ABSTRACT
Fetal autoimmune atrioventricular block (AVB) is a rare but potentially life-threatening condition. It results from the passage of maternal anti-SSA/Ro or Anti SSB/La auto-antibodies into the fetal circulation, leading to inflammation and fibrosis of the AV node and often to irreversible damage. Besides AVB, these antibodies can also cause cardiomyopathies, but there is no evidence linking them to tachyarrhythmias. We present the case of a patient with significant risk factors for fetal AVB: a prior history of hydrops fetalis, high anti-SSA/Ro antibody levels and hypothyroidism. In this case, the use of dexamethasone and intravenous immunoglobulin may have contributed to reversing the first-degree atrioventricular block detected at 19 weeks of gestation. Additionally, at 21 weeks, the fetus developed a tachyarrhythmia that needed treatment with flecainide. Soon after the birth, the newborn underwent ECG Holter and Wolff-Parkinson-White Syndrome (WPWS) was diagnosed. To our knowledge, the coexistence of fetal AVB and WPWS has never been described.
Subject(s)
Antibodies, Antinuclear , Atrioventricular Block , Tachycardia , Wolff-Parkinson-White Syndrome , Humans , Female , Pregnancy , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/immunology , Wolff-Parkinson-White Syndrome/diagnosis , Wolff-Parkinson-White Syndrome/immunology , Tachycardia/diagnosis , Tachycardia/etiology , Atrioventricular Block/diagnosis , Atrioventricular Block/immunology , Atrioventricular Block/etiology , Adult , Infant, Newborn , Fetal Diseases/diagnosis , Fetal Diseases/immunology , Immunoglobulins, Intravenous/therapeutic useABSTRACT
The aim of this study was to evaluate maternal serological status and fetal sonographic findings of Cytomegalovirus (CMV) infection. This is a retrospective study performed at Perinatology Department of Istanbul Basaksehir Çam and Sakura City Hospital. A computerized search was conducted to identify cases who underwent prenatal diagnosis of fetal CMV infection between September 2020 and December 2023. We identified nine cases with fetal CMV infection. The clinical data of the patients, gestational age at the time of diagnosis, serological, sonographic findings, and pregnancy outcomes were analyzed. A computer search of the database was made for the seroprevalance of CMV-IgM and CMV-IgG in our population. The CMV-IgM and IgG results of the 1235 patients who underwent CMV screening in the first trimester between September 2020 and December 2023 were evaluated. Fetal CMV infection was identified in nine patients. None of the 9 cases showed maternal CMV-IgM positivity. Seven of the 9 patients showed high IgG avidity index. Pregnant population had 98 % positivity for CMV-IgG. The evaluation of serologic tests for CMV is not straightforward in the second and third trimester. IgM and IgG avidity should be interpreted with caution in the second and third trimester. In the presence of ultrasound findings suggesting fetal CMV infection and CMV-IgG positivity, invasive diagnostic tests rather than serological test should be discussed with the patient, and non-primary infections should always be considered to minimize overlooked fetal cytomegalovirus infections and missed antiviral treatment opportunity.
Subject(s)
Antibodies, Viral , Cytomegalovirus Infections , Cytomegalovirus , Immunoglobulin M , Pregnancy Complications, Infectious , Humans , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/immunology , Female , Pregnancy , Immunoglobulin M/blood , Retrospective Studies , Adult , Cytomegalovirus/immunology , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , Antibodies, Viral/blood , Ultrasonography, Prenatal , Immunoglobulin G/blood , Fetal Diseases/virology , Fetal Diseases/immunology , Fetal Diseases/diagnosis , Fetal Diseases/bloodABSTRACT
Most cases of fetal and neonatal thrombocytopenia (FNAIT) are caused by maternal anti-human platelet antigen-1a antibodies (anti-HPA-1a). Anti-HPA-5b antibodies are the second most common antibodies in suspected FNAIT cases. Given the high prevalence of anti-HPA-5b antibodies in pregnant women delivering healthy newborns, the association with FNAIT may be coincidental. This review of the literature related to FNAIT using the MEDLINE database was conducted according to PRISMA guidelines. A retrospective analysis of a single-centre cohort of 817 suspected FNAIT cases was conducted. The pooled prevalence of anti-HPA-5b antibodies in unselected pregnant women of European descent was 1.96% (n = 3113), compared with 3.4% (n = 5003) in women with suspected FNAIT. We found weak evidence that a small proportion of pregnant women presenting with anti-HPA-5b antibodies will give birth to a newborn with mild thrombocytopenia. The neonatal platelet counts were not different between suspected FNAIT cases (n = 817) with and without maternal anti-HPA-5b antibodies. The prevalence of maternal anti-HPA-5b antibodies was not different between neonates with intracranial haemorrhage and healthy controls. The current experimental and epidemiological evidence does not support the hypothesis that anti-HPA-5b antibodies cause severe thrombocytopenia or bleeding complications in the fetus or newborn.
