Pregnant women have both the local immune tolerance at the maternal-fetal interface and the systemic immune defense against pathogens. To date, regardless of the extensive investigation on the maternal-fetal immune tolerance, the maintenance of systemic immune defense in pregnant women still remains poorly understood. In the present study, we demonstrate that the immunoregulatory molecule T cell Ig and mucin domain (Tim)-3 plays important roles in innate and adaptive immunity of human pregnancy. During pregnancy, Tim-3 is strikingly up-regulated in peripheral blood of pregnant women, most by monocytes but not by T or B cells. The increased IL-4/STAT6 signaling may contribute to such up-regulation of Tim-3. In turn, the increased Tim-3 enhances not only innate immunity but also Th1-associated immune responses of pregnant women against pathogens. In contrast, our clinical data show that abnormal Tim-3 expression level might be connected to the pregnancy loss. In conclusion, our data show in this study that an immune regulatory molecule Tim-3, by virtue of its up-regulation in innate immune cells in pregnant women, enhances both innate and adaptive immune responses. Nevertheless, the abnormality of Tim-3 in pregnant woman may be deleterious to normal pregnancy.

Background: Bisphenol A (BPA) levels are high in women with polycystic ovary syndrome (PCOS). The mechanism by which BPA induces abnormal glucose metabolism in PCOS patients is largely unknown. Methods: Serum and urine samples were collected from women with and without PCOS (control) at the reproductive medicine center with informed consent. Non-PCOS patients who received in vitro fertilization were recruited for collection of ovarian follicular fluid and granular cells. Wild-type C57BL/6 and AhR^−/− mice were used to verify the effects of BPA on PCOS. Real-time PCR, western blotting, and ELISA were conducted to analyze the function of BPA. Chip-qPCR verified the role of AhR in GLUT4 transcription. Flow cytometry was performed to determine glucose uptake. Results: A positive correlation was observed between BPA concentration and serum BPA levels in PCOS patients. BPA aggravated the changes in PCOS with abnormal glucose metabolism, impaired fertility, and increased body fat. Mechanistically, we showed that BPA activated AhR and led to decreased glucose transport via GLUT4 downregulation in ovarian granular cells. Therefore, the use of inhibitors or knockout of AhR could effectively rescue BPA-induced metabolic disorders in PCOS mice. Conclusions: Our results revealed that BPA suppressed GLUT4 expression and induced abnormal glucose metabolism by activating AhR, causing insulin resistance, and is thus a potential contributor to the development of PCOS. Therefore, AhR could be a potential new therapeutic target for PCOS.

Research question: Is there an association between intrauterine hematoma (IUH), vanishing twin syndrome (VTS), and subsequent complications in twin pregnancies after in vitro fertilization (IVF)? What are the risk factors for these complications?Design: Women who presented with two live gestational sacs following double embryo transfer were included. Patients with systematic diseases, artificial fetal reduction, and incomplete data were excluded. Further stratification of IUH pregnancies was performed according to IUH-related characteristics (i.e., volume, changing pattern, and relationship with fetal cardiac activities). The primary outcome was the incidence of VTS, while adverse outcomes in the surviving singleton and the gestational age of VTS were secondary outcomes.Results: The incidence of IUH was 13.8%. A total of 1,078 twin pregnancies including 539 IUH pregnancies and 539 non-IUH pregnancies were included. IUH pregnancy was associated with higher risks of VTS (26.9% vs. 18.7%, p = 0.001) as well as a higher incidence of preterm birth (p = 0.001, crude OR = 1.98, 95% CI 1.28–3.09, adjusted OR = 1.19, 95% CI 1.09–1.24), threatened abortion (p < 0.001, crude OR = 9.12, 95% CI 2.90–28.69, adjusted OR = 6.63, 95% CI 1.69–14.67), and postpartum hemorrhage (p = 0.024, crude OR = 3.13, 95% CI 1.09–8.99, adjusted OR = 1.16, 95% CI 1.08–1.32) in the surviving singleton. There was no significant difference in risks of other complications. The absence of fetal cardiac activities at the diagnosis of IUH predicted VTS (p < 0.001, crude OR 4.67, 95% CI 3.67–5.78, adjusted OR 3.33, 95% CI 1.56–5.14) and fetal loss at smaller gestational age (7.81 ± 2.10 vs. 11.39 ± 5.60 weeks, p < 0.001), while an IUH with an increasing volume did not increase the risk of VTS but might induce threatened abortion in the surviving fetus (p < 0.001, crude OR 1.84, 95% CI 1.32–2.55, adjusted OR 1.72, 95% CI 1.13–2.13).Conclusions: IUH was a risk factor for VTS in twin pregnancies following double embryo transfer and elevated the risks of threatened abortion, preterm birth, and postpartum hemorrhage in the surviving singleton. The absence of fetal cardiac activities at the diagnosis of IUH elevated the risks of VTS, while an IUH with an increasing volume was associated with threatened abortion without elevating the risks of VTS. An IUH diagnosed before the presence of fetal cardiac activities also resulted in an earlier miscarriage. The study suggests that attention be paid to twin pregnancies with first-trimester IUH to prevent VTS and subsequent adverse perinatal outcomes.Highlights: First-trimester intrauterine hematoma (IUH) following double embryo transfer is associated with a higher incidence of vanishing twin syndrome (VTS) and elevated subsequent risk of threatened abortion, preterm birth, and postpartum hemorrhage in the surviving singleton. Other perinatal outcomes were not associated with the diagnosis of first-trimester IUH. The absence of fetal cardiac activities at the diagnosis of IUH was of predictive value toward VTS, while an IUH with an increasing size was associated with threatened abortion without elevating the risk of VTS. Incomplete fetal cardiac activities and earlier detection of an IUH might also predict miscarriage at smaller gestational age.