No evidence of a causal relationship between miscarriage and 25-hydroxyvitamin D: a Mendelian randomization study.

STUDY QUESTION: Is there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage? SUMMARY ANSWER: In this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages. WHAT IS KNOWN ALREADY: Associations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear. STUDY DESIGN SIZE DURATION: The latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis. PARTICIPANTS/MATERIALS SETTING METHODS: This study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: There was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (ß = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (ß = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found. LIMITATIONS REASONS FOR CAUTION: This study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups. WIDER IMPLICATIONS OF THE FINDINGS: These findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Study on the immunomodulatory mechanism of vitamin D in patients with unexplained recurrent spontaneous abortion.

Background: To investigate the mechanism of vitamin D level on the regulation of peripheral blood lymphocyte subsets and serum Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion (URSA). Methods: Eighty female patients with URSA attending Sichuan Jinxin Xinan Women's and Children's Hospital from January 2020 to May 2021 were selected as the study group, and 30 age-matched women with a history of healthy deliveries were chosen as the control group, and peripheral blood lymphocyte subpopulations and serum Th1/Th2 cytokines of people with different levels of vitamin D were detected in the study group by flow cytometry, respectively. The results of immune factors before and after supplementation were analyzed in 40 of these patients with low vitamin D levels. The results of lymphoid subpopulations and Th1/Th2 cytokines in 19 patients with normal pregnancy before and after vitamin D supplementation and after normal pregnancy were also analyzed comparatively. Results: (1) Serum 25(OH)D in the study group was lower than in the control group; peripheral blood Th cells, B cells and NK cells in the study group were higher than in the control group; IL-2, TNF-α, IFN-γ and IL-6 in the study group were higher than in the control group, while IL-4 and IL-10 in the study group were lower than in the control group (P < 0.05). (2) Th cells, B cells and NK cells of URSA patients in the vitamin D low level group were higher than those in the vitamin D normal group; serum cytokines IL-2, TNF-α and IFN-γ of patients in the vitamin D low level group were higher than those in the vitamin D normal group (P < 0.05); (3) Th cells, B cells and NK cells in URSA patients after vitamin D supplementation were lower than before vitamin D supplementation; serum cytokines IL-2, TNF-α and IFN-γ after vitamin D supplementation were lower than before vitamin D supplementation, IL-4 and IL-10 after vitamin D supplementation were higher than before vitamin D supplementation (P < 0.05), and there was no significant difference in IL-6 before and after vitamin D supplementation. (4) Th cells, B cells and NK cells in patients with normal pregnancy after vitamin D supplementation and after pregnancy were lower than those before vitamin D supplementation; serum cytokines IL-2, TNF-α and IFN-γ after vitamin D supplementation and after pregnancy were lower than those before vitamin D supplementation, and serum cytokines IL-4 and IL-10 after vitamin D supplementation and after pregnancy were higher than those before vitamin D supplementation, TNF -α, IFN-γ after pregnancy were lower than after vitamin D supplementation (P < 0.05), IL-6 was not significantly different before and after vitamin D supplementation and after pregnancy. Conclusion: Vitamin D deficiency rate was high in URSA patients. Th、B、NK cells and IL-2, TNF-α, IFN-γ, IL-6 cytokines were high, while IL-6 and IL-10 were low in URSA patients. IL-2, TNF-α, IFN-γ cytokines and Th, B, NK cells were increased in vitamin D deficient URSA patients, and Vitamin D deficiency may be an important cause or aggravating factor of immune dysfunction in URSA patients. Vitamin D has an immunomodulatory effect on URSA patients, promoting successful pregnancy by down-regulating peripheral blood Th, B, and NK cells and IL-2, TNF-α, and IFN-γ cytokines, while up-regulating IL-4 and IL-10.

CPY27B1-related vitamin D deficiency contributes to the impaired function of CD4+T cells in Recurrent spontaneous miscarriage.