Subject(s)
Antigens, Human Platelet , Fetal Diseases , Infant, Newborn, Diseases , Thrombocytopenia, Neonatal Alloimmune , Antibodies , Antigens, Human Platelet/immunology , Female , Fetal Diseases/diagnosis , Fetal Diseases/immunology , Fetus , Humans , Infant, Newborn , Integrin beta3 , Platelet Count , Pregnancy , Prenatal Care , Retrospective Studies , Thrombocytopenia, Neonatal Alloimmune/diagnosis , Thrombocytopenia, Neonatal Alloimmune/immunologyABSTRACT
Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay. Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Graves' disease (GD) results from the passage of thyrotropin receptor antibodies (TRAbs) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking thyroid-stimulating hormone receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism, but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child's prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.
Subject(s)
Fetal Diseases/diagnosis , Thyroid Diseases/diagnosis , Thyroid Gland/physiopathology , Adult , Autoantibodies/blood , Autoantibodies/immunology , Female , Fetal Diseases/immunology , Fetal Diseases/physiopathology , Humans , Infant, Newborn , Neonatal Screening , Thyroid Diseases/immunology , Thyroid Diseases/physiopathology , Thyroid Gland/immunology , Thyrotropin/immunologyABSTRACT
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.
Subject(s)
Fetal Diseases/immunology , Fetus/immunology , Inflammation/immunology , Macrophages/immunology , Premature Birth/immunology , Adult , Animals , Animals, Newborn , CD11b Antigen/genetics , Cytokines , Decidua/immunology , Decidua/metabolism , Female , Fetus/metabolism , Homeostasis/immunology , Humans , Mice , Myometrium/immunology , Myometrium/metabolism , Obstetric Labor, Premature/immunology , Obstetric Labor, Premature/metabolism , Pregnancy , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Young AdultABSTRACT
INTRODUCTION: Neonatal hyperthyroidism is a disease that can cause mortality and sequelae. To date, there is no clinical series of cases that allows us to know the local reality of this condition. OBJECTIVE: to charac terize the children of mothers with Graves' disease (GD) from a clinical and biochemical point of view. SUBJECTS AND METHOD: A prospective follow-up of all newborns (NB) of mothers with history of GD was performed in two public hospitals in Santiago, during 5 years. Clinical and laboratory variables of mother-child pairs and thyroid-stimulating hormone receptor antibodies (TRAbs) le vels were analyzed looking for associations between these variables and the development of neonatal hyperthyroidism. RESULTS: Seventy-six mother-child pairs were included (0.2% of all deliveries). Five neonates (6.6%) presented biochemical hyperthyroidism, and 3 of them developed clinical disease and required treatment. All 5 NBs who developed hyperthyroidism had mothers with positive or indeterminate TRAbs. No child of TRAbs-negative mothers developed the disease. TRAbs could be determined in only 65% of the mothers and 72% of the NBs. There was a significant correlation bet ween maternal TRAbs titers (p < 0.03), neonatal TRAbs titers (p < 0.008), and neonatal TSH between days 2-6 (p < 0.006), with the subsequent development of hyperthyroidism. All cases of neonatal hyperthyroidism were transient. There was no mortality in our series. CONCLUSIONS: This is the first national case series of children of mothers with GD. Maternal and neonatal TRAbs and TSH between days 2-6 of life were predictors of neonatal hyperthyroidism.
Subject(s)
Fetal Diseases/blood , Graves Disease/blood , Hyperthyroidism/diagnosis , Pregnancy Complications/epidemiology , Prenatal Exposure Delayed Effects/therapy , Thyrotoxicosis , Biomarkers/blood , Child of Impaired Parents , Female , Fetal Diseases/etiology , Fetal Diseases/immunology , Graves Disease/complications , Humans , Hyperthyroidism/blood , Hyperthyroidism/congenital , Infant, Newborn , Infant, Newborn, Diseases , Mothers , Pregnancy , Prenatal Exposure Delayed Effects/blood , Prospective Studies , Thyroid Function Tests , ThyrotropinABSTRACT
Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.
Subject(s)
Fetal Diseases/immunology , Immune Tolerance/genetics , Infant, Low Birth Weight/immunology , Infant, Premature/immunology , Systemic Inflammatory Response Syndrome/immunology , Adult , Female , Fetal Blood , Fetal Diseases/blood , Fetal Diseases/diagnosis , Fetal Diseases/genetics , Gene Expression Profiling , Humans , Infant, Low Birth Weight/blood , Infant, Newborn , Infant, Premature/blood , Male , Maternal Age , Retrospective Studies , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/genetics , Young AdultABSTRACT
OBJECTIVE: Investigate the characteristics and serology of pregnant women with cytomegalovirus (CMV) immunoglobulin (Ig)G seroconversion during pregnancy to understand the risk factors associated with primary CMV infection and the occurrence of fetal congenital CMV infection. MATERIALS AND METHODS: We retrospectively studied 3202 pregnant women who were CMV IgG-negative in early pregnancy and were retested for IgG in late pregnancy. Characteristics were compared between participants with and without IgG seroconversion, and serological parameters were compared between participants with and without fetal congenital CMV infection. RESULTS: Twenty-six participants showed CMV IgG seroconversion and fifteen showed fetal congenital CMV infection. Seroconversion rates were significantly higher in teens (5.0%) than in older women (20s: 0.8%; 30s and over: 0.6%) (p < 0.001). Titers of CMV IgM at IgG seroconversion were higher in women without (median 8.66) than with (median 6.54) congenital infection (p = 0.045). The congenital infection rate was high when IgM titers at IgG seroconversion were low (47.1% with 4.00-12.00 titers and 100% with 1.21-3.99 IgM titers) (p = 0.048). CONCLUSIONS: Nulliparous pregnant teenagers have a high risk of CMV IgG seroconversion and the CMV IgM titer at IgG seroconversion may help predict the occurrence of fetal congenital CMV infection.
Subject(s)
Cytomegalovirus/immunology , Fetal Diseases/immunology , Immunoglobulin G/blood , Immunoglobulins, Intravenous/blood , Pregnancy Complications, Infectious/virology , Adult , Cytomegalovirus Infections/embryology , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/transmission , Female , Fetal Diseases/virology , Humans , Immunoglobulin G/immunology , Immunoglobulins, Intravenous/immunology , Japan , Pregnancy , Pregnancy Complications, Infectious/immunology , Retrospective Studies , Risk Factors , SeroconversionABSTRACT
INTRODUCTION: Maternal Cytomegalovirus (CMV) infection in the first trimester (T1) of pregnancy is a public health concern, as it increases the risk of severe neurodevelopmental outcomes associated with congenital infection compared to infections occurring later during pregnancy. OBJECTIVES: To determine CMV seroprevalence in T1 of pregnancy, its trend, risk factors and the incidence rate of primary infection during pregnancy. METHODS: Using the biobank of the prospective cohort "Grossesse en Santé de Québec" collected between April 2005 and March 2010 at the Québec-Laval Hospital, Québec, Canada, maternal CMV serology was determined using Abbott Architect Chemiluminescence microparticle immunoassays for immunoglobulin G(IgG), immunoglobulin M(IgM) titration and IgG avidity testing. Changepoint detection analysis was used to assess temporal trends. Risk factors associated with seropositivity were determined by multivariable logistic regression. RESULTS: CMV seroprevalence in T1 of pregnancy was 23.4% (965/4111, 95% CI, 22.1-24.7%). The incidence rate for CMV primary infection during pregnancy was 1.8 (95% CI, 1.2-2.6) per 100 person-years. No changepoint was identified in the maternal CMV-seroprevalence trend. Multivariable analyses showed that T1 maternal CMV seropositivity was associated with having one child OR 1.3 (95% CI, 1.10-1.73) or two or more children OR 1.5 (95%CI, 1.1-2.1), ethnicity other than Caucasian OR 2.1 (95% CI, 1.1-3.8) and country of birth other than Canada and the USA OR 2.8 (95% CI, 1.5-4.9). CONCLUSIONS: In this cohort, maternal seroprevalence in T1 of pregnancy and seroconversion rate were low. This information and identified risk factors could help guide the development and implementation of preventive actions and evidence-based health policies to prevent CMV infection during pregnancy.
Subject(s)
Cytomegalovirus Infections/etiology , Cytomegalovirus Infections/virology , Pregnancy Complications, Infectious/genetics , Adolescent , Adult , Antibodies, Viral/immunology , Cytomegalovirus/immunology , Cytomegalovirus Infections/immunology , Female , Fetal Diseases/etiology , Fetal Diseases/immunology , Fetal Diseases/virology , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Infectious Disease Transmission, Vertical , Male , Parturition/immunology , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology , Pregnancy Trimester, First/immunology , Prospective Studies , Quebec , Risk Factors , Seroepidemiologic Studies , Young AdultABSTRACT
RATIONALE: Fetal alloimmune thrombocytopenia (FAIT) is a serious life-threatening disease caused by platelet-antigen incompatibility between the mother and fetus. FAIT can lead to fetal thrombocytopenia, intracranial hemorrhage (ICH), fetal death and severe neurological disorders after birth. Noninvasive prenatal diagnosis technology has not been widely used in China, and thus few cases of FAIT can be diagnosed prenatally. In this study, we report a case of prenatal diagnosis and treatment of FAIT. PATIENT CONCERNS: A 29-year-old female was admitted at 32 weeks' gestational age (GA). Fetal ultrasound at 32 weeks' GA showed a hemorrhagic focus area in the left lateral ventricle and the sign of severe fetal anemia. Hence, fetal umbilical cord puncture was ordered to identify the etiology. DIAGNOSES: The fetal cord blood test revealed a normal hemoglobin level but severe fetal thrombocytopenia (platelet count, 23 × 109/L). Antibodies of human platelet antigens and human leukocyte antigens between mother and fetus were positive, and thus the diagnosis of FAIT was confirmed. INTERVENTIONS: The patient refused intravenous immunoglobulin (IVIG) therapy owing to financial consideration. She was treated with dexamethasone acetate tablets (Xianju Company, China) 0.75âmg twice a day until delivery and cesarean section was performed at 34 weeks' GA. The newborn received postnatal anti-platelet antibody treatment. OUTCOMES: The platelet count of the newborn progressively decreased until the third day after birth and it increased to normal level after postnatal treatment. The neonatal cerebral ultrasound showed the area of hemorrhage was in the process of absorption. During the postnatal one-year follow-up, the neonate showed normal developmental milestones and had no abnormal signs of neurological symptoms. LESSONS: For FAIT, the fetal umbilical cord puncture can be carried out by skilled fetal medical teams. Dexamethasone acetate tablets can be an alternative choice for patients from underdeveloped areas.
Subject(s)
Fetal Blood/immunology , Fetal Diseases/diagnosis , Prenatal Diagnosis/methods , Thrombocytopenia, Neonatal Alloimmune/diagnosis , Adult , Antigens, Human Platelet/blood , Antigens, Human Platelet/immunology , Female , Fetal Diseases/immunology , HLA Antigens/blood , HLA Antigens/immunology , Humans , Infant, Newborn , Platelet Count , Pregnancy , Thrombocytopenia, Neonatal Alloimmune/immunologyABSTRACT
Fetal anemia is common in malaria-endemic areas and a risk factor for anemia as well as mortality during infancy. Placental malaria (PM) and red cell abnormalities have been proposed as possible etiologies, but the relationship between PM and fetal anemia has varied in earlier studies, and the role of red cell abnormalities has not been studied in malaria-endemic areas. In a Tanzanian birth cohort study designed to elucidate the pathogenesis of severe malaria in young infants, we performed a cross-sectional analysis of risk factors for fetal anemia. We determined PM status, newborn red cell abnormalities, and maternal and cord blood levels of iron regulatory proteins, erythropoietin (EPO), cytokines and cytokine receptors. We examined the relationship between these factors and fetal anemia. Fetal anemia was present in 46.2% of the neonates but was not related to PM. Maternal iron deficiency was common (81.6%), most frequent in multigravidae, and interacted with parity to modify risk of fetal anemia, but it was not directly related to risk. Among offspring of iron-deficient women, the odds of fetal anemia increased with fetal α+-thalassemia, as well as these patterns of cord blood cytokines: increased cord IL-6, decreased TNF-RI, and decreased sTfR. The EPO response to fetal anemia was low or absent and EPO levels were significantly decreased in newborns with the most severe anemia. This study from an area of high malaria transmission provides evidence that 1) fetal α+-thalassemia and cytokine balance, but not PM at delivery, are related to fetal anemia; 2) maternal iron deficiency increases the risk that other factors may cause fetal anemia; and 3) fetal anemia has a multifactorial etiology that may require a variety of interventions, although measures that reduce maternal iron deficiency may be generally beneficial.
Subject(s)
Anemia/etiology , Cytokines/blood , Erythropoietin/blood , Fetal Diseases/etiology , Fetus/metabolism , Malaria/parasitology , Placenta/parasitology , Pregnancy Complications, Parasitic/parasitology , alpha-Thalassemia/complications , Adult , Anemia/blood , Anemia/immunology , Anemia/parasitology , Biomarkers/blood , Cross-Sectional Studies , Female , Fetal Diseases/blood , Fetal Diseases/immunology , Fetal Diseases/parasitology , Fetus/immunology , Hemoglobins/metabolism , Humans , Infant, Newborn , Iron/blood , Iron Deficiencies , Malaria/blood , Malaria/immunology , Male , Maternal Health , Parity , Placenta/immunology , Placenta/metabolism , Pregnancy , Pregnancy Complications, Parasitic/blood , Pregnancy Complications, Parasitic/immunology , Risk Assessment , Risk Factors , Tanzania , Transferrin/metabolism , Young Adult , alpha-Thalassemia/blood , alpha-Thalassemia/immunologyABSTRACT
Hemophilia is an X-linked recessive bleeding disorder. In pregnant women carrier of hemophilia, the fetal sex can be determined by non-invasive analysis of fetal DNA circulating in the maternal blood. However, in case of a male fetus, conventional invasive procedures are required for the diagnosis of hemophilia. Fetal cells, circulating in the maternal bloodstream, are an ideal target for a safe non-invasive prenatal diagnosis. Nevertheless, the small number of cells and the lack of specific fetal markers have been the most limiting factors for their isolation. We aimed to develop monoclonal antibodies (mAbs) against the ribosomal protein RPS4Y1 expressed in male cells. By Western blotting, immunoprecipitation and immunofluorescence analyses performed on cell lysates from male human hepatoma (HepG2) and female human embryonic kidney (HEK293) we developed and characterized a specific monoclonal antibody against the native form of the male RPS4Y1 protein that can distinguish male from female cells. The availability of the RPS4Y1-targeting monoclonal antibody should facilitate the development of novel methods for the reliable isolation of male fetal cells from the maternal blood and their future use for non-invasive prenatal diagnosis of X-linked inherited disease such as hemophilia.
Subject(s)
Antibodies, Monoclonal/immunology , Cell-Free Nucleic Acids/immunology , Fetal Diseases/immunology , Hemophilia A/immunology , Prenatal Diagnosis/methods , Ribosomal Proteins/immunology , Antibody Specificity/immunology , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/metabolism , Female , Fetal Diseases/blood , Fetal Diseases/diagnosis , HEK293 Cells , Hemophilia A/blood , Hemophilia A/diagnosis , Hep G2 Cells , Humans , Male , Pregnancy , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolism , Sensitivity and SpecificityABSTRACT
Type I interferon (IFN) signaling in fetal tissues causes developmental abnormalities and fetal demise. Although pathogens that infect fetal tissues can induce birth defects through the local production of type I IFN, it remains unknown why systemic IFN generated during maternal infections only rarely causes fetal developmental defects. Here, we report that activation of the guanine nucleotide-binding protein-coupled estrogen receptor 1 (GPER1) during pregnancy is both necessary and sufficient to suppress IFN signaling and does so disproportionately in reproductive and fetal tissues. Inactivation of GPER1 in mice halted fetal development and promoted fetal demise, but only in the context of maternal inflammation. Thus, GPER1 is a central regulator of IFN signaling during pregnancy that allows dynamic antiviral responses in maternal tissues while also preserving fetal health.
Subject(s)
Fetal Diseases/immunology , Inflammation/immunology , Maternal-Fetal Exchange/immunology , Pregnancy Complications, Infectious/immunology , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Benzodioxoles/pharmacology , CRISPR-Cas Systems , Female , Fetal Diseases/virology , Fetus/immunology , Fetus/virology , Humans , Influenza A virus/immunology , Influenza, Human/immunology , Interferon Type I/immunology , Mice , Mice, Inbred C57BL , Placenta/immunology , Placenta/virology , Pregnancy , Quinolines/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Receptors, G-Protein-Coupled/antagonists & inhibitorsABSTRACT
BACKGROUND: Fetal complete atrioventricular block (CAVB) is usually autoimmune mediated. The risk of developing CAVB is 2% to 3% in anti-Ro/SS-A seropositive pregnancies and it increases 10 times after previous CAVB in siblings. Despite being a rare complication, CAVB carries a 20% mortality rate and substantial morbidity, as about 65% of newborns will eventually need life-long pacing. Once found, fetal CAVB is almost always irreversible, despite aggressive immunotherapy. This poor outcome prompted some research groups to address this situation. All groups followed anti-Ro/SS-A seropositive pregnancies on a weekly basis during the second trimester of pregnancy and tried to detect first degree atrioventricular block (AVB) using accurate echocardiographic tools, assuming they may characterize the initiation of the immune damage to the A-V conduction system, at which point the process might still be reversible. Some of the groups treated fetuses with first degree AVB with maternal oral fluorinated steroids. We summarized the results of all groups, including our group. We describe a case of a fetus that developed CAVB 6 days after normal sinus rhythm (NSR), who under aggressive dexamethasone therapy gradually reverted to NSR. This fetus had a previous sibling with CAVB. We assumed the immune damage to the conduction system in this small group of fetuses with a previous CAVB sibling may have occurred more quickly than usual. We therefore recommend a twice-weekly follow-up with these fetuses.
Subject(s)
Atrioventricular Block/drug therapy , Dexamethasone/administration & dosage , Fetal Diseases/drug therapy , Adult , Atrioventricular Block/diagnosis , Atrioventricular Block/immunology , Female , Fetal Diseases/diagnosis , Fetal Diseases/immunology , Glucocorticoids/administration & dosage , Humans , Infant, Newborn , Pregnancy , Pregnancy Trimester, Second , Prenatal Diagnosis/methods , Treatment OutcomeABSTRACT
The central nervous system (CNS) harbors its own immune system composed of microglia in the parenchyma and CNS-associated macrophages (CAMs) in the perivascular space, leptomeninges, dura mater, and choroid plexus. Recent advances in understanding the CNS resident immune cells gave new insights into development, maturation and function of its immune guard. Microglia and CAMs undergo essential steps of differentiation and maturation triggered by environmental factors as well as intrinsic transcriptional programs throughout embryonic and postnatal development. These shaping steps allow the macrophages to adapt to their specific physiological function as first line of defense of the CNS and its interfaces. During infancy, the CNS might be targeted by a plethora of different pathogens which can cause severe tissue damage with potentially long reaching defects. Therefore, an efficient immune response of infant CNS macrophages is required even at these early stages to clear the infections but may also lead to detrimental consequences for the developing CNS. Here, we highlight the recent knowledge of the infant CNS immune system during embryonic and postnatal infections and the consequences for the developing CNS.
Subject(s)
Central Nervous System/immunology , Encephalomyelitis/immunology , Macrophages/immunology , Animals , Candidiasis/embryology , Candidiasis/immunology , Central Nervous System/embryology , Central Nervous System/growth & development , Cytokines/immunology , Female , Fetal Diseases/immunology , Fetus/immunology , Humans , Infant , Infectious Disease Transmission, Vertical , Maternal-Fetal Exchange , Placenta/physiology , Pregnancy , Pregnancy Complications, Infectious/immunology , Prenatal Exposure Delayed Effects , Rats , Receptors, Pattern Recognition/immunology , Streptococcal Infections/embryology , Streptococcal Infections/immunology , Toxoplasmosis, Congenital/immunