IL-10 to TNF alpha ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses

Abstract Problem Embryo implantation and placentation require a careful immunological balance. Cytokines such as IL-10 and TNFα have been implicated as markers of dysregulation, but have only been studied at a single time point or after a pregnancy lost. Our objective was to determine normative patterns of serum levels of IL-10 and TNFα and their ratio throughout the first trimester in healthy pregnancies, and to determine if this pattern differs from pregnancy loss. Methods Two prospective longitudinal cohorts of gravidae including in vitro fertilization (IVF) and naturally conceived pregnancies with serial blood draws. Cytokines were assayed using SimplePlex. In the IVF cohort we monitored from the implantation day up to 6 weeks of gestation; whereas in the naturally conceived cohort, sample collection began at 4 weeks and throughout the whole first trimester. Results IL-10 concentrations in normal pregnancies were significantly higher than in pregnancies ending in a loss starting at 6-8 weeks of gestation while TNFα concentrations were significantly lower in normal than in pregnancies ending in a loss starting at 3-5 of gestation weeks. The IL-10 to TNFα ratio in normal pregnancies was significantly higher from 4 to 9 weeks compared to pregnancies that were lost (t-test, pPeer reviewe

Mirtazapine exposure in pregnancy and fetal safety:A nationwide cohort study

OBJECTIVE: To investigate the association between mirtazapine exposure in pregnancy and risk of specific adverse pregnancy outcomes. METHODS: A register‐based nationwide cohort study was conducted including all registered pregnancies in Denmark from 1997 to 2016. Mirtazapine‐exposed pregnancies were compared with mirtazapine unexposed pregnancies in a 1:4 ratio matched according to propensity scores. Outcomes were major congenital malformations analyzed using log binomial models, and spontaneous abortion, stillbirth and neonatal death analyzed using Cox proportional hazard regression. RESULTS: From a source population of 1,650,649 pregnancies, the propensity score‐matched cohort included 4475 pregnancies (895 mirtazapine exposed) in the analysis of major congenital malformations. The analyses of spontaneous abortion included 9 500 pregnancies (1900 mirtazapine exposed), and for the analyses of stillbirths and neonatal deaths 9725 (1 945 mirtazapine‐exposed) and 4485 pregnancies (897 mirtazapine‐exposed) were included, respectively. Thirty‐one (3.5%) children were diagnosed with major congenital malformation among the mirtazapine exposed compared with 152 (4.3%) among the unexposed pregnancies (OR=0.81, 95% CI 0.55–1.20). Spontaneous abortion occurred in 237 (12.5%) of the mirtazapine exposed compared with 931 (12.3%) of the unexposed pregnancies (HR = 1.04%, 95% CI 0.91–1.20). The analyses revealed no increased risk of stillbirth (HR = 0.88%, 95% CI 0.34–2.29) or neonatal death (HR = 0.60%, 95% CI 0.18–2.02). CONCLUSIONS: In this nationwide Danish register study, mirtazapine exposure in pregnancy was not associated with major congenital malformations, spontaneous abortion, stillbirth, or neonatal death. Clinicians and patients can be reassured that mirtazapine is safe in pregnancy

Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function

Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast-secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast-secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast-induced macrophages. Using in vitro models, we found that human trophoblast-educated macrophages were CD14(+)CD206(+)CD86(-) and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN-beta expression. IFN-beta further enhances the constitutive production of soluble programmed cell death ligand 1 (PD-L1) from trophoblast cells. PD-1 blockage inhibited trophoblast-induced macrophage differentiation. Soluble PD-L1 (sPD-L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN-beta promotes sPD-L1 expression/secretion by trophoblast cells, which can then initiate a PD-L1/PD-1-mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD-L1 by the trophoblasts through IFN-beta production induced through TLR4 ligation.Peer reviewe

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes