART has been of much concern, and adverse cardiovascular health outcomes have been reported by previous studies., Objective: To assess the cardiovascular health of children conceived by ART., Design, Setting, and Participants: This cohort study was conducted among participants recruited from November 2017 to February 2019. Participants were 382 children conceived by ART who were selected from a single reproductive center and 382 children who were naturally conceived, randomly selected from a primary school, and matched by sex, age, and maternal age at the child's birth (2 years older or younger). Data were analyzed from March 2019 through December 2019., Exposures: Conception by ART., Main Outcomes and Measures: Blood pressure was measured, and echocardiography was performed to determine left ventricular structural and functional parameters. Adjusted relative wall thickness (aRWT) was found for age, with high RWT defined as an aRWT of 0.375 or more., Results: Among 764 children aged 6 to 10 years, 382 children were conceived by ART (mean [SD] age, 7.20 [1.21] years; 201 [52.6%] boys) and 382 children were naturally conceived (mean [SD] age, 7.20 [1.21] years; 201 [52.6%] boys). Children conceived by ART had statistically significantly increased mean (SD) height (130.2 [9.5] cm vs 128.5 [8.1] cm; P = .007) and body mass index (17.6 [3.6] vs 17.1 [2.7]; P = .03). Those conceived by ART, compared with children in the matched control group, had statistically significantly increased blood pressure (mean [SD] systolic blood pressure, 105.5 [6.9] mm Hg vs 103.5 [8.4] mm Hg; adjusted P < .001; mean [SD] diastolic blood pressure, 67.2 [5.6] mm Hg vs 62.2 [6.3] mm Hg ; adjusted P < .001), left ventricular systolic dysfunction (mean [SD] left ventricular ejection fraction, 64.61% [3.20%] vs 66.70% [3.89%]; adjusted P < .001), and diastolic dysfunction (mean [SD] early/late mitral/tricuspid diastolic velocities ratio, 1.66 [0.28] vs 2.21 [0.36]; adjusted P < .001). They also had statistically significantly increased parameters of left ventricular structure, including mean (SD) left ventricular mass index (31.97 [5.04] g/m2.7 vs 28.28 [3.54] g/m2.7; adjusted P < .001) and RWT (3.30 [0.41] mm vs 2.98 [0.14] mm; adjusted P < .001). Additionally, children conceived by ART had statistically significantly increased prevalence of left ventricular hypertrophy (9 children [2.4%] vs 2 children [0.5%]; P = .03), high RWT (61 children [16.0%] vs 0 children; P < .001), and left ventricle remodeling patterns, including concentric remodeling (60 children [15.7%] vs 0 children), eccentric hypertrophy (8 children [2.1%] vs 2 children [0.5%]), and concentric hypertrophy (1 child [0.3%] vs 0 children) (P for left ventricle remodeling < .001)., Conclusions and Relevance: This study found that children conceived by ART had increased blood pressure and unfavorable changes in left ventricular structure and function compared with children who were naturally conceived. These findings suggest that further studies are needed to investigate the potential mechanisms and long-term outcomes associated with these differences.

