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Opioid use during pregnancy continues to rise at alarming rates with a parallel trend in the number of infants and children exposed to opioid medications each year. Prenatal opioid exposure (POE) occurs at a critical timepoint in neurodevelopment disrupting intricate pathways essential for neural-immune maturation with the potential for devastating long-term consequences. Understanding the mechanisms underlying injury associated with POE is essential to address long-term outcomes and identify diagnostic and therapeutic biomarkers in this vulnerable patient population. Using an established preclinical model of POE, we investigated changes in cerebral and peripheral inflammation and peripheral blood mononuclear cell (PBMC) activity. We hypothesized that neuroinflammation, as defined by changes in specific cerebral immune cell populations, would exist in adult rats following POE concomitant with sustained peripheral immune hyperreactivity (SPIHR). Our data demonstrated alterations in cerebral immune cells at postnatal day 60 (P60) typified by increased regulatory T cells (p < 0.01) and neutrophils (p < 0.05) in rats with POE compared to controls. Evaluation of serum revealed increased levels of IL-6 (p < 0.05) and CXCL1 (p < 0.05) at P21 in rats with POE compared to controls with no significant difference in cytokine or chemokine levels between the two groups at P60. Additionally, PBMCs isolated from rats with POE at P21 demonstrated baseline hypersecretion of IL-6 (p < 0.01) and SPIHR with increased levels of TNF-α (p < 0.05) and CXCL1 (p < 0.05) following stimulation with LPS. At P60, however, there was no significant difference found in cytokine or chemokine levels secreted by PBMCs isolated from rats with POE at baseline or with LPS stimulation when compared to controls. Taken together, these data demonstrate cerebral inflammation months after prenatal opioid exposure and long after the resolution of systemic inflammation and SPIHR seen at toddler age equivalent. Chronic alterations in the cerebral immune cell populations secondary to prenatal opioid exposure may underly long-term consequences of developmental brain injury including deficits in cognition and attention. These findings may be invaluable to further investigations of precise biomarkers of injury and targeted therapeutics for this vulnerable population.

Immunoperinatology is an emerging field. Transdisciplinary efforts by physicians, physician-scientists, basic science researchers, and computational biologists have made substantial advancements by identifying unique immunologic signatures of specific diseases, discovering innovative preventative or treatment strategies, and establishing foundations for individualized neonatal intensive care of the most vulnerable neonates. In this review, we summarize the immunobiology and immunopathology of pregnancy, highlight omics approaches to study the maternal-fetal interface, and their contributions to pregnancy health. We examined the importance of transdisciplinary, multiomic (such as genomics, transcriptomics, proteomics, metabolomics, and immunomics) and machine-learning strategies in unraveling the mechanisms of adverse pregnancy, neonatal, and childhood outcomes and how they can guide the development of novel therapies to improve maternal and neonatal health. IMPACT: Discuss immunoperinatology research from the lens of omics and machine-learning approaches. Identify opportunities for omics-based approaches to delineate infection/inflammation-associated maternal, neonatal, and later life adverse outcomes (e.g., histologic chorioamnionitis [HCA]).

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44+, Sca-1+, CD45−, CD34−, CD11b−, and CD11c− by flow cytometry and sorted by fluorescence-activated cell sorting (FACS). Dams were assigned to four groups: phosphate-buffered saline (PBS) + PBS, PBS + BMMSCs, lipopolysaccharide (LPS) + PBS, and LPS + BMMSCs. Following maternal IUI, there was a significant increase in CD8+ T cells in the placentas. Maternally administered BMMSCs trafficked to the fetal side of the placenta and resulted in significantly decreased placental CD8+ T cells. Furthermore, fetal trafficking of maternally administered BMMSCs correlated with an improved performance on offspring neurobehavioral testing in LPS + BMMSC group compared with LPS + PBS group. Our data support that maternal administration of BMMSCs can alleviate perinatal inflammation-induced brain injury and improve neurobehavioral outcomes in the offspring via CD8+ T cell immunomodulation at the feto-placental interface.

Heme oxygenase-1 (HO-1) is an evolutionarily conserved stress response enzyme and important in pregnancy maintenance, fetal and neonatal outcomes, and a variety of pathologic conditions. Here, we investigated the effects of an exposure to systemic inflammation late in gestation [embryonic day (E)15.5] on wild-type (Wt) and HO-1 heterozygous (Het, HO-1+/-) mothers, fetuses, and offspring. We show that alterations in fetal liver and spleen HO homeostasis during inflammation late in gestation can lead to a sustained dysregulation of innate immune cell populations and intracellular myeloid HO-1 expression in the spleen through young adolescence [postnatal day 25] in mice.

Perinatal brain injury may lead to long-term morbidity and neurodevelopmental impairment. Improvements in perinatal care have resulted in the survival of more infants with perinatal brain injury. The effects of hypoxia-ischemia, inflammation, and infection during critical periods of development can lead to a common pathway of perinatal brain injury marked by neuronal excitotoxicity, cellular apoptosis, and microglial activation. Various interventions can prevent or improve the outcomes of different types of perinatal brain injury. The objective of this article is to review the mechanisms of perinatal brain injury, approaches to prevention, and outcomes among children with perinatal brain injury.

Chorioamnionitis (CHORIO), placental insufficiency, and preterm birth are well-known antecedents of perinatal brain injury (PBI). Heme-oxygenase-1 (HO-1) is an important inducible enzyme in oxidative and inflammatory conditions. In the brain, HO-1 and the iron regulatory receptor, transferrin receptor-1 (TfR1), are known to be involved in iron homeostasis, oxidative stress, and cellular adaptive mechanisms. However, the role of HO pathway in the pathophysiology of PBI has not been previously studied. In this study, we set out to define the ontogeny of the HO pathway in the brain and determine if CHORIO changed its normal developmental regulation. We also aimed to determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation in a clinically relevant rat model of PBI. We show that HO-1, HO-2, and TfR1 expression are developmentally regulated in the brain during the perinatal period. CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early postnatal period and results in sustained increase in HO-1/TfR1 ratios in the brain. This is associated with neuroinflammatory and peripheral immune phenotype supported by a significant increase in brain mononuclear cells and peripheral blood double negative T cells suggesting a role of HO-1/TfR1 pathway dysregulation in CHORIO-induced neuroinflammation.

Melatonin has been shown to reduce oxidative stress and mitigate hypercoagulability. We hypothesized that maternally administered melatonin may reduce placental oxidative stress and hypercoagulability associated with exposure to intrauterine inflammation (IUI) and consequently improve fetoplacental blood flow and fetal sequelae. Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. The systolic/diastolic ratio, resistance index, and pulsatility index in uterine artery (UtA) and umbilical artery (UA) were significantly increased in L compared with other groups when analyzed by Doppler ultrasonography. The expression of antioxidant mediators in the placenta was significantly decreased, while that of pro-inflammatory mediators was significantly increased in L compared to C and ML. Vascular endothelial damage and thrombi formation, as evidenced by fibrin deposits, were similarly increased in L compared to other groups. Maternal pretreatment with melatonin appears to modulate maternal placental malperfusion, fetal cardiovascular compromise, and fetal neuroinflammation induced by IUI through its antioxidant properties.

The objective of this study was to determine if mouse bone marrow-derived mesenchymal stem cells (BMMSCs) ameliorate preterm birth and perinatal brain injury induced by intrauterine inflammation (IUI). A mouse model of IUI-induced perinatal brain injury at embryonic (E) day 17 was utilized. BMMSCs were derived from GFP-transgenic mice and phenotypically confirmed to be CD44

Exposure to intrauterine inflammation (IUI) is associated with short- and long-term adverse perinatal outcomes. However, little data exist on utilizing placenta to prognosticate fetal injury in this scenario. Our study aimed to utilize imaging modalities to evaluate mechanisms contributing to placental injury following IUI exposure and correlated it to concomitant fetal brain injury. CD1 pregnant dams underwent laparotomies and received intrauterine injections of either lipopolysaccharide (LPS; a model of IUI) or phosphate-buffered saline (PBS). In utero ultrasound Doppler velocimetry of uterine and umbilical arteries and magnetic resonance imaging (MRI) of placental volumes with confirmatory immunohistochemical (vimentin) and histochemistry (fibrin) analyses were performed. ELISA for thrombosis markers, fibrinogen and fibrin was performed to analyze thrombi in placenta. Fetal brain immunohistochemistry was performed to detect microglial activation (ionized calcium-binding adaptor molecule 1, Iba1). On ultrasound, LPS group demonstrated elevated resistance indices, pulsatility indices and a greater occurrence of absent end-diastolic flow in the umbilical and uterine arteries. In the fetus, there was an increased cardiac Tei indices in the LPS group. MRI revealed decreased volume of placenta in the LPS group associated with placental thinning and placental endothelial damage on immunohistochemistry. Decreased fibrinogen content and more thrombi staining in placenta exposed to maternal LPS indicated the hypercoagulability. Furthermore, the expression of Iba1was significantly associated with placental thickness (r = -0.7890, Pearson correlation coefficient). Our data indicate that IUI can trigger events leading to maternal placental malperfusion and fetal vessel resistance, as well as predispose the developing fetus to cardiac dysfunction and brain damage. Furthermore, our data suggest that prenatal ultrasound can be a real-time clinical tool for assessing fetal risk for adverse neurologic outcomes following the potential IUI exposure.

Introduction: Magnesium sulfate (MgSO4) is utilized for fetal neuroprotection in preterm birth but its mechanism of action is still poorly understood. P2X7 receptor (P2X7R) is required for secretion of IL-1β, and can be blocked by divalent cations such as magnesium (Mg) and its own antagonist, Brilliant Blue G (BBG). We sought to determine, whether during inflammation MgSO4 can block endothelial IL-1β secretion, using an in-vitro model. Methods: Human umbilical vein endothelial cell (HUVEC) cultures were treated with varying doses of LPS, 2’(3)-O-(4-Benzoylbenzoyl) adenosine-5’-triphosphate (BzATP), BBG and MgSO4 for 3- or 24-hours. We determined cell cytotoxicity, apoptosis, IL-1β mRNA expression, IL-1β production and secretion and P2X7R expression on HUVECs. Results: We demonstrated that MgSO4 is efficacious in blocking IL-1β-mediated-inflammation in HUVECs, at both the initiation and propagation phases of inflammation. MgSO4 exerts these anti-inflammatory effects via downregulation of P2X7Rs on HUVECs. Conclusion: LPS-exposure increases IL-1β production and secretion in HUVECs, which is further intensified by P2X7R agonist, BzATP while MgSO4 inhibits IL-1β in both presence and absence of BzATP. This effect is similar to the results of P2X7R antagonist, BBG, suggesting that the anti-inflammatory effects of MgSO4is through P2X7R.

Interleukin-1 beta (IL-1β) is a cytokine mediator of perinatal brain injury. The effect of sub-chronic systemic IL-1β exposure in perinatal and offspring outcomes is unclear. The aim of this study was to examine the effects of maternal IL-1β exposure on pregnancy and offspring outcomes. At E15, CD1 dams were allocated to receive intraperitoneal injection of phosphate buffered saline or mouse recombinant IL-1β (1 mcg) for four consecutive days. We analyzed pup survivaland neurobehavioral status. At E18, placental HE staining and fetal brain Nissl staining was performed. Placental gene expression was analyzed by qPCR and T cell infiltration was analyzed by flow cytometry. Effects of inflammation on feto-placental blood flow were analyzed by Doppler ultrasonography. IL-1β decreased pup survival (P .0001) and adversely affected offspring performance on neurodevelopmental tests (P .05). Placentas of exposed dams exhibited significant thinning of maternal and fetal sides, and fetal brain exhibited cortical thinning. Placental qPCR analysis revealed significant upregulation of NFκB2 (P = .0021) and CXCL11 (P = .0401). While maternal IL-1β exposure did not affect feto-placental blood flow, placental flow cytometry showed an increase in placental infiltration of CD4

Perinatal brain injury may lead to long-term morbidity and neurodevelopmental impairment. Improvements in perinatal care have resulted in the survival of more infants with perinatal brain injury. The effects of hypoxia-ischemia, inflammation, and infection during critical periods of development can lead to a common pathway of perinatal brain injury marked by neuronal excitotoxicity, cellular apoptosis, and microglial activation. Various interventions can prevent or improve the outcomes of different types of perinatal brain injury. The objective of this article is to review the mechanisms of perinatal brain injury, approaches to prevention, and outcomes among children with perinatal brain injury.

Objective Hypoxic-ischemic encephalopathy (HIE) may be associated with intrapartum sentinel events or may be unexplained. We sought to identify risk factors for unexplained HIE cases and compare their morbidity and mortality to cases associated with sentinel events. Study Design Retrospective cohort study of all neonates admitted with suspected HIE treated with whole-body hypothermia from January 2007 through July 2017. Cases of unexplained HIE were compared with those with a sentinel event. Results A total of 223 neonates met the inclusion criteria, of which 86 (38.6%) experienced a sentinel event and 137 (61.4%) did not. Placental histopathology was performed for 28/31 (90.3%) and 48/53 (90.6%) inborn neonates with and without sentinel events, respectively. Placentas from unexplained HIE cases more often exhibited histologic chorioamnionitis (43.8% vs. 17.9%, p = 0.02) and funisitis (25% vs. 3.6%, p = 0.02). Neonatal morbidity and mortality were similar. On multivariable regression, nulliparity (odds ratio [OR], 4.11, 95% confidence interval [CI]: 1.24–13.62) and histologic funisitis (OR, 20.33, 95% CI: 1.11–373.4) remained significant. Conclusion Other than nulliparity and infection which could be identified on umbilical cord examination following delivery but not on clinical assessment prior to delivery, there are no other identifiable risk factors for HIE in the absence of a sentinel event, and morbidity and mortality are similar between groups.

PROBLEM: We investigated the mechanisms by which CD8(+) T cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8(+) T cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). METHOD OF STUDY: Maternal CD8(+) T cells were depleted with anti-CD8(+) antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan(®) gene assays, and neurobehavioral tests. RESULTS: DEP did not significantly prevent LPS-induced preterm birth, but improved neurobehavioral performance (p

We aimed to compare clinical presentation and risk factors associated with the development of pneumothorax among newborns of different birth weight (BW) categories.We collected clinical and respiratory data on all newborns diagnosed with pneumothorax over a 10-year period. Infants were classified into two groups with BW ≥ 2500 g and2500 g.From 13,811 infants, we identified 77 with pneumothorax (BW ≥ 2500 g in 33 and BW2500 g in 44 infants). The prevalence of pneumothorax in the two BW categories was 0.27% and 2.5%, respectively. Infants with BW ≥ 2500 g were diagnosed with neumothorax at a median age of 5.5 h, and mostly (70%) did not require intubation. Infants with BW2500 g were diagnosed with pneumothorax at a median age of 34 h, presenting with hypercarbia and increased requirement for supplemental oxygen. The majority of these infants (89%) received mechanical ventilation after pneumothorax. When compared to matched controls, there was a lower proportion of African-American infants in the pneumothorax group (48% versus 73%, p = 0.029) and a higher rate of bronchopulmonary dysplasia (30% versus 7%, p = 0.004).Onset, presentation and management of pneumothorax varied according to BW. Preterm infants with pneumothorax are at increased risk for developing bronchopulmonary dysplasia.

Pregnancy is a state of immunotolerance and loss of this immunotolerance may lead to fetal rejection, pregnancy complications, and neonatal complications. Immunobiology of pregnancy is complex and involves unique immune cell populations specific to pregnancy, changes in mucosal immune cells and peripheral immune system, and reciprocal adaptations between the mother and the fetus. The mechanisms required for sustaining a healthy feto-placental barrier and a healthy pregnancy such as activation of regulatory immune responses with a predominance of regulatory T cells lead to immune evasion and propagation of cancer. It is intriguing to note that the immune pathways which are effective in limiting or eliminating cancer form the very basis for loss of feto-maternal tolerance. In this article, we aim to compare and contrast immunobiology of healthy and pathological pregnancies mirroring with cancer immunobiology with a focus on immune checkpoint receptors.

To assess the fetal neuroprotective potential of progesterone using a well-validated mouse model of lipopolysaccharide (LPS)-induced intrauterine inflammation (IUI). Embryonic day 17 pregnant mouse dams (n = 69) were randomly allocated to receive 17-hydroxyprogesterone caproate (17-OHPC), micronized progesterone (MP), or vehicle 1 hour prior to intrauterine injection of phosphate-buffered saline (PBS) or LPS. After 6 hours, mice were killed for the collection of placentas and fetal brains, or pregnancy continued for the evaluation of preterm birth (PTB) and offspring neuromotor function. Placentas and fetal brains were analyzed by mini-mRNA array for 96 immune markers with individual confirmatory qPCR. Progesterone pre-treatment before LPS-induced IUI improved neuromotor tests in offspring at PND5 compared to no pre-treatment (P < .05). In placentas, 17-OHPC, but not MP, significantly reduced CXCL9 (P < .05) with a trend toward a lower level of CXCL10. In fetal brains, 17-OHPC significantly reduced CXCL9 compared to no pre-treatment (P < .05) and IL-1β compared to pre-treatment with MP (P < .01). Progesterone pre-treatment prior to LPS-induced IUI improved offspring neuromotor outcomes. 17-OHPC, but not MP, resulted in greater immunomodulation of T cell-mediated immunity in placenta and fetal brain, suggesting a possible mechanism for the observed neuroprotective effects.

