Low-molecular-weight heparin in the prevention of unexplained recurrent miscarriage: a systematic review and meta-analysis.

The etiology of recurrent pregnancy loss (RPL) is complex and multifactorial and in half of patients it remains unexplained (U-RPL). Recently, low-molecular-weight heparin (LMWH) has gained increasing relevance for its therapeutic potential. On this regard, the aim of this systematic review and meta-analysis is to analyze the efficacy of low molecular weight heparin (LMWH) from the beginning of pregnancy in terms of live birth rates (LBR) in U-RPL. Registered randomized controlled trials (RCTs) were included. We stratified findings based on relevant clinical factors including number of previous miscarriages, treatment type and control type. Intervention or exposure was defined as the administration of LMWH alone or in combination with low-dose aspirin (LDA). A total of 6 studies involving 1016 patients were included. The meta-analysis results showed that LMWH used in the treatment of U-RPL was not associated with an increase in LBR with a pooled OR of 1.01, a medium heterogeneity (26.42%) and no publication bias. Results of other sub-analyses according to country, treatment type, and control type showed no significant effect of LMWH on LBR in all subgroups, with a high heterogeneity. The results highlight a non-significant effect of LMWH in U-RPL on LBR based on moderate quality evidence.Registration number: PROSPERO: ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022326433 ).

Real-world utilization pattern of dydrogesterone in 7287 Indian women with obstetric and gynecological conditions: data from multicentric, retrospective study.

Objective: Despite the literature on dydrogesterone, studies on dydrogesterone utilization patterns are largely lacking in Indian patients. Methods: This was a multi-center, retrospective, observational, cross-sectional, and descriptive study across 817 centers in India. Data of patients who received dydrogesterone in past and provided consent for future use of their medical record for research purpose was were retrieved and analyzed. Results: Data of 7287 subjects (aged 29.55±4.84 years) was analyzed. Threatened abortion was the most common indication for which the subjects received dydrogesterone (46.9%) followed by recurrent pregnancy loss. Polycystic ovary syndrome (PCOS), thyroid disorders and anemia were the most common comorbid conditions and prior pregnancy loss, advanced maternal age and obesity were the most common risk factors seen in subjects who received dydrogesterone. Total 27.5% of subjects received a loading dose of dydrogesterone, and majority (64%) received 40 mg as loading dose. 10 mg dose was used as maintenance or regular dose in 81.4% of the subjects. Twice daily (BID) was the most common dosing frequency (66.6%). The most common concomitant medications being taken by the subjects on dydrogesterone included folic acid (45.1%), iron supplements (30.3%) and calcium and vitamin D3 supplements (25.5%). Another progesterone preparation (oral, injection, vaginal, tubal) other than dydrogesterone was used concurrently in 7.8% of subjects. Conclusion: The study helped to identify the patient population that is benefitted by dydrogesterone and the preferred indications, risk factors, comorbid conditions and concomitant medication used in this patient population at real-life scenario.

The safety and efficacy of tumor necrosis factor-alpha inhibitor on pregnancy outcomes in patients with unexplained recurrent miscarriage.

