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Problem: Intravenous immunoglobulin G (IVIG) is an emerging regimen for women with reproductive failures (RF) during- or pre-pregnancy who have aberrant cellular immune reactions. Studies investigating teratogenicity of IVIG have been limited. Herein, we evaluated the fetal teratogenicity of IVIG and IVIG-related obstetric complications., Method of Study: Women who used IVIG during pregnancy due to RF with cellular immune aberrances were enrolled from four medical centers in Korea. The pregnancy outcomes were collected., Results: A total of 370 RF women who used IVIG during their pregnancy were enrolled. Most of the patients started the IVIG therapy before 12 weeks of gestation and 229 women continued IVIG treatment beyond 12 weeks of gestation. The mean age of the subjects was 34.8 years and the mean total dosage of IVIG was 125.3 g. A total of 307 women had livebirths and six of them were twins. Of 301 singleton livebirths, obstetric complications were developed as follows: preterm births (12.0%), gestational diabetes (7.0%), preeclampsia (4.0%), placental abruption (1.3%), placenta previa (4.3%), and placenta accrete (1.7%). Total six cases (1.99%) had major fetal anomalies in livebirths. The incidence of birth defects is similar to those of the general population in Korea and the previous report in infertile women. No IVIG -related viral contamination was noted., Conclusion: IVIG use during pregnancy did not increase obstetric complications and fetal teratogenicity. This study can be an evidence of maternal and fetal safety of IVIG administration during pregnancy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pathological maternal inflammation and abnormal placentation contribute to several pregnancy-related disorders, including preterm birth, intrauterine growth restriction, and preeclampsia. TANK-binding kinase 1 (TBK1), a serine/threonine kinase, has been implicated in the regulation of various physiological processes, including innate immune response, autophagy, and cell growth. However, the relevance of TBK1 in the placental pro-inflammatory environment has not been investigated. In this study, we assessed the effect of TBK1 inhibition on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human trophoblast cell lines and mouse placenta. TBK1 phosphorylation was upregulated in the trophoblasts and placenta in response to LPS. Pharmacological and genetic inhibition of TBK1 in trophoblasts ameliorated LPS-induced NLRP3 inflammasome activation, placental inflammation, and subsequent interleukin (IL)-1 production. Moreover, maternal administration of amlexanox, a TBK1 inhibitor, reversed LPS-induced adverse pregnancy outcomes. Notably, TBK1 inhibition prevented LPS-induced NLRP3 inflammasome activation by targeting the mammalian target of rapamycin complex 1 (mTORC1). Thus, this study provides evidence for the biological significance of TBK1 in placental inflammation, suggesting that amlexanox may be a potential therapeutic candidate for treating inflammation-associated pregnancy-related complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Shin, Kim, Shin, Lee and Park.)

Problem: Maternal obesity induces elevated saturated fatty acid palmitate levels in the blood and causes pregnancy complications such as gestational diabetes, preeclampsia, fetal growth abnormalities, and stillbirth. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, the effects of Sestrin2 on trophoblast cells have not yet been investigated. Here, we investigated the role of Sestrin2 in palmitate-induced lipotoxicity and its underlying mechanisms in human first-trimester trophoblast cells (Sw.71)., Method of Study: Mouse placental tissues were obtained from low-fat diet-fed mice (n = 14) and high-fat diet-fed mice (n = 14) at gestation day 17.5. Sw.71 cells were treated with palmitate or bovine serum albumin as vehicle controls. The role of Sestrin2 in palmitate-induced lipotoxicity was examined by immunocytochemistry, immunoblot analysis, quantitative real-time PCR, and invasion assay., Results: Expression of placental Sestrin2 was elevated in high-fat diet-fed dams compared to that of low-fat diet-fed dams. Prolonged treatment of Sw.71 cells with palmitate-induced endoplasmic reticulum (ER) stress-dependent expressions of Sestrin2 protein and mRNA, and the treatment also triggered apoptosis. Knockdown of Sestrin2 increased palmitate-mediated ER stress, inflammatory signaling, and apoptosis. Furthermore, Sestrin2 suppressed impaired trophoblast invasion caused by palmitate and attenuated palmitate-induced ER stress and inflammation via AMPK/mTORC1 pathways., Conclusion: Our study provides the relationship between Sestrin2, AMPK/mTORC1 pathway, and trophoblast function, suggesting that Sestrin2 may be a novel potential therapeutic target for the prevention of pregnancy complications., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Problem: Vitamin D deficiency increases the risk of developing pregnancy-related complications, including preeclampsia and small-for-gestational-age infants. Vitamin D was demonstrated to promote the invasiveness of human extravillous trophoblasts (EVTs). However, whether vitamin D induces the epithelial-mesenchymal transition (EMT) of EVTs remains unclear. Therefore, we investigated whether vitamin D promotes EMT and the related signaling pathways., Method of Study: In this study, we performed EMT experiments using JAR cells based on the expression of the mesenchymal markers and vitamin D receptor. JAR cells were treated with calcitriol, the active form of vitamin D. Western blotting was performed to evaluate EMT markers and key molecules of signaling pathways. Invasion assays were conducted. Expression and secretion of MMPs were analyzed by real-time PCR and zymography., Results: Calcitriol significantly enhanced EMT and the invasive capability of JAR cells, along with increased expression and secretion of MMP-2 and MMP-9. Moreover, ERK signaling pathway was activated by calcitriol. The effects of calcitriol were neutralized by ERK signaling blocker., Conclusion: Calcitriol facilitated EMT induction and expression of MMPs via ERK signaling pathway, which promoted the invasive capability of EVTs. Further studies are warranted to elucidate the potential application of vitamin D in the prevention of pregnancy complications., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Reproductive failure (RF) is the inability to conceive or to carry a pregnancy to term, and its prevalence is not negligible. Pregnancy is a prothrombotic condition, which can be abnormally exaggerated in women with thrombophilia. Antiphospholipid syndrome is a cause of RF and effectively managed with heparin and aspirin. However, there are yet insufficient data in patients with RF and inherited thrombophilia. This review focuses on the significance of inherited thrombophilia and RF and the role of anticoagulants in pregnancy outcomes. A few randomized case‐control studies have investigated the effect of anticoagulation in RF with thrombophilia, and the results are yet debatable. Some inherited thrombophilia including mutations of factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase and protein S deficiency are associated with RF and/or late pregnancy complications. There are several implications which influence the diagnosis and treatment. First, there is a lack of studies revealing appropriate thrombophilia markers and its cutoff values for RF specifically. Second, some thrombophilia markers change with sex and age. Lastly, the study designs of previous studies are heterogeneous in selecting the thrombophilia markers and drugs. Further studies to find adequate thrombophilia markers of RF are warranted and eventually elucidate the subgroups beneficial to anticoagulation treatment. [ABSTRACT FROM AUTHOR]

Problem We investigated the therapeutic effect of intravenous immunoglobulin (IVIG) in women with recurrent pregnancy loss (RPL). Method of study This was a retrospective observational study. Total 189 RPL women who experienced ≥2 miscarriages were enrolled and investigated conventional etiologies, thrombophilia, and cellular immunity. Patients were divided into four groups; known etiology with (Gr1) and without cellular immune abnormality (Gr2), unknown etiology with (Gr3) and without cellular immune abnormality (Gr4). IVIG was administrated from early pregnancy to 30 weeks of gestation to women with cellular immune abnormality (Gr1 + Gr3). Results Cellular immune abnormalities (increased level or cytotoxicity of NK cells and Th1/Th2 ratio) were present in 111 of 189 RPL women (58.7%). Live birth rates of women with and without cellular immune abnormality were not different (Gr1 + Gr3, 84.8% versus Gr2 + Gr4, 89.7%). Furthermore, IVIG success rates were the same between Gr1 and Gr3, those who had cellular immune abnormality. Nevertheless lack of an appropriate control in this study, our IVIG outcome demonstrated better live birth rate compared with those of other investigators. Conclusion Treatment modalities stratified by underlying etiologies of RPL may improve pregnancy outcome. Administration of IVIG is likely to have clinical efficacy in RPL women with cellular immune abnormality. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that aberrant maternal inflammation is associated with several pregnancy-related disorders such as preeclampsia, preterm birth, and intrauterine growth restriction. Sirtuin1 (SIRT1), a class III histone deacetylase, is involved in the regulation of various physiopathological processes including cellular inflammation and metabolism. However, the effect of SIRT1 on the placental proinflammatory environment remains to be elucidated. In this study, we investigated the effect of SIRT1 on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human first-trimester trophoblasts (Sw.71 and HTR-8/SVneo cells). Treatment with LPS elevated SIRT1 expression and induced NLRP3 inflammasome activation in mouse placental tissues and human trophoblasts. Knockdown of SIRT1 enhanced LPS-induced NLRP3 inflammasome activation, inflammatory signaling, and subsequent interleukin (IL)-1β secretion. Furthermore, knockdown of NLRP3 considerably attenuated the increase of IL-1β secretion in SIRT1-knockdown cells treated with LPS. Moreover, SIRT1 inhibited LPS-induced NLRP3 inflammasome activation by reducing oxidative stress. This study revealed a novel mechanism via which SIRT1 exerts anti-inflammatory effects, suggesting that SIRT1 is a potential therapeutic target for the prevention of inflammation-associated pregnancy-related complications. [ABSTRACT FROM AUTHOR]

Problem: Dysregulation of extravillous trophoblast (EVT) invasion leads to pregnancy complications, such as pre‐eclampsia, fetal growth restriction, and placenta accreta. The aim of this study was to explore the role of SIRT1 in EVT invasion and its underlying mechanism. Method of study: SIRT1‐specific siRNA was transfected into Swan 71 cells, an immortalized first trimester trophoblast cell line. The Boyden chamber invasion assay, the scratch wound healing assay, and cell proliferation assay were performed. The expression levels of epithelial‐to‐mesenchymal transition (EMT) markers, matrix metalloproteinase‐2 (MMP‐2), MMP‐9, p‐Akt, Akt, p‐p38MAPK, p38MAPK, p‐ERK, ERK, p‐JNK, JNK, Fas, and Fas ligand (FasL) were examined by western blot. Tube formation assay was conducted by using Matrigel. Results: SIRT1 knockdown by siRNA significantly enhanced invasion and migration as well as the expression of MMP‐2, MMP‐9, and EMT markers in Swan 71 cells, but reduced proliferation. The effects of SIRT1 knockdown on invasion, migration, proliferation, and endothelial‐like tube formation in Swan 71 cells were reversely regulated by blockade of Akt and p38MAPK signaling. In addition, SIRT1 knockdown markedly promoted colocalization of Swan 71 cells to human umbilical vein endothelial cell (HUVEC) networks and induced reduction in Fas and enhancement of FasL. Conditioned media of SIRT1 knockdown‐Swan 71 cells caused reduction in cell proliferation and augmentation of cytotoxicity along with increased Fas expression in HUVECs. Conclusion: Our results suggest that SIRT1 may be associated with placental development by controlling EVT invasion and spiral artery remodeling via modulation of EMT, MMP‐2, MMP‐9, Akt/p38MAPK signaling, and Fas/FasL. [ABSTRACT FROM AUTHOR]

25-hydroxycholesterol (25HC) is an oxysterol derived from cholesterol and plays a role in various cellular processes, such as lipid metabolism, inflammatory responses, and cell survival. Extravillous trophoblasts (EVTs) are a major cell type found in the placenta, which are highly energetic cells with proliferative and invasive properties. EVT dysfunction can lead to pregnancy complications, including preeclampsia and intrauterine growth restriction. This study investigated the effects and underlying mechanisms of action of 25HC on EVT proliferation. Swan 71 cells, an EVT cell line, were treated with different concentrations of 25HC. Next, cell proliferation was assessed. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potentials (MMPs), lipid peroxidation (LPO), and glutathione (GSH) levels were measured. Apoptosis, ferroptosis, and autophagy were evaluated by western blotting and flow cytometry. The results revealed that 25HC significantly inhibited proliferation and decreased the metabolic activity of EVTs. Moreover, 25HC caused oxidative stress by altering mtROS, LPO, MMPs, and GSH levels. Additionally, 25HC induces apoptosis, ferroptosis, and autophagy through the modulation of relevant protein levels. Interestingly, pretreatment with Z-VAD-FMK, an apoptosis inhibitor, and ferrostatin-1, a ferroptosis inhibitor, partially restored the effects of 25HC on cell proliferation, oxidative stress, and cell death. In summary, our findings suggest that 25HC treatment inhibits EVT proliferation and triggers apoptosis, ferroptosis, and autophagy, which are attributable to oxidative stress. [Display omitted] • 25-Hydroxycholesterol (25HC) inhibited proliferation and triggered oxidative stress in Swan 71 cells. • 25HC induced apoptosis by regulating the levels of p53, Bax, cleaved PARP, Bcl2, and caspase-3/7. • 25HC resulted in ferroptosis by elevating Fe2+ level and modulating the levels of NCOA4, FTH1, SLC7A11, and GPX4. • 25HC induced autophagy by increasing the levels of LAMP1 and LC3B-II and regulating the phosphorylation of AMPK and Akt. • Inhibition of apoptosis and ferroptosis partially alleviated 25HC-induced cell death. [ABSTRACT FROM AUTHOR]

Objective The balance of apoptosis and proliferation is an important part in the embryonic development during pregnancy. It has been reported that the p53 gene plays a significant role in angiogenesis and placental development, namely in reproduction and is suggested as a potential mediator of pregnancy. This study was performed to investigate whether the genetic polymorphism of the p53 gene is associated with idiopathic recurrent pregnancy loss (RPL). Study design We conducted a case–control study in the Korean population. Study subjects consisted of 294 patients with idiopathic RPL and 300 postmenopausal controls. The genotyping for the p53 codon 72 polymorphism was performed using a Taqman assay. Continuous variables were compared using Student's t test and the χ 2 test was used to evaluate differences in the genotype distributions between the RPL and the controls. Results There were no significant differences in the genotype distributions or allele frequencies of the p53 codon 72 polymorphism between the RPL and control group. There was also no significant association between the p53 codon 72 polymorphism and RPL risk in both recessive (Pro/Pro vs. Arg-carriers, p = 0.314) and dominant model (Pro-carriers vs. Arg/Arg, p = 0.383: data not shown). Conclusion The codon 72 polymorphism in the p53 gene did not show any correlation with idiopathic RPL in Korean women, implying that it may not be susceptible allelic variants or be insufficient to cause RPL. [ABSTRACT FROM AUTHOR]