Individual and combined association between nutritional trace metals and the risk of preterm birth in a recurrent pregnancy loss cohort.

Background: Recurrent pregnancy loss (RPL) was associated with an elevated risk of pregnancy complications, particularly preterm birth (PTB). However, the risk factors associated with PTB in RPL remained unclear. Emerging evidence indicated that maternal exposure to metals played a crucial role in the development of PTB. The objective of our study was to investigate the individual and combined associations of nutritional trace metals (NTMs) during pregnancy with PTB in RPL. Methods: Using data from a recurrent pregnancy loss cohort (n = 459), propensity score matching (1:3) was performed to control for covariates. Multiple logistic regression and multiple linear regression were employed to identify the individual effects, while elastic-net regularization (ENET) and Bayesian kernel machine regression (BKMR) were used to examine the combined effects on PTB in RPL. Results: The logistic regression model found that maternal exposure to copper (Cu) (quantile 4 [Q4] vs. quantile 1 [Q1], odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.05, 0.74) and zinc (Zn) (Q4 vs. Q1, OR: 0.19, 95%CI: 0.04, 0.77) was inversely associated with total PTB risk. We further constructed environmental risk scores (ERSs) using principal components and interaction terms derived from the ENET model to predict PTB accurately (p < 0.001). In the BKMR model, we confirmed that Cu was the most significant component (PIP = 0.85). When other metals were fixed at the 25th and 50th percentiles, Cu was inversely associated with PTB. In addition, we demonstrated the non-linear relationships of Zn with PTB and the potential interaction between Cu and other metals, including Zn, Ca, and Fe. Conclusion: In conclusion, our study highlighted the significance of maternal exposure to NTMs in RPL and its association with PTB risk. Cu and Zn were inversely associated with PTB risk, with Cu identified as a crucial factor. Potential interactions between Cu and other metals (Zn, Ca, and Fe) further contributed to the understanding of PTB etiology in RPL. These findings suggest opportunities for personalized care and preventive interventions to optimize maternal and infant health outcomes.

Diagnostic workup of endocrine dysfunction in recurrent pregnancy loss: a cross-sectional study in Northeast China.

Objective: To evaluate the prevalence of abnormal endocrine dysfunction for recurrent pregnancy loss (RPL) amongst patients with two versus three or more pregnancy losses. Methods: This cross-sectional study retrospectively collected pre-pregnancy data of 537 women diagnosed with RPL in Shengjing Hospital of China Medical University from 2017 to 2022, including the baseline data of patients and the test results of endocrine factors. Several endocrine dysfunction included in this study were: thyroid dysfunction, obesity, hyperprolactinemia, polycystic ovary syndrome and blood glucose abnormality. Furthermore, vitamin D level were collected to study its relationship with endocrine dysfunction. Finally, we subdivided the patients according to the number of previous pregnancy loss and compared the prevalence of endocrine dysfunction between subgroups. Results: Among 537 RPL patients, 278 (51.8%) patients had abnormal endocrine test results. The highest incidence of endocrine dysfunction was thyroid dysfunction (24.39%, 131/537), followed by hyperprolactinemia (17.34%, 85/490), obesity (10.8%, 58/537), polycystic ovary syndrome (10.50%, 56/533), and abnormal blood glucose (5.29%, 27/510). Only 2.47%(13/527) of patients have vitamin D level that reach the standard. After subdividing the population according to the number of pregnancy loss, we did not find that the incidence of endocrine dysfunction (P=0.813), thyroid dysfunction (P=0.905), hyperprolactinemia (P=0.265), polycystic ovary syndrome (P=0.638), blood glucose abnormality (P=0.616) and vitamin D deficiency (P=0.908) were different among patients with two versus three or more pregnancy losses. However, obesity (P=0.003) was found more frequently observed in patients with more times of pregnancy loss. Conclusion: The prevalence of endocrine dysfunction in RPL population is high. There is no difference in the prevalence of endocrine dysfunction, except for obesity, among patients with two or more pregnancy losses, which may suggest investigations of endocrine dysfunction when patients have two pregnancy losses.