OBJECTIVES: Although tumor necrosis factor-alpha inhibitor (TNFi) treatment may improve pregnancy outcomes in unexplained recurrent miscarriage (URM) patients, evidence for its efficacy and safety is still insufficient. The goal of this study was to evaluate the efficacy and safety of TNFi on pregnancy outcomes in patients with URM. METHODS: This retrospective study was conducted at a single institution in China, involving 121 patients treated with TNFi for URM from 2019 to 2022. Patients enrolled were divided into treatment group (receiving TNFi and heparin therapy) and control group (receiving heparin therapy). The outcome variables were the 24-week live birth rate, miscarriage rate, ectopic pregnancy rate, neonatal outcomes, and adverse events. RESULTS: In our study, patients receiving TNFi treatment exhibited a significant increase in live birth rates, achieving 71.2 % compared to the 50.9 % observed in the control group (OR 2.507, 95 % CI: 1.127-5.579). Concurrently, there was a discernible reduction in the miscarriage rate within the TNFi-treated group, marking 24.2 %, in contrast to 43.6 % in the control group (OR 0.387, 95 % CI: 0.170-0.884). Subgroup analyses further illuminated that those under the age of 35 benefitted remarkably from TNFi treatment, with live birth rates soaring to 62.5 % (OR 2.525, 95 % CI: 1.041-6.125). For patients with a history of two miscarriages, the TNFi regimen significantly augmented the live birth rate to 58.9 % (OR 3.044, 95 % CI: 1.039-8.921). Patients with a normal weight range registered a 58.4 % live birth rate post-TNFi treatment (OR 4.261, 95 % CI: 1.539-11.397). Notably, an evident interaction between BMI and TNFi treatment was identified, suggesting a potential modulatory role of BMI on the therapeutic efficacy of TNFi. About safety assessments, neither the TNFi-treated group nor the control manifested any significant disparities in liver function abnormalities, platelet count anomalies, or other pregnancy-related complications. CONCLUSIONS: TNFi, alongside basic therapy, notably enhances the live birth rate in URM patients under 35, with two prior miscarriages or a normal BMI, without increasing adverse event risk. Further prospective studies are essential to validate these observations.

Prognostic model on pregnancy outcomes for women with recurrent spontaneous abortions treated with cyclosporin A: A single-institution experience.

BACKGROUND: This study aimed to identify prognostic factors for pregnancy outcomes and construct a prognostic model for pregnancy outcomes in women with Recurrent Spontaneous Abortions (RSA) treated with cyclosporin A. METHODS: A total of 154 RSA patients treated with cyclosporin A between October 2016 and October 2018 were retrospectively recruited. Multivariate logistic regression was applied to identify the prognostic factors for pregnancy success in RSA women treated with cyclosporin A. The Receiver Operating Characteristic (ROC) curve was applied to construct prognostic value, and the prognostic performance was assessed using area under the ROC. RESULTS: After adjusting potential confounding factors, the authors noted increased age (OR = 0.771; 95 % CI 0.693‒0.858; p < 0.001) and positive antinuclear antibodies (OR = 0.204; 95 % CI 0.079‒0.526; p = 0.001) were associated with a reduced incidence of pregnancy success, while positive anti-ß2 glycoprotein-I-antibody (OR = 21.941; 95 % CI 1.176‒409.281; p = 0.039) was associated with an increased incidence of pregnancy success after treated with cyclosporin A. The AUC of combining these variables for predicting pregnancy failure was 0.809 (95 % CI 0.735‒0.880). CONCLUSIONS: This study systematically identified the prognostic factors for pregnancy success in women treated with cyclosporin A, and the constructed prognostic model based on these factors with relatively higher prognostic value. Further large-scale prospective studies should be performed to validate the prognostic value of the constructed model.

Levothyroxine for subclinical hypothyroidism during pregnancy: an updated systematic review and meta-analysis of randomized controlled trials.

PURPOSE: We aimed to perform a systematic review and meta-analysis addressing the efficacy of levothyroxine therapy in pregnant women with subclinical hypothyroidism considering most recent evidence and subgroups of interest for clinical practice. METHODS: PubMed, Embase, and Cochrane Central were searched from inception for randomized controlled trials (RCTs) comparing levothyroxine with placebo or no intervention in pregnant women with subclinical hypothyroidism. We used a random-effects model and conducted subgroup analyses based on thyroid peroxidase antibody status, thyroid stimulating hormone levels, fertility treatment, and recurrent miscarriage. RESULTS: We included 11 RCTs comprising 2,749 pregnant women with subclinical hypothyroidism. Patients treated with levothyroxine (1,439; 52.3%) had significantly lower risk of pregnancy loss (risk ratio 0.69; 95% confidence interval 0.52-0.91; p < 0.01; 6 studies). However, there was no significant association between levothyroxine and live birth (risk ratio 1.01; 95% confidence interval 0.99-1.03; p = 0.29; 8 studies). No statistically significant interaction was observed across subgroups (p > 0.05). CONCLUSION: Levothyroxine replacement therapy for subclinical hypothyroidism during pregnancy may decrease pregnancy loss when early prescribed. Nevertheless, further investigation is needed in patients with thyroid stimulating hormone above four milliunits per liter, especially when associated with recurrent miscarriage or infertility.

