Exploration of the molecular characteristics and potential clinical significance of shared immune-related genes between preterm preeclampsia and term preeclampsia.

BACKGROUND: Preeclampsia is a severe obstetric disorder that significantly affects the maternal and neonatal peri-partum safety and long-term quality of life. However, there is limited research exploring the common mechanisms and potential clinical significance between early-onset preeclampsia and full-term preeclampsia from an immunological perspective. METHODS: In this study, data analysis was conducted. Initially, immune-related co-expressed genes involving both subtypes of preeclampsia were identified through Weighted Gene Co-expression Network Analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were further employed to investigate the shared pathways regulated by immune-related genes. Binary logistic regression identified co-expressed genes with diagnostic value for preeclampsia, and a diagnostic model was constructed. Gene Set Enrichment Analysis (GSEA) predicted the potential biological functions of the selected genes. Lasso and Cox regression analyses identified genes closely associated with gestational duration, and a risk score model was established. A 4-gene feature, immune-related gene model for predicting the risk of preterm birth in preeclamptic pregnant women, was developed and validated through qPCR experiments. Immune cell infiltration analysis determined differences in immune cell infiltration between the two subtypes of preeclampsia. RESULTS: This study identified 4 immune-related co-expressed genes (CXCR6, PIK3CB, IL1RAP, and OSMR). Additionally, diagnostic and preterm birth risk prediction models for preeclampsia were constructed based on these genes. GSEA analysis suggested the involvement of these genes in the regulation of galactose metabolism, notch signaling pathway, and RIG-I like receptor signaling pathway. Immune pathway analysis indicated that the activation of T cell co-inhibition could be a potential intervention target for immunotherapy in early-onset preeclampsia. CONCLUSION: Our study provides promising insights into immunotherapy and mechanistic research for preeclampsia, discovering novel diagnostic and intervention biomarkers, and offering personalized diagnostic tools for preeclampsia.

Effects of Maternal SARS-CoV-2 Infection During Pregnancy on Fetal Development.

BACKGROUND: The severe acute respiratory syndrome coronavirus (SARS-CoV-2) outbreak in 2019 has necessitated investigating its potential adverse effects on pregnancy outcomes and fetal development. OBJECTIVE: This study aimed to review the evidence on the impact of SARS-CoV-2 infection during pregnancy on fetal outcomes. METHOD OF STUDY: Literatures since the outbreak of COVID-19 from PubMed and Web of Science were summarized in this narrative review, to show the effects of maternal SARS-CoV-2 infection during pregnancy on fetal development. RESULTS: SARS-CoV-2 infection during pregnancy can be transmitted vertically through the placenta, both in utero and perinatally, affecting the maternal-fetal immune interface and placental function. Viral infections during pregnancy have been linked to central nervous system development impairments and disorders such as autism. Changes in the structure and function of the respiratory, immune, and visceral systems have also been reported. SARS-CoV-2 infection during pregnancy has been linked with increased risks of stillbirth and preterm birth. However, the mechanisms involved remain unclear and may include cytokine storms, macrophage mediation, genetic mutations, methylation, and other epigenetic changes. Exploring the protective effects of antiviral treatment and other interventions in animal and clinical studies may help improve outcomes. CONCLUSION: SARS-CoV-2 infection during pregnancy activates the maternal-fetal immune interface through vertical transmission, and has short- and long-term effects on fetal development, including the central nervous system. Future long-term studies may help provide evidence that can inform interventions to reduce the risk of adverse outcomes.

Neutrophils and monocyte toll like receptors 2 and 4 expression in preterm versus term delivery.