The risk factors of progestational anxiety, depression, and sleep disturbance in women with recurrent pregnancy loss: A cross-sectional study in China.

Background: The risk factors of progestational anxiety, depression, and sleep disturbance in women with a history of recurrent pregnancy loss (RPL) remain controversial, additional study is needed to investigate the incidence and risk factors of progestational anxiety, depression, and sleep quality in RPL women. Methods: A cross-sectional study was conducted among 663 non-pregnant RPL women in Northeast China from October 2019 to July 2022. We assessed the state of anxiety, depression, and sleep quality before pregnancy using structured questionnaires, including sociodemographic characteristics, state-trait anxiety scale (STAI), center for epidemiological survey, depression scale (CES-D), Pittsburgh sleep quality index (PSQI), and symptom self-rating scale (SCL-90). Logistic regression was used to evaluate the association between sleep quality and anxiety, depression. Pearson's correlation was used to evaluate the correlation between anxiety and depression. Multivariate logistic regression analysis was used to find the risk factors of depression symptoms. The receiver operating characteristic curve (ROC) was used to evaluate the predictive value of the model. Results: The incidence of state anxiety, trait anxiety, depression, and sleep disturbance in RPL women were 60.3, 51.7, 33.9, and 31.2%, respectively. The level of anxiety and depression in RPL women varied at different stages of treatment. In a longitudinal study (25 pairs), we found the level of state anxiety and trait anxiety were significantly lower after the cause was identified. Sleep disturbance is positively correlated with anxiety and depression. Logistic regression showed that the number of miscarriages ≥4 (Odds ratio (OR) = 2.268, 95%CI 1.300-3.956), Low household family income (OR = 1.613, 95%CI 1.036-2.513/OR = 2.361, 95%CI 1.095-5.092), interval since last miscarriage <6 months (OR = 2.154, 95%CI 1.246-3.726) and sleep disturbance (OR = 5.523, 95%CI 3.542-8.614) were associated with the occurrence of depressive symptoms. At the same time, anxiety can be used as a predictor of depression. Conclusion: Recurrent pregnancy loss women have a certain degree of anxiety, depression, and sleep disturbance. Education level, interval since the last miscarriage <6 months, and sleep disturbance are risk factors for anxiety and depression. A history of pregnancy loss after 14 weeks and no living birth are also closely related to anxiety. Therefore, it is necessary to pay close attention to the psychological state of RPL women and provide appropriate psychosocial support to reduce the occurrence of negative emotions.

Clinical phenotype, treatment strategy and pregnancy outcome of non-criteria obstetric antiphospholipid syndrome.

PROBLEM: To illustrate the clinical features, treatment strategy, and pregnancy outcome of patients with obstetric antiphospholipid syndrome (OAPS), non-criteria obstetric antiphospholipid syndrome (NC-OAPS) METHOD OF STUDY: A single-center nested case-control study was designed. Patients with a diagnosis of OAPS and NC-OAPS were enrolled. The medical history, coagulation status, and antibody profile data were collected. Patients were given standard anticoagulation therapy with or without glucocorticoids (GC) and/or hydroxychloroquine (HCQ) during pregnancy and were observed for their pregnancy outcome. RESULTS: A total of 47 patients with OAPS and 120 patients with NC-OAPS were finally included, of whom 55 patients met the clinical criteria (subgroup C) and 65 met the laboratory criteria (subgroup L). Pregnancy morbidity showed significant differences: gravida, pregnancy loss in OAPS versus NC-OAPS. The coagulation function was not significantly different between OAPS and NC-OAPS groups, while TT and FIB were significantly higher in the subgroup C. Thromboelastography (TEG) results showed a significantly lower ANGEL in the NC-OAPS group, a higher ANGEL and lower EPL, LY30 in the subgroup L. No differences between groups were observed in treatment strategy. The pregnancy outcomes were not significantly different between NC-OAPS and OAPS groups. CONCLUSIONS: Clinical and laboratory differences were found between OAPS and NC-OAPS groups in this study. Patients in different subgroups of NC-OAPS could be identified with different clinical phenotypes. A relatively hypercoagulable status existed in the OAPS group compared to NC-OAPS, and also in the subgroup L.

The predictive value of NKG2C+NK cells and LILRB1+NK cells in recurrent spontaneous abortion.

PROBLEM: The maternal-fetal immune abnormalities can result in recurrent spontaneous abortion (RSA). The role of NKG2C+ and LILRB1+ pNK subsets in predicting pregnancy loss is uncertain. METHOD OF STUDY: In this study, we aimed to compare the percentage of CD3- CD56+ NK cells, NKG2C+ NK cells, and LILRB1+ NK cells in peripheral blood between healthy pregnant women (HC group), RSA women followed by normal pregnancy (RSA-N group) and RSA women followed by abortion (RSA-A group) in the first trimester via flow cytometry, and explore the prediction value of NKG2C+ and LILRB1+ NK cells for pregnancy loss in RSA via ROC curve. The MFI of NKG2C and LILRB1 of dNK were compared between and HC and RSA-A groups. RESULTS: The percentage of CD3-CD56+ pNK cells between HC, RSA-N, and RSA-A groups shows no significant difference. In peripheral blood, the percentage of NKG2C+ NK cells were significantly increased in the RSA-A group than HC group and RSA-N group, and the percentage of LILRB1+ NK cell were significantly decreased in the RSA-A group. The MFI of NKG2C and LILRB1 of dNK showed a similar trend with peripheral blood between HC and RSA-A groups. The NKG2C+ and LILRB1+ NK cells were an independent risk factor for predicting pregnancy loss in RSA patients, with an area under the ROC curves (AUC) of .77 and .71 respectively. CONCLUSION: Women with recurrent spontaneous abortion have abnormal NKG2C+ and LILRB1+ pNK subsets, which could reflect immune abnormalities at the maternal-fetal interface, and NKG2C+ and LILRB1+ pNK subsets could be a good indicator for the prediction of pregnancy loss.

WTAP dysregulation-mediated HMGN3-m6A modification inhibited trophoblast invasion in early-onset preeclampsia.

Early-onset preeclampsia (ePE) originates from abnormal implantation and placentation that involves trophoblast invasion, but its pathophysiology is not entirely understood. N6-methyladenosine (m6A) regulators mediate the progression of various cancers. The invasiveness of trophoblast cells is similar to that of tumor cells. However, little is known regarding the potential role of m6A modification in ePE and the underlying mechanism. This study aimed to explore the m6A level in placental tissue samples collected from ePE patients and to investigate whether m6A modification was an essential part of PE pathogenesis. The m6A level in placental tissue samples of 80 PE participants was examined. MeRIP-microarray, RNA-Seq, luciferase reporter assay, and RNA immunoprecipitation chip (RIP) assay were performed. The m6A level in the ePE group was significantly reduced compared with the control group. Wilms' tumor 1-associating protein (WTAP) regulated trophoblast cell migration and invasion. Mechanistically, the high mobility group nucleosomal binding domain 3 (HMGN3) gene was a target gene of WTAP in trophoblast (p < .05). WTAP enhanced the stability of HMGN3 mRNA through binding with its 3'-UTR m6A site(+485A, +522A). HMGN3 was recognized by m6A recognition protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which was inhibited when knocking down WTAP. Both m6A and WTAP levels were downregulated in ePE. The m6A modification mediated by WTAP/IGF2BP1/HMGN3 axis might contribute to abnormal trophoblast invasion. Our work provided a foundation for further exploration of RNA epigenetic regulatory patterns in ePE, and indicated a new treatment strategy for ePE.

Static laser speckle suppression using liquid light guides.

