ABSTRACT Gestational diabetes mellitus (GDM), which is primarily characterized by insulin resistance and impaired pancreatic β‐cell function, is one of the most prevalent adverse pregnancy outcomes. The exact pathogenesis of GDM is still unclear. Ferroptosis is a type of programmed cell death, characterized by the accumulation of iron, unrestrained lipid peroxidation, and failure of antioxidant defenses, particularly depletion of glutathione peroxidase. Interestingly, accumulating evidence suggests that ferroptosis is critically involved in the development of GDM. This review outlines the mechanisms of ferroptosis, its contribution to the pathogenesis of GDM, and emerging therapeutic interventions for GDM.

BACKGROUND: Although guidelines suggest administering antibiotics 12 to 18 hours after the rupture of membranes in women with term premature rupture of membranes, in practice, clinicians tend to initiate prophylactic antibiotics as soon as possible to avoid risk of infection. OBJECTIVE: This study aimed to assess whether early administration of prophylactic antibiotics for term premature rupture of membranes reduces the incidence of maternal and neonatal infections. STUDY DESIGN: This multicenter prospective cohort study included women with term premature rupture of membranes. The participants were divided into early and late administration groups according to the duration between rupture of membranes and antibiotic use. The effectiveness outcomes included the incidence of puerperal infection, the incidence of total maternal infection, and the rate of neonatal sepsis, whereas the safety outcomes included the incidence of adverse reactions. Antibiotic use density was used to assess antibiotic consumption. The propensity score matching method was used to control for confounding factors. RESULTS: A total of 1099 women with term premature rupture of membranes were enrolled: 459 in the early 6-hour group (antibiotic administration within 6 hours) and 640 in the late 6-hour group (antibiotic administration after 6 hours) and 707 in the early 12-hour group (antibiotic administration within 12 hours) and 392 in the late 12-hour group (antibiotics administration after 12 hours). After propensity score matching, there were 300 women in each 6-hour group and 230 women in each 12-hour group. The baseline characteristics showed no significant difference between the matched groups (P>.05). The early 6-hour and 12-hour groups had lower maternal C-reactive protein levels than the late 6hour and 12-hour groups (P<.05). However, no significant difference was observed in other maternal and neonatal outcomes (P<.05). Adverse reactions showed no statistically significant difference between the early and late treatment groups (P=1.000). Antibiotic use density was higher in the early treatment groups by 10.1 defined daily doses (6-hour groups) and 11.7 defined daily doses (12-hour groups). CONCLUSION: There was no substantial difference in the efficacy and safety of antibiotics administered within 6 to 12 hours after rupture of membranes compared with that administered after 6 to 12 hours in women with term premature rupture of membranes. Delayed antibiotic use substantially reduced antibiotic consumption.

OBJECTIVE:To investigate the effect of low-molecular-weight heparin (LMWH) on placenta-mediated fetal growth restriction (FGR).METHODS:A cohort of 570 pregnant women diagnosed with placenta-mediated FGR were enrolled from January 1, 2015 through to December 31, 2021. A birth database, including demographic data, antenatal complications, and detailed delivery and newborn data, was created to collect variables from the Hospital Information System (HIS) Database. The unique personal registration number, assigned to each patient on first registration with HIS in the West China Second University Hospital, was used to link these patients. LMWH use was defined as at least 1-week prescription from diagnosis of placenta-mediated FGR. Pregnant women received LMWH (Enoxaparin 4000 IU/day) by self-administered subcutaneous injection only when they agreed and signed informed consent. Primary outcome was intrauterine fetal death after 20 weeks of pregnancy. Secondary outcomes included preterm birth (PB), Apgar score less than 7 at 1 min, admission to neonatal intensive care unit (NICU), and birth weight. Logistic regression analysis was conducted to compute adjusted odds ratio (aOR) with 95% confidence intervals (CI) for outcomes.RESULTS:After controlling for confounders, LMWH use was associated with a decreased risk of intrauterine fetal death (aOR 2.49, 95% CI 1.35-4.57, P = 0.003), PB before 37 weeks of pregnancy (aOR 3.35, 95% CI 2.14-5.23, P < 0.001), PB before 34 weeks of pregnancy (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), Apgar score less than 7 at 1 min (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), NICU admission (aOR 2.29, 95% CI 1.48-3.55, P < 0.001). Using LMWH increased the mean birth weight in PB before 32 weeks of pregnancy (mean ± standard deviation [SD] 1126.4 ± 520.0 g, P = 0.020), PB before 37 weeks of pregnancy (mean ± SD 1563.9 ± 502.7 g, P = 0.019), early-onset FGR (mean ± SD 2125.2 ± 665.7 g, P < 0.001), late-onset FGR (mean ± SD 2343.4 ± 507.9, P < 0.001), and non-severe FGR (mean ± SD 2231.1 ± 607.2 g, P < 0.001).CONCLUSION:Use of LMWH can significantly improve the fetal and neonatal outcomes among pregnant women with placenta-mediated FGR, particularly reducing the risk of intrauterine fetal death.

Background Wound complications are a major source of morbidity after cesarean section (CS) and contribute to increased risks in subsequent pregnancies. In the present study, we aim to investigate the wound healing potential of a kind of oligopeptide compound, mainly derived from the marine fish peptides (MFPs), in rats after CS by biomechanical, biochemical, and histological methods. Methods Eighty-four pregnant Sprague–Dawleyrats were randomly assigned to four groups, namely the control group and 1.1, 2.2, and 4.4 mg/kg MFP groups, respectively. The MFPs or normal saline of the equal volume was intragastrically administered every morning on the second day after CS. On days 5, 10, and 15 after the surgery, seven rats from each group were randomly selected. The samples of skin wound and uterus were harvested and then used for the following experiments and analyses. Results Using the CS rat model, this study demonstrated that in the MFP groups, the skin tensile strength, uterine bursting pressure, and hydroxyproline (Hyp) were significantly higher than those in the control group at all three time points (P < 0.05). The formation of collagen and smooth muscle fibers and the expression of CD34 and connective tissue growth factor at the incision site were increasingly observed in the MFP groups (P < 0.05). Conclusions MFPs have a great potential to accelerate the process and quality of wound healing in rats after CS.

Abstract Rationale: Klippel–Trenaunay Syndrome (KTS) is a congenital vascular disease characterized by cutaneous hemangiomas, venous varicosities, and limb hypertrophy. Although extremely rare in pregnant women, the present vascular alterations may be aggravated, consequent to postural and hormonal changes inherent to the pregnancy. Pregnancy is not advised in KTS women due to increased obstetrical risk. Patient concerns: A 31-year-old pregnancy woman presented with prominent vascularity in pelvis, right lower limb, spleen, and liver at 28 weeks of gestation. We started administration of anticoagulant therapy and obstetrics management. Diagnosis: MRI and ultrasound revealed that multiple varicosities in her pelvis, right lower limb, spleen, and liver. She was diagnosed with KTS. Interventions: At her first visit at 28 weeks of gestation, multidisciplinary evaluation had been done. Blood transfusion and iron supplement had been given for anemia correction. Anticoagulant therapy was performed to prevent potential thrombus risk. She had a vaginal delivery with a healthy newborn in her second visit without any complications at the gestation of 36+6 weeks due to rupture of preterm membranes. Outcomes: After successful management, the patient was discharged without any complications 2 days after vaginal delivery. No symptoms of hemorrhage or thrombus were observed. At 6 months follow-up, her right lower toes enlarged obviously, MRI revealed that no obvious changes of hemangiomas was found compared to those during the pregnancy and ultrasound revealed that there was no thrombus in her right lower limb. Lessons: Patients with KTS can be pregnant and have healthy babies safely with regularly monitor and reasonable treatment during pregnancy. A careful follow-up and guidance are necessary.

Objective: To explore the role of ubiquitin proteasome system in the pathogenesis of infection related preterm birth. Materials and Methods: Thirteen women with spontaneous preterm delivery and 13 controls were included in present case-controlled study. The mRNA and protein levels of lib-conjugating enzyme E2Q1 (UBE2Q) and Carboxyl-terminus of Hsc70 interacting protein (CHIP) in the placenta were measured by immunohistochemistry, real-time RT-PCR, and Western blotting methods. Statistical significance (p < 0.05) was determined using student's t-test. Results: The mRNA levels of UBE2Q1 (0.48 +/- 0.05 vs. 0.67 +/- 0.07, p = 0.047) and CHIP (1.59 +/- 0.23 vs. 5.62 +/- 1.00, p = 0.002) in the placentas of preterm delivery were significant lower than those of term delivery. The protein levels of UBE2Q1 (0.64 +/- 0.09 vs. 1.49 +/- 0.22, p < 0.001) and CHIP (0.76 +/- 0.08 vs. 1.33 +/- 0.23, p = 0.001) in the placentas of preterm delivery were also significant lower than those of term delivery. Conclusions: Decreased mRNA and protein expression of UBE2Q1 and CHIP were both found in the syncytiotrophoblast and cytotrophoblast of placenta in pretem birth patients, which was speculated to play a role in the pathogenesis of infection related preterm birth.

PROBLEM:Apoptosis is a normal constituent of trophoblast turnover in the placenta; however in some cases, this process is related to pregnancy complications such as preeclampsia. Recognition and engulfment of these apoptotic trophoblast cells is important for clearance of dying cells. The aim of this study was to show the cross talk between human endometrial endothelial cells (HEECs) and apoptotic trophoblast cells in an in vitro coculture model and its effect on cytokine production by HEECs. METHOD OF STUDY:Fluorescent-labeled HEECs were cocultured with fluorescent-labeled apoptotic human trophoblast cells. Confocal microscopy and flow cytometry were used to show the interaction between these two types of cells. Cytokine profiles were determined using multiplex analysis. RESULTS:HEECs are capable to phagocytose apoptotic trophoblasts. This activity is inhibited by the phagocytosis inhibitor cytochalasin B. Phagocytosis of apoptotic trophoblast cells induced the secretion of the proinflammatory cytokines interleukin-6 and monocyte chemoattractant protein-1 by HEECs. CONCLUSION:This study provides the first evidence that HEECs have an ability to phagocytose apoptotic trophoblasts. Furthermore, we demonstrated an inflammatory response of HEECs after phagocytosing the apoptotic trophoblast cells. This event may contribute to the inflammatory response in both normal pregnancy and pathologic pregnancy such as preeclampsia.

Problem Toll-like receptors (TLRs) recognize conserved sequences on the surface of pathogens and trigger effector cell functions. Previously, we described the expression of TLR3 by human trophoblast and their ability to respond to (Poly[I:C]). Here we evaluate the effect of Poly[I:C] on mouse pregnancy and characterize the local and systemic response. Method of study C57B/6 wild type (wt) and TLR3 knockout (TLR3KO) mice were treated with Poly[I:C] at 16.5 dpc and pregnancy outcome recorded. Morphologic changes, cytokines and chemokines levels in blood and utero-placental tissue were determined. NF-κB pathway was evaluated in vivo and in vitro . Results Poly[I:C] in C57B/6 wt mice caused preterm delivery within 24 hr (4.5 mg/kg). No effect was observed in TLR3KO mice. In addition, we observed local (placenta) and systemic (serum) response characterized by increased production of proinflammatory cytokines and chemokines. The NF-κB pathway was activated by Poly[I:C] in human and mice trophoblast cells . Conclusion We report that Poly[I:C] induces preterm delivery via TLR3-dependent manner. Furthermore, we demonstrate that the trophoblast is able to recognize Poly[I:C] through TLR3 and respond to viral infection, modulating the immune system at the feto-maternal interface.

PROBLEM:Toll-like receptors (TLRs) recognize conserved sequences on the surface of pathogens and trigger effector cell functions. Previously, we described the expression of TLR3 by human trophoblast and their ability to respond to (Poly[I:C]). Here we evaluate the effect of Poly[I:C] on mouse pregnancy and characterize the local and systemic response. METHOD OF STUDY:C57B/6 wild type (wt) and TLR3 knockout (TLR3KO) mice were treated with Poly[I:C] at 16.5 dpc and pregnancy outcome recorded. Morphologic changes, cytokines and chemokines levels in blood and utero-placental tissue were determined. NF-kappaB pathway was evaluated in vivo and in vitro. RESULTS:Poly[I:C] in C57B/6 wt mice caused preterm delivery within 24 hr (4.5 mg/kg). No effect was observed in TLR3KO mice. In addition, we observed local (placenta) and systemic (serum) response characterized by increased production of proinflammatory cytokines and chemokines. The NF-kappaB pathway was activated by Poly[I:C] in human and mice trophoblast cells. CONCLUSION:We report that Poly[I:C] induces preterm delivery via TLR3-dependent manner. Furthermore, we demonstrate that the trophoblast is able to recognize Poly[I:C] through TLR3 and respond to viral infection, modulating the immune system at the feto-maternal interface.

OBJECTIVE:To investigate the distribution of human leukocyte antigen (HLA)-G and E on human first trimester placenta and its relationship with unexplained recurrent spontaneous abortion (RSA).METHODS:Fifteen women with normal first trimester pregnancy and fifteen patients with RSA were included in this study. In situ hybridization and immunohistochemical staining were employed to detect the mRNA and protein of HLA-G, E in first trimester placenta.RESULTS:The HLA-G, E mRNA were detected in all trophoblasts, including syncytiotrophoblast, villous and extravillous cytotrophoblast. HLA-G protein was only found at extravillous trophoblast by mAb 4H84 specific to HLA-G. The same expression sites were observed for both HLA- E protein and its mRNA. The expression of HLA-G, E mRNA in the RSA group were much lower than those in the control group. The HLA-G, E protein were also expressed at low level in RSA group.CONCLUSION:The inconsistency of the distribution of HLA-G mRNA and protein was probably due to the monoclone antibody 4H84. There is strong correlation between lack of the mRNA and protein expression of HLA-G, E found in the trophoblasts at the fetal-maternal interface and RSA.

OBJECTIVE:To investigate the expression of human leucocyte antigen G (HLA-G) on human placenta and its gene polymorphism in relation to intrahepatic cholestasis of pregnancy (ICP). METHODS:Immunohistochemistry was utilized to detect the HLA-G protein expression on third trimester placenta of fifteen normal pregnant women (control group 1), fifteen ICP patients treated with dexamethasone (ICP group with dexamethasone treatment) and ten ICP patients treated without dexamethasone (ICP group without dexamethasone treatment). We used polymerase chain reaction with sequence-specific primer (PCR-SSP) method to detect the 14 bp deletion polymorphism in exon 8 of HLA-G gene of thirty normal pregnant women and their babies (control group 2), thirty ICP patients and their babies (ICP group). RESULTS:(1) The positive expression of HLA-G on placenta extravillous cytotrophoblast and its mean optical density of ICP group without dexamethasone treatment 56 +/- 8 was significantly lower than those of normal control group 70 +/- 10 and ICP group with dexamethasone treatment 66 +/- 9 (P < 0.05). No significant differences were found between normal control group and ICP group with dexamethasone treatment (P > 0.05). (2) There were no statistical differences between the control group and the ICP group with regard to the allele and genotype of the 14 bp deletion polymorphism in exon 8 of HLA-G gene (P > 0.05). CONCLUSIONS:The reduced expression of HLA-G on placenta in ICP patients may alter the maternal-fetal immune response and thus be involved in the pathogenesis of this disorder. Dexamethasone can upregulate the expression of HLA-G on placenta. The 14 bp deletion polymorphism in exon 8 of HLA-G gene might not have a significant influence on the development of ICP.

OBJECTIVE:To investigate the relationship between human leucocyte antigen (HLA)-G, E and intrahepatic cholestasis of pregnancy (ICP).METHODS:In situ hybridization and immunohistochemistry methods were adopted in this study to detect the expression of HLA-G and HLA-E mRNA and protein in the placentae of three groups, namely normal control group, ICP group with dexamethasone (DEX) treatment, and ICP group without DEX treatment.RESULTS:No significant differences in respect to HLA-G, HLA-E mRNA expression on extrovillous cytotrophoblasts (EVCT ) of the placentae were found between the normal control group, the ICP group with DEX treatment and the ICP group without DEX treatment. However, the protein expression of HLA-G and HLA-E on the placental EVCT of ICP group without DEX treatment was significantly lower than that of the normal control group and the ICP group with DEX treatment.CONCLUSION:The decreased EVCT expression of HLA-G, HLA-E protein may cause the disturbance of the maternal-fetal immune tolerance of ICP patient and play a role in the pathogenesis of ICP. DEX can upregulate the EVCT expression of HLA-G, HLA-E protein; this may be one of the underlying mechanisms for its use in the treatment of ICP.

OBJECTIVE:To study the perinatal outcomes of intrahepatic cholestasis of pregnancy (ICP).METHODS:The clinical data of 1210 cases of ICP in recent ten years were retrospectively analyzed.RESULTS:The incidence rates of perinatal outcomes of ICP were as follows: 19.0% (230/1210) for threatened premature labor, 24.0% (290/1210) for premature delivery; 23.2% (281/1210) for meconium stained amniotic fluid, 7.1% (86/1210) for neonatal asphyxia, 22.5 per thousand (27/1210) for perinatal mortality, 85.9% (1039/1210) for cesarean section, 0.9% (11/1210) for fetal growth restriction (FGR), 1.4% (17/1210) for postpartum hemorrhage, and 8.1% (101/1210) for preeclampsia. Threatened premature labor occurred beyond the gestation gestation period of 32 weeks in 88.7% (204/230) of the patients, and the fetal death rate in threatened premature labor was 46.7% (7/15). Premature delivery occurred after 34 weeks of gestation in 96.2% of the patients (279/290) 89.7% (260/290) of which were caused by cesarean section because of abnormal fetal monitoring. 41.3% of the cases with meconium stained amniotic fluid (116/281) occurred before the onset of labor. Fetal death accounted for 56% (15/27) of perinatal death, 80% (12/15) of which happened after the gestation week of 35 (36.5 +/- 1.2) with normal fetal heart rate monitoring. 95% (19/20) of the fetal death and stillbirth occurred after threatened premature labor and occasional uterine contractions, or at the early stage of labor.CONCLUSION:The rates of FGR, postpartum hemorrhage, and preeclampsia in ICP are almost the same as those of the normal pregnancy. Routine fetal heart rate monitoring methods cannot predict fetal death. The important measures to decrease the perinatal mortality include paying attention to fetal monitoring when threatened premature labor, occasional uterine contractions and prenatal meconium occur, and at the early stage of labor, and management of threatened premature labor and timely intervention of pregnancy (at the gestation period of 34 - 37 weeks).