Pregnancy results in an increase in immune cells, especially monocytes, which enhances the innate immune system. The increase of inflammatory cytokines in pregnant women's amniotic fluid, can cause uterine contraction, is linked to preterm labor. These inflammatory responses are controlled by Toll-like receptors (TLRs), which are largely expressed on neutrophils and monocytes. This study aimed to determine the role of neutrophils and monocyte subsets, as well as their expression of TLR-2 and TLR-4 in women with preterm and full-term delivery. The study involved a total of 74 women, comprising of 29 preterm labor, 25 full-term labor, and 20 non-pregnant women. The distribution of three monocyte subsets, namely (CD14++CD16-), (CD14+CD16+), and (CD14-/dim CD16++) was measured. Also, the expression of TLR2 and TLR4 in monocytes and neutrophils was analyzed using flow cytometry. Non-classical monocytes and intermediate monocytes were significantly higher in the preterm group than the control and full-term groups (p=0.041, p=0.043, and p=0.004, p= 0.049, respectively). Women in the preterm group showed significantly TLR2 expression on nonclassical monocytes compared to the control and full-term groups (p=0.002, and p=0.010, respectively). Also, preterm group expression of TLR4 was significantly higher in classical monocytes and nonclassical monocytes in comparison to the control group (p=0.019, and p≤0.0001, respectively). Besides, TLR4 expression was significantly up regulated in the preterm group compared to full-term in non-classical monocyte subset (p < 0.0001). Moreover, the expression of TLR-4 in neutrophils from the preterm group was statistically higher than expression from the full-term labor and control groups (p < .0001 for both). Such findings highlight the important role of monocyte subsets and neutrophils in activating the innate immune system and initiating strong pro-inflammatory responses that induce preterm labor. Additionally, TLR4 and TLR2 expressions on non-classical monocytes may be used as a marker to assess the probability of preterm labor.

Inflammatory mechanisms of preterm labor and emerging anti-inflammatory interventions.

Preterm birth is a major public health concern, requiring a deeper understanding of its underlying inflammatory mechanisms and to develop effective therapeutic strategies. This review explores the complex interaction between inflammation and preterm labor, highlighting the pivotal role of the dysregulation of inflammation in triggering premature delivery. The immunological environment of pregnancy, characterized by a fragile balance of immune tolerance and resistance, is disrupted in preterm labor, leading to a pathological inflammatory response. Feto-maternal infections, among other pro-inflammatory stimuli, trigger the activation of toll-like receptors and the production of pro-inflammatory mediators, promoting uterine contractility and cervical ripening. Emerging anti-inflammatory therapeutics offer promising approaches for the prevention of preterm birth by targeting key inflammatory pathways. From TLR-4 antagonists to chemokine and interleukin receptor antagonists, these interventions aim to modulate the inflammatory environment and prevent adverse pregnancy outcomes. In conclusion, a comprehensive understanding of the inflammatory mechanisms leading to preterm labor is crucial for the development of targeted interventions in hope of reducing the incidence of preterm birth and improving neonatal health outcomes.

The vaginal immunoproteome for the prediction of spontaneous preterm birth: A retrospective longitudinal study.

Background: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB. Methods: Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations. Results: Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB. Conclusions: The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes. Funding: This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.

Human pregnancies last 40 weeks on average. Preterm births, defined as live births before 37 weeks, occur in about one in ten pregnancies. Being born too early is the main cause of a number of diseases and death in newborn babies. Preterm births are further divided into those that happen early ­ before 34 weeks ­ and those that happen late ­ between 34 and 37 weeks. There are also differences between preterm births in which the amniotic sac ruptures before or after the start of labor. Although several factors can lead to spontaneous preterm birth, bacteria getting into the amniotic fluid around the fetus are a well-known trigger. These bacteria usually come from the vagina. In the past, researchers have studied the number and types of bacteria in the vagina of people who had a normal pregnancy and those that had a preterm birth to predict who is more at risk of preterm birth. However, predictions based only on data about bacteria have been less useful so far. Instead, it might be better to investigate a person's immune response during pregnancy. Shaffer et al. addressed this gap by asking whether measuring the levels of proteins involved in the immune response could help predict preterm births. Shaffer et al. collected vaginal fluids from 739 individuals of predominately African American ethnicity with an average BMI of 28.7 ­ representing a population at high risk for spontaneous preterm birth. The swabs were taken at multiple points during their pregnancy, and 31 different immune-related proteins in those fluids were measured. The researchers further noted whether these individuals had a normal or a preterm birth. The data showed that, compared to normal births, preterm births are associated with higher levels of proteins that attract white blood cells and promote inflammation, such as IL-6 and IL-1ß. Vaginal fluids from individuals who went on to have an early preterm birth where the amniotic sac ruptured before labor, contained lower levels of proteins known as defensins, which defend the body from bacteria. With these new data from vaginal swabs, Shaffer et al. could make better predictions about the likelihood of preterm birth in general and early preterm birth with the amniotic sac ruptured before labor. For the latter scenario, the predictions were not improved when combining immune protein data with other characteristics of the pregnant person, such as age. These findings suggest that clinicians may be able to use measurements of immune-related proteins to help predict preterm births, so that pregnant individuals at high risk can receive extra care. Further research will have to validate the data and determine whether the findings apply more widely.