Static laser speckle suppression using multimode fibers has practical limitations as the technique requires an extremely long fiber to achieve an acceptable speckle contrast. An effective method based on liquid light guides was developed in this study to suppress laser speckle. In this study, a speckle simulation model of the liquid light guide was established for numerically calculating the speckle contrast without solving the analytical solution of the photon diffusion equation. The obtained simulation results were compared with the experimental results for the dependence of speckle contrast on the required length and numerical aperture with different liquid core types of liquid light guides. A speckle contrast of 12% and a speckle suppression efficiency of 5 was achieved at the end of a 2.4 m long liquid light guide. For the same fiber length, liquid light guides were found to suppress speckle more efficiently when compared to multimode fibers.

Screening and Identification of Prognostic Tumor-Infiltrating Immune Cells and Genes of Endometrioid Endometrial Adenocarcinoma: Based on The Cancer Genome Atlas Database and Bioinformatics.

BACKGROUND: Endometrioid endometrial adenocarcinoma (EEA) is one of the most common tumors in the female reproductive system. With the further understanding of immune regulation mechanism in tumor microenvironment, immunotherapy is emerging in tumor treatment. However, there are few systematic studies on EEA immune infiltration. METHODS: In this study, prognostic tumor-infiltrating immune cells (TIICs) and related genes of EEA were comprehensively analyzed for the first time through the bioinformatics method with CIBERSORT algorithm as the core. Gene expression profile data were downloaded from the TCGA database, and the abundance ratio of TIICs was obtained. Kaplan-Meier analysis and Cox regression analysis were used to identify prognostic TIICs. EEA samples were grouped according to the risk score in Cox regression model. Differential analysis and functional enrichment analyses were performed on high- and low-risk groups to find survival-related hub genes, which were verified by Tumor Immune Estimation Resource (TIMER). RESULT: Four TIICs including memory CD4+ T cells, regulatory T cells, natural killer cells and dendritic cells were identified. And two hub gene modules were found, in which six hub genes including APOL1, CCL17, RBP4, KRT15, KRT71, and KRT79 were significantly related to overall survival and were closely correlated with some certain TIICs in the validation of TIMER. CONCLUSION: In this study, four prognostic TIICs and six hub genes were found to be closely related to EEA. These findings provided new potential targets for EEA immunotherapy.

Systematic Identification of Hub Genes in Placenta Accreta Spectrum Based on Integrated Transcriptomic and Proteomic Analysis.

Placenta accreta spectrum (PAS) is a pathological condition of the placenta with abnormal adhesion or invasion of the placental villi to the uterine wall, which is associated with a variety of adverse maternal and fetal outcomes. Although some PAS-related molecules have been reported, the underlying regulatory mechanism is still unclear. Compared with the study of single gene or pathway, omics study, using advanced sequencing technology and bioinformatics methods, can increase our systematic understanding of diseases. In this study, placenta tissues from 5 patients with PAS and 5 healthy pregnant women were collected for transcriptomic and proteomic sequencing and integrated analysis. A total of 728 messenger RNAs and 439 proteins were found to be significantly different between PAS group and non-PAS group, in which 23 hub genes were differentially expressed in both transcriptome and proteome. Functional enrichment analysis showed that the differentially expressed genes were mainly related to cell proliferation, migration and vascular development. Totally 18 long non-coding RNA were found that might regulate the expression of hub genes. Many kinds of single nucleotide polymorphism, alternative splicing and gene fusion of hub genes were detected. This is the first time to systematically explore the hub genes and gene structure variations of PAS through integrated omics analysis, which provided a genetic basis for further in-depth study on the underlying regulatory mechanism of PAS.

Prediction of iatrogenic preterm birth in patients with scarred uterus: a retrospective cohort study in Northeast China.