The study aimed to explore the relationship between the expression of cytochrome P450 family 27 subfamily B member 1 (CYP27B1), vitamin D, and impaired T cell subsets in recurrent spontaneous miscarriage (RSM). A Total of 779 healthy women of childbearing age and 1031 women with a history of RSM were involved in this study. The results of flow cytometry showed that the proportion of Tregs was higher in healthy women than in the women with RSM. For cytokines, the levels of interleukin-17 (IL-17) and interferon-gamma (IFN-γ) were significantly higher in RSM patients than in healthy women, while IL-10 was notably lower in RSM patients. Furthermore, compared to healthy individuals, RSM patients had lower levels of serum 25(OH)D detected by chemiluminescence. The frequency of Tregs was negatively correlated with 25(OH)D. Specifically, for every 10 ng/ml increase in 25(OH)D, the percentage of Tregs increased by 0.58 as calculated. IL-17 and IFN-γ were inversely correlated with 25(OH)D, while the serum interleukin-10 (IL-10) level was positively correlated with 25(OH)D. CYP27B1 was found to be expressed in both cytotrophoblast and extracellular villi trophoblast cells. However, reduced expression of CYP27B1 was observed in the placenta with RSM. Notably, the level of 25(OH)D increased in the supernatant of CYP27B1 knockdown BeWo compared to normal cells, while human chorionic gonadotropin (hCG) was significantly reduced. The hCG secretion of CYP27B1 KO BeWo cells was partially restored after 1,25(OH)2D3 supplementation. In addition, 1,25(OH)2D3 treatment could induce more CD4+ T cells to convert to Foxp3+iTreg, which in turn inhibited the secretion of IL-17, IFN-γ. In summary, this research unveiled a connection between reduced CYP27B1 and vitamin D deficiency in RSM. Our study underscores the potential benefits of vitamin D treatment supplementation in the context of RSM. However, it is important to note that further research is imperative to validate these observations.

Contraception after abortion, miscarriage, ectopic and molar pregnancy.

Regardless of whether a pregnancy ends in abortion, miscarriage or ectopic pregnancy, fertility and sexual activity can resume quickly. For those who do not plan to become pregnant again immediately, effective contraception is therefore required. Although a contraceptive discussion and the offer to provide contraception is considered an integral part of abortion care, health care providers may not always offer this same standard of care to those whose pregnancy ends in miscarriage or ectopic due to sensitivities or assumptions around this and future fertility intentions. Yet, evidence-based recommendations support the safety of initiating contraception at these times. Provision of a chosen method of contraception may be convenient for women and valued by them. As part of holistic care, healthcare professionals who care for women around these reproductive events should therefore offer quality information on contraception and help them access their chosen method to better meet their ongoing reproductive health needs.

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage.

Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of FOLR2+ macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.

Association Between Serum Glycated Hemoglobin Levels at Early Gestation and the Risk of Subsequent Pregnancy Loss in Pregnant Women Without Diabetes Mellitus: Prospective Cohort Study.

BACKGROUND: As a severe morbidity during pregnancy, the etiology of spontaneous pregnancy loss (SPL) remains largely unknown. Serum glycated hemoglobin (HbA1c) level is an established predictor of SPL risk among women with diabetes, but little is known about whether such an association exists among pregnant women without diabetes when glycemic levels are within the normal range. OBJECTIVE: This study aimed to quantify the association between maternal HbA1c levels in early pregnancy and subsequent SPL risk in a cohort of pregnant women without diabetes. METHODS: This prospective cohort study involved 10,773 pregnant women without diabetes enrolled at their first antenatal care visit at a hospital's early pregnancy clinic from March 2016 to December 2018 in Shanghai, China. HbA1c and fasting blood glucose (FBG) levels were examined at enrollment. Participants with diabetes before or pregnancy or those diagnosed with gestational diabetes were excluded. Diagnosis of SPL, defined as fetal death occurring before 28 gestational weeks, was derived from medical records and confirmed via telephone interviews. We used generalized linear models to quantify the associations of continuous and dichotomized maternal HbA1c levels with SPL risk and reported crude and adjusted risk ratios (RRs) and 95% CIs. A restricted cubic spline (RCS) regression model was used to assess the potential nonlinear dose-response relationship. Adjusted covariates included maternal age, education level, preconception BMI, gestational weeks, gravidity, history of adverse pregnancy outcomes, family history of diabetes, folic acid supplementation, and smoking and drinking during the periconception period. RESULTS: In total, 273 (2.5%) SPL cases occurred. Every 0.5% increase in HbA1c levels was linearly associated with a 23% increase in SPL risk (adjusted RR [aRR] 1.23; 95% CI 1.01-1.50). The RCS model revealed that this association was linear (P=.77 for the nonlinearity test). Analyses based on dichotomized HbA1c levels showed a significantly increased risk of SPL when HbA1c levels were ≥5.9% (aRR 1.67; 95% CI 0.67-3.67), and the significance threshold was ≥5.6% (aRR 1.60; 95% CI 1.01-2.54). Sensitivity analyses showed similar results when including the participants with missing SPL records or HbA1c data. Linear associations of HbA1c levels remained significant even in the subgroups without overweight, alcohol consumption, and a family history of diabetes and adverse pregnancy outcomes. Every 1 mmol/L increment in maternal FBG levels was associated with a >2-fold higher risk of SPL (aRR 2.12; 95% CI 1.61-2.80; P<.001). CONCLUSIONS: Higher HbA1c levels in early pregnant women without diabetes are associated with an increased SPL risk in a dose-response manner. Pregnant women with an HbA1c level above 5.6% at early gestation need attention for its potentially increased risk for SPL. Our findings support the need to monitor HbA1c levels to identify individuals at high risk of subsequent SPL in the general population of pregnant women. TRIAL REGISTRATION: ClinicalTrials.gov NCT02737644; https://clinicaltrials.gov/study/NCT02737644.

Ethics, Abortion Access, and Emergency Care Post-Dobbs: The Gray Areas.

Clinical management of emergency pregnancy care, such as ectopic pregnancy or heavy bleeding with pregnancy of unknown location, includes upholding legal and ethical standards. For health care providers unwilling to provide evidence-based life-saving abortion care due to personal beliefs, clear guidance dictates disclosure of these limitations to the patient and colleagues, followed by immediate referral for appropriate care. However, this decision-making pathway may not be engaged due to a variety of factors: providers' beliefs preclude adherence to referral responsibilities, political discourse confuses patients as to their options and rights, and a constantly changing state and national legal landscape leads providers to question their ability to practice to their full scope of clinical care. Although this disruption of evidence-based standard of care existed pre-Dobbs, the moral disorder is now heightened. This Clinical Rounds highlights a patient vignette describing the risks of abortion restrictions for patients and providers alike, particularly when an individual provider's concerns for violating institutional guidelines sets a precedent for nursing response and forecloses on collaborative input or ethics consultation. The history of physician-only abortion exceptionalism and exclusion of nurses and midwives despite a significant history of nurses and midwives in abortion care grounds an argument for focusing on the impact of unethical and substandard care on the interprofessional care team leading to moral distress and negative patient outcomes. Patient-centered models of care, such as frameworks common in nursing and midwifery, offer opportunities to consider how all providers practicing to their full scope in interprofessional and collaborative ways, such as in emergency rooms and labor departments, might mitigate obstructions to abortion care that risk pregnant people's lives.

PREVENTION OF REPRODUCTIVE LOSSES ASSOCIATED WITH INTRAPLANTAR ACCUMULATION OF RADIONUCLIDES. / ПРОФІЛАКТИКА РЕПРОДУКТИВНИХ ВТРАТ, ПОВ'ЯЗАНИХ З ВНУТРІШНЬОПЛАЦЕНТАРНИМ НАКОПИЧЕННЯМ РАДІОНУКЛІДІВ.

The materials of the article are based on the results of our past studies of morphological and immunohistochemical features of placental damage due to 137Cs incorporation. OBJECTIVE: to determine the effectiveness of radioprotective therapy in preventing reproductive losses and perinatal consequences associated with the incorporation of radionuclides in the placenta. MATERIALS AND METHODS: According to the research design, the first group consisted of 153 women with reproductive losses in anamnesis and signs of termination of the current pregnancy. The control consisted of 30 women with a physiological pregnancy and an uncomplicated history. Based on the fact that one of the causes of premature termination of pregnancy is the vulnerable effect of 137Cs incorporated in the placenta, «Apple Pectin Antioxidant¼ (the «APA¼) with a high sorption potential was included in preventive measures regarding reproductive losses and perinatal consequences. The effectiveness of therapy with the inclusion of «Apple Pectin Antioxidant¼ was evaluated based on indicators of the fetoplacental complex and pregnancy scenarios. The results were compared with the effectiveness of standard treatment for habitual miscarriage of pregnancy. RESULTS: It was established that the destructive effect of incorporated 137Cs leads to placental dysfunction and fetal distress. Therapy with the inclusion of «APA¼ more significantly than standard treatment increases the progesterone-synthesizing function of the placenta, microcirculation, adaptation potential, and antioxidant protection of cells with the efficiency of 7.5 %, 10.7 %, 17.7 %, and 43.4 %, respectively. «APA¼ has a positive effect on the scenarios of pregnancy. «APA¼ in the composition of therapy to preserve pregnancy contributed to a decrease in the frequency of premature births by 11.4 % and an extension of their term to 34 weeks of gestation. Extending the gestational age of preterm birth reduced the frequency of severe asphyxia by 18.7 %, hypoxic-ischemic central nervous system injury by 13.5 %, respiratory distress by 17.3 %, and intraventricular hemorrhage 2nd and 3rd degrees by 12.7 %.All children were born alive due to the preservation of the compensatory ability of the placenta. CONCLUSIONS: Termination of pregnancy is a universal reaction of the mother and the fetus to negative exogenous and endogenous influences. Placental dysfunction is the most frequent cause of reproductive losses. Incorporated 137Cs is one of the factors that disturb the architecture of the placenta. Extreme effects depend on the number of incorporated 137Cs and the compensatory capacity of the placenta. Today, the possibility of internal exposure to 137Cs is associated due to consumption of agricultural products. Unfortunately, the level of food contamination with radionuclides remains higher than permissible. Living in an area with a standard radiation background does not guarantee a person the radiation safety of agricultural products. The confirmation is the accumulation of 137Cs in the placentas of women from different regions of Ukraine. The high efficiency of therapy with «APA¼ is associated with the removal of radionuclides and the minimization of the effect of internal irradiation, which made it possible to reduce the frequency of termination of pregnancy by 28.0 % due to the reduction of cases of premature births (-11.4 %), spontaneous abortions (-11.0 %), termination of pregnancy (-5.5 %). The «APA¼ is advisable to prescribe from pregravid and during pregnancy to all women, regardless of the region of residence.

BaP/BPDE suppressed endothelial cell angiogenesis to induce miscarriage by promoting MARCHF1/GPX4-mediated ferroptosis.

Environmental benzo(a)pyrene (BaP) and its ultimate metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) are universal and inevitable persistent organic pollutants and endocrine disrupting chemicals. Angiogenesis in placental decidua plays a pivotal role in healthy pregnancy. Ferroptosis is a newly identified and iron-dependent cell death mode. However, till now, BaP/BPDE exposure, ferroptosis, defective angiogenesis, and miscarriage have never been correlated; and their regulatory mechanisms have been rarely explored. In this study, we used assays with BPDE-exposed HUVECs (human umbilical vein endothelial cells), decidual tissues and serum samples collected from unexplained recurrent miscarriage and their matched healthy control groups, and placental tissues of BaP-exposed mouse miscarriage model. We found that BaP/BPDE exposure caused ferroptosis and then directly suppressed angiogenesis and eventually induced miscarriage. In mechanism, BaP/BPDE exposure up-regulated free Fe2+ level and promoted lipid peroxidation and also up-regulated MARCHF1 (a novel E3 ligase of GPX4) level to promote the ubiquitination degradation of GPX4, both of which resulted in HUVEC ferroptosis. Furthermore, we also found that GPX4 protein down-regulated the protein levels of VEGFA and ANG-1, two key proteins function for angiogenesis, and thus suppressed HUVEC angiogenesis. In turn, supplement with GPX4 could suppress ferroptosis, recover angiogenesis, and alleviate miscarriage. Moreover, the levels of free Fe2+ and VEGFA in serum might predict the risk of miscarriage. Overall, this study uncovered the crosstalk among BaP/BPDE exposure, ferroptosis, angiogenesis, and miscarriage, discovering novel toxicological effects of BaP/BPDE on human reproductive health. This study also warned the public to avoid exposure to polycyclic aromatic hydrocarbons during pregnancy to effectively prevent adverse pregnancy outcomes.

Knight by force and wounded, protecting without a shield: A meta-ethnography of men's experiences after an involuntary pregnancy loss.

OBJECTIVE: To synthesize the available body of qualitative research regarding the experiences of men after an involuntary pregnancy loss. DESIGN: Noblit and Hare's interpretive meta-ethnography of 13 original qualitative articles was carried out. RESULTS: After reciprocal and refutational translations, the lines of argument synthesis were developed, together with the metaphor "Knight by force and wounded, protecting without a shield." This metaphor symbolizes the experience of men after an involuntary pregnancy loss. CERQual assessment showed that the results are a (highly) reasonable representation of the phenomenon of interest. CONCLUSIONS: The men attempted to cope with the loss of fatherhood and suffering, while managing the lack of social recognition and social expectations of masculinity in terms of their behaviour and expression of suffering. They tended to be strong, although they did not always have the necessary support or knowledge. IMPLICATIONS FOR PRACTICE: Comprehensive and individualized care that includes the man is required. This requires the theoretical-practical training of nurses and midwives, and the provision of tools that help the emotional management of emotionally demanding care.

Pregnancy after perinatal loss: A meta-ethnography from a women's perspective.