Association of systemic chronic inflammation during pregnancy in different periods and its trajectories with preterm birth.

PROBLEM: Systemic chronic inflammation (SCI) is a prevalent characteristic observed in various diseases originating from different tissues, while the association of SCI with preterm birth (PTB) remains uncertain. This study aimed to analyze the association between a nonspecific biomarker of SCI and PTB, while also exploring the trajectories of SCI in pregnant women at risk of PTB. METHOD OF STUDY: The study used data from the Electronic Medical Record System (EMRS) of a hospital in Zhejiang, China and 9226 pregnant women were included. The duration of pregnancy was categorized into four distinct periods: the first, early-second, late-second, and third trimester. Latent class trajectory modeling (LCTM) was used to identify the trajectories of SCI during pregnancy. RESULTS: The elevated WBC counts in the late-second (OR = 1.14, 95% CI: 1.06-1.23) and third (OR = 1.16, 95% CI: 1.09-1.24) trimester were both positively associated with an evaluated risk of PTB. Moreover, significant dose-response relationships were observed. There were three distinct SCI trajectories found: progressing SCI (2.89%), high SCI (7.13%), and low SCI (89.98%). Pregnant women with progressive SCI had the highest risk of PTB (OR = 3.03, 95% CI: 1.47-6.25). CONCLUSIONS: In conclusion, elevated SCI after 23 weeks was a risk factor for PTB in healthy women, even if the SCI indicator was within normal range. Pregnant women with progressive SCI during pregnancy had the highest risk of PTB.

Predicting Spontaneous Preterm Birth Using the Immunome.

Throughout pregnancy, the maternal peripheral circulation contains valuable information reflecting pregnancy progression, detectable as tightly regulated immune dynamics. Local immune processes at the maternal-fetal interface and other reproductive and non-reproductive tissues are likely to be the pacemakers for this peripheral immune "clock." This cellular immune status of pregnancy can be leveraged for the early risk assessment and prediction of spontaneous preterm birth (sPTB). Systems immunology approaches to sPTB subtypes and cross-tissue (local and peripheral) interactions, as well as integration of multiple biological data modalities promise to improve our understanding of preterm birth pathobiology and identify potential clinically actionable biomarkers.

The protective effects of Ferrostatin-1 against inflammation-induced preterm birth and fetal brain injury.

INTRODUCTION: Recent studies have suggested the involvement of ferroptosis in preterm birth. Despite compelling evidence, the underlying mechanism remains unknown. This investigation aimed to determine the therapeutic effects of Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, in preterm birth and fetal brain injury. METHODS: Human placenta samples and clinical data of participants were collected to ascertain whether placental ferroptosis was associated with preterm birth. Lipopolysaccharide (LPS)-induced preterm birth mouse model was used to examine the protective effects of Fer-1 on preterm birth. Fetal brain tissues and offspring mice at 5 and 8 weeks were studied to determine the effects of Fer-1 on the cognitive function of offspring. RESULTS: We examined the mechanism of spontaneous preterm birth and discovered that placental ferroptosis was associated with preterm birth. Fer-1 inhibited preterm birth by ameliorating placental ferroptosis and maternal inflammation, thus improving LPS-induced intrauterine inflammation to maintain pregnancy. Antenatal administration of Fer-1 prevented LPS-induced fetal brain damage in the acute phase and improved long-term neurodevelopmental impairments by improving placental neuroendocrine signaling and maintaining placental function. CONCLUSION: Fer-1 inhibited preterm birth and fetal brain injury by inhibiting maternal inflammation and improving placental function. Our findings provide a novel therapeutic strategy for preterm birth.

TLR8-activating miR-146a-3p is an intermediate signal contributing to fetal membrane inflammation in response to bacterial LPS.