Zishen Yutai Pills Promote Angiogenesis at the Maternal-Fetal Interface in Recurrent Spontaneous Abortion Mice by Regulating miR-187/VEGF Axis.

Ethnopharmacological Relevance: Zishen Yutai pills (ZYP), a traditional Chinese patent medicine, was listed in China in 1981. It is composed of 15 traditional Chinese medicines and has the effects of regulating menstruation, helping pregnancy, and preventing abortion. In clinical practice, it is effective in preventing habitual and threatened miscarriages, and continuing to explore its mechanism of action is very meaningful research. Aim of the Study: To explore the possible mechanism of ZYP promoting angiogenesis at the maternal-fetal interface in recurrent spontaneous abortion (RSA). Materials and Methods: In vitro experiments, placental trophoblast cells (PTCs) were isolated from the placental tissue of RSA mice and divided into six groups: Control group, Model group, ZYP group, miR-187 inhibitor NC group, miR-18 7 inhibitor group, and miR-187 inhibitor+ZYP group. Cell viability and cell cycle were measured using CCK8 and flow cytometry, respectively. The expression levels of miR-187, VEGF, VEGF-R1, and VEGF-R2 were measured using RT-qPCR, WB, and IF staining. Animal experiments first establish an RSA mice model (CBA/J × DBA/2) and then randomly divide the mice into four groups (n=10): normal pregnancy group, RSA model group, ZYP group, and progesterone capsule group. Observed the changes in embryo absorption rate, pathological morphology of decidual tissue, and ultrastructure of vascular endothelial cells in each group of mice. RT-qPCR, WB, and IF staining methods were used to determine the expression of miR-187, VEGF, VEGF-R1, and VEGF-R2. Results: In vitro, ZYP promoted the viability of PTCs and regulated their cell cycle, and ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2 levels. miR-187 inhibitor showed the same effects, and further ZYP intervention enhanced the effects. In vivo, ZYP remarkably reduced embryo resorption rates, and improved the pathological morphology of decidual tissues and ultrastructure of vascular endothelial cells. Moreover, ZYP down-regulated miR-187, up-regulated VEGF, VEGF-R1 and VEGF-R2. Conclusion: In summary, ZYP can regulate the expression of VEGF via miR-187, then promote the angiogenesis at the maternal-fetal interface, and playing a therapeutic role in RSA.

Fondaparinux Results in Similar Pregnancy Outcomes with Lower Adverse Reaction Rates Compared to Low Molecular Weight Heparin in Chinese Recurrent Miscarriage Women.

Fondaparinux inhibits thrombin generation by inactivating factor Xa, which has the potential to treat recurrent miscarriage (RM). However, more clinical evidence is required to support its application in Chinese women with RM. This research aimed to compare the live birth rate, gestational weeks at delivery, birth weight, Apgar score of newborns, and adverse reaction rates between fondaparinux and low molecular weight heparin (LMWH) in Chinese women with RM. Totally, 132 women with RM treated with fondaparinux or LMWH were included in this retrospective study. According to the corresponding treatment, women with RM were divided into the fondaparinux cohort (N = 45) and LMWH cohort (N = 87). The live birth rate was 68.9% in the fondaparinux cohort and 56.3% in the LMWH cohort, which was not different between the two cohorts (P = 0.161). Multivariable logistics regression analysis suggested that only previous miscarriage times (≥ 4 times vs. < 4 times) were independently related to a lower possibility of live birth in women with RM (odds ratio = 0.431, P = 0.036). It was also observed that gestational weeks at delivery (38.1 ± 1.4 vs. 37.7 ± 1.7 weeks) (P = 0.258), birth weight (2,923.7 ± 355.0 vs. 2,807.8 ± 334.0 g) (P = 0.144), and Apgar score of newborns (9.8 ± 0.5 vs. 9.6 ± 0.8) (P = 0.175) were not different between the fondaparinux cohort and LMWH cohort. Inspiringly, the total adverse reaction rate was reduced in the fondaparinux cohort vs. the LMWH cohort (20.0% vs. 37.9%) (P = 0.036). Fondaparinux results in similar pregnancy outcomes with lower adverse reaction rates compared to LMWH in Chinese women with RM.

