Maternal Systemic Inflammation Research Articles

Associations of inflammation related prenatal adversities with neurodevelopment of offspring in one year: a longitudinal prospective birth cohort study

BackgroundThe recent Maternal Immune Activation (MIA) theory suggests maternal systemic inflammation may serve as a mediator in associations between prenatal maternal adversities and neurodevelopmental diseases in offspring. Given the co-exposure to multiple adversities may be experienced by pregnant person, it is unclear whether a quantitative index can be developed to characterize the inflammation related exposure level, and whether this index is associated with neurodevelopmental delays in offspring.MethodsBased on Jiangsu Birth Cohort (JBC), a total of 3051 infants were included in the analysis. Inflammation related Prenatal Adversity Index (IPAI) was constructed using maternal data. Neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, third edition, screening test in one year. Multivariate linear regression and Poisson regression model were performed to analyze the associations between IPAI and neurodevelopment in offspring.ResultsCompared with “low IPAI” group, offspring with “high IPAI” have lower scores of cognition, receptive communication, expressive communication, and fine motor. The adjusted β were − 0.23 (95%CI: -0.42, -0.04), -0.47 (95%CI: -0.66, -0.28), -0.30 (95%CI: -0.49, -0.11), and − 0.20 (95%CI: -0.33, -0.06). Additionally, the elevated risk for noncompetent development of cognition and receptive communication among “high IPAI” group was observed. The relative risk [RR] and 95% confidence interval [CI] were 1.35 (1.01, 1.69) and 1.37 (1.09, 1.72).ConclusionsOur results revealed a significant association between higher IPAI and lower scores across cognition, receptive communication, expressive communication, and fine motor domains, and an increased risk of noncompetent development in the cognition and receptive communication domains.

Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation

Increasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks’ gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother–child pairs were recruited by 28 weeks’ gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks’ gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks’ gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the ‘modern wholefoods’ and ‘processed’ maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.

Gestational administration of Bifidobacterium dentium results in intergenerational modulation of inflammatory, metabolic, and social behavior

Prenatal stress (PNS) profoundly impacts maternal and offspring health, with enduring effects including microbiome alterations, neuroinflammation, and behavioral disturbances such as reductions in social behavior. Converging lines of evidence from preclinical and clinical studies suggest that PNS disrupts tryptophan (Trp) metabolic pathways and reduces gut Bifidobacteria, a known beneficial bacterial genus that metabolizes Trp. Specifically, previous work from our lab demonstrated that human prenatal mood disorders in mothers are associated with reduced Bifidobacterium dentium in infants at 13 months. Given that Bifidobacterium has been positively associated with neurodevelopmental and other health benefits and is depleted by PNS, we hypothesized that supplementing PNS-exposed pregnant dams with B. dentium would ameliorate PNS-induced health deficits. We measured inflammatory outputs, Trp metabolite levels and enzymatic gene expression in dams and fetal offspring, and social behavior in adult offspring. We determined that B. dentium reduced maternal systemic inflammation and fetal offspring neuroinflammation, while modulating tryptophan metabolism and increasing kynurenic acid and indole-3-propionic acid intergenerationally. Additional health benefits were demonstrated by the abrogation of PNS-induced reductions in litter weight. Finally, offspring of the B. dentium cohort demonstrated increased sociability in males primarily and increased social novelty primarily in females. Together these data illustrate that B. dentium can orchestrate interrelated host immune, metabolic and behavioral outcomes during and after gestation for both dam and offspring and may be a candidate for prevention of the negative sequelae of stress.

A Narrative Review on the Pathophysiology of Preeclampsia.