Preterm birth is the largest contributor to neonatal morbidity and is often associated with chorioamnionitis, defined as inflammation/infection of the fetal membranes (FMs). Chorioamnionitis is characterised by neutrophil infiltration of the FMs and is associated with elevated levels of the neutrophil chemoattractant, interleukin (IL)-8 and the proinflammatory cytokine, IL-1ß. While FMs can respond to infections through innate immune sensors, such as toll-like receptors (TLRs), the downstream mechanisms by which chorioamnionitis arises are not fully understood. A novel group of non-classical microRNAs (miR-21a, miR-29a, miR-146a-3p, Let-7b) function as endogenous danger signals by activating the ssRNA viral sensors TLR7 and TLR8. In this study, the pro-inflammatory roles of TLR7/TLR8-activating miRs were examined as mediators of FM inflammation in response to bacterial lipopolysaccharide (LPS) using an in vitro human FM explant system, an in vivo mouse model of pregnancy, and human clinical samples. Following LPS exposure, miR-146a-3p was significantly increased in both human FM explants and wild-type mouse FMs. Expression of miR-146a-3p was also significantly elevated in FMs from women with preterm birth and chorioamnionitis. FM IL-8 and inflammasome-mediated IL-1ß production in response to LPS was dependent on miR-146a-3p and TLR8 downstream of TLR4 activation. In wild-type mice, LPS exposure increased FM IL-8 and IL-1ß production and induced preterm birth. In TLR7-/-/TLR8-/- mice, LPS exposure was able to initiate but not sustain preterm birth, and FM inflammation was reduced. Together, we demonstrate a novel signalling mechanism at the maternal-fetal interface in which TLR8-activating miR-146a-3p acts as an intermediate danger signal to drive FM inflammasome-dependent and -independent mechanisms of inflammation and, thus, may play a role in chorioamnionitis and subsequent preterm birth.

Antiphospholipid antibodies and the risk of adverse pregnancy outcomes in patients with systemic lupus erythematosus: a systematic review and meta-analysis.

OBJECTIVE: This article aims to evaluate the magnitude of adverse pregnancy outcomes (APOs) risks associated with different antiphospholipid antibody (aPL) profiles in women with systemic lupus erythematosus (SLE). METHODS: Multiple databases were investigated to identify articles that explored the relationship between aPLs and APOs in SLE patients. A random effects model was used for calculating pooled odds ratios (OR). Stata version 15.0 was utilized to conduct the meta-analysis. RESULTS: There were 5234 patients involved in 30 studies. Overall aPL was linked to an increased incidence of any kind of APOs, fetal loss, and preterm birth. Any kind of APOs and preterm delivery were more common in patients with lupus anticoagulant (LA) positive. Anticardiolipin antibody (aCL) was associated with an increased risk of any kind of APOs and fetal loss. The association between aCL-IgM and fetal loss was also significant. Patients with anti-beta2-glycoprotein1 antibody (antiß2GP1) positivity had an increased risk of fetal loss. CONCLUSIONS: Both LA and aCL were risk factors of APOs in patients with SLE. Not only ACL, particularly aCL-IgM, but antiß2GP1 were associated with an increased risk of fetal loss, while LA appeared to indicate the risk of preterm birth.PROSPERO (CRD42023388122).

Pharmacological blockade of the interleukin-1 receptor suppressed Escherichia coli lipopolysaccharide-induced neuroinflammation in preterm fetal sheep.