Problem Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring. Method of study Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry. Results CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI. Conclusion Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

We investigated the mechanisms by which CD8+ T-cell trafficking in placenta contributes to perinatal brain injury by studying effects of maternal CD8+ T-cell depletion (DEP) in a mouse model of intrauterine inflammation (IUI). Maternal CD8+ T cells were depleted with anti-CD8+ antibodies. IUI was induced with lipopolysaccharide (LPS). DEP was confirmed using flow cytometry. Preterm birth rate was evaluated. Offspring neurologic sequelae were assessed by Nissl staining, immune arrays, confirmatory individual TaqMan® gene assays, and neurobehavioral tests. DEP did not significantly prevent LPS-induced preterm birth but improved neurobehavioral performance (P

Pregnancy can be defined as a “permissible” process, where a semi-allogeneic fetus and placenta are allowed to grow and survive within the mother. Similarly, in tumor growth, antigen-specific malignant cells proliferate and evade into normal tissues of the host. The microenvironments of the placenta and tumors are amazingly comparable, sharing similar mechanisms exploited by fetal or cancer cells with regard to surviving in a hypoxic microenvironment, invading tissues via degradation and vasculogenesis, and escaping host attack through immune privilege. Heme oxygease-1 (HO-1) is a stress-response protein that has anti-oxidative, anti-apoptotic, pro-angiogenic, and anti-inflammatory properties. Although a large volume of research has been published in recent years investigating the possible role(s) of HO-1 in pregnancy and in cancer development, the molecular mechanisms that regulate these “yin-yang” processes have still not been fully elucidated. Here, we summarize and compare pregnancy and cancer development, focusing primarily on the function of HO-1 in cellular invasion, cytoprotection, angiogenesis, and immunomodulation. Due to the similarities of both processes, a thorough understanding of the molecular mechanisms of each process may reveal and guide the development of new approaches to prevent not only pregnancy disorders; but also, to study cancer.

Haemophagocytic syndromes are the clinical manifestation of an increased macrophagic activity with haemophagocytosis. Infection-associated HS was originally described by Risdall in 1979, in viral disease. Since the initial description HS has also been documented in patients with bacterial, parasitic or fungal infections. We describe a case of Micrococcus sedentarius bacteraemia in a previously healthy 10-y-old boy with haemophagocytic syndrome. Species of micrococci are generally considered as non-pathogenic commensals that colonize the skin, mucosae and oropharynx. We report the first case of Microccoccus sedentarius bacteraemia in an immunocompetent host and first case of HS associated with Micrococcus species.

We examined the relationship between the use of nasal continuous positive airway pressure (CPAP) and nasal colonization among low-birth-weight (LBW) infants. We prospectively cultured the nares of LBW infants on admission and weekly until hospital discharge. The modality of respiratory support during each culture was recorded. Bivariate and multivariate analyses were conducted to test the relationship between CPAP and nasal colonization. Analyses were repeated after stratifying infants into three birth-weight categories: 1500 to 2499 g, 1000 to 1499 g, and < 1000 g. In total, 766 nasal cultures were obtained from 167 infants. Nasal colonization with gram-negative bacilli was increased with the use of CPAP in all birth-weight categories ( P < 0.05) and with vaginal delivery in infants weighing < 1000 g and 1500 to 2499 g ( P = 0.04 and P = 0.02, respectively). Nasal colonization with any potential pathogen increased with the use of CPAP in all birth-weight categories ( P < 0.001), with the presence of chorioamnionitis in infants < 1000 g ( P = 0.055) and at younger gestational age in infants 1000 to 1499 g ( P = 0.0026). Caucasian infants 1500 to 2499 g had less colonization than infants of other races ( P = 0.01). Nasal CPAP is associated with increased colonization with gram-negative bacilli.

Bone marrow transplantation (BMT) is currently the treatment of choice for patients with globoid cell leukodystrophy (GLD), particularly in the early phases of the disease. Elevated interleukin (IL)-6 levels in the central nervous system of the twitcher mouse, an animal model for GLD, have been held responsible for severe graft versus host disease (GVHD), and IL-6 knock-out mice have shown lower incidence of GVHD after BMT. Here we report an eight-year-old girl with late-onset advanced stage of GLD who developed severe GVHD and died following unrelated 5/6 matched cord blood transplantation. Serum IL-6 levels pre-BMT and at day +38 were elevated (20 pg/ml and 15 pg/ml, respectively). This observation may support the findings in twitcher mice suggesting a possible role for IL-6 in the pathogenesis of GVHD in transplanted patients with GLD.