Impact of Recombinant Human Granulocyte Colony-Stimulating Factor Combined with Aspirin on Clinical Pregnancy Outcomes and Endometrial Receptivity in Patients with Recurrent Abortion: A Retrospective Study.

Objective: This study investigates the impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and aspirin on endometrial receptivity and clinical pregnancy outcomes in individuals with a history of recurrent abortions. Methods: In this retrospective study, 131 individuals with recurrent abortions treated at our facility from July 2019 to December 2020 were split into two groups: mixed therapy and control. The mixed therapy group received aspirin and rhG-CSF, while the control group had no specific treatment. Primary endpoint: live birth rate; secondary: pregnancy rate at 20 weeks. We also evaluated abortion rates, newborn weight, pre-eclampsia, premature delivery, fetal/newborn congenital malformations, and maternal drug adverse reactions. Additionally, we analyzed endometrial blood flow three weeks post-treatment. Results: The analysis encompassed 131 individuals, with 65 in the control group and 66 in the mixed therapy group. Notably, the mixed therapy group (n = 54) exhibited a markedly higher live birth rate than the control group (P < .05). In terms of medication-related side effects, the control group showed no adverse reactions, while the mixed therapy group reported mild effects (skin itching in three cases, leukocytosis in seven, and bone pain in one case) that did not significantly impact outcomes. Pre-treatment, the mixed therapy group had a notably lower resistive index, pulsatility index, and systolic-to-diastolic ratio compared to the control group, with statistical significance (P < .05). The control group's indices remained unchanged (P > .05). Conclusions: In women with a history of recurrent abortions, the administration of recombinant human granulocyte colony-stimulating factor and aspirin can effectively and safely improve live birth rates. This improvement may be associated with enhanced endometrial receptivity.

Uncovering the pharmacological mechanism of Shou Tai Wan on recurrent spontaneous abortion: A integrated pharmacology strategy-based research.

ETHNOPHARMACOLOGICAL RELEVANCE: Shou Tai Wan (STW), a traditional Chinese medicine formula, has been historically used for the treatment of recurrent spontaneous abortion (RSA). Despite its long-standing usage, the exact mechanism underlying the therapeutic effects of STW remains unclear in the existing literature. AIMS OF THIS STUDY: To explore the Pharmacological Mechanism of STW on RSA. METHODS: A network pharmacological methodology was utilized to predict the active compounds and potential targets of STW, collect the RSA targets and other human proteins of STW, and analyze the STW related networks. The animal experiments were also performed to validate the effect of STW on RSA. RESULTS: The results of network analysis showed that STW may regulate PI3K/AKT, MAPK, FoxO signaling pathways and so on. Animal experiment established the RSA model with CBA/J × DBA/2 mice. It was found that STW can reduce the embryo absorption rate of RSA group (p < 0.05) and balance the expression of Th 1/Th2 type cytokines compared with the model group. After 14 days of administration, the decidual and placental tissues were taken and the CD4+ T cells were isolated, and the phosphorylation level of signaling pathway was detected by Springbio720 antibody microarray. This experiment found that STW can significantly up-regulate the phosphorylation levels of STAT3 and STAT6 proteins in the STAT signaling pathway, and down-regulating the phosphorylation level of STAT1 protein. STW also significantly up-regulated the phosphorylation levels of Raf1, A-Raf, Ask1, Mek1, Mek2, JKK1, ERK1, ERK2, c-fos, c-Jun and CREB proteins in the MAPK signaling pathway, and down-regulate the phosphorylation levels of MEK6 and IKKb proteins. Compared with the RSA group, the STW group increased the expression levels of ERK1/2 mRNA and proteins and p-ERK1/2 proteins, and there was a statistical difference (p < 0.05). This is consistent with the chip results. CONCLUSION: STW may achieve therapeutic effects by interfering with the signaling pathways, biological processes and targets discovered in this study. It provides a new perspective for revealing the immunological mechanism of STW in the treatment of RSA, and also provides a theoretical basis for the clinical use of STW in the treatment of RSA.

Preconceptual administration of doxycycline in women with recurrent miscarriage and chronic endometritis: protocol for the Chronic Endometritis and Recurrent Miscarriage (CERM) trial, a multicentre, double-blind, placebo-controlled, adaptive randomised trial with an embedded translational substudy.

INTRODUCTION: Recurrent miscarriage is a common condition with a substantial associated morbidity. A hypothesised cause of recurrent miscarriage is chronic endometritis (CE). The aetiology of CE remains uncertain. An association between CE and recurrent miscarriage has been shown. This study will aim to determine if preconceptual administration of doxycycline, in women with recurrent miscarriages, and CE, reduces first trimester miscarriages, increasing live births. METHODS AND ANALYSIS: Chronic Endometritis and Recurrent Miscarriage is a multicentre, double-blind adaptive trial with an embedded translational substudy. Women with a history of two or more consecutive first trimester losses with evidence of CE on endometrial biopsy (defined as ≥5 CD138 positive cells per 10 mm2) will be randomised to oral doxycycline or placebo for 14 days. A subset will be recruited to a mechanistic substudy in which microbial swabs and preintervention/postintervention endometrial samples will be collected. Up to 3062 women recruited from 29 National Health Service (NHS) hospital sites across the UK are expected to be screened with up to 1500 women randomised in a 1:1 ratio. Women with a negative endometrial biopsy (defined as <5 CD138 positive cells per 10 mm2) will also be followed up to test validity of the tool. The primary outcome is live births plus pregnancies ≥24 + 0 weeks gestation at the end of the trial, in the first or subsequent pregnancy. Secondary clinical outcomes will also be assessed. Exploratory outcomes will assess the effect of doxycycline treatment on the endometrial microbiota, the differentiation capacity of the endometrium and the senescent profile of the endometrium with CE. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the NHS Research Ethics Committee Northwest-Haydock (19/NW/0462). Written informed consent will be gained from all participants. The results will be published in an open-access peer-reviewed journal and reported in the National Institute for Health and Care Research journals library. TRIAL REGISTRATION NUMBER: ISRCTN23947730.

Intrauterine perfusion of dexamethasone improves pregnancy outcomes in recurrent reproductive failure patients with elevated uterine natural killer cells. A retrospective cohort study.

OBJECTIVE: To determine the effect of intrauterine perfusion of dexamethasone (DXM) on pregnancy outcomes in recurrent reproductive failure (RRF) patients with elevated uNK cells. METHODS: This retrospective cohort study included 132 RRF patients with elevated uNK cells: 56 patients received DXM treatment and 76 patients refused it in the frozen-thawed embryo transfer cycles. To determine the efficacy of intrauterine perfusion of DXM, multivariate logistic regression models and diagnosis-based subgroup analysis were performed. We also compared the pregnancy outcomes of patients with different responsiveness to DXM treatment. RESULTS: Intrauterine perfusion of DXM significantly improved clinical pregnancy rate (aOR: 3.188, 95% CI: 1.395-7.282, P = .006) and live birth rate (aOR: 3.176, 95% CI: 1.318-7.656, P = .010) in RRF patients with elevated uNK cells, but there was no significant association with miscarriage rate. Subgroup analysis revealed that intrauterine perfusion of DXM in patients with recurrent implantation failure (RIF) showed significant improvement in clinical pregnancy rate (aOR: 6.110, 95% CI: 1.511-24.713, P = .011) and live birth rate (aOR: 9.904, 95% CI: 1.963-49.968, P = .005), but there was insufficient evidence of benefit in recurrent pregnancy loss (RPL) patients. Additionally, uNK cell levels dropped to normal range was achieved in only 35.90% of RRF patients after DXM treatment, no significant difference was found in pregnancy outcomes among patients with different responsiveness to DXM treatment (all P > .05). CONCLUSION: Intrauterine perfusion of DXM was a promising and effective treatment to enhance clinical pregnancy rate and live birth rate in RRF women with abnormally elevated uNK cells, and RIF patients are more likely to benefit than RPL patients.

Treatment of recurrent pregnancy loss in women with euthyroid-based thyroid peroxidase antibody syndrome.

Recurrent pregnancy loss (RPL) due to thyroid peroxidase antibody (TPOAb) syndrome remains a significant challenge in pregnancy. The current study offers better insights into miscarriages that occur due to the presence of TPOAb with euthyroid in pregnant women with a history of RPL. Out of the 347 women confirmed with unexplained RPL, only 70 (20.2%) tested positive for TPOAb (215±53). After eight women were excluded from the study due to failure to follow up, 62 participants (age range: 33±4.8 years; body mass index (BMI):25-30kg/m2 (58%) and >30kg/m2 (42%)) were included. The TPOAb-dependent RPL patients were divided according to their RPL types into 23 (30.7%) nulliparous (1˚) and 39 (69.3%) multiparous (2˚) patients, respectively. Out of the sample, 69.2% and 30.8% had a history of miscarriages during the 1st and 2nd trimesters, respectively. For treatment purposes, while screening for the TPOAb, the women received 50µg/day of L-thyroxine (LTx) for three months prior to pregnancy and during the first three months of pregnancy and were followed up until giving birth or miscarriage. Thyroxine treatment was correlated to successful normal births in 56.6% and 21.2% of pregnant women after 36 and during 28-36 weeks of gestation, respectively. However, miscarriages occurred in 18.1% and 4.1% of patients during 14-28 weeks and before 14 weeks of gestation, respectively. The current findings show the promising use of thyroxine in the control of RPL caused by euthyroid-based thyroid peroxidase antibody syndrome. This treatment has led to a significant number of women experiencing successful full-term pregnancies and giving birth to healthy babies.

Pregnancy outcomes and adverse events in patients with recurrent miscarriage receiving fondaparinux versus low molecular-weight heparin: A meta-analysis.

OBJECTIVE: Current opinion on the superiority of fondaparinux versus low molecular-weight heparin (LMWH) in treating recurrent miscarriage is controversial. This meta-analysis aimed to comprehensively compare the pregnancy outcomes and adverse events in patients with recurrent miscarriage receiving fondaparinux versus LMWH. METHODS: EMBASE, PubMed, Cochrane, China National Knowledge Internet (CNKI), Wanfang Database, and China Science and Technology Journal Database (CQVIP) databases were searched for articles reporting fondaparinux versus LMWH in treating recurrent miscarriage till June 10, 2022. Inclusion criteria for study screening were: (i) randomized, controlled trials (RCT), non-randomized controlled studies, or observational studies; (ii) patients aged over 18 years; (iii) patients with recurrent miscarriage during gestation period; (iv) patients in the experimental/observational group who received FD, and patients in the control group who received LMWH; (v) studies involving at least one outcome of interest for the current analysis. Exclusion criteria were: (i) systematic reviews, meta-analyses, case reports, or animal studies; (ii) duplicated studies; (iii) incomplete or inconsistent data. Quality assessment was conducted with Newcastle-Ottawa Scale criteria or Cochrane Collaboration. Data of live birth, abortion, birth weight, fetal growth restriction (FGR), and adverse events were extracted and synthesized. RESULTS: Six eligible studies (4 observational studies and 2 RCTs) with 321 patients receiving fondaparinux and 546 patients receiving LMWH were enrolled. Live birth (relative risks (RR) = 1.05, 95% confidence interval (CI) = 0.97 âˆ¼ 1.14, P = 0.217), abortion (RR = 0.73, 95% CI = 0.50 âˆ¼ 1.08, P = 0.113), birth weight (weighted mean difference = 167.20, 95% CI = -236.89 âˆ¼ 571.30, P = 0.417), and FGR (RR = 0.95, 95% CI = 0.25 âˆ¼ 3.59, P = 0.942) were of no difference between patients receiving fondaparinux and LMWH. Regarding adverse events, the incidence of ecchymosis (RR = 0.11, 95% CI = 0.03 âˆ¼ 0.46, P = 0.002) and skin reaction at injection site (RR = 0.15 95% CI = 0.05 âˆ¼ 0.44, P = 0.001) were lower in patients receiving fondaparinux compared with those receiving LMWH, while that of thrombocytopenia (RR = 0.45, 95% CI = 0.09 âˆ¼ 2.14, P = 0.315), vagina bleeding (RR = 1.03, 95% CI = 0.62 âˆ¼ 1.71, P = 0.646), and oral mucosa hemorrhage (RR = 1.08, 95% CI = 0.33 âˆ¼ 3.51, P = 0.899) did not vary between these patients receiving these two treatments. However, most studies were conducted in China, which could induce regional and ethnic bias. CONCLUSION: Fondaparinux is attributable to fewer adverse events and similar pregnancy outcomes compared with LMWH in patients with recurrent miscarriage.

Tacrolimus improved the pregnancy outcomes of patients with refractory recurrent spontaneous abortion and immune bias disorders: a randomized controlled trial.

OBJECTIVE: To investigate the effect of tacrolimus treatment on refractory recurrent spontaneous abortion (RSA) patients with elevated serum IL-33/ST2 levels. METHODS: This study was a randomized controlled trial (RCT) of refractory RSA patients with elevated peripheral blood IL-33/ST2 levels or an elevated Th1/Th2 cell ratio. A total of 149 women were enrolled, each of whom had had at least 3 serial miscarriages and was confirmed to have elevated peripheral blood IL-33/ST2 levels or an elevated Th1/Th2 cell ratio. These women were randomly divided into two groups. The tacrolimus group (n = 75) received basic therapy with the addition of tacrolimus (Prograf). Tacrolimus was administered at a dose of 0.05 ~ 0.1 mg/kg/day from the end of the menstrual period to the beginning of the next menstrual period or to the 10th week of pregnancy. In contrast, basic therapy with the addition of placebo was given to the placebo group (n = 74). The main study outcome was the delivery of healthy newborns without deformities. RESULTS: A total of 60 (80.00%) patients in the tacrolimus group and 47 (63.51%) patients in the placebo group delivered healthy newborns [P = 0.03, odds ratio = 2.30; 95% confidence interval (1.10 ~ 4.81)]. The peripheral blood IL-33/ST2 levels and Th1/Th2 cell ratio of the tacrolimus group were much lower than those of the placebo group (P < 0.05). CONCLUSION: We validated our previous finding that serum IL-33 and sST2 concentrations are related to RSA. Immunosuppressive treatment with tacrolimus was demonstrated to be a promising method to treat refractory RSA with immune bias disorders.

Efficacy and safety of recombinant human granulocyte colony-stimulating factor in patients with unexplained recurrent spontaneous abortion: A systematic review and meta-analysis.

INTRODUCTION: Published data regarding efficacy of intrauterine perfusion of recombinant human granulocyte colony-stimulating factor for patients with unexplained recurrent spontaneous abortion (URSA) is inconclusive. This study aims at evaluating the efficacy and safety of G-CSF in URSA. MATERIALS AND METHODS: Electronic databases were searched including Cochrane Library, PubMed, Embase, China Biology Medicine disc, China Science and Technology Journal Database, Wanfang Database and China National Knowledge Infrastructure Database (last search was performed on Sep 10th, 2022). A systematic review and meta-analysis was conducted with R-language software. Combined relative risk (RRs), and 95% confidence intervals (CIs) were calculated to estimate efficacy and safety. RESULTS: Compared with placebo, the efficacy of G-CSF in the treatment of URSA patients was significant in conception rate (RR=1.34, 95%CI: 1.03-1.74, P = 0.028), and was none of significance in live birth rate (RR=1.35, 95%CI: 0.99-1.84, P = 0.06). Subgroup analysis showed that the ovulation-period-medication was the protective factor for conception rate, while "Ethnicity Asian" and "ovulation-period medication" were the protective factors for live birth rate. When it comes to the safety of rhG-CSF on URSA, meta-analysis showed that rhG-CSF had no significant effect on the incidence of adverse events (AEs) (RR=1.13, 95% CI: 0.89-1.43, P = 0.322), and subgroup analysis showed that the incidence of AEs in each subgroup did not increase significantly (P > 0.05). CONCLUSION: Based on our meta-analysis, intrauterine perfusion of rhG-CSF in ovulation period is an effective and safe way to improve conception rate in URSA.

Quantitative analyses of cytokine profiles reveal hormone-mediated modulation of cytokine profiles in recurrent spontaneous miscarriage.

PURPOSE: Cytokines play important roles in pregnancy complications. Some hormones such as estrogen, progesterone, and dydrogesterone have been shown to alter cytokine profiles. Understanding how cytokine profiles are affected by these hormones is therefore an important step towards immunomodulatory therapies for pregnancy complications. We analyse previously published data on the effects of estrogen, progesterone, and dydrogesterone on cytokine balances in women having recurrent spontaneous miscarriages. MATERIALS AND METHODS: Levels of eight cytokines (IFN-γ, IL-2, IL-6, IL-10, IL-13, IL-17, IL-23, TNF-α) from n = 22 women presenting unexplained recurrent spontaneous miscarriages were studied. Cytokine values were recorded after in vitro exposure of peripheral blood cells to estrogen, progesterone, and dydrogesterone. We expand on earlier analysis of the dataset by employing different statistical techniques including effect sizes for individual cytokine values, a more powerful statistical test, and adjusting p-values for multiple comparisons. We employ multivariate analysis methods, including to determine the relative magnitude of the effects of the hormone therapies on cytokines. A new statistical method is introduced based on pairwise distances able to accommodate complex relations in cytokine profiles. RESULTS: We report several statistically significant differences in individual cytokine values between the control group and each hormone treated group, with estrogen affecting the fewest cytokines, and progesterone and dydrogesterone both affecting seven out of eight cytokines. Exposure to estrogen produces no large effects sizes however, while IFN-γ and IL-17 show large effect sizes for both progesterone and dydrogesterone, among other cytokines. Our new method for identifying which collections (i.e. subsets) of cytokines best distinguish contrasting groups identifies IFN-γ, IL-10 and IL-23 as especially noteworthy for both progesterone and dydrogesterone treatments. CONCLUSIONS: While some statistically significant differences in cytokine levels after exposure to estrogen are found, these have small effect sizes and are unlikely to be clinically relevant. Progesterone and dydrogesterone both induce statistically significant and large effect-size differences in cytokine levels, hence therapy with these two progestogens is more likely to be clinically relevant. Univariate and multivariate methods for identifying cytokine importances provide insight into which groups of cytokines are most affected and in what ways by therapies.