BACKGROUND: To build a novel and simple model to predict iatrogenic preterm birth in pregnant women with scarred uteri. METHODS: In this retrospective, observational, single-centre cohort study, data from 2315 patients with scarred uteri were collected. Multiple logistic regression analysis and mathematical modelling were used to develop a risk evaluation tool for iatrogenic preterm birth. After modelling, the calibration and discrimination of the model along with decision curve analysis were checked and performed to ensure clinical applicability. RESULTS: Among the 2315 patients, 417 (18.0%) had iatrogenic preterm births. The following variables were included in the model: interpregnancy interval (0 to < 12 months, OR 5.33 (95% Cl 1.79-15.91), P = 0.003; 13 to < 24 months (reference), 25 to < 60 months, OR 1.80 (95% CI 0.96-3.40), P = 0.068; ≥ 60 months, OR 1.60 (95% Cl 0.86-2.97), P = 0.14), height (OR 0.95, (95% CI 0.92-0.98), P = 0.003), parity (parity ≤1 (reference), parity = 2, OR 2.92 (95% CI 1.71-4.96), P < 0.0001; parity ≥3, OR 8.26, (95% CI 2.29-29.76), P = 0.001), number of vaginal bleeding (OR 1.81, (95% Cl 1.36-2.41), P < 0.0001), hypertension in pregnancy (OR 9.52 (95% CI 6.46-14.03), P < 0.0001), and placenta previa (OR 4.21, (95% CI 2.85-6.22), P < 0.0001). Finally, a nomogram was developed. CONCLUSIONS: In this study, we built a model to predict iatrogenic preterm birth for pregnant women with scarred uteri. The nomogram we created can assist doctors in evaluating the risk of iatrogenic preterm birth and help in making referrals; thus, better medical care can be given to improve the prognosis of patients and foetuses.

Nomogram to predict postpartum hemorrhage in cesarean delivery for women with scarred uterus: A retrospective cohort study in China.

AIM: To develop nomograms predicting the risk of postpartum hemorrhage (PPH) in cesarean delivery for singleton pregnant women with a scarred uterus in the north of China. METHODS: A retrospective cohort study was conducted. Totally 3722 singleton pregnant women with a scarred uterus who underwent a cesarean delivery in a large teaching hospital of north China between January 2013 and December 2017 were enrolled. Nomograms, a kind of user-friendly tool, were developed to predict PPH (blood loss ≥1000 mL or accompanied by signs or symptoms of hypovolemia within 24 h after the birth process) based on the model generated by logistic regression analysis. The discrimination and calibration of models were evaluated, and decision curve analysis was developed. RESULTS: Among 3722 enrolled women, 243 (6.53%) had PPH. There are six identified factors associated with PPH: maternal age, placental location, placenta previa, hypertensive disorders of pregnancy, fetal position and placenta accreta spectrum (PAS). The model achieved a good calibration (Hosmer-Lemeshow test P value 0.77) and discrimination (area under curve c-statistics 0.90, 95% confidence interval 0.86-0.93). Decision curve analysis showed the threshold probability by using our model is between 1.0% and 85.7%. A nomogram was developed accordingly. And another nomogram for women without placenta previa and PAS was also developed. CONCLUSION: Two nomograms were first generated to predict PPH, respectively, for women with a scarred uterus and for women with a scarred uterus who do not have placenta previa or PAS. Placental location and fetal position were found to be closely related to PPH.

Circadian clock gene Clock is involved in the pathogenesis of preeclampsia through hypoxia.

OBJECTIVE: To study the effect of the circadian clock gene Clock on the biological behavior of trophoblasts and its role in the pathogenesis of preeclampsia. METHODS: Quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expression of Clock mRNA. Western blot and immunohistochemistry were used to detect the expression and localization of Clock protein. CoCl2 was used to induce the hypoxic trophoblast cells. Cell invasion assay, wound healing assay and MTT assays were used to detect the invasion, migration, and proliferation ability. Reduced uterine perfusion pressure (RUPP) rat model was established by surgically clamping the abdominal aorta and uterine arteries. Transfection of si-Clock was used to silencing the expression of Clock. RESULTS: Clock mRNA expression was increased in placenta of preeclampsia and CoCl2-induced hypoxic trophoblasts, while protein was decreased. But the trend was opposite in RUPP rat models. Hypoxia can also change the expression rhythm of Clock. The proliferation, migration and invasion ability of trophoblasts decreased after hypoxia, while these abilities restored to near normal level after silencing Clock. CONCLUSION: The expression of Clock gene in human placenta tissue, hypoxia cell model and RUPP rat model suggests that it may regulate the biological behavior of trophoblast cells through hypoxia, and then participate in the pathogenesis of preeclampsia.

The optimal timing of immunotherapy may improve pregnancy outcome in women with unexplained recurrent pregnancy loss: A perspective follow-up study in northeastern China.

PROBLEM: To determine whether patients with unexplained recurrent pregnancy loss (URPL) can benefit from pre-conception immunotherapy or on the early phase of the first trimester. METHOD OF STUDY: The prospective follow-up study which involved pre-conception patients diagnosed with URPL following rigorous etiology screening in the medical center of recurrent pregnancy loss. In this study, pre-conception immunotherapy included lymphocyte immunotherapy (pre-LIT). Post-conception immunotherapy (post-IM) included LIT or intravenous immunoglobulin (IVIG). Patients were recommended to undergo post-IM immediately from human chorionic gonadotrophin (hCG) elevation. Autoimmune antibodies (AIA) and anti-paternal lymphocytotoxic antibodies (APLA) were tested before and after pre-LIT. Favorable outcome was defined as pregnancy over 14 weeks. Unfavorable outcomes included biochemical pregnancy loss (BPL) and pregnancy loss with clear implantation location (PLCIL). RESULTS: In this study, URPL accounted for 12.9% of recurrent pregnancy loss (217/1682). Frequency of BPL was significantly lower in patients with post-IM than that without post-IM [2.8% vs 28.2%; adjusted relative risk (aRR), 0.06; 95% confidence interval (CI), 0.01-0.24]. There was a significant positive conversion in the AIA induced by pre-LIT (0.0% vs 31.0%). Frequency of PLCIL in patients with positive iatrogenic AIA conversion induced by pre-LIT was higher than that in patients without AIA conversion [30.4% vs 5.8%; aRR, 7.53; 95% CI, 1.31-43.34]. CONCLUSION: Pre-LIT of patients with URPL contributed to a positive iatrogenic AIA conversion, which was associated with an increased risk of PLCIL. Post-IM immediately initiated from the time of hCG elevation can reduce the incidence of BPL.

The effects of beta-blocker use on cancer prognosis: a meta-analysis based on 319,006 patients.

BACKGROUND: Beta-blockers are antihypertensive drugs and have shown potential in cancer prognosis. However, this benefit has not been well defined due to inconsistent results from the published studies. METHODS: To investigate the association between administration of beta-blocker and cancer prognosis, we performed a meta-analysis. A literature search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify all relevant studies published up to September 1, 2017. Thirty-six studies involving 319,006 patients were included. Hazard ratios were pooled using a random-effects model. Subgroup analyses were conducted by stratifying ethnicity, duration of drug use, cancer stage, sample size, beta-blocker type, chronological order of drug use, and different types of cancers. RESULTS: Overall, there was no evidence to suggest an association between beta-blocker use and overall survival (HR=0.94, 95% CI: 0.87-1.03), all-cause mortality (HR=0.99, 95% CI: 0.94-1.05), disease-free survival (HR=0.59, 95% CI: 0.30-1.17), progression-free survival (HR=0.90, 95% CI: 0.79-1.02), and recurrence-free survival (HR=0.99, 95% CI: 0.76-1.28), as well. In contrast, beta-blocker use was significantly associated with better cancer-specific survival (CSS) (HR=0.78, 95% CI: 0.65-0.95). Subgroup analysis generally supported main results. But there is still heterogeneity among cancer types that beta-blocker use is associated with improved survival among patients with ovarian cancer, pancreatic cancer, and melanoma. CONCLUSION: The present meta-analysis generally demonstrates no association between beta-blocker use and cancer prognosis except for CSS in all population groups examined. High-quality studies should be conducted to confirm this conclusion in future.