Context: Obesity management prior to infertility treatment remains a challenge. To date, results from randomized clinical trials involving weight loss by lifestyle interventions have shown no evidence of improved live birth rate., Objective: This work aimed to determine whether pharmacologic weight-loss intervention before in vitro fertilization and embryo transfer (IVF-ET) can improve live birth rate among overweight or obese women., Methods: We conducted a randomized, double-blinded, placebo-controlled trial across 19 reproductive medical centers in China, from July 2017 to January 2019. A total of 877 infertile women scheduled for IVF who had a body mass index of 25 or greater were randomly assigned to receive orlistat (n = 439) or placebo (n = 438) treatment for 4 to 12 weeks. The main outcome measurement was the live birth rate after fresh ET., Results: The live birth rate was not significantly different between the 2 groups (112 of 439 [25.5%] with orlistat and 112 of 438 [25.6%] with placebo; P = .984). No significant differences existed between the groups as to the rates of conception, clinical pregnancy, or pregnancy loss. A statistically significant increase in singleton birth weight was observed after orlistat treatment (3487.50 g vs 3285.17 g in the placebo group; P = .039). The mean change in body weight during the intervention was -2.49 kg in the orlistat group, as compared to -1.22 kg in the placebo group, with a significant difference (P = .005)., Conclusion: Orlistat treatment, prior to IVF-ET, did not improve the live birth rate among overweight or obese women, although it was beneficial for weight reduction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Anti-Müllerian hormone (AMH) is crucial for folliculogenesis. Prenatal exposure to AMH in mice produces a phenocopy of polycystic ovary syndrome (PCOS) in the adult female offspring. The aim of this study was to determine whether genetic variation in AMH gene contribute to PCOS in women of Chinese ancestry., Methods: We conducted a case-control genetic study in 383 PCOS case and 433 control women of Chinese ancestry. The exons and the 5' flanking region of AMH were sanger sequenced. Bioinformatic prediction of variant deleteriousness was performed., Results: Seven novel heterozygous variants along with 15 rare known variants in AMH were identified in women with PCOS but not in controls. The novel variants included one frameshift variant (c.125&#95;129delACTTG), one synonymous variant (c.1095C>T), one variant (c.-14T>C) in the 5'-untranslated region (UTR), four variants(c.-775C>T, c.-682C>T, c.-333A>G, c.-137A>T) in 5' flanking sequence. Of all the AMH variants identified in women with PCOS, eight were predicted to be deleterious by bioinformatic analysis. The PCOS carriers of predicted-to-be-deleterious PCOS-specific AMH variants had increased total follicle numbers compared to PCOS noncarriers (p = 0.021)., Conclusions: Our findings suggest the AMH plays a role in the development of PCOS. The exact mechanisms by which the predicted-to-be-deleterious novel and rare AMH variants described in our study affect AMH function requires further study.

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population ( n  = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.

Context: The high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown., Objective: We sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation., Patients and Cells: mRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study., Main Outcome Measures: mRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study., Results: HMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS., Conclusions: The HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS., (Copyright © 2019 Endocrine Society.)

Background: Elective single embryo transfer (eSET) has been increasingly advocated, but concerns about the lower pregnancy rate after reducing the number of embryos transferred have encouraged transfer of multiple embryos. Extended embryo culture combined with electively freezing all embryos and undertaking a deferred frozen embryo transfer might increase pregnancy rate after eSET. We aimed to establish whether elective frozen single blastocyst transfer improved singleton livebirth rate compared with fresh single blastocyst transfer., Methods: This multicentre, non-blinded, randomised controlled trial was undertaken in 21 academic fertility centres in China. 1650 women with regular menstrual cycles undergoing their first cycle of in-vitro fertilisation were enrolled from Aug 1, 2016, to June 3, 2017. Eligible women were randomly assigned to either fresh or frozen single blastocyst transfer. The randomisation sequence was computer generated, with block sizes of two, four, or six, stratified by study site. For those assigned to frozen blastocyst transfer, all blastocysts were cryopreserved and a delayed frozen-thawed single blastocyst transfer was done. The primary outcome was singleton livebirth rate. Analysis was by intention to treat. This trial is registered at the Chinese Clinical Trial Registry, number ChiCTR-IOR-14005405., Findings: 825 women were assigned to each group and included in analyses. Frozen single blastocyst transfer resulted in higher rates of singleton livebirth than did fresh single blastocyst transfer (416 [50%] vs 329 [40%]; relative risk [RR] 1·26, 95% CI 1·14-1·41, p<0·0001). The risks of moderate or severe ovarian hyperstimulation syndrome (four of 825 [0·5%] in frozen single blastocyst transfer vs nine of 825 [1·1%] in fresh single blastocyst transfer; p=0·16), pregnancy loss (134 of 583 [23·0%] vs 124 of 481 [25·8%]; p=0·29), other obstetric complications, and neonatal morbidity were similar between the two groups. Frozen single blastocyst transfer was associated with a higher risk of pre-eclampsia (16 of 512 [3·1%] vs four of 401 [1·0%]; RR 3·13, 95% CI 1·06-9·30, p=0·029)., Interpretation: Frozen single blastocyst transfer resulted in a higher singleton livebirth rate than did fresh single blastocyst transfer in ovulatory women with good prognosis. The increased risk of pre-eclampsia after frozen blastocyst transfer warrants further studies., Funding: The National Key Research and Development Program of China., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Study Question: Is the total dose of exogenous gonadotropins associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women?, Summary Answer: The total dose of exogenous gonadotropins is not significantly associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women., What Is Known Already: The administration of gonadotropins in ovarian stimulation leads to supraphysiological steroid concentrations compared with those seen during natural cycles. The rate of euploid blastocytes is negatively associated with female age., Study Design, Size, Duration: This is a retrospective study using anonymised data on PGS cycles performed in China from 2013 to 2017. Data from 1088 PGS cycles and 3219 embryos were analysed by array-comparative genomic hybridization (array-CGH)., Participants/materials, Setting, Methods: The study included 944 women who underwent PGS cycles with COH. All cycles were analysed by the total dose of exogenous gonadotropins (<1500, 1500-3000 and >3000 IU), patient age (<35 and ≥35 y.o.) and number of oocytes retrieved (1-5, 6-10, 11-15 and >15 oocytes)., Main Results and the Role of Chance: In the group of younger women (<35 y.o., 537 PGS cycles), the incidence of aneuploidy ranged from 36.9 to 43.4% when data was stratified by gonadotropins dose. After adjusting for confounding factors, the dose of exogenous gonadotropins was not associated with the blastocyst aneuploidy rate. Similar results were shown in the group of women with advanced maternal age (≥35 y.o., 551 PGS cycles), with no difference in the rate of blastocyst aneuploidy among different gonadotropins dose groups (<1500 IU, 58.0%; 1500-3000 IU, 59.8%; and >3000 IU, 59.8%; P = 0.86). The live-birth rates after single cryopreserved blastocyst transfers were also not significantly associated with the gonadotropins dose., Limitations, Reasons for Caution: Limitations include the retrospective study design and the heterogeneity of the included patients. Additionally, array-CGH may not be able to correctly identify mosaicism., Wider Implications of the Findings: The finding that gonadotropin dosage is not associated with embryonic aneuploidy or live-birth rates in Chinese women suggests that the high doses of gonadotropins used in ART cycles may be safe. The findings are consistent with those of prior studies in other populations., Study Funding/competing Interest(s): This study was supported by the National Natural Science Foundation of China (81671522) and National Key Research and Development Program of China (2016YFC1000202)., Trial Registration Number: N/A.