OBJECTIVE: This study uses a meta-ethnography to synthesize qualitative research on the experiences of women during pregnancies after one or more perinatal losses. DESIGN: This interpretive meta-ethnography followed the Noblit and Hare approach and the eMERGe Meta-ethnography Reporting Guidance. Manual searches and a comprehensive systematic search were conducted in Pubmed, Scopus, Cinahl, Web of Science, and Psycinfo. Eleven studies met the research objective and inclusion criteria. RESULTS: After reciprocal and refutational translations, the metaphor "The rainbow in the storm" and the following three themes emerged: (i) Between ambivalent feelings; (ii) being careful in the new pregnancy; and (iii) leaning on others. CERQual assessment showed that the results are (highly) reasonable representations of the phenomenon of interest. CONCLUSIONS: Most women experienced their subsequent pregnancy with ambivalent feelings and needed to reduce expectations, continuously monitor the pregnancy's viability, and eliminate risky behavior to protect themselves. Understanding and recognition by others is needed and appreciated. IMPLICATIONS FOR PRACTICE: Nurses and midwives play a crucial role in subsequent pregnancies and need to establish a care communion and ethical care during their encounters with affected women whose specific needs need to be incorporated into the guidelines and training curricula of care professionals to equip them with the necessary gender and cultural competences.

Efficacy and safety of Gushen Antai Pills combined with dydrogesterone in the treatment of threatened miscarriage: a systematic review and meta-analysis.

Background: Despite some progress has been made in the pathogenesis and treatment of threatened miscarriage (TM), conventional treatment remains suboptimal. Thus, complementary medicine gradually become a new treatment option for treating threatened miscarriage. Gushen Antai Pills (GAP), a classic prescription of Traditional Chinese medicine (TCM), has became a popular complementary therapy to conventional western medicine (dydrogesterone) in treating threatened miscarriage in recent years. However, a systematic summary and analysis for its therapeutic effects is lacking. This meta-analysis aimed to systematically evaluate the effectiveness and safety of Gushen Antai Pills combined with dydrogesterone in the treatment of threatened miscarriage. Methods: A systematic search across seven electronic databases was conducted from inception to 17 September 2022. Studies were included if they were randomized controlled trials (RCTs) evaluating the effect of integrating Gushen Antai Pills and dydrogesterone in patients with threatened miscarriage, and reported the outcomes of interest. All statistical analyses were conducted using the Revman5.3 and Stata 13 software. The GRADE system was used to evaluate the quality of evidence. Results: Ten eligible randomized controlled trials involving 950 participants were contained in this meta-analysis. The pooled analysis showed that Gushen Antai Pills combined with dydrogesterone can significantly reduce the incidence of early pregnancy loss (RR: 0.29; 95% CI: 0.19-0.42; p < 0.00001) and alleviate clinical symptoms (RR: 1.39; 95% CI: 1.22-1.59; p < 0.00001), compared with treatment of dydrogesterone alone. Also, meta-analysis indicated that integrating Gushen Antai Pills and dydrogesterone is more effective than using dydrogesterone alone in improving hormone levels (serum levels of progesterone, ß-HCG and estradiol) for women with threatened miscarriage (all p < 0.00001). Meanwhile, the combined effects with significant heterogeneity also showed favorable consistency in the sensitivity analyses, indicating a good stability of present results. Moreover, no significant differences between Gushen Antai Pills combined with dydrogesterone and control group on adverse events was identified. The overall GRADE qualities were low to moderate. Conclusion: The overall available evidence suggested that Gushen Antai Pills combined with dydrogesterone had significant effects in improving pregnancy success rate, clinical symptoms and hormone levels for women with threatened miscarriage, with considerable safety and reliability. However, due to the partial heterogeneity, suboptimal quality and high risk of bias of some included studies, further rigorously designed randomized controlled trials are required. Systematic Review Registration: identifier https://INPLASY2022120035, https://inplasy.com/inplasy-2022-12-0035/.

Zishen yutai pill as an adjuvant therapy in threatened Miscarriage:A meta-analysis of 23 randomized controlled trials.

Objective: The purpose of this study was to evaluate the efficacy and safety of Zishen Yutai Pill combined with western medicine for the treatment of women with threatened miscarriage during the first trimester of pregnancy. Methods: Randomized controlled trials published before the end of Apr 1, 2023 on Zishen Yutai Pill and threatened miscarriage were systematically retrieved from China National Knowledge Infrastructure, Wanfang, Sinomed, VIP, PubMed, EMBASE, Web of Science and the Cochrane Library. The international clinical trial registration platform and the Chinese clinical trial registration platform of clinical trials was searched from their inception until Apr 1, 2023. Meta analysis of random effect model was used to combine the research data. Chi-squared test and I2 statistics were used for heterogeneity test. Results: Twenty-three trials (enrolling 2411 participants) were included in the review. Zishen Yutai pill combined with western medicine therapy showed significant improvement on human chorionic gonadotropin [MD 19.33 IU/ml, 95% CI (15.84, 22.81)], the total effective rate [RR 1.19, 95% CI (1.15-1.23)], progesterone [MD 7.14 ng/ml, 95% CI (6.14, 8.13)], estradiol [MD 33.69 pg/ml, 95% CI (27.42, 39.96)], duration of abdominal pain [MD -2.36 d, 95% CI (- 3.54, - 1.18)], duration of vaginal bleeding [MD -1.94 d, 95% CI (- 2.93, - 0.94)], and fibrinogen [MD -0.34 g/L, 95% CI (- 0.57, - 0.11)]. There was no significant difference in hematocrit [MD 0.68%, 95% CI (- 0.08, 1.44)] between the experimental and the control group. Zishen Yutai Pill may improve the clinical symptoms in women with threatened miscarriage, such as human chorionic gonadotropin the total effective rate, progesterone, estradiol, duration of abdominal pain, duration of vaginal bleeding, and fibrinogen. Especially for progesterone, the effect of treatment ≦2 weeks is significantly better than treatment of >2 weeks. For estradiol, the effect of treatment >2 weeks is significantly better than treatment of ≦ 2 weeks. Conclusion: Zishen Yutai Pill, as a complementary therapy, significantly improved human chorionic gonadotropin, the total effective rate, progesterone, estradiol, abdominal pain, vaginal bleeding, and fibrinogen in patients with threatened miscarriage in first-trimester pregnancy. However, the systematic review has some limitations, such as degraded information quality, no blinding of patients or doctors, etc. Due to the small sample size and low quality of research, it needs to be further confirmed by large sample and high-quality randomized controlled trials, such as blinding of patients, doctors and outcome assessment should be complemented, clinical follow-up, live birth rate, fetal growth should be supplemented. Systematic review registration: INPLASY202320039.

The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.

PURPOSE: The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. METHODS: A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. RESULTS: 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). CONCLUSION: This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.

Dysregulated Gln-Glu-α-ketoglutarate axis impairs maternal decidualization and increases the risk of recurrent spontaneous miscarriage.

Recurrent spontaneous miscarriage (RSM) affects 1%-2% of fertile women worldwide and poses a risk of future pregnancy complications. Increasing evidence has indicated that defective endometrial stromal decidualization is a potential cause of RSM. Here, we perform liquid chromatography with mass spectrometry (LC-MS)-based metabolite profiling in human endometrial stromal cells (ESCs) and differentiated ESCs (DESCs) and find that accumulated α-ketoglutarate (αKG) derived from activated glutaminolysis contributes to maternal decidualization. Contrarily, ESCs obtained from patients with RSM show glutaminolysis blockade and aberrant decidualization. We further find that enhanced Gln-Glu-αKG flux decreases histone methylation and supports ATP production during decidualization. In vivo, feeding mice a Glu-free diet leads to a reduction of αKG, impaired decidualization, and an increase of fetal loss rate. Isotopic tracing approaches demonstrate Gln-dependent oxidative metabolism as a prevalent direction during decidualization. Our results demonstrate an essential prerequisite of Gln-Glu-αKG flux to regulate maternal decidualization, suggesting αKG supplementation as a putative strategy to rectify deficient decidualization in patients with RSM.

The association between abortion restrictions and patient-centered care for early pregnancy loss at US obstetrics-gynecology residency programs.

BACKGROUND: Early pregnancy loss is a common medical problem, and the recommended treatments overlap with those used for induced abortions. The American College of Obstetricians and Gynecologists recommends the incorporation of clinical and patient factors when applying conservative published imaging guidelines to determine the timing of intervention for early pregnancy loss. However, in places where abortion is heavily regulated, clinicians who manage early pregnancy loss may cautiously rely on the strictest criteria to differentiate between early pregnancy loss and a potentially viable pregnancy. The American College of Obstetricians and Gynecologists also notes that specific treatment modalities that are frequently used to induce abortion, including the use of mifepristone in medical therapy and surgical aspiration in an office setting, are cost-effective and beneficial for patients with early pregnancy loss. OBJECTIVE: This study aimed to determine how US-based obstetrics and gynecology residency training institutions adhere to the American College of Obstetricians and Gynecologists recommendations for early pregnancy loss management, including the timing and types of interventions, and to evaluate the relationship with institutional and state abortion restrictions. STUDY DESIGN: From November 2021 to January 2022, we conducted a cross-sectional study of all 296 US-based obstetrics and gynecology residency programs by emailing them and requesting that a faculty member complete a survey about early pregnancy loss practices at their institution. We asked about location of diagnosis, use of imaging guidelines before offering intervention, treatment options available at their institution, and program and personal characteristics. We used chi-square tests and logistic regressions to compare the availability of early pregnancy loss care based on institutional indication-based abortion restrictions and state legislative hostility to abortion care. RESULTS: Of the 149 programs that responded (50.3% response rate), 74 (49.7%) reported that they did not offer any intervention for suspected early pregnancy loss unless rigid imaging criteria were met, whereas the remaining 75 (50.3%) programs reported that they incorporated imaging guidelines with other factors. In an unadjusted analysis, programs were less likely to incorporate other factors with imaging criteria if they were in a state with legislative policies that were hostile toward abortion (33% vs 79%; P<.001) or if the institution restricted abortion by indication (27% vs 88%; P<.001). Mifepristone was used less often in programs located in hostile states (32% vs 75%; P<.001) or in institutions with abortion restrictions (25% vs 86%; P<.001). Similarly, office-based suction aspiration use was lower in hostile states (48% vs 68%; P=.014) and in institutions with restrictions (40% vs 81%; P<.001). After controlling for program characteristics, including state policies and affiliation with family planning training programs or religious entities, institutional abortion restrictions were the only significant predictor of rigid reliance on imaging guidelines (odds ratio, 12.3; 95% confidence interval, 3.2-47.9). CONCLUSION: In training institutions that restrict access to induced abortion based on indication for care, residency programs are less likely to holistically incorporate clinical evidence and patient priorities in determining when to intervene in early pregnancy loss as recommended by the American College of Obstetricians and Gynecologists. Programs in restrictive institutional and state environments are also less likely to offer the full range of early pregnancy loss treatment options. With state abortion bans proliferating nationwide, evidence-based education and patient-centered care for early pregnancy loss may also be hindered.

Chinese herbal medicine for threatened miscarriage: An updated systematic review and meta-analysis.

Objective: To conduct an updated systematic review and meta-analysis on the efficacy and safety of Chinese herbal medicine (CHM) for threatened miscarriage. Data Sources: Electronic databases were searched from inception to 30 June 2022. Study Eligibility Criteria: Only randomized controlled trials (RCTs) that assessed the efficacy and safety of CHM or combined CHM and Western medicine (CHM-WM) and compared with other treatments for threatened miscarriage were included for analysis. Methods: Three review authors independently evaluated included studies, assessed the risk of bias and extracted data for meta-analysis (continuation of pregnancy after 28 gestational weeks, continuation of pregnancy after treatment, preterm birth, adverse maternal outcomes, neonatal death, TCM syndrome severity, ß-hCG levels after treatment), sensitivity analysis (ß-hCG level) and subgroup analysis (TCM syndrome severity, ß-hCG level). The risk ratio and 95% confidence interval were calculated by RevMan. Certainty of the evidence was assessed according to GRADE. Results: Overall, 57 RCTs involving 5,881 patients met the inclusion criteria. Compared with WM alone, CHM alone showed significant higher incidence of continuation of pregnancy after 28 gestational weeks (Risk Ratio (RR) 1.11; 95% CI 1.02 to 1.21; n = 1; moderate quality of evidence), continuation of pregnancy after treatment (RR 1.30; 95% CI 1.21 to 1.38; n = 10; moderate quality of evidence), higher ß-hCG level (Standardized Mean Difference (SMD) 6.88; 95% CI 1.74 to 12.03; n = 4) and lower Traditional Chinese medicine (TCM) syndrome severity (SMD -2.94; 95% CI -4.27 to -1.61; n = 2). Compared with WM alone, combined CHM-WM showed significant higher incidence of continuation of pregnancy after 28 gestational weeks (RR 1.21; 95% CI 1.16 to 1.27; n = 15; moderate quality of evidence), continuation of pregnancy after treatment (RR 1.19; 95% CI 1.16 to 1.23; n = 41; moderate quality of evidence), higher ß-hCG level (SMD 2.27; 95% CI 1.72 to 2.83; n = 37) and lower TCM syndrome severity (SMD -1.74; 95% CI -2.21 to -1.27; n = 15). No significant differences in reducing the adverse maternal outcomes and neonatal death were found in combined CHM-WM compared with WM alone (RR 0.97; 95% CI 0.62 to 1.52; n = 8; RR 0.39; 95% CI 0.12 to 1.21; n = 2). Conclusion: Current evidence supported CHM could be a potential treatment for threatened miscarriage. However, results should be interpreted with caution considering the low to moderate quality of the available evidence. Systematic Review Registration: [https://inplasy.com/inplasy-2022-6-0107/], identifier [INPLASY20220107].

Acupuncture Treatment for Threatened Abortion.

