Context Dysregulated immune hemostasis occurs in unexplained recurrent spontaneous abortion (URSA). Synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), hydrogen sulfide (H2S) promotes regulatory T-cell differentiation and regulates immune hemostasis; yet, its role in URSA is elusive. Objective To determine if H2S plays a role in early pregnancy and if dysregulated H2S signaling results in RSA. Design First-trimester placenta villi and decidua were collected from normal and URSA pregnancies. Protein expression were examined by immunohistochemistry and immunoblotting. Human trophoblast HTR8/SVneo and JEG3 cells were treated with H2S donors; HTR8/SVneo cells were transfected with CBS RNAi or cDNA. Cell migration and invasion were determined by trans-well assays; trophoblast transcriptomes were determined by RNA-seq. Wild-type, CBS-deficient, and CBA/J × DBA/2 mice were treated with CBS and CSE inhibitors or H2S donors to determine the role of H2S in early pregnancy in vivo. Results CBS and CSE proteins showed cell-specific expressions but only CBS decreased in the villous cytotrophoblast in URSA vs. normal subjects. H2S donors promoted migration and invasion and MMP-2 and VEGF expression in HTR8/SVneo and JEG3 cells, similar to forced CBS expression in HTR8/SVneo cells. The CBS-responsive transcriptomes in HTR8/SVneo cells contained differentially regulated genes, i.e., IL-1R and PGTS2, that are associated with nuclear factor-κB-mediated inflammatory response. In vivo, dysregulated CBS/H2S signaling significantly increased embryonic resorption and decidual Th1/Th2 imbalance in mice, which was partially rescued by H2S donors. Conclusion CBS/H2S signaling maintains early pregnancy possibly via regulating maternal-fetal interface immune hemostasis, offering opportunities for H2S-based immunotherapies for URSA.

Insufficient extravillous trophoblast (EVT) invasion during early placentation has been shown to contribute to recurrent pregnancy loss (RPL). However, the regulatory factors involved and their involvement in RPL pathogenesis remain unknown. Here, we found aberrantly decreased growth differentiation factor 15 (GDF15) levels in both first‐trimester villous and serum samples of unexplained recurrent pregnancy loss (URPL) patients as compared with normal pregnancies. Moreover, GDF15 knockdown significantly reduced the invasiveness of both HTR‐8/SVneo cells and primary human EVT cells and suppressed the Jagged‐1 (JAG1)/NOTCH3/HES1 pathway activity, and JAG1 overexpression rescued the invasion phenotype of the GDF15 knockdown cells. Induction of a lipopolysaccharide‐induced abortion model in mice resulted in significantly reduced GDF15 level in the placenta and serum, as well as increased rates of embryonic resorption, and these effects were reversed by administration of recombinant GDF15. Our study thus demonstrates that insufficient GDF15 level at the first‐trimester maternal–foetal interface contribute to the pathogenesis of URPL by impairing EVT invasion and suppressing JAG1/NOTCH3/HES1 pathway activity, and suggests that supplementation with GDF15 could benefit early pregnancy maintenance and reduce the risk of early pregnancy.

Background PGT-A has been widely used for RPL couples to help improve pregnancy outcomes by selecting euploid embryos. However, there is still insufficient evidence to determine the effectiveness of PGT-A in RPL couples, especially on the cumulative live birth rate. This study aims to investigate whether preimplantation genetic testing for aneuploidy (PGT-A) could improve the cumulative live birth rate in patients with recurrent pregnancy loss (RPL). Methods A retrospective large cohort study with 1003 RPL couples (799 in the PGT-A group, and 204 in the conventional IVF/ICSI group) was conducted in a university-affiliated reproductive center. Stratified analysis was performed according to female age (< 35 years and ≥ 35 years). The associations between embryo selection with PGT-A and cumulative pregnancy outcomes were further analyzed by a binary logistic regression model. Results The cumulative live birth rates were similar between the PGT-A group and the conventional IVF/ICSI group both in women under 35 years old [53.32% vs. 61.97%, adjusted OR (95%CI): 0.853(0.547–1.330), P = 0.483] and in women aged ≥ 35 years [28.75% vs. 30.65%, adjusted OR (95%CI): 1.314(0.671–2.574), P = 0.426]. Whereas, a significantly lower cumulative rates of biochemical pregnancy loss (10.13% vs. 32.56%, P < 0.05) and clinical pregnancy loss [20.89% vs. 37.21%, adjusted OR (95%CI): 0.408(0.173–0.966), P = 0.042] were found in the PGT-A group compared with the control group, only among women aged ≥ 35 years. The numbers of embryo transfers were significant less in PGT-A women with < 35 years old [1(1;2) vs. 1(1;2), P < 0.05] and with ≥ 35 years old [1(1;1) vs. 1(1;2), P < 0.05]. Conclusions PGT-A could not improve cumulative live birth rate in RPL couples regardless maternal age.

Objective To assess whether the subendometrial blood flow condition detected by Doppler ultrasound could predict pregnancy outcomes in patients with thin endometrium during in vitro fertilization (IVF) treatment. Design Retrospective cohort study. Setting Reproductive Hospital affiliated with Shandong University, Jinan, Shandong, China Population or Sample The study included 3830 frozen embryo transfer (FET) cycles of 3,830 IVF patients between January 2017 to December 2019. Methods Endometrial thickness, endometrial blood flow, and subendometrial blood flow were measured using transvaginal color Doppler ultrasound, evaluated by experienced clinical ultrasound physicians on the day of endometrial transformation. Logistic binary regression was used to analyze the effects of subendometrial blood flow on successful embryo implantation. Pregnancy outcomes of these patients were documented in clinic medical records during follow-up. Main Outcome Measures Pregnancy outcomes (biochemical pregnancy rate, clinical pregnancy rate and live birth rate) Results A total of 3830 frozen embryo transfer cycles were retrospectively analyzed. Our results show that patients with subendometrial blood flow exhibit higher average success rates of live birth, clinical pregnancy, and embryo implantation compared to those without subendometrial blood flow when endometrial thickness is ≤ 0.7 cm. In detail, in thin endometrium patient group, the presence of subendometrial blood flow is correlated with 7.2% higher biochemical pregnancy rate, 7.0% higher clinical pregnancy rate, and 6.2% higher live birth rate compared to those without subendometrial blood flow. Conclusions Endometrial and subendometrial blood flow conditions have predictive value for pregnancy outcomes after frozen embryo transfer in patients with thin endometrium