Background: Obese women have fewer oocytes retrieved, an increased cancelation rate, a higher miscarriage rate, and a lower live birth rate after assisted reproductive technology (ART) treatment compared with women with normal weight. Weight loss before ART treatment can significantly improve pregnancy rates and/or live births. An orlistat plus diet intervention could promote weight loss, but there is no evidence from randomized clinical trials evaluating the effect of orlistat preconceptional treatment on pregnancy outcome in overweight and obese women., Methods/design: We are conducting a multicenter, randomized placebo-controlled, double-blind clinical trial in overweight and obese women aged 20-40 years undergoing in-vitro fertilization and embryo transfer (IVF-ET) with or without intracytoplasmic sperm injection, to evaluate whether orlistat treatment for 1-3 months before IVF-ET can improve the live birth rate. The primary outcome is live birth., Discussion: The results of this study will provide evidence for the effect of preconceptional orlistat treatment on IVF outcome in overweight/obese women., Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IPR-17011629 . Registered on 11 June 2017.

Semen from 5210 sperm bank donors was analyzed and trends in semen quality were evaluated at Shandong Human Sperm Bank between 2008 and 2014. After 2-7 days of abstinence, semen samples were collected. Measurements of semen volume, sperm concentration, sperm forward motility, and total sperm count were performed. There were significant declining trends in semen volume, sperm concentration, sperm forward motility, and total sperm count. Our results indicate that the quality of semen in this cohort of sperm donors had decreased during the study period.

Objective: To investigate whether the common variant rs2305957 spanning PLK4 (Polo-like kinase 4) confers risk to embryo development in Northern Chinese Han (CHN) women., Design: Genetic association study., Setting: University hospital., Patient(s): A total of 2,015 infertile women who underwent in vitro fertilization (IVF), 530 women with early recurrent miscarriage (ERM), and 600 fertile control women in the CHN population., Intervention(s): Genotyping of rs2305957 was performed by means of high-resolution melting analysis., Main Outcome Measure(s): Blastocyst formation, implantation, early miscarriage, and live birth rates in infertile women; genotype distribution at rs2305957 in ERM case and control subjects., Result(s): In the first cohort of this study, infertile women with AA genotype had a lower blastocyst formation rate than those with AG or GG genotype. No significant differences were observed in implantation rate, early miscarriage rate, or live birth rate among AA, AG, and GG subgroups. In the second cohort, common variant rs2305957 was related to ERM. Genotype frequency differences were also significant in both additive model and dominant model., Conclusion(s): Common variant rs2305957 is associated with blastocyst formation and ERM in CHN women. Further investigations of PLK4 gene during embryo development could be worthwhile., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Aims: To evaluate the association between preeclampsia (PE) and the single nucleotide polymorphism (SNP) rs13333226, located in the promoter region of the UMOD gene., Methods: A total of 1248 pregnant Han Chinese women (716 controls and 532 patients with PE) were included in this study. Genotyping of the rs13333226 polymorphism was performed by real-time PCR using a TaqMan-minor groove binder (MGB) probe assay., Results: No significant differences were detected in the allele (p = 0.62, OR = 1.08, 95% CI = 0.81-1.44) and genotype frequencies of rs13333226 (padditive = 0.38, pdominant = 0.45, precessive = 0.31) between cases and controls. When patients were divided into subgroups, no association was found with mild preeclampsia (M PE), severe preeclampsia (S PE), early onset PE, or late-onset PE. Furthermore, no significant differences were detected in the genotype and allele frequencies of rs1333226 between patients with M PE and S PE (p > 0.05) or between patients with late and early onset of the disease (p > 0.05)., Conclusions: UMOD rs13333226 does not appear to be associated with PE in Han Chinese women.