Background: Threatened abortion, also known as threatened miscarriage, is a common complication in pregnant women; it seriously harms their physical and mental health. However, there are only a few reports on acupuncture treatment to address threatened abortion. Case: A woman had a threatened abortion. She experienced vaginal bleeding and had an intrauterine hematoma after embryo transfer. She declined medication use because of concerns about the adverse effects to the embryo. Therefore, acupuncture treatment was performed to relieve her pain and save the fetus. Results: After the 4th treatment, her vaginal bleeding stopped, and her uterine effusion was reduced to 27 × 22 mm. After the 11th treatment, the uterine effusion decreased even more-to 40 × 7 mm-and disappeared completely after the 16th treatment. No adverse events occurred during her treatment, and her bleeding and uterine effusion did not recur. The fetus developed normally, and the child was born. This child is currently healthy and growing. Conclusions: By stimulating the body's acupoints, acupuncture can be used to adjust the Qi and Blood, and consolidate Extraordinary Vessels, mainly in Chong and Ren, to prevent miscarriage. This case report provided information about the treatment of a threatened abortion and illustrated how acupuncture was be used to stop a threatened abortion. This report can be utilized to support high-quality randomized controlled trials. Given that there is a lack of standardized and safe procedures for treating threatened abortion by using acupuncture, this research is needed.

Mendelian randomization study of maternal coffee consumption and its influence on birthweight, stillbirth, miscarriage, gestational age and pre-term birth.

BACKGROUND: Coffee consumption has been associated with several adverse pregnancy outcomes, although data from randomized-controlled trials are lacking. We investigate whether there is a causal relationship between coffee consumption and miscarriage, stillbirth, birthweight, gestational age and pre-term birth using Mendelian randomization (MR). METHODS: A two-sample MR study was performed using summary results data from a genome-wide association meta-analysis of coffee consumption (N = 91 462) from the Coffee and Caffeine Genetics Consortium. Outcomes included self-reported miscarriage (N = 49 996 cases and 174 109 controls from a large meta-analysis); the number of stillbirths [N = 60 453 from UK Biobank (UKBB)]; gestational age and pre-term birth (N = 43 568 from the 23andMe, Inc cohort) and birthweight (N = 297 356 reporting own birthweight and N = 210 248 reporting offspring's birthweight from UKBB and the Early Growth Genetics Consortium). Additionally, a one-sample genetic risk score (GRS) analysis of coffee consumption in UKBB women (N up to 194 196) and the Avon Longitudinal Study of Parents and Children (N up to 6845 mothers and 4510 children) and its relationship with offspring outcomes was performed. RESULTS: Both the two-sample MR and one-sample GRS analyses showed no change in risk of sporadic miscarriages, stillbirths, pre-term birth or effect on gestational age connected to coffee consumption. Although both analyses showed an association between increased coffee consumption and higher birthweight, the magnitude of the effect was inconsistent. CONCLUSION: Our results suggest that coffee consumption during pregnancy might not itself contribute to adverse outcomes such as stillbirth, sporadic miscarriages and pre-term birth or lower gestational age or birthweight of the offspring.

Restoration of serum estradiol and reduced incidence of miscarriage in patients with low serum estradiol during pregnancy: a retrospective cohort study using a multifactorial protocol including DHEA.

Background: Low serum estradiol in early pregnancy is associated with an elevated risk of miscarriage. We sought to determine whether efforts to restore low blood estradiol via estradiol or dehydroepiandrosterone (DHEA) supplementation would reduce the risk of miscarriage as part of a multifactorial symptom-based treatment protocol. Methods: This retrospective cohort study included women with low serum estradiol levels in early pregnancy, defined as ≤50% of reference levels by gestational age. Estradiol or DHEA were administered orally, and the primary outcome measure was serum estradiol level, in reference to gestational age. The secondary outcome measures included miscarriage, birth weight, and gestational age at birth. Results: We found no significant effect of estradiol supplementation on serum estradiol levels referenced to gestational age, while DHEA supplementation strongly increased estradiol levels. For pregnancies with low estradiol, the miscarriage rate in the non-supplemented group was 45.5%, while miscarriage rate in the estradiol and DHEA supplemented groups were 21.2% (p = 0.067) and 17.5% (p = 0.038), respectively. Birth weight, size, gestational age, and preterm deliveries were not significantly different. No sexual abnormalities were reported in children (n = 29) of DHEA-supplemented patients after 5-7 years follow-up. Conclusions: In conclusion, DHEA supplementation restored serum estradiol levels, and when included in the treatment protocol, there was a statistically significant reduction in miscarriage.