BACKGROUND: Intraamniotic inflammation is associated with preterm birth, especially in cases occurring before 32 weeks' gestation, and is causally linked with an increased risk for neonatal mortality and morbidity. Targeted anti-inflammatory interventions may assist in improving the outcomes for pregnancies impacted by intrauterine inflammation. Interleukin-1 is a central upstream mediator of inflammation. Accordingly, interleukin-1 is a promising candidate target for intervention therapies and has been targeted previously using the interleukin-1 receptor antagonist, anakinra. Recent studies have shown that the novel, noncompetitive, allosteric interleukin-1 receptor inhibitor, rytvela, partially resolved inflammation associated with preterm birth and fetal injury. In this study, we used a preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela and anakinra, administered in the amniotic fluid in the setting of intraamniotic Escherichia coli lipopolysaccharide exposure. OBJECTIVE: We hypothesized that both rytvela and anakinra would reduce lipopolysaccharide-induced intrauterine inflammation and protect the fetal brain. STUDY DESIGN: Ewes with a singleton fetus at 105 days of gestation (term is ∼150 days) were randomized to one of the following groups: (1) intraamniotic injections of 2 mL saline at time=0 and time=24 hours as a negative control group (saline group, n=12); (2) intraamniotic injection of 10 mg Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2 mL saline at time=0 hours and time=24 hours as an inflammation positive control group (lipopolysaccharide group, n=11); (3) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2.5 mg rytvela at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of rytvela (lipopolysaccharide + rytvela group, n=10); or (4) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 100 mg anakinra at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of anakinra (lipopolysaccharide + anakinra group, n=12). Amniotic fluid was sampled at time 0, 24, and 48 hours (ie, at each intervention and at delivery). Fetal umbilical cord blood was collected at delivery for differential blood counts and chemical studies. Inflammation was characterized by the analysis of fetal tissue cytokine and chemokine levels using quantitative polymerase chain reaction, enzyme-linked inmmunosorbent assay, and histology. The primary study outcome of interest was the assessment of anakinra and rytvela brain-protective effects in the setting of Escherichia coli lipopolysaccharide-induced intrauterine inflammation. Secondary outcomes of interest were to assess protection from fetal and intrauterine (ie, amniotic fluid, chorioamnion) inflammation. RESULTS: Intraamniotic administration of lipopolysaccharide caused inflammation of the fetal lung, brain, and chorioamnionitis in preterm fetal sheep. Relative to treatment with saline only in the setting of lipopolysaccharide exposure, intraamniotic administration of both rytvela and anakinra both significantly prevented periventricular white matter injury, microglial activation, and histologic chorioamnionitis. Anakinra showed additional efficacy in inhibiting fetal lung myeloperoxidase activity, but its use was associated with metabolic acidaemia and reduced fetal plasma insulin-like growth factor-1 levels at delivery. CONCLUSION: Intraamniotic administration of rytvela or anakinra significantly inhibited fetal brain inflammation and chorioamnionitis in preterm fetal sheep exposed to intraamniotic lipopolysaccharide. In addition, anakinra treatment was associated with potential negative impacts on the developing fetus.

Microbial-driven preterm labour involves crosstalk between the innate and adaptive immune response.

There has been a surge in studies implicating a role of vaginal microbiota in spontaneous preterm birth (sPTB), but most are associative without mechanistic insight. Here we show a comprehensive approach to understand the causative factors of preterm birth, based on the integration of longitudinal vaginal microbiota and cervicovaginal fluid (CVF) immunophenotype data collected from 133 women at high-risk of sPTB. We show that vaginal depletion of Lactobacillus species and high bacterial diversity leads to increased mannose binding lectin (MBL), IgM, IgG, C3b, C5, IL-8, IL-6 and IL-1ß and to increased risk of sPTB. Cervical shortening, which often precedes preterm birth, is associated with Lactobacillus iners and elevated levels of IgM, C3b, C5, C5a and IL-6. These data demonstrate a role for the complement system in microbial-driven sPTB and provide a scientific rationale for the development of live biotherapeutics and complement therapeutics to prevent sPTB.

Antibody microarray analysis of amniotic fluid proteomes in women with cervical insufficiency and short cervix, and their association with pregnancy latency length.

INTRODUCTION: This study aimed to investigate amniotic fluid (AF) proteins that were differentially expressed between patients with cervical insufficiency (CI) and asymptomatic short cervix (SCX, ≤ 25 mm), and whether these proteins could be predictive of spontaneous preterm birth (SPTB) in these patients. METHOD: This was a retrospective cohort study of 129 singleton pregnant women with CI (n = 80) or SCX (n = 49) at 17 to 26 weeks who underwent amniocentesis. An antibody microarray was used to perform comparative proteomic profiling of AF from matched CI (n = 20) and SCX (n = 20) pregnancies. In the total cohort, an ELISA validation study was performed for 15 candidate proteins of interest. Subgroup analyses of patients with CI and SCX were conducted to evaluate the association between the 15 proteins and SPTB at < 32 weeks of gestation. RESULTS: Eighty-six proteins showed intergroup differences. ELISA validation confirmed significantly higher levels of AF EN-RAGE, IL-8, lipocalin-2, MMP-9, S100A8/A9, thrombospondin-2, and TNFR2 in patients with CI than in those with SCX. Multivariable analysis showed that increased AF levels of EN-RAGE, S100A8/A9, and uPA were independently associated with SPTB at < 32 weeks in patients with CI; whereas in patients with SCX, high AF levels of APRIL, EN-RAGE, LBP, and TNFR2 were independently associated with SPTB at < 32 weeks. CONCLUSIONS: Multiple AF proteins show altered expression in patients with CI compared with SCX controls. Moreover, several novel mediators involved in inflammation were identified as potential biomarkers for predicting SPTB after the diagnosis of CI and SCX. These results provide new insights into target-specific molecules for targeted therapies to prevent SPTB in patients with CI/SCX.