Context: A recent genome-wide association study (GWAS) has identified three susceptibility loci (8p32.1, 11p14.1, and 9q22.32) for polycystic ovary syndrome (PCOS) in women of European ancestry. The 9q22.32 locus was previously found in our Chinese PCOS GWAS. Replication of the other two loci is necessary to determine whether the same variants confer risk to PCOS in Han Chinese women., Objective: This study aimed to investigate the effect of the European GWAS loci on PCOS susceptibility in Han Chinese women., Design, Setting, and Patients: This was a genetic association study at a university hospital in composed of 1601 PCOS cases and 1238 age-matched controls. Interventions and Main Outcome Measure: After screening of the regions that cover 500 kb upstream and downstream of the two single-nucleotide polymorphisms (SNPs) using our previous Chinese GWAS data, rs11031010, located in the region of follicle-stimulating hormone B polypeptide (FSHB) gene, was selected for further replication. The other SNPs near rs804279 (GATA4/NEIL2) were excluded based on our previous GWAS data. Then, the variant rs11031010 was genotyped in an independent cohort and the associations with PCOS, endocrine and metabolic traits were assessed., Results: In the current replication study, rs11031010 was associated with PCOS in Han Chinese women (P = 2.76 × 10(-3)), even after adjustment for age and body mass index. Meta-analysis with our previous GWAS data showed that the allele frequency difference of rs11031010 between PCOS and controls reached genome-wide significance (P = 4.27 × 10(-8)). PCOS women with AA and AC genotypes had a significantly higher LH level than individuals carrying the CC genotype (P =1.60 × 10(-4)). The genetic risk score based on sixteen total Chinese PCOS-risk SNPs, calculated by total number of risk alleles for each subject, was associated with the diagnosis of PCOS (P < 1.00 × 10(-4))., Conclusions: Variants in FSHB gene are associated with PCOS and LH levels in Han Chinese women. FSHB is thus likely to play an important role in the etiology of PCOS, regardless of ethnicity.

HELQ, a member of DNA repair gene family, is an enzyme required for DNA strands cross-links repair and closely related to age at natural menopause. It also possesses a critical role in the germ cell maintenance, and loss of HELQ gene leads to subfertility. The aim of the present study was to investigate whether mutations in HELQ contribute to premature ovarian failure (POF) in Chinese women. A cohort of 192 patients with POF was enrolled. All exons and exon-intron boundaries of genomic DNA were amplified and sequenced. Six known single-nucleotide polymorphisms were identified in both POF and control groups, including rs1494961, rs13141136, rs7665103, rs11099600, rs2047210 and rs12645412. No mutation was identified. Our study indicates for the first time that mutations in the coding sequence of the HELQ gene may not be responsible for premature ovarian failure in Chinese Han population., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Premature ovarian failure (POF) is a heterogeneous disease. Though dozens of candidate genes have been identified for the genetic etiology of POF, it is largely unexplained in majority of patients. Recently, Wt1(+/R394W) mice was found to present POF-like phenotype, which indicates that WT1 might be a plausible candidate gene for non-syndromic POF. The coding region of WT1 gene was screened in 384 patients with POF and 6 novel variations were identified, including two missense mutations (p. Pro126Ser in exon1 and p. Arg370His in exon7) and four intronic variants (c.647-27C > T, c.647-13G > C, c.647-13G > A in intron1 and c.950 + 14T > C in intron 4). In vitro experiments showed that both mutant p. Pro126Ser and p. Arg370His repressed the expression of Amh and Cdh1, and induced the expression of Fshr and Cyp19 in mRNA level (P < 0.05). The expression changes of AMH, FSHR, CYP19 and CDH1 were confirmed by western blot. These genes (AMH, FSHR, CYP19 and CDH1) are required for granular cells (GCs) proliferation, differentiation and oocyte-GCs interaction. The novel mutant p. P126S and p. R370H in the WT1 gene potentially impaired GCs differentiation and oocyte-GCs interaction, which might result in loss of follicles prematurely. Therefore, WT1 is a plausible causal gene for POF.

In this retrospective study, the relationship between demographic characteristics, past medical history, general lifestyle habits and susceptibility of premature ovarian failure (POF) in Han Chinese population was investigated. Five hundred and fifty-three patients with POF and 400 women with normal ovarian function were recruited. A questionnaire was designed to gather information from responders. Logistic regression was carried out to calculate odds ratios (OR), 95% confidence intervals (95% CI) and P-values. History of pelvic surgery, mumps, having relatives with menstrual abnormalities and exposure to chemical agents were significantly associated with increased risk of POF (OR 5.53 [2.15 to 14.23]; 3.26 [2.38 to 4.47]; 28.12 [8.84 to 89.46]; 4.47 [2.09 to 9.58]). Vegetarian diet, tea and mineral water consumption reduced the risk of POF (OR 0.27 [0.19 to 0.37]; 0.04 [0.03 to 0.07]; 0.63 [0.47 to 0.85], respectively). Heredity, pelvic surgery, mumps and exposure to chemical agents were identified as risk factors for POF, whereas vegetarian diet, tea consumption and mineral water drinking were protective. Therefore, genetic consultation could help those women whose relatives manifested an early or premature menopause to avoid the consequences of possible premature ovarian function cessation. Avoidance of exposure to endocrine disrupters and flavonoids intake should be considered., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Study Question: Do mutations and/or polymorphisms in coding sequences in Wingless-Type MMTV Integration Site Family, Member 6 (WNT6) play a role in unexplained recurrent miscarriage (unexplained RM) in Chinese couples?, Summary Answer: We found four mutations in the coding sequences of WNT6 which appear to exist in a small proportion of Chinese women with unexplained RM., What Is Known Already: WNT6 has been proved to be essential for stromal cell proliferation during decidualization in mice, but in humans WNT6 has not been studied in recurrent miscarriage populations., Study Design, Size, Duration: For this study, 100 couples with unexplained RM (at least three or more unexplained spontaneous miscarriages), and 100 ethnically matched fertile couples (at least one live birth and no history of pregnancy pathologies) were recruited. All the participants were chosen over a 7-year period from the National Research Center for Assisted Reproductive Technology and Reproductive Genetics at Shandong University, Jinan, China., Participants/materials, Setting, Methods: Patients were recruited following extensive clinical studies. Genomic DNA was isolated from peripheral blood. Mutation analysis in the coding regions of WNT6 was performed by PCR amplification and DNA sequences testing in all participants. Functional effects of missense variants were predicted using Polyphen-2 and sorting intolerant from tolerant (SIFT)., Main Results and the Role of Chance: Four rare novel mutations, including one missense mutation, were found in intron 1, exon 3 and the 3' untranslated region of WNT6 in four women with unexplained RM. Gene software predictions showed that the missense mutation in exon 3 could alter the function of WNT6. No mutations or polymorphisms were detected in the male partners of the unexplained RM patients or in the fertile controls. To further validate the findings, we continued to screen this missense mutation site in another 100 peripheral blood samples of normal fertile females, and there was still no positive result., Limitations, Reasons for Caution: There is no direct evidence to validate whether these novel mutations discovered in the present research are related to unexplained RM. Further studies are warranted to investigate the role of WNT6 in unexplained RM, including larger studies in an independent group., Wider Implications of the Findings: These results provide evidence to suggest the importance of WNT6 in reproductive failure and may support the hypothesis that WNT6 is essential for stromal cell proliferation during decidualization., Study Funding/competing Interests: This work was supported by Science and Technology Development Planning of Shandong (2013GGE27001), the National Natural Science Foundation of China (81300459), the Science Projection of Bureau of Public Health in Weifang (2012044) and the Science Research Foundation Item of No-earnings Health Vocation. The authors have no competing interests to declare., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

KIAA0319L, PXK and JAZF1 gene polymorphisms were investigated to determine whether they conferred susceptibility to unexplained recurrent pregnancy loss (URPL) in a group of Chinese Han patients. Genotyping and sequencing of the single nucleotide polymorphisms (SNP) rs2275247(A/G) in KIAA0319L, rs2176082(C/T) and rs6445975(G/T) in PXK and the rs1635852(C/T) in JAZF1 were carried out in 84 couples with URPL and 102 healthy couples with at least one live birth. Frequencies of the SNP rs2176082(C/T) in PXK gene were significantly different between women with URPL and control women: P < 0.05; OR 95% CI 0.530 (0.287 to 0.979); OR 95% CI 0.482 (0.254 to 0.911) but were not significantly different after Bonferroni correction. The frequencies of the SNP rs2176082(C/T) in PXK gene showed no difference between the husband of a woman with URPL and a control husband: OR 95% CI 1.494 (0.821 to 2.721); OR 95% CI 1.567 (0.841 to 2.921). No statistically significant differences were observed in the distribution of any genotype or allele frequency or any genetic model of the other three SNPs between couples with URPL and control couples. Therefore, the rs2176082(C/T) polymorphism of PXK might play a possible role in the development of URPL in Chinese Han women., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate whether mutations in the KISS1 gene are present in 170 Chinese patients with idiopathic hypogonadotropic hypogonadism (IHH)., Methods: Mutational screening of the KISS1 gene was performed in 170 Chinese patients with IHH (133 male cases and 37 female cases) and 187 matched controls (94 males and 93 females)., Results: Two known single-nucleotide polymorphisms (SNP), c. 58G > A in exon 1 and c. 242C > G in exon 2, were identified. However, no difference of genotype and allelic frequencies between cases and controls was observed., Conclusions: The results suggest that mutations in the coding sequence of KISS1 are not common in patients with IHH in this Chinese population.

A previous genome-wide association study of polycystic ovary syndrome (PCOS) identified several susceptibility loci. TOX3 is the nearest gene to signal rs4784165. In the present study, all exons and exon-intron boundaries of TOX3 were amplified and sequenced in 200 Chinese women with PCOS. A 3-bp nucleotide deletion of CAG repeat and two known single nucleotide polymorphisms were identified. No plausible pathogenic mutations were detected. The results suggest that mutations in TOX3 are not common in Chinese Han women with PCOS., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

HOXA genes in groups 7-13 have been proven to play a role in determining positional identity along the genitalia axis. The aim of the present study was to explore the relationship between HOXA7 and HOXA9 mutations and Müllerian duct abnormalities (MDA). One hundred and ninety-two Chinese patients with MDA abnormalities and 192 healthy controls were recruited. All coding regions of HOXA7 and HOXA9 were amplified and sequenced directly. Rs2301721 and rs2301720 in HOXA7, rs35355140 and rs7810502 in HOXA9 were identified in patients with MDA and controls. One rare single nucleotide polymorphism rs189587233 in 3' UTR of HOXA9 gene was detected in one patient with didelphic uterus and absent in the 192 controls. This polymorphism, however, is known to exist in the normal Chinese population. Our results indicated that variants in the HOXA7 and HOXA9 genes were not common in Chinese women with Müllerian duct abnormalities., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Preeclampsia, characterized by hypertension and proteinuria, remains a leading cause of maternal morbidity and mortality. Recently, a genome-wide association study (GWAS) identified the single-nucleotide polymorphism, rs2681472, as a new hypertension susceptibility genetic variant. The purpose of this study was to evaluate the association between preeclampsia and rs268172 in a Northern Han Chinese population. We genotyped 1218 unrelated Northern Han Chinese women, including 515 patients with preeclampsia and 703 healthy controls. No significant differences were detected in the allele frequencies between patients and controls (P = .23). When patients were divided into early-onset and late-onset preeclampsia according to gestational age of disease onset, the allele frequencies significantly differed between controls and patients with early-onset preeclampsia (P = .02). Genotype frequencies also were significantly different between controls and patients early-onset preeclampsia when data were analyzed under additive (P = .03) and dominant (P = .009) models. We replicated this association in an independent Northern Han Chinese population and observed a significant difference in the allele frequencies between patients with early-onset preeclampsia and controls (P = .011). We report that rs2681472 is associated with early-onset preeclampsia in Northern Han Chinese women., (© The Author(s) 2014.)