Maternal Inflammatory Response Research Articles

Gestational exposure to air pollutants perturbs metabolic and placenta-fetal phenotype

Air pollution (AP) is detrimental to pregnancies including increasing risk factors of gestational diabetes mellitus. We hypothesized that exposure to AP causes cardiovascular and metabolic disruption thereby altering placental gene expression, which in turn affects the placental phenotype and thereby embryonic/fetal development. To test this hypothesis, we investigated the impact of intra-nasal instilled AP upon gestational day 16–19 maternal mouse cardiovascular and metabolic status, placental nutrient transporters, and placental-fetal size and morphology. To further unravel mechanisms, we also examined placental total DNA 5’-hydroxymethylation and bulk RNA sequenced gene expression profiles. AP exposed pregnant mice and fetuses were tachycardic with a reduction in maternal left ventricular fractional shortening and increased uterine artery with decreased umbilical artery systolic peak velocities. In addition, they were hyperglycemic, glucose intolerant and insulin resistant, with changes in placental glucose (Glut3) and fatty acid (Fatp1 & Cd36) transporters, and a spatial disruption of cells expressing Glut10 that imports L-dehydroascorbic acid in protecting against oxidative stress. Placentas revealed inflammatory cellular infiltration with associated cellular edema and necrosis, with dilated vascular spaces and hemorrhage. Placental and fetal body weights decreased in mid-gestation with a reduction in brain cortical thickness emerging in late gestation. Placental total DNA 5’-hydroxymethylation was 2.5-fold higher, with perturbed gene expression profiles involving key metabolic, inflammatory, transcriptional, cellular polarizing and processing genes and pathways. We conclude that gestational exposure to AP incites a maternal inflammatory response resulting in features mimicking maternal gestational diabetes mellitus with altered placental DNA 5’-hydroxymethylation, gene expression, and associated injury.

Acute rapamycin treatment reveals novel mechanisms of behavioral, physiological, and functional dysfunction in a maternal inflammation mouse model of autism and sensory over-responsivity.

Maternal inflammatory response (MIR) during early gestation in mice induces a cascade of physiological and behavioral changes that have been associated with autism spectrum disorder (ASD). In a prior study and the current one, we find that mild MIR results in chronic systemic and neuro-inflammation, mTOR pathway activation, mild brain overgrowth followed by regionally specific volumetric changes, sensory processing dysregulation, and social and repetitive behavior abnormalities. Prior studies of rapamycin treatment in autism models have focused on chronic treatments that might be expected to alter or prevent physical brain changes. Here, we have focused on the acute effects of rapamycin to uncover novel mechanisms of dysfunction and related to mTOR pathway signaling. We find that within 2 hours, rapamycin treatment could rapidly rescue neuronal hyper-excitability, seizure susceptibility, functional network connectivity and brain community structure, and repetitive behaviors and sensory over-responsivity in adult offspring with persistent brain overgrowth. These CNS-mediated effects are also associated with alteration of the expression of several ASD-,ion channel-, and epilepsy-associated genes, in the same time frame. Our findings suggest that mTOR dysregulation in MIR offspring is a key contributor to various levels of brain dysfunction, including neuronal excitability, altered gene expression in multiple cell types, sensory functional network connectivity, and modulation of information flow. However, we demonstrate that the adult MIR brain is also amenable to rapid normalization of these functional changes which results in the rescue of both core and comorbid ASD behaviors in adult animals without requiring long-term physical alterations to the brain. Thus, restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing both primary sensory and social behavior phenotypes, and compensatory repetitive behavior phenotypes.

A Case of Partial Molar Pregnancy Complicated by HELLP and PRES

Introduction: The term gestational trophoblastic disease encompasses premalignant and malignant conditions arising from trophoblastic cells. Premalignant disorders include complete or partial hydatidiform mole, whereas malignant disorders include invasive mole, choriocarcinoma, and placental-site trophoblastic tumor. Partial hydatidiform moles are triploid in nature and occur when 2 sperm fertilize a single ovum. Preeclampsia is a syndrome complicating 2-8% of pregnancies which presents as new-onset hypertension plus proteinuria. The occurrence of hemolysis, elevated liver enzymes and low platelet count, referred to as HELLP syndrome, is a severe form of preeclampsia. A related severe manifestation is posterior reversible encephalopathy syndrome (PRES) - a clinicoradiological syndrome characterized by symptoms including headache, seizures, altered consciousness and visual disturbances. PRES is commonly associated with acute hypertension. The symptoms of PRES vary widely: i.e., the visual disturbance can vary from blurred vision and homonymous hemianopsia to cortical blindness. Seizures and status epilepticus are common. Although preeclampsia and HELLP syndrome rarely occur before 20-weeks of gestation, reports have suggested early occurrences of these hypertensive disorders specifically in the setting of a molar pregnancy. Case Report: The patient is a 23-year-old, female gravida 1 at 16 week 5 days who presented to an outside emergency department with a 3-day history of progressive abdominal pain which radiated to her back, arms, and shoulders. At the outside facility, the patient had multiple systolic blood pressures greater than 160 mmHg and had a witnessed 30-second seizure which resolved with an intravenous (IV) injection of 2-mg of Lorazepam and 4-gram magnesium sulfate loading dose. She was initiated on magnesium sulfate maintenance pending transfer to our institution. On admission, the patient met criteria for eclampsia and HELLP (platelets 79,000 K/uL, AST 144 U/L, ALT 96 U/L, LDH 482 U/L, Hemoglobin 8.7 g/dL). The beta human chorionic gonadotropin level (HCG) was greater than 200,000 mIU/mL. Bedside ultrasound suggested the presence of an enlarged cystic placenta and a growth restricted fetus (estimated fetal weight 124g, 2%). The patient and her family were counseled and the decision was made to proceed with misoprostol induction and termination of the pregnancy due to maternal indications. During the induction, the patient developed significant vaginal bleeding and was taken to the operating room for an uncomplicated dilation and evacuation. After the procedure, the patient developed progressive visual blurring with 4+ hyperreflexia. Magnetic resonance imaging (MRI) of the brain with and without contrast was obtained with findings significant for PRES. The MRI revealed T2 high-signal lesions within the cortex of the bilateral occipital lobes. Neurology was consulted and recommended blood pressure control and initiation of levetiracetam for seizure prophylaxis. She was initiated on long-acting nifedipine with subsequent blood pressure control. Patient’s visual symptoms and hyperreflexia resolved. Her liver function tests, platelets, and LDH also returned to normal. The patient received contraceptive counseling to prevent pregnancy during gestational neoplastic disease surveillance period. She underwent weekly beta-hCG until negative, followed by three weekly consecutive negative levels before spacing measurements to every 3 months for a period of six months per National Comprehensive Cancer Network (NCCN) guidelines. The pathology results indicated the presence of chorionic villi composed of both large hydropic and smaller normal-appearing villi, a 69.3-gram female fetus compatible with caudal neurocutaneous defect with abnormal localization of brain tissue. The genetic profile of the villous tissue consisted of two sets of dispermic paternal alleles in addition to one set of maternal alleles consistent with a partial mole diagnosis. Discussion: There is an association between preeclampsia and molar pregnancy. Of partial hydatidiform molar pregnancies, 41.9% will develop the symptoms of preeclampsia if left untreated. Although the pathophysiology of eclampsia spectrum disorders is incompletely understood, some evidence points to the role of increased death of trophoblasts and the maternal inflammatory response to trophoblast deportation. Additional evidence points to angiogenic factor imbalance and interestingly, molar placentas produce high levels of antiangiogenic factors. Other causative agents include placental factors that trigger maternal endothelial activation. It is known that trophoblastic debris shed from the placenta into the maternal blood is associated with this condition. It has been demonstrated that trophoblastic debris from molar pregnancies also induces endothelial cell activation through heat-shock protein 70 (HSP70) expressed on a hydatidiform molar placenta, which may be a pathogenic signal to endothelial cells. This case reiterates the association between hydatidiform moles and the hypertensive disorders of pregnancy possibly supporting the theories that such disorders may share an etiologic linkage through trophoblast debris and angiogenic factor imbalance. This case also supports screening molar pregnancies for severe preeclampsia syndrome.

A Case of Partial Molar Pregnancy Complicated by HELLP and PRES

Introduction: The term gestational trophoblastic disease encompasses premalignant and malignant conditions arising from trophoblastic cells. Premalignant disorders include complete or partial hydatidiform mole, whereas malignant disorders include invasive mole, choriocarcinoma, and placental-site trophoblastic tumor. Partial hydatidiform moles are triploid in nature and occur when 2 sperm fertilize a single ovum. Preeclampsia is a syndrome complicating 2-8% of pregnancies which presents as new-onset hypertension plus proteinuria. The occurrence of hemolysis, elevated liver enzymes and low platelet count, referred to as HELLP syndrome, is a severe form of preeclampsia. A related severe manifestation is posterior reversible encephalopathy syndrome (PRES) - a clinicoradiological syndrome characterized by symptoms including headache, seizures, altered consciousness and visual disturbances. PRES is commonly associated with acute hypertension. The symptoms of PRES vary widely: i.e., the visual disturbance can vary from blurred vision and homonymous hemianopsia to cortical blindness. Seizures and status epilepticus are common. Although preeclampsia and HELLP syndrome rarely occur before 20-weeks of gestation, reports have suggested early occurrences of these hypertensive disorders specifically in the setting of a molar pregnancy. Case Report: The patient is a 23-year-old, female gravida 1 at 16 week 5 days who presented to an outside emergency department with a 3-day history of progressive abdominal pain which radiated to her back, arms, and shoulders. At the outside facility, the patient had multiple systolic blood pressures greater than 160 mmHg and had a witnessed 30-second seizure which resolved with an intravenous (IV) injection of 2-mg of Lorazepam and 4-gram magnesium sulfate loading dose. She was initiated on magnesium sulfate maintenance pending transfer to our institution. On admission, the patient met criteria for eclampsia and HELLP (platelets 79,000 K/uL, AST 144 U/L, ALT 96 U/L, LDH 482 U/L, Hemoglobin 8.7 g/dL). The beta human chorionic gonadotropin level (HCG) was greater than 200,000 mIU/mL. Bedside ultrasound suggested the presence of an enlarged cystic placenta and a growth restricted fetus (estimated fetal weight 124g, 2%). The patient and her family were counseled and the decision was made to proceed with misoprostol induction and termination of the pregnancy due to maternal indications. During the induction, the patient developed significant vaginal bleeding and was taken to the operating room for an uncomplicated dilation and evacuation. After the procedure, the patient developed progressive visual blurring with 4+ hyperreflexia. Magnetic resonance imaging (MRI) of the brain with and without contrast was obtained with findings significant for PRES. The MRI revealed T2 high-signal lesions within the cortex of the bilateral occipital lobes. Neurology was consulted and recommended blood pressure control and initiation of levetiracetam for seizure prophylaxis. She was initiated on long-acting nifedipine with subsequent blood pressure control. Patient’s visual symptoms and hyperreflexia resolved. Her liver function tests, platelets, and LDH also returned to normal. The patient received contraceptive counseling to prevent pregnancy during gestational neoplastic disease surveillance period. She underwent weekly beta-hCG until negative, followed by three weekly consecutive negative levels before spacing measurements to every 3 months for a period of six months per National Comprehensive Cancer Network (NCCN) guidelines. The pathology results indicated the presence of chorionic villi composed of both large hydropic and smaller normal-appearing villi, a 69.3-gram female fetus compatible with caudal neurocutaneous defect with abnormal localization of brain tissue. The genetic profile of the villous tissue consisted of two sets of dispermic paternal alleles in addition to one set of maternal alleles consistent with a partial mole diagnosis. Discussion: There is an association between preeclampsia and molar pregnancy. Of partial hydatidiform molar pregnancies, 41.9% will develop the symptoms of preeclampsia if left untreated. Although the pathophysiology of eclampsia spectrum disorders is incompletely understood, some evidence points to the role of increased death of trophoblasts and the maternal inflammatory response to trophoblast deportation. Additional evidence points to angiogenic factor imbalance and interestingly, molar placentas produce high levels of antiangiogenic factors. Other causative agents include placental factors that trigger maternal endothelial activation. It is known that trophoblastic debris shed from the placenta into the maternal blood is associated with this condition. It has been demonstrated that trophoblastic debris from molar pregnancies also induces endothelial cell activation through heat-shock protein 70 (HSP70) expressed on a hydatidiform molar placenta, which may be a pathogenic signal to endothelial cells. This case reiterates the association between hydatidiform moles and the hypertensive disorders of pregnancy possibly supporting the theories that such disorders may share an etiologic linkage through trophoblast debris and angiogenic factor imbalance. This case also supports screening molar pregnancies for severe preeclampsia syndrome.

Association of prothrombin time, thrombin time and activated partial thromboplastin time levels with preeclampsia: a systematic review and meta-analysis

BackgroundPreeclampsia (PE), an obstetric disorder, remains one of the leading causes of maternal and infant mortality worldwide. In individuals with PE, the coagulation-fibrinolytic system is believed to be among the most significantly impacted systems due to maternal inflammatory responses and immune dysfunction. Therefore, this systematic review and meta-analysis aimed to assess the association of prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) levels with preeclampsia.MethodsThis systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines. Articles relevant to the study, published from July 26, 2013, to July 26, 2023, were systematically searched across various databases including PubMed, Scopus, Embase, and Hinari. The methodological quality of the articles was evaluated using the Joanna Briggs Institute critical appraisal checklist. Utilizing Stata version 14.0, a random-effects model was employed to estimate the pooled standardized mean difference (SMD) along with the respective 95% CIs. The I2 statistics and Cochrane Q test were utilized to assess heterogeneity, while subgroup analyses were performed to explore its sources. Furthermore, Egger’s regression test and funnel plot were employed to assess publication bias among the included studies.ResultsA total of 30 articles, involving 5,964 individuals (2,883 with PE and 3,081 as normotensive pregnant mothers), were included in this study. The overall pooled SMD for PT, APTT, and TT between PE and normotensive pregnant mothers were 0.97 (95% CI: 0.65–1.29, p < 0.001), 1.05 (95% CI: 0.74–1.36, p < 0.001), and 0.30 (95% CI: -0.08-0.69, p = 0.11), respectively. The pooled SMD indicates a significant increase in PT and APTT levels among PE patients compared to normotensive pregnant mothers, while the increase in TT levels among PE patients was not statistically significant.ConclusionsThe meta-analysis underscores the association between PE and prolonged PT and APTT. This suggests that evaluating coagulation parameters like PT, APTT, and TT in pregnant women could offer easily accessible and cost-effective clinical indicators for assessing PE. However, multicenter longitudinal studies are needed to evaluate their effectiveness across various gestational weeks of pregnancy.

Placental Histopathological Lesions and Adverse Neonatal Outcomes in Patients with Inflammatory Bowel Diseases- A retrospective Cohort Study.

Inflammatory bowel diseases (IBD) are significantly associated with adverse pregnancy and neonatal outcomes, though the pathomechanism is yet unknown. To investigate the relationship between IBD and adverse pregnancy outcomes by comparing neonatal outcomes and placental histopathology in two matched groups of patients with and without IBD. In this retrospective study, data of all patients who gave birth between 2008-2021 and were diagnosed with IBD were reviewed and compared to a control group matching two control cases for every IBD case. Neonatal outcomes and placental pathology were compared between the groups. Compared to the control group (n=76), the placentas of patients with IBD (n=36) were characterized by significantly lower placental weight (p < 0.001), and higher rates of maternal vascular malperfusion lesions (MVM, p < 0.001) and maternal and fetal inflammatory response lesions (p < 0.001). Neonates of patients with IBD were more frequently small for gestational age (SGA) (p=0.01), with increased rates of need for phototherapy (p = 0.03), respiratory morbidity and NICU admission (p < 0.001 for both outcomes). Multivariate logistic regression analyses adjusting for possible confounders (including maternal age, gestational age, chronic hypertension, smoking, and thrombophilia) confirmed the independent association between IBD and composite MVM lesions (aOR 4.31, p < 0.001), maternal inflammatory responses (aOR 40.22, p < 0.001) and SGA infants (aOR 4.31, p = 0.013). IBD is associated with increased rates of placental histopathological lesions and adverse pregnancy outcomes, including SGA infants. These novel findings imply the role of placental malperfusion and inflammatory processes in pregnancy complications of IBD patients, which should be followed accordingly. Approval of local ethics committee # WOMC-0219-20.

Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes

Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages the use of existing medications and hinders new drug development. One potential solution is the use of lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, and lack of fetal accumulation. Here, we describe LNPs for efficacious mRNA delivery to maternal organs in pregnant mice via several routes of administration. In the placenta, our lead LNP transfected trophoblasts, endothelial cells, and immune cells, with efficacy being structurally dependent on the ionizable lipid polyamine headgroup. Next, we show that LNP-induced maternal inflammatory responses affect mRNA expression in the maternal compartment and hinder neonatal development. Specifically, pro-inflammatory LNP structures and routes of administration curtailed efficacy in maternal lymphoid organs in an IL-1β-dependent manner. Further, immunogenic LNPs provoked the infiltration of adaptive immune cells into the placenta and restricted pup growth after birth. Together, our results provide mechanism-based structural guidance on the design of potent LNPs for safe use during pregnancy.

Nicotine regulates abnormal macrophage polarization and trophoblast invasion associated with preterm labor via the α7nAChR/SIRT1 axis

IntroductionPreterm birth (PTB) frequently results from the syndrome of preterm labor (PTL). PTL is linked to an atypical maternal inflammatory response, as well as intrauterine inflammation and/or infection. In this study, we explored the mechanisms involved in nicotine-mediated abnormal macrophage polarization and trophoblast invasion associated with PTL. MethodsFirst, THP-1-M0 macrophages were generated by treating the human monocytic leukemia cell line (THP-1) with phorbol 12-myristate 13-acetate for a duration of 24 h. Afterward, nicotine treatment was administered, followed by coculturing with the HTR-8/SVneo trophoblast cell line (HTR-8) at a ratio of 1:1. Next, we transfected sh-α7nAChR and treated THP-1-M0 macrophages and HTR-8 cells with nicotine. In addition, we transfected THP-1-M0 macrophages with sh-NC or sh-SIRT1 or subjected them to 4 nM nicotinamide adenine dinucleotide (NAD) metabolic inhibitor FK866 treatment. Moreover, HTR-8 cells were treated with nicotine, after which THP-1-M0 macrophages were cocultured with HTR-8 cells. Finally, we constructed an in vivo RU486-induced PTL rat model to verify the effect of nicotine and the mechanisms involved. ResultsWe found that nicotine affected polarization and α7nAChR expression in HTR-8 cocultured THP-1-M0 macrophages. Knocking down α7nAChR blocked the effect of nicotine on the proliferation and invasion of HTR-8 cells. Furthermore, nicotine activated the α7nAChR/SIRT1 axis to regulate THP-1-M0 macrophage polarization through the cholinergic anti-inflammatory pathway. Additionally, NAD metabolism mediated the role of the α7nAChR/SIRT1 axis in nicotine-induced polarization of HTR-8 cocultured THP-1-M0 macrophages. In vivo experiments demonstrated that nicotine alleviated inflammation in PTL rats, which involved the α7nAChR/SIRT1 axis. ConclusionNicotine regulated abnormal macrophage polarization and trophoblast invasion associated with PTL via the α7nAChR/SIRT1 axis.

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

Maternal quercetin supplementation improved lipopolysaccharide-induced cognitive deficits and inflammatory response in a rat model of maternal immune activation

BackgroundThere is strong evidence that prenatal infection during a specific period of brain development increases the risk of neurodevelopmental disorders, partly through immune-inflammatory pathways. This suggests that anti-inflammatory agents could prevent these disorders by targeting the maternal inflammatory response. In the present study, we used a rat model of maternal immune activation (MIA) to examine whether maternal quercetin (QE) supplementation can alleviate behavioral deficits and inflammatory mediators in the prefrontal cortex (PFC) and hippocampus of adult male offspring. MethodsPregnant rats were supplemented with QE (50 mg/kg) or vehicle throughout pregnancy and injected with either lipopolysaccharide (0.5 mg/kg) or saline on gestational days 15/16. At postnatal day 60, we evaluated the offspring's behavior, hippocampal and prefrontal cortex glial density, pro-inflammatory gene expression, and neuronal survival. ResultsOur data showed that maternal QE supplementation can prevent working and recognition memory impairments in adult MIA offspring. This behavioral improvement correlates with the decrease in MIA-induced expression of pro-inflammatory genes, microglia, and astrocyte densities, without affecting neuronal survival, in both PFC and CA1 hippocampus areas. ConclusionTherefore, our study supports the potential preventive effect of QE on MIA-induced behavioral dysfunctions, at least in part, by suppressing the glial-mediated inflammatory response.

Prevalence of Fetal Inflammatory Response Syndrome and Villitis of Unknown Etiology in the Placenta of Saudi Women and Their Association with Baby Sex.

Long-term health consequences are influenced by circumstances that occur during pregnancy. The convergence of the maternal and fetal circulations occurs in the placenta, which is the first organ to develop. Placental pathology provides an accurate diagnosis of amniotic sac inflammation, and pathological alterations in preterm placentas provide evidence for the causes of numerous perinatal pathologies, including spontaneous preterm births. This retrospective study aimed to re-examine placentas regarded as normal by the Obstetrics and Gynecology Department at our institution. Thirty-seven male and forty-seven female placentas were collected following full-term delivery, and the grading and staging of any evident inflammatory responses were evaluated and correlated with the babies' sex. Full-thickness placental samples that were considered normal and not sent to the histopathology department were obtained from the central and marginal regions of placental discs. Morphological examination of the fresh placenta was conducted, and fetal and maternal inflammatory response syndromes were assessed. In addition, placental villitis of unknown etiology (VUE) and chronic deciduitis were evaluated. Immunohistochemistry was performed to evaluate the patterns of inflammation in the placenta using anti-CD8 and anti-CD68 antibodies. The correlation between silent pathologies and clinical complications or the development of fetal inflammatory response syndrome was measured. In this study, 17 (20%) maternal and 10 (12%) fetal samples showed inflammatory responses. The frequencies of chronic deciduitis and VUE were higher among pregnant Saudi women than previously reported, probably because fetal inflammatory response syndrome goes unnoticed in Saudi Arabia. In addition, the prevalence of fetal and maternal inflammatory responses was higher in the placentas of the mothers of males than in those of females, suggesting that differences occur in the inflammatory response in the placenta depending on the sex of the newborn. Grading placental inflammation (in cases of VUE) typically predicts the degree of maternal anti-fetal cellular rejection; therefore, increasing the number of placental samples sent for microscopic inspection may be preferable because of their significance in identifying the causes of chronic disorders.

Prenatal exposure to intra-amniotic infection with Ureaplasma species increases the prevalence of bronchopulmonary dysplasia

Objectives The present study investigated the relationship between bronchopulmonary dysplasia (BPD) and intra-amniotic infection with Ureaplasma species. Methods This was a single-center, retrospective cohort study. Patients with singleton pregnancies who underwent inpatient management at our department for preterm premature rupture of membranes (PPROM), preterm labor, cervical insufficiency, and asymptomatic cervical shortening at 22–33 gestational weeks were included. Amniocentesis was indicated for patients with PPROM or an elevated maternal C-reactive protein level (≥0.58 mg/dL). Patients with an amniotic fluid IL-6 concentration ≥3.0 ng/mL were diagnosed with intra-amniotic inflammation, while those with positive aerobic, anaerobic, M. hominis, and Ureaplasma spp. cultures were diagnosed with microbial invasion of the amniotic cavity (MIAC). Patients who tested positive for both intra-amniotic inflammation and MIAC were considered to have intra-amniotic infection. An umbilical vein blood IL-6 concentration >11.0 pg/mL indicated fetal inflammatory response syndrome (FIRS). The maternal inflammatory response (MIR) and fetal inflammatory response (FIR) were staged using the Amsterdam Placental Workshop Group Consensus Statement. Results Intra-amniotic infection with Ureaplasma spp. was diagnosed in 37 patients, intra-amniotic infection without Ureaplasma spp. in 28, intra-amniotic inflammation without MIAC in 58, and preterm birth without MIR/FIR and FIRS in 86 as controls. Following an adjustment for gestational age at birth, the risk of BPD was increased in patients with intra-amniotic infection with Ureaplasma spp. (adjusted odds ratio: 10.5; 95% confidence interval: 1.55–71.2), but not in those with intra-amniotic infection without Ureaplasma spp. or intra-amniotic inflammation without MIAC. Conclusion BPD was only associated with intra-amniotic infection with Ureaplasma species.

Gestational hypertension and risk of atopic diseases in offspring, a national-wide cohort study

IntroductionGestational hypertension can lead to complications, such as preeclampsia. Preeclampsia is one of leading causes of perinatal morbidity and mortality. Abnormal placentation, immune dysregulation, and maternal inflammatory response are possible etiologies. The burden of atopic diseases is increasing worldwide. Prenatal exposure might play a role in the pathogenesis of these two diseases. The aim of this study was to evaluate the association between gestational hypertension and atopic diseases from a nationwide perspective.Material and methodsThe primary data were retrieved from Taiwan's National Health Insurance Research Database. The Maternal and Child Health Database was used to generate links between mothers and children. From 2004 to 2019, mothers with a diagnosis of gestational hypertension were identified as cases. The control groups were matched to the cases by maternal age, neonatal gender, date of birth, at a control-to-case ratio of 4:1. Each child was reviewed to confirm the diagnosis of atopic disease. Covariates including both maternal and neonatal factors were also collected.ResultsA total of 1,935,874 primiparas were enrolled in this study. After excluding 16,851 mothers with a history of hypertension, a total of 1,919,023 offspring were included in the study for the period 2004–2019. Gestational hypertension was associated with asthma (HR, 1.12, 95% CI, 1.02–1.23) and atopic dermatitis (HR, 1.10, 95% CI, 1.00–1.21) in offspring after controlling for cofactors. Nevertheless, gestational hypertension did not play an independent factor for allergic rhinitis (HR, 1.02, 95% CI, 0.95–1.10) or urticaria (HR, 1.02, 95% CI, 0.91–1.15).ConclusionMaternal gestational hypertension increases the cumulative risk for asthma and atopic dermatitis in offspring.

Modulation of vagal activity may help reduce neurodevelopmental damage in the offspring of mothers with pre-eclampsia.

Maternal Immune Activation (MIA) has been linked to the pathogenesis of pre-eclampsia and adverse neurodevelopmental outcomes in the offspring, such as cognitive deficits, behavioral abnormalities, and mental disorders. Pre-eclampsia is associated with an activation of the immune system characterized by persistently elevated levels of proinflammatory cytokines, as well as a decrease in immunoregulatory factors. The Cholinergic Anti-inflammatory Pathway (CAP) may play a relevant role in regulating the maternal inflammatory response during pre-eclampsia and protecting the developing fetus from inflammation-induced damage. Dysregulation in the CAP has been associated with the clinical evolution of pre-eclampsia. Some studies suggest that therapeutic stimulation of this pathway may improve maternal and fetal outcomes in preclinical models of pre-eclampsia. Modulation of vagal activity influences the CAP, improving maternal hemodynamics, limiting the inflammatory response, and promoting the growth of new neurons, which enhances synaptic plasticity and improves fetal neurodevelopment. Therefore, we postulate that modulation of vagal activity may improve maternal and fetal outcomes in pre-eclampsia by targeting underlying immune dysregulation and promoting better fetal neurodevelopment. In this perspective, we explore the clinical and experimental evidence of electrical, pharmacological, physical, and biological stimulation mechanisms capable of inducing therapeutical CAP, which may be applied in pre-eclampsia to improve the mother's and offspring's quality of life.

Association of maternal thyroid peroxidase antibody during pregnancy with placental morphology and inflammatory and oxidative stress responses.

Studies suggest that thyroid peroxidase antibody (TPOAb) positivity exposure during pregnancy may contribute to changes in placental morphology and pathophysiology. However, little is known about the association of maternal TPOAb during pregnancy with placental morphology and cytokines. This study focuses on the effect of repeated measurements of maternal TPOAb during pregnancy on the placental morphology and cytokines. Based on Ma'anshan Birth Cohort (MABC) in China, maternal TPOAb levels were retrospectively detected in the first, second and third trimesters. Placental tissues were collected 30 minutes after childbirth, placental morphological indicators were obtained by immediate measurement and formula calculation, and cytokine mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR) afterward. Generalized linear models and linear mixed models were analyzed for the relationships of maternal TPOAb in the first, second and third trimesters with placental indicators. Totally 2274 maternal-fetal pairs were included in the analysis of maternal TPOAb levels and placental morphology, and 2122 pairs were included in that of maternal TPOAb levels and placental cytokines. Maternal TPOAb levels in early pregnancy were negatively associated with placental length, thickness, volume, weight and disc eccentricity, while positively correlated with placental IL-6, TNF-α, CRP, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78. In mid-pregnancy, maternal TPOAb levels were negatively correlated with placental length, width and area. In late pregnancy, maternal TPOAb levels were negatively correlated with placental length, area, volume and weight. Repeated measures analysis showed that maternal TPOAb positivity tended to increase placental TNF-α, CD68 and MCP-1 while decreasing placental length, width and area than TPOAb negativity. Repeated measures analysis showed that maternal TPOAb levels were positively correlated with placental IL-6, TNF-α, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78, while negatively correlated with placental length, area, volume, weight, and disc eccentricity. There may be trimester-specific associations between maternal TPOAb levels and placental morphology and inflammatory and oxidative stress responses. The effect of maternal TPOAb levels on placental morphology is present throughout pregnancy. Early pregnancy may be the critical period for the association between maternal TPOAb levels and placental inflammatory and oxidative stress responses.

Serum cytokines in second trimester pregnancy and their relationship with spontaneous preterm births in the Ribeirão Preto and São Luiz cohorts

ObjectiveTo evaluate the association between second trimester plasma cytokine levels in asymptomatic pregnant women and preterm births (PTB) in an attempt to identify a possible predictor of preterm birth.MethodsThe study design was a nested case–control study including women with singleton a gestational age between 20–25(+ 6) weeks from two Brazilian cities. The patients were interviewed, Venous blood samples were collected. The participants were again evaluated at birth. A total of 197 women with PTB comprised the case group. The control group was selected among term births (426 patients). Forty-one cytokines were compared between groups.ResultsWhen only spontaneous PTB were analyzed, GRO, sCD40L and MCP-1 levels were lower in the case group (p < 0.05). Logarithmic transformation was performed for cytokines with discrepant results, which showed increased levels of IL-2 in the group of spontaneous PTB (p < 0.05). In both analyses, the incidence of maternal smoking and of a history of preterm delivery differed significantly between the case and control groups. In multivariate analysis, only serum GRO levels differed between the case and control groups.ConclusionLower second trimester serum levels of GRO in asymptomatic women are associated with a larger number of PTB. This finding may reflect a deficient maternal inflammatory response.

Retrospective analysis of leukemoid reactions in extremely preterm infants in a tertiary NICU from 2018–2021

Background Neonatal leukemoid reaction is associated with higher risk of mortality, chronic lung disease and has been associated with chorioamnionitis. Literature on extremely low birth weight infants with leukemoid reaction is limited. Objectives The aim of our study was to characterize the maternal and placental factors associated with neonatal leukemoid reaction and to describe outcomes of these ELBW infants. Our objective was to assess if there were maternal factors that would assist the decision-making process regarding the delivery of preterm infants at risk of chorioamnionitis and the sequelae of this inflammatory process. Methods This was a retrospective case-control study performed in a single, tertiary Maternity Hospital in Dublin. Two matched controls were identified for each case based on gestation and year of birth and data was collected on both the infants and their mothers. Results 7 extremely preterm neonates were identified as having a leukemoid reaction, defined as a total white cell count of >50,000 or in the first seven days of life. Baseline characteristics between the groups were similar. The median gestational age in the cases group was 24 + 4 weeks and in the control group was 24 + 1. The mean birthweight was 650 g in the cases group vs. 655 g in the control group. There was a higher percentage of males in the control group, 42.9% vs 28.6% in the cases. The preterm infants with leukemoid reaction had a longer duration of ventilation with a median of 18 days (7.5–23.5 days) compared to 6.5 days (2.8–24.5 days) in the control group. More infants in the leukemoid reaction group required inotropes for hypotension in the first 72 h after delivery (42.9% vs 7.1% in the controls, p value .169). Death or Bronchopulmonary dysplasia (BPD) occurred in 85.7% of the cases identified with a leukemoid reaction vs 71.4% of the controls matched. Median maternal CRP was higher in cases prior to delivery vs the controls (66 vs 18.1 mg/L, p-value = .2151). There was histological evidence of maternal inflammatory response in all cases with fetal inflammatory response in 71% of cases. Conclusions Leukemoid reaction in ELBW infants with evidence of maternal and fetal inflammatory response syndrome on placental histology is associated with a longer duration of initial ventilation, increased need for inotropes in the first 72 h after birth, higher rates of death, and BPD. Prospective studies are required to identify potential biomarkers such as proinflammatory cytokines, IL-6, which might aid the decision-making process in delivery.

Defined, low threshold for caesarean section and multidisciplinary team management improves fetal outcome from acute pancreatitis in pregnancy

BackgroundAcute pancreatitis in pregnancy (APIP) is associated with increased maternal and fetal mortality. ObjectivesWe sought to determine whether a low threshold for cesarean section (C-section) in severe acute pancreatitis (SAP) or Predict SAP improves maternal and fetal outcomes in patients with APIP. MethodsWe identified patients with APIP at a single institution from a prospective database and studied fetal and maternal health in APIP before (2005–2014) and after (2015–2019) introduction of multidisciplinary team management with a defined, lowered threshold for C-section. The primary end point was fetal mortality comprising abortion and perinatal death. Risk factors associated with fetal mortality were analyzed by univariable and multivariable logistic regression analysis. ResultsA total of 165 patients with APIP were eligible for analysis. There was a highly significant increase in patients undergoing C-section from 37 (30.8%) of 120 during 2005–2014 to 27 (60%) of 45 in 2015–2019 (P = 0.001), with a highly significant fall in fetal mortality from 37 (30.8%) of 120 to 3 (6.7%) of 45 between the same periods (P = 0.001), when maternal mortality fell from 6 to zero (P = 0.19). Maternal early systemic inflammatory response syndrome (SIRS) (odds ratio [OR] 6.98, 95% confidence interval [CI] 1.53, 30.80, P = 0.01) and SAP (OR 3.64, 95%CI 1.25, 10.60, P = 0.02) were two independent risk factors associated with fetal mortality. ConclusionsMultidisciplinary collaboration and a defined, low threshold for C-section improve fetal outcomes in patients with APIP.

Placental inflammation and overweight or obesity in term singleton stillbirths in Stockholm County 2002-2018; a case control study.

Stillbirth is a severe pregnancy complication. Maternal obesity is one of the most important modifiable risk factors of stillbirth, yet the biological mechanisms behind this association remain unclear. The adipose tissue is an endocrine organ which, in persons with obesity, causes a hyperinflammatory state. The aim of this study was to investigate inflammation as a contributing mechanism to the risk of stillbirth in women with obesity and if there are possible signs of different BMI phenotypes with different risk. This was a case control study based on all cases of term singleton stillbirth without major fetal malformation in Stockholm County between 2002-2018. Placentas have been examined according to a standardized protocol. Placental inflammatory lesions were compared both between placentas from pregnancies with live born and stillborn infants with different class of body mass index (BMI) as well as among women with stillborn and live born infants with different classes of BMI, respectively. All inflammatory placental lesions were more common in placentas from women with stillbirth compared to placentas from women with live born infants. Vasculitis, funisitis and chronic villitis as well as overall fetal and maternal inflammatory response were present with a significantly increased proportion with increasing BMI in placentas from women with term stillbirth however, there were no differences between placentas from women in different BMI classes with term live born infants. Both acute and chronic inflammatory placental lesions were more common in cases of stillbirth compared to pregnancies with live born infants. There were increased proportions of both acute and chronic placental inflammation (vasculitis, chronic villitis, funisitis and overall fetal and maternal inflammatory response) with increasing BMI among cases with term stillbirth, however no differences among controls with term live born infants.

Infection Induced Fetal Inflammatory Response Syndrome (FIRS): State-of- the-Art and Medico-Legal Implications-A Narrative Review.

Fetal inflammatory response syndrome (FIRS) represents the fetal inflammatory reaction to intrauterine infection or injury, potentially leading to multiorgan impairment, neonatal mortality, and morbidity. Infections induce FIRS after chorioamnionitis (CA), defined as acute maternal inflammatory response to amniotic fluid infection, acute funisitis and chorionic vasculitis. FIRS involves many molecules, i.e., cytokines and/or chemokines, able to directly or indirectly damage fetal organs. Therefore, due to FIRS being a condition with a complex etiopathogenesis and multiple organ dysfunction, especially brain injury, medical liability is frequently claimed. In medical malpractice, reconstruction of the pathological pathways is paramount. However, in cases of FIRS, ideal medical conduct is hard to delineate, due to uncertainty in diagnosis, treatment, and prognosis of this highly complex condition. This narrative review revises the current knowledge of FIRS caused by infections, maternal and neonatal diagnosis and treatments, the main consequences of the disease and their prognoses, and discusses the medico-legal implications.