Preeclampsia (PE) is a multifactorial pregnancy disorder characterized by hypertension and proteinuria, posing significant risks to both maternal and fetal health. Despite extensive research, its complex pathophysiology remains incompletely understood. This narrative review aims to elucidate the intricate mechanisms contributing to PE, focusing on abnormal placentation, maternal systemic response, oxidative stress, inflammation, and genetic and epigenetic factors. This review synthesizes findings from recent studies, clinical trials, and meta-analyses, highlighting key molecular and cellular pathways involved in PE. The review integrates data on oxidative stress biomarkers, angiogenic factors, immune interactions, and mitochondrial dysfunction. PE is initiated by poor placentation due to inadequate trophoblast invasion and improper spiral artery remodeling, leading to placental hypoxia. This triggers the release of anti-angiogenic factors such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), causing widespread endothelial dysfunction and systemic inflammation. Oxidative stress, mitochondrial abnormalities, and immune dysregulation further exacerbate the condition. Genetic and epigenetic modifications, including polymorphisms in the Fms-like tyrosine kinase 1 (FLT1) gene and altered microRNA (miRNA) expression, play critical roles. Emerging therapeutic strategies targeting oxidative stress, inflammation, angiogenesis, and specific molecular pathways like the heme oxygenase-1/carbon monoxide (HO-1/CO) and cystathionine gamma-lyase/hydrogen sulfide (CSE/H2S) pathways show promise in mitigating preeclampsia's effects. PE is a complex disorder with multifactorial origins involving abnormal placentation, endothelial dysfunction, systemic inflammation, and oxidative stress. Despite advances in understanding its pathophysiology, effective prevention and treatment strategies remain limited. Continued research is essential to develop targeted therapies that can improve outcomes for both mothers and their babies.

Implication of viruses in the etiology of preeclampsia.

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

Synergy between Iron Deficiency and Inflammation Adversely Affects Pregnancy

Iron is essential for maternal and fetal health during pregnancy. In many developing countries, nutritional deficiencies are common, with anemia affecting upwards of 60% of pregnancies. In addition, infection and inflammation, which are known to be detrimental to pregnancy, are also very prevalent in these regions. Even in high-resource countries, approximately 22% of pregnant women are anemic, and obesity and diabetes are common causes of maternal inflammation. Thus, iron deficiency and inflammation commonly co-exist. In our studies, we noted in mice a striking synergistic adverse interaction between maternal iron deficiency and inflammation that resulted in embryotoxicity, not observed in either condition alone. Considering the high global prevalence of concomitant iron deficiency and inflammation in pregnant women, the issue has outstanding translational importance. We induced iron deficiency in mice by feeding females an iron-poor diet (4ppm) for 1-3 weeks prior to mating and for the duration of pregnancy. This resulted in development of iron deficiency and anemia in both mothers and embryos by term [embryonic day (E)18.5] and placental iron concentrations decreased by half, compared to pregnancies fed control diet (100ppm iron). To model acute systemic maternal inflammation, pregnant females received a single moderate dose of LPS (E. coli serotype O55:B5, 0.5μg/g bodyweight subcutaneously), either in the “2nd” (E8.5) or “3rd” (E15.5) trimester. Embryos and placentas from the E8.5 LPS treatment were collected at E18.5, while those from the E15.5 LPS treatment were collected after 24h. Consistent with other reports, LPS injection alone resulted in some adverse pregnancy outcomes: injection on E8.5 in iron replete dams caused abortion in 22% of dams (total n=9 dams) and at E15.5 caused preterm birth in 50% of dams (n=8) but no embryo malformations or resorption were noted. In contrast, when pregnant dams were both iron-depleted and LPS-injected, we observed a striking synergistic effect resulting in embryo death and resorption in all E8.5 treated pregnancies (n=3 dams). In E15.5-treated pregnancies, 60% of embryos were dead and resorbing (n=42 embryos from 5 dams). This dramatic interaction between iron deficiency and inflammation has not been reported previously. Our data suggest the mechanism appears to be, at least in part, related to activation of the TNFα/TNF-R1 pathway and apoptosis of placental endothelial cells. To test the contribution of the TNFα/TNF-R1 pathway to adverse synergy between iron deficiency and inflammation, we generated endothelial TNF-R1 knockout (KO) mice using two different Cre drivers ( Tnfsfr1 f/f;VEC-Cre + or Tnfsfr1 f/f;Tie2-Cre +). Tnfsfr1 f/f and KO females were iron-depleted and mated with Tnfsfr1 f/fmales. Pregnant dams received a single subcutaneous dose of LPS at E15.5 and pregnancy outcomes were assessed after 24h. Embryos from KO dams were protected from LPS-induced embryotoxicity (30% death, n=7 dams) compared to embryos from WT dams (70% death, n=3 dams). Surprisingly, embryo genotype did not play a role in adverse synergy. Our data suggest that maternal TNFR signaling facilitates adverse interactions between iron deficiency and inflammation during pregnancy, which results in embryo death. These studies are ongoing and our results could provide a mechanistic explanation for known adverse outcomes in complicated human pregnancies, and eventually help inform interventions to optimize outcomes in such pregnancies

