Impact of a previous late miscarriage on subsequent pregnancy outcomes: A retrospective cohort study over 10 years.

OBJECTIVE: To explore the prognostic impact of a previous late miscarriage (LM) on the subsequent pregnancy outcomes of women with infertility. METHOD: This retrospective cohort study included couples who had experienced LM following their first embryo transfer during an in vitro fertilization (IVF) cycle from January 2008 to December 2020. Subgroup analysis and binary logistic regression were performed to evaluate the associations between LM due to different causes and subsequent pregnancy outcomes. RESULTS: A total of 1072 women who had experienced LM were included in this study, comprising 458, 146, 412, and 56 women with LM due to unexplained factors (unLM), fetal factors (feLM), cervical factors (ceLM; i.e. cervical incompetence), and trauma factors (trLM), respectively. Compared with the general IVF (gIVF) population, the early miscarriage rate was significantly higher in the unLM group (8.28% vs. 13.47%, adjusted odds ratio [OR] 1.60, 95% confidence interval [95% CI] 1.12-2.28; P = 0.01). Furthermore, women in the unLM and ceLM groups had a dramatically increased risk of recurrent LM (unLM: 4.24% vs. 9.43%, aOR 1.91, 95% CI 1.24-2.94; P = 0.003; ceLM: 4.24% vs.15.53%, aOR 2.68, 95% CI 1.82-3.95; P < 0.001) and consequently a reduced frequency of live birth (unLM: 49.96% vs. 43.01%, aOR 0.75, 95% CI 0.61-0.91; P = 0.004; ceLM: 49.96% vs. 38.59%, aOR 0.61, 95% CI 0.49-0.77; P < 0.001) compared with the gIVF population. CONCLUSION: A previous LM due to an unexplained factor or cervical incompetence was significantly associated with a higher risk of miscarriage and a lower live birth rate after subsequent embryo transfer.

Growth hormone supplementation ameliorates blastocyst euploidy rates and improves pregnancy outcomes in women undergoing preimplantation genetic testing for aneuploidy cycles.

Background: Growth hormone (GH) supplementation has been shown to improve oocyte quality and live birth, but few studies have examined whether GH can reduce embryonic aneuploidy. Chromosomal abnormalities in preimplantation embryos have been regarded as the principal cause of implantation failure and miscarriage, and an increased percentage of aneuploid embryos has been observed in patient cohorts with unexplained recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), and advanced maternal age. Methods: This prospective cohort study was conducted on women whose previous PGT-A cycle ended up with no transferrable blastocysts, or the aneuploidy rate was above 50% and no live birth was acquired. The participants were divided into GH co-treatment and comparison groups according to whether GH was administered in the subsequent PGT-A cycle. In addition, within the GH co-treatment group, the previous failed cycle constituted the self-control group. Results: 208 women were recruited in the study (GH co-treatment group: 96 women, comparison group: 112 women). Compared to the self-control and comparison groups, the rate of euploid blastocysts was significantly higher in the GH co-treatment group (GH vs self-control: 32.00% vs 9.14%, odds ratio [OR]: 4.765, 95% confidence interval [CI]: 2.420-9.385, P < 0.01; GH vs comparison: 32.00% vs. 21.05%, OR: 1.930, 95% CI: 1.106-3.366, P = 0.021), and their frozen embryo transfers resulted in more pregnancies and live births. In the subgroup analysis, for the <35 and 35-40 years groups, the euploidy rate in the GH co-treatment group was significantly higher than those in the self-control and comparison groups, but in the >40 years group, there was no difference in euploidy rate. Conclusion: Our study presents preliminary evidence that GH supplementation may ameliorate blastocyst aneuploidy and improve pregnancy outcomes in women who have previously experienced pregnancy failures along with high aneuploidy rates, particularly in those younger than 40 years. Therefore, the use of GH in such women should be considered. However, considering the limited sample size and mixed indications for PGT-A, further scientific research on the underlying mechanism as well as clinical trials with larger sample sizes are needed to confirm the effects and optimal protocols.

Blastocyst euploidy rates in low-prognosis patients according to the POSEIDON criteria: a retrospective analysis of 3016 embryos.

RESEARCH QUESTION: Do embryo euploidy rates differ in the four groups of women with low prognosis as stratified by the POSEIDON criteria? DESIGN: This was a retrospective cohort study of low-prognosis patients who met the POSEIDON criteria and underwent preimplantation genetic testing for aneuploidies (PGT-A) from January 2013 to June 2020 at the Center for Reproductive Medicine, Shandong University, China. A total of 3016 blastocysts from 1269 PGT-A cycles were included in the study. The primary outcome was the euploidy rate of the blastocysts. For each group, regression analyses were performed to quantitatively describe the relationship between maternal age and embryo euploidy rate. RESULTS: The euploidy rate of embryos in women with poor ovarian response (POR) was 39.1% in total. There were 727, 1052, 275 and 962 blastocysts in groups 1, 2, 3 and 4, respectively, with corresponding embryo euploidy rates of 57.2%, 34.9%, 52.4% and 26.2% (P < 0.001). Within each group, the euploidy rate decreased with age, especially in women aged 35 years or older (i.e. groups 2 and 4). CONCLUSIONS: Euploidy rates were more favourable in groups 1 and 3, of a young age, re-emphasizing that oocyte quality is the primary factor determining embryo euploidy rate. The study's findings demonstrated the reasonability of categorizing women with POR by the POSEIDON criteria depending on female age and ovarian reserve biomarkers. These results also provide information for women with POR in different subgroups so they can receive proper counselling on the possible prognosis.

MiR-148a-3p may contribute to flawed decidualization in recurrent implantation failure by modulating HOXC8.

PURPOSE: To evaluate whether miR-148a-3p overexpression is associated with disrupted decidualization of recurrent implantation failure (RIF). METHODS: Endometrial miRNA and mRNA expression profiles during the implantation window derived from women with and without RIF were identified using microarray and RT-qPCR. Immortalized human endometrial stromal cells (HESCs) were cultured for proliferation and in vitro decidualization assays after enhancing miR-148a-3p expression or inhibiting putative target gene homeobox C8 (HOXC8) expression. RT-qPCR, western blot, and luciferase reporter assays were used to confirm the relationship between miR-148a-3p and HOXC8 gene. RESULTS: MiR-148a-3p was significantly upregulated in RIF endometrial tissues. Forced expression of miR-148a-3p notably attenuated HESC in vitro decidualization. Mechanistic studies revealed that miR-148a-3p directly bounds to the HOXC8 3' untranslated region (3'UTR) and suppressed HOXC8 expressions in both mRNA and protein levels. Further investigations demonstrated that inhibition of HOXC8 in HESCs induced similar effects on decidual process as those induced by miR-148a-3p overexpression. CONCLUSION: Taken together, our findings suggested that elevated miR-148a-3p might account for flawed decidualization in RIF by negatively regulating HOXC8, raising the possibility that miR-148a-3p might be a novel therapeutic target in RIF.

Interaction of acrocentric chromosome involved in translocation and sex of the carrier influences the proportion of alternate segregation in autosomal reciprocal translocations.

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.

The Effect of Tamoxifen on Thin Endometrium in Patients Undergoing Frozen-Thawed Embryo Transfer.

Tamoxifen has played a vital role in endocrine therapy for the treatment of estrogen receptor-positive breast cancer. We examined the effect of tamoxifen in patients with a thin endometrium in frozen-thawed embryo transfer (FET) cycles and compared the improvement in endometrial thickness (EMT) and pregnancy outcomes stratified by different etiologies of thin endometrium. A total of 226 women were recruited for a new tamoxifen protocol; all had an EMT of less than 7.5 mm in previous cycles, including natural cycle (NC), hormone replacement treatment (HRT), and ovulation induction (OI) cycles. Compared with previous cycles, tamoxifen cycles showed a significantly increased EMT (from 6.11 ± 0.98 mm to 7.87 ± 1.48 mm in the NC group, from 6.24 ± 1.01 mm to 8.22 ± 1.67 mm in the HRT group, and from 6.34 ± 1.03 mm to 8.05 ± 1.58 mm in the OI group; all P < .001). Patients were further divided into 3 groups based on the causes of their thin endometrium: (1) history of intrauterine adhesion (n = 34), (2) history of uterine curettage (n = 141), and (3) polycystic ovary syndrome (PCOS; n = 51). Patients with PCOS obtained the thickest EMT (9.31 ± 1.55 mm), the lowest cycle cancellation rate (11.76%), and the highest rate of clinical pregnancy (60%) and live birth (55.56%) per transfer ( P < .001). Multivariable regression analysis showed that EMT was related to live birth (odds ratio: 1.487; 95% confidence interval: 1.172-1.887). A tamoxifen protocol improves EMT in patients after NC, HRT, and OI cycles during FET. Patients with PCOS show the most benefit from tamoxifen and achieve better pregnancy outcomes.

The feasibility of establishing classification system for ovarian function.

The occurrence, development, and decline of ovarian function are the foundation in women's whole life stages, which reflect the process beginning from embryo formation to the aging. Correct assessment of ovarian function is significant for evaluating the potential reproductive ability and predicting the age of menopause, as well as providing both individualized and proper treatment and preventive care based on physiological characteristics of women in different phases. Ovarian reserve (OR) is used to predict the potential fertility of women by evaluating the follicles and the quantity and quality of eggs. Currently, there are multiple indexes used to evaluate ovarian reserve, including anti-Millerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol (E2), inhibin B, antral follicle count (AFC), etc. Although some scholars combine multiple indexes to evaluate the ovarian function, these indexes are far less accurate, detailed, and comprehensive. To find an ideal method for evaluation of ovarian reserve is the hotspot in research of reproductive endocrine. The present authors, for the first time, put forward a classification system of ovarian reserve function after summarizing numerous cases. It can both accurately and effectively evaluate the ovarian function quantitatively. It is of great help in making clinical decisions and of great significance in future development.

Risk Factors and Early Predictors for Heterotopic Pregnancy after In Vitro Fertilization.

This study investigated the risk factors and early predictors for heterotopic pregnancy (HP) after in vitro fertilization and embryo transfer (IVF-ET). From January 2008 to January 2013, 41 cases of HP and 72 cases of intrauterine twin pregnancy after IVF-ET were recruited and retrospectively analyzed. Compared with intrauterine twin pregnancy group, the HP group had a lower basal luteinizing hormone (LH) level (P = 0.005) and more cases had a history of hydrosalpinx (P = 0.008). After 14 days of IVF-ET, the serum ß-HCG (ß-human chorionic gonadotropin), E2 (Estradiol) and P (Progesterone) levels were lower in HP group (P<0.001, respectively). Moreover, vaginal bleeding and abdominal pain were the significant features of HP before diagnosis (P<0.001, respectively). Further by logistic regression, serum ß-hCG, P levels on the 14th day after ET, and vaginal bleeding were identified as the independent factors of HP. These results indicate that when two or more embryos transferred in IVF procedure, ß-hCG, P levels on the 14th day after ET, and vaginal bleeding could be taken as predictors for HP.

White blood cell differential counts in patients with polycystic ovary syndrome: a pilot study on Chinese women.

OBJECTIVE: A state of systemic chronic low grade inflammation has been observed in polycystic ovary syndrome (PCOS). It has been suggested that inflammation is a potential mechanism influencing the ovaries or endocrine system and might therefore contribute to the pathophysiology of PCOS. The aim of this study was to compare the total white blood cell (WBC), neutrophil granulocyte and lymphocyte differential counts between women with PCOS and controls. In addition, we estimated if the WBC differential counts had a relationship with body mass index (BMI), total testosterone levels, estradiol levels and luteinizing hormone levels of women with PCOS. STUDY DESIGN: 1016 subjects with PCOS and 1016 age-matched healthy women from a Han Chinese population were enrolled in this case-control study. Blood samples were taken from all the patients and controls to test total WBC counts, lymphocyte counts, neutrophil counts and related serum hormones. RESULTS: Total WBC counts and lymphocyte counts were elevated in PCOS subjects (t-test P<0.01). Higher lymphocyte counts which contributed to higher total WBC counts in PCOS women were compared to age-matched controls. When the data were adjusted by BMI, the difference of WBC counts and lymphocyte counts between patients and controls remained significant. CONCLUSIONS: The state of chronic low grade inflammation in patients with PCOS might be associated with immunological factors. Obesity and hyperandrogenism may be due to the underlying low grade inflammation.

Variants in DENND1A and LHCGR are associated with endometrioid adenocarcinoma.

OBJECTIVE: The aim of this study was to explore the polycystic ovary syndrome (PCOS) related single nucleotide polymorphisms (SNPs) rs13405728 (in gene LHCGR), rs13429458 (in gene THADA) and rs2479106 (in gene DENND1A) in women with endometrial carcinoma. METHODS: We conducted a case-control study comprising 96 Han Chinese women with endometrial carcinoma, and 192 healthy controls. SNPs rs13405728, rs13429458 and rs2479106 were genotyped by polymerase chain reaction (PCR) and direct sequencing. The effects of body mass index (BMI) and age were evaluated using an unconditional logistic regression model adjusted for potential confounders. RESULTS: The allele frequencies of SNPs rs2479106 and rs13405728 were significantly different (P<0.05) between endometrial carcinoma group and control group, and the difference was especially significant in the subgroup of endometrioid adenocarcinoma. Genotyping analysis showed that allele G in rs2479106 and allele A in rs13405728 could confer risk to endometrioid adenocarcinoma. CONCLUSIONS: Our results suggest that SNPs rs2479106 in gene DENND1A and rs13405728 in gene LHCGR are associated with endometrioid adenocarcinoma.

LHX1 mutation screening in 96 patients with müllerian duct abnormalities.

OBJECTIVE: To investigate whether LHX1 gene mutations exist in Han Chinese patients with müllerian duct abnormalities (MDAs). DESIGN: Mutation screening. SETTING: University hospital. PATIENT(S): Ninety-six MDA patients and 105 control subjects from a Han Chinese population. The parents of the patients carrying the genetic variation were also screened. INTERVENTION(S): Gene sequencing. MAIN OUTCOME MEASURE(S): Karyotype, LHX1 gene sequencing. RESULT(S): We found no significant mutation in coding regions of LHX1. However, there is a new rare polymorphism of LHX1 gene, c.1070-1081del, found in 1 out of 77 incomplete müllerian fusion patients and 1 out of 105 control individuals in the Han Chinese population (thus affecting ∼1% of Han Chinese). CONCLUSION(S): No causative perturbation was identified in the LHX1 gene. Mutations in the coding regions of LHX1 may not be a common genetic etiologic factor involved in Han Chinese MDA patients.

Variants of the WNT7A gene in Chinese patients with müllerian duct abnormalities.

OBJECTIVE: To search for WNT7A gene mutations in a cohort of 191 Chinese Han patients with müllerian duct abnormalities (MDAs). DESIGN: Phenotypic and mutational study. SETTING: University hospital. PATIENT(S): A total of 191 Chinese Han patients with MDAs and 192 healthy control individuals. INTERVENTION(S): Genomic DNA extracted from blood samples, all coding regions amplified by polymerase chain reaction (PCR) then directly sequenced to screen variants. MAIN OUTCOME MEASURE(S): Not applicable. RESULT(S): The sequence analysis revealed one novel synonymous variant and three known single-nucleotide polymorphisms (SNPs). CONCLUSION(S): The results indicate that mutations in the coding sequence of WNT7A are not responsible for müllerian duct abnormalities in the Chinese population.

Analysis of PBX1 mutations in 192 Chinese women with Müllerian duct abnormalities.

We examined the PBX1 gene in 192 Chinese women with Müllerian duct abnormalities and revealed 2 known single nucleotide polymorphisms: c.61 > A in exon 1 and c.998-1330A>G in intron 7. Future studies in large cohorts of different ethnic populations are warranted to establish definite associations between the PBX1 gene and Müllerian duct abnormalities.