Pregnancy Outcome in Women With APECED (APS-1): A Multicenter Study on 43 Females With 83 Pregnancies.

CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. OBJECTIVE: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. DESIGN AND SETTING: A multicenter registry-based study including 5 national patient cohorts. PATIENTS: 321 females with APECED. MAIN OUTCOME MEASURE: Number of pregnancies, miscarriages, and deliveries. RESULTS: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. CONCLUSIONS: Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.

Outcomes of pregnancy in autoimmune hepatitis: A population-based study.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) disproportionately affects young women, which may have implications in pregnancy. However, data on pregnancy outcomes in women with AIH are limited. APPROACH AND RESULTS: Using weighted discharge data from the United States National Inpatient Sample from 2012 to 2016, we evaluated pregnancies after 20 weeks gestation and compared outcomes in AIH to other chronic liver diseases (CLD) or no CLD in pregnancy. The association of AIH with maternal and perinatal outcomes was assessed by logistic regression. Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Temporal trends in pregnancies with AIH remained stable from 2008 to 2016 with 1.4-6.8/100,000 pregnancies per year (p = 0.25). On adjusted analysis, the odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2, 95% CI: 1.5-3.9, p < 0.001; hypertensive complications: OR: 1.8, 95% CI: 1.0-3.2, p = 0.05) and also compared to no CLD in pregnancy (GDM: OR: 2.4, 95% CI: 1.6-3.6, p < 0.001; hypertensive complications: OR: 2.4, 95% CI: 1.3-4.1, p = 0.003). AIH was also associated with preterm births when compared with women without CLD (OR: 2.0, 95% CI: 1.2-3.5, p = 0.01). AIH was not associated with postpartum hemorrhage, maternal, or perinatal death. CONCLUSIONS: Rates of pregnancy in women with AIH have remained stable in recent years, although AIH is associated with notable maternal and perinatal risks, such as GDM, hypertensive complications, and preterm birth. Whether these risks are influenced by steroid use and/or AIH disease activity warrants evaluation. These data support a low risk of postpartum hemorrhage and favorable survival of mothers and infants.

Inflammatory cytokines, placental pathology, and neurological outcomes in infants born to preterm preeclamptic mothers.

Preeclampsia is both a vascular and inflammatory disorder. Since the placenta is a conduit for fetal development, preeclampsia should be a presumed cause of adverse infant outcomes. Yet, the relationship of placental pathology, inflammation and neurological outcomes after preeclampsia are understudied. We prospectively examined a cohort of maternal-infant dyads with preeclampsia for maternal inflammatory cytokines at time of preeclampsia diagnosis and delivery, and fetal cord blood cytokines (IL-1ß, IL-6, IL-8, and TNF-α). Placentas were analyzed for inflammatory and vascular pathologies. Neurodevelopmental assessment of infants utilizing the Pediatric Stroke Outcome Measure (PSOM) was conducted at 6-month corrected gestational age. Eighty-one maternal-newborn dyads were examined. Worse neurological outcomes were not associated with elevated maternal / fetal cytokines. Early preterm birth (gestational age ≤ 32 weeks) was associated with worse neurological outcomes at 6-months regardless of maternal/ fetal cytokine levels, placental pathology, or cranial ultrasound findings (OR 1.70, [1.16-2.48], p = 0.006). When correcting for gestational age, elevated IL-6 approached significance as a predictor for worse developmental outcome (OR 1.025 [0.985-1.066], p = 0.221). Pathological evidence of maternal malperfusion and worse outcomes were noted in early preterm, although our sample size was small. Our study did not demonstrate an obvious association of inflammation and placental pathology in preeclampsia and adverse neurodevelopmental outcome at 6-month corrected age but does suggest maternal malperfusion at earlier gestational age may be a risk factor for worse outcome.

Significance of inhibitory maternal killer-cell immunoglobulin-like receptor (KIR) and fetal KIR ligand genotype combinations in placenta related obstetric complications.

Some maternal killer-cell immunoglobulin-like receptor (KIR) and fetal KIR ligand genotypes are associated with obstetric complications, such as recurrent miscarriage, fetal growth restriction, preeclampsia, and preterm birth. However, how KIR/KIR ligand genotypes affect these placenta-related obstetric complications has not been fully understood. We aimed to demonstrate the association of maternal KIR-fetal KIR ligand genotype combinations with immunological/metabolic risk factor associated placenta-related obstetric complications. This study consisted of three groups of pregnant women: 1) Miscarriage group (n = 30), 2) Complicated Pregnancy (CP) group (n = 30), and 3) Control group (n = 30). The observed maternal genotype frequencies of all inhibitory and activating KIRs were similar in all groups (p > 0.05). However, inhibitory 2DL3 was quite frequent in the miscarriage group (p = 0.052). There was no difference between groups in terms of centromeric and telomeric maternal haplotypes (p > 0.05). The fetal group 1 HLA-C genotype was frequently detected in the miscarriage and CP groups with rates of 83.3 % and 93.3 % respectively, while the observed frequency was 70 % in the control group. The fetal group 2 HLA-C genotype was the same in all groups. The results demonstrated significantly less fetal group 2 HLA-C homozygosity in the CP groups when compared to the control group (p = 0.020). The fetal HLA-Bw4 genotype was detected more frequently in the miscarriage and CP groups (p = 0.028 and p = 0.001, respectively). The inhibitory KIR/KIR ligand genotype combinations of 2DL3-C1 and 3DL1-Bw4 were more frequent in the miscarriage and CP groups (p = 0.045 and p = 0.002, respectively). Enhanced NK cell inhibition may be one of the mechanisms underlying placenta-related obstetric complications.

Macrophages exert homeostatic actions in pregnancy to protect against preterm birth and fetal inflammatory injury.

Macrophages are commonly thought to contribute to the pathophysiology of preterm labor by amplifying inflammation - but a protective role has not previously been considered to our knowledge. We hypothesized that given their antiinflammatory capability in early pregnancy, macrophages exert essential roles in maintenance of late gestation and that insufficient macrophages may predispose individuals to spontaneous preterm labor and adverse neonatal outcomes. Here, we showed that women with spontaneous preterm birth had reduced CD209+CD206+ expression in alternatively activated CD45+CD14+ICAM3- macrophages and increased TNF expression in proinflammatory CD45+CD14+CD80+HLA-DR+ macrophages in the uterine decidua at the materno-fetal interface. In Cd11bDTR/DTR mice, depletion of maternal CD11b+ myeloid cells caused preterm birth, neonatal death, and postnatal growth impairment, accompanied by uterine cytokine and leukocyte changes indicative of a proinflammatory response, while adoptive transfer of WT macrophages prevented preterm birth and partially rescued neonatal loss. In a model of intra-amniotic inflammation-induced preterm birth, macrophages polarized in vitro to an M2 phenotype showed superior capacity over nonpolarized macrophages to reduce uterine and fetal inflammation, prevent preterm birth, and improve neonatal survival. We conclude that macrophages exert a critical homeostatic regulatory role in late gestation and are implicated as a determinant of susceptibility to spontaneous preterm birth and fetal inflammatory injury.

Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth.

The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

Maternal and Infant Immune Repertoire Sequencing Analysis Identifies Distinct Ig and TCR Development in Term and Preterm Infants.

Preterm labor (PTL) is the leading cause of neonatal morbidity and mortality worldwide. Whereas many studies have investigated the maternal immune responses that cause PTL, fetal immune cell activation has recently been raised as an important contributor to the pathogenesis of PTL. In this study, we analyzed lymphocyte receptor repertoires in maternal and cord blood from 14 term and 10 preterm deliveries, hypothesizing that the high prevalence of infection in patients with PTL may result in specific changes in the T cell and B cell repertoires. We analyzed TCR ß-chain (TCR-ß) and IgH diversity, CDR3 lengths, clonal sharing, and preferential usage of variable and joining gene segments. Both TCR-ß and IgH repertoires had shorter CDR3s compared with those in maternal blood. In cord blood samples, we found that CDR3 lengths correlated with gestational age, with shorter CDR3s in preterm neonates suggesting a less developed repertoire. Preterm cord blood displayed preferential usage of a number of genes. In preterm pregnancies, we observed significantly higher prevalence of convergent clones between mother/baby pairs than in term pregnancies. Together, our results suggest the repertoire of preterm infants displays a combination of immature features and convergence with maternal TCR-ß clones compared with that of term infants. The higher clonal convergence in PTL could represent mother and fetus both responding to a shared stimulus like an infection. These data provide a detailed analysis of the maternal-fetal immune repertoire in term and preterm patients and contribute to a better understanding of neonate immune repertoire development and potential changes associated with PTL.