Dieta proinflamatoria en el embarazo y resultado perinatal adverso: revisión sistemática de literatura

Pregnancy involves a state of mild maternal systemic inflammation, in which the placenta produces a variety of immunomodulatory hormones and pro-inflammatory cytokines. In contrast, many secondary metabolites from food are capable of providing some anti-inflammatory activity, thus promoting homeostasis. In order to find out the relationship between the pro-inflammatory diet and the adverse perinatal outcome, the present systematic review was carried out, in which 7 studies were included following the method recommended in the Cochrane guidelines. As main result, some association was found between the inflammatory index of the diet and C-reactive protein in the second trimester, low birth weight or newborns small for gestational age and lack of statistically significant association with preeclampsia, gestational diabetes or preterm delivery. The need to expand the studies is concluded to better understand the metabolic processes intrinsic to proinflammatory eating behaviors.

6.54 The Role of Postpartum Moderate Maternal Alcohol Use on Maternal Systemic Inflammation and Child Negative Affectivity

6.54 The Role of Postpartum Moderate Maternal Alcohol Use on Maternal Systemic Inflammation and Child Negative Affectivity

Prenatal environmental adversity and child neurodevelopmental delay: the role of maternal low-grade systemic inflammation and maternal anti-inflammatory diet.

Maternal inflammation has been proposed as a possible pathway connecting prenatal environmental adversity (PEA), which includes maternal overweightness or obesity, diabetes, hypertensive disorders, and mood or anxiety disorders, to child neurodevelopmental delay. However, effective preventive measures have not yet been reported. Herein, we aimed to investigate whether a maternal anti-inflammatory diet reduced the risk of PEA-induced neurodevelopmental delay, by inhibiting inflammation. This prospective study included 7438 mother-child pairs. Maternal overweightness or obesity, diabetes, and hypertensive disorders were diagnosed before 28week gestation. Maternal depression disorders were identified using the Edinburgh postnatal depression survey (EPDS) during mid-pregnancy. During mid- and late pregnancy, maternal high-sensitivity C-reactive protein (hs-CRP) levels were measured to evaluate systemic inflammation. The inflammatory potential of the diet was evaluated using the food-based empirical dietary inflammatory pattern (EDIP) score during mid-pregnancy. Pregnant women were classified into high- or low-score groups based on the median EDIP score. The outcomes of neurodevelopmental delay at 6-36month postpartum were extracted from the Register of Child Healthcare. Among the 7438 mother-child pairs, 2937 (39.5%) were exposed to PEA, and neurodevelopmental delay occurred in 540 (7.3%). Children exposed to PEA had a higher risk of neurodevelopmental delay than those not exposed. PEA exposure was associated with increased hs-CRP during pregnancy in a PEA monotonic manner, an interquartile range increase in hs-CRP in mid- and late pregnancy was associated with an increased risk of child neurodevelopmental delay. Higher maternal persistent inflammation partially mediated the effect of PEA exposure on child neurodevelopmental delay by 17.19%. An increased risk of PEA-related neurodevelopmental delay was observed only in the children of mothers with high-EDIP rather than low-EDIP. These results suggest that increased systemic inflammation through mid- and late pregnancy mediates the association between PEA and child neurodevelopmental delay. A maternal anti-inflammatory diet may improve PEA-induced neurodevelopmental delay, by inhibiting inflammation.

Mediators of the association between maternal body mass index and breastfeeding duration in 3 international cohorts

BackgroundMaternal obesity has been associated with shorter breastfeeding duration, but little is known about mediating factors explaining this association. It is important to assess these relationships across diverse populations because breastfeeding is culturally patterned. ObjectivesWe investigated the association of prepregnancy maternal body mass index (BMI) with breastfeeding outcomes and potential mediators of this relationship in 3 culturally diverse international cohorts. MethodsWe analyzed 5120 singleton pregnancies from mother–child cohorts in Spain (INfancia y Medio Ambiente), Greece (Rhea), and the United States (Project Viva). Outcome variables were duration of any and exclusive breastfeeding. A priori hypothesized mediators in the association of maternal prepregnancy BMI with breastfeeding were birthweight (BW), maternal prenatal C-reactive protein (CRP), cesarean delivery, maternal dietary inflammatory index (DII) during pregnancy, gestational age at delivery, and gestational diabetes mellitus (GDM). We estimated the association between BMI and breastfeeding duration using linear regression adjusting for confounders. Mediation analysis estimated direct and indirect effects of maternal overweight/obesity on breastfeeding for each mediator. ResultsWomen with overweight and obesity had shorter duration of any and exclusive breastfeeding compared with normal-weight women (any: overweight β = −0.79 mo, 95% CI: −1.17, −0.40; obese β = −1.75 mo 95% CI: −2.25, −1.25; exclusive: overweight β = −0.30 mo, 95% CI: −0.42, −0.16; obese β = −0.73 mo, 95% CI: −0.90, −0.55). Significant mediators (% change in effect estimate) of this association were higher CRP (exclusive: 5.12%), cesarean delivery (any: 6.54%; exclusive: 7.69%), and higher DII (any: 6.48%; exclusive: 7.69%). GDM, gestational age, and BW did not mediate the association of maternal weight status with breastfeeding. ConclusionsHigher prepregnancy BMI is associated with shorter duration of any and exclusive breastfeeding. Maternal dietary inflammation, systemic inflammation, and mode of delivery may be key modifiable mediators of this association. Identification of mediators provides potential targets for interventions to improve breastfeeding outcomes.

The fetal response to maternal inflammation is dependent upon maternal IL-6 in a murine model

BackgroundThe induction of maternal inflammation in mice leads to fetal injury that is believed to be IL-6 dependent. The fetal inflammatory response, defined by elevated fetal or amniotic fluid IL-6, has been described as a potential mechanism for subsequent fetal injury. The role of maternal IL-6 production and signaling in the fetal IL-6 response is currently unclear. MethodsGenetic and anti-IL-6 antibody strategies were used to systematically block the maternal IL-6 response during inflammation. Chorioamnionitis was induced using intraperitoneal injection of lipopolysaccharide (LPS) at mid gestation (E14.5) and late gestation (E18.5). This model was used in pregnant C57Bl/6 dams, IL6-/- dams, C57Bl/6 dams treated with anti-IL-6 (blocks both classical and trans-signaling) or anti-gp130 antibodies (blocks trans-signaling only) and IL6+/− dams. Six hours following LPS injection, maternal serum, placental tissue, amniotic fluid and fetal tissue or serum were collected. A bead-based multiplex assay was used to evaluate levels of IL-6, KC, IL-1β, TNF, IL-10, IL-22, IFN-γ, IL-13 and IL-17A. ResultsChorioamnionitis in C57Bl/6 dams was characterized by elevated maternal serum levels of IL-6, KC and IL-22 with litter loss during mid gestation. The fetal response to maternal inflammation in C57Bl/6 mice was primarily characterized by elevated levels of IL-6, KC and IL-22 in the placenta, amniotic fluid and fetus during both mid and late gestation. A global IL-6 knockout (IL6-/-) eradicated the maternal, placental, amniotic fluid and fetal IL-6 response to LPS during mid and late gestation and improved litter survival, while minimally influencing the KC or IL-22 responses. Blocking maternal classical IL-6 signaling in C57Bl/6 dams at the time of LPS exposure diminished the maternal, placental, amniotic fluid and fetal IL-6 response during mid and late gestation, while blocking maternal IL-6 trans-signaling only affected fetal IL-6 expression. To evaluate whether maternal IL-6 was crossing the placenta and reaching the fetus, IL-6+/− dams were utilized in the chorioamnionitis model. IL-6+/− dams mounted a systemic inflammatory response following injection with LPS, characterized by elevated IL-6, KC and IL-22. IL-6-/- pups born to IL6+/− dams had decreased amniotic fluid levels of IL-6 and undetectable levels of fetal IL-6 compared to IL-6+/+ littermate controls. ConclusionThe fetal response to systemic maternal inflammation is dependent upon maternal IL-6 signaling, but maternal IL-6 is not crossing the placenta and reaching the fetus at detectable levels.

Phenotypic and functional alteration of CD45+ immune cells in the decidua of preeclampsia patients analyzed by mass cytometry (CyTOF).

Preeclampsia (PE) is a severe placenta-related pregnancy disease that has been associated with maternal systemic inflammation and immune system disorders. However, the distribution and functional changes in immune cells of the maternal-placental interface have not been well characterized. Herein, cytometry by time-of-flight mass spectrometry (CyTOF) was used to investigate the immune atlas at the decidua, which was obtained from four PE patients and four healthy controls. Six superclusters were identified, namely, T cells, B cells, natural killer (NK) cells, monocytes, granulocytes, and others. B cells were significantly decreased in the PE group, among which the reduction in CD27+CD38+ regulatory B cell (Breg)-like cells may stimulate immune activation in PE. The significantly increased migration of B cells could be linked to the significantly overexpressed chemokine C-X-C receptor 5 (CXCR5) in the PE group, which may result in the production of excessive autoantibodies and the pathogenesis of PE. A subset of T cells, CD11c+CD8+ T cells, was significantly decreased in PE and might lead to sustained immune activation in PE patients. NK cells were ultimately separated into four subsets. The significant reduction in a novel subset of NK cells (CD56-CD49a-CD38+) in PE might have led to the failure to suppress inflammation at the maternal-fetal interface during PE progression. Moreover, the expression levels of functional markers were significantly altered in the PE group, which also inferred that shifts in the decidual immune state contributed to the development of PE and might serve as potential treatment targets. This is a worthy attempt to elaborate the differences in the phenotype and function of CD45+ immune cells in the decidua between PE and healthy pregnancies by CyTOF, which contributes to understand the pathogenesis of PE, and the altered cell subsets and markers may inspire the immune modulatory therapy for PE.

Maternal behaviours and adult offspring behavioural deficits are predicted by maternal TNFα concentration in a rat model of neurodevelopmental disorders

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.

Fetal and maternal NLRP3 signaling is required for preterm labor and birth.

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and -sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.

Human leukocyte antigen HLA-C, HLA-G, HLA-F, and HLA-E placental profiles are altered in early severe preeclampsia and preterm birth with chorioamnionitis

The extravillous trophoblast expresses each of the nonclassical major histocompatibility complex class I antigens-human leukocyte antigens E, F, and G-and a single classical class I antigen, human leukocyte antigen C. We recently demonstrated dynamic expression patterns of human leukocyte antigens C, G, and F during early extravillous trophoblast invasion and placentation. This study aimed to investigate the hypothesis that the immune inflammatory mediated complications of pregnancy such as early preeclampsia and preterm labor may show altered expression profiles of nonclassical human leukocyte antigens. Real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry were performed on placental villous tissues and basal plate sections from term nonlaboring deliveries, preterm deliveries, and severe early-onset preeclampsia, both with and without small-for-gestational-age neonates. Human leukocyte antigen G is strongly and exclusively expressed by the extravillous trophoblast within the placental basal plate, and its levels increase in pregnancies complicated by severe early-onset preeclampsia with small-for-gestational-age neonates relative to those of healthy term controls. Human leukocyte antigen C shows a similar profile in the extravillous trophoblast of preeclamptic pregnancies, but significantly decreases in the villous placenta. Human leukocyte antigen F protein levels are decreased in both extravillous trophoblast and villous placenta of severe early-onset preeclamptic pregnancies, both with and without small-for-gestational-age neonates, compared with those found in term and preterm birth deliveries. Human leukocyte antigen E decreases in blood vessels in placentas from preeclamptic pregnancies relative to its levels in term and preterm birth deliveries. Placental levels of human leukocyte antigens F and C are increased in cases of preterm birth with chorioamnionitis relative to those of cases of idiopathic preterm birth. Dysregulation of placental human leukocyte antigen expression at the maternal-fetal interface may contribute to compromised maternal tolerance in preterm birth with chorioamnionitis and excessive maternal systemic inflammation associated with severe early-onset preeclampsia.

Prepregnancy body mass index, gestational weight gain, and maternal prepartum inflammation in normal pregnancies: findings from a Chinese cohort

BackgroundObesity has been linked to systemic inflammation in population studies.ObjectiveTo examine the associations of prepregnancy body mass index (pBMI) and total gestational weight gain (tGWG) with maternal prepartum low-grade inflammation (LGI) and clinically significant inflammation (CSI) defined by serum C-reactive protein (CRP) concentration.MethodsFive thousand four hundred seventy-six Chinese women with uncomplicated pregnancies and recorded data on pBMI and prepartum body weight were included in this study. Blood samples were drawn before delivery for high-sensitivity CRP assay. Inadequate, optimal, and excessive tGWG were defined using the Institute of Medicine's recommendation. Multivariable Poisson regressions were used to estimate relative risks (RRs) for having prepartum LGI and CSI (defined as CRP concentration 3–10 and > 10 mg/L, respectively) across pBMI and tGWG categories.ResultsThe mean pBMI, mean tGWG, and median maternal prepartum CRP concentration were 20.4 kg/m2, 13.9 kg, and 3.3 mg/L, respectively. The prevalence of prepartum CSI and LGI was 7.2% and 47.8%. The adjusted RRs (95% confidence interval) of CSI for normal (18.5–24.9 kg/m2) and high (≥ 25 kg/m2) vs. low pBMI (< 18.5 kg/m2) were 1.35 (1.05–1.74) and 2.28 (1.53–3.39), respectively. The respective adjusted RRs of LGI were 1.19 (1.11–1.28) and 1.59 (1.42–1.77). The adjusted RRs for excessive vs. optimal tGWG was 1.18 (0.94–1.48) for CSI and 1.14 (1.07–1.21) for LGI.ConclusionsPrepregnancy overweight/obesity and excessive tGWG increase the risk of maternal prepartum systemic inflammation, which further highlights the importance of weight management before and during pregnancy.

257 Primary cilia in placental mesenchymal stem/stromal cells: Implication in placental development and preeclampsia

Introduction and aims of the study: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including placental mesenchymal stem/stromal cells (pMSCs). Defective pMSCs have been reported in preeclampsia (PE), a gestational hypertensive disease, characterized by maternal endothelial dysfunction and systemic inflammation. We were interested if pMSCs are ciliated and if altered ciliation is responsible for defective pMSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, important for various cellular activities.

Molecular and Physiological Aspects of SARS-CoV-2 Infection in Women and Pregnancy.

Whilst scientific knowledge about SARS-CoV-2 and COVID-19 is rapidly increasing, much of the effects on pregnant women is still unknown. To accommodate pregnancy, the human endometrium must undergo a physiological transformation called decidualization. These changes encompass the remodeling of endometrial immune cells leading to immunotolerance of the semi-allogenic conceptus as well as defense against pathogens. The angiotensin converting enzyme 2 (ACE2) plays an important regulatory role in the renin-angiotensin-system (RAS) and has been shown to be protective against comorbidities known to worsen COVID-19 outcomes. Furthermore, ACE2 is also crucial for decidualization and thus for early gestation. An astounding gender difference has been found in COVID-19 with male patients presenting with more severe cases and higher mortality rates. This could be attributed to differences in sex chromosomes, hormone levels and behavior patterns. Despite profound changes in the female body during pregnancy, expectant mothers do not face worse outcomes compared with non-pregnant women. Whereas mother-to-child transmission through respiratory droplets during labor or in the postnatal period is known, another question of in utero transmission remains unanswered. Evidence of placental SARS-CoV-2 infection and expression of viral entry receptors at the maternal-fetal interface suggests the possibility of in utero transmission. SARS-CoV-2 can cause further harm through placental damage, maternal systemic inflammation, and hindered access to health care during the pandemic. More research on the effects of COVID-19 during early pregnancy as well as vaccination and treatment options for gravid patients is urgently needed.

Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia

BackgroundThe development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities.MethodsIn the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student’s t test (two-tailed and paired or homoscedastic) or an unpaired Mann–Whitney U test (two-tailed).ResultsThe results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs’ proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation.ConclusionsThese data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.

Murine Double Hit Model for Neonatal Cardiopulmonary Diseases: Bronchopulmonary Dysplasia (BPD) and Pulmonary Hypertension Associated with BPD.

Bronchopulmonary dysplasia (BPD) and pulmonary hypertension associated with BPD (BPD-PH) are of multifactorial origin and share common risk factors. Most murine models of BPD expose newborn pups to only one of these risk factors-more commonly postnatal hyperoxia-thereby mimicking the vital increased fraction of inspired oxygen (FiO2) that preterm infants in neonatal intensive care units often require. To improve representation of the multifactorial origins of BPD and BPD-PH, we established a double hit model, combining antenatal systemic inflammation followed by postnatal hyperoxia. On embryonic day 14, pups are exposed to systemic maternal inflammation via a single intraperitoneal injection of 150 µg/kg of lipopolysaccharide to the dam. Within 24 h after birth, pups and dams are randomized and exposed to gas with either an FiO2 of 0.21 (room air) or 0.65 (hyperoxia 65%). In our BPD and BPD-PH double hit model, we can obtain multiple readouts from individual pups that include echocardiography, lung histology and immunohistochemistry, ex vivo X-ray micro computed tomography, and pulmonary and plasmatic immunity by RNA, protein, or flow cytometry. This protocol was validated in: Sci Transl Med (2022), DOI: 10.1126/scitranslmed.aaz8454 Graphical abstract Figure 1. Murine double hit model of cardiopulmonary disease. On embryonic day (E)14, pups are exposed to systemic maternal inflammation via a single intraperitoneal injection of 150 µg/kg lipopolysaccharide to the dam. Within 24 h after birth, pups and dams are randomized to be exposed to gas with either a fraction of inspired oxygen (FiO 2 ) of 0.21 (air; 21% O 2 ) or 0.65 (hyperoxia; 65% O 2 ) for a maximum of 28 days. According to the murine stage of lung development ( Schittny, 2017 ), experimental endpoints include postnatal day (D)3, D5, D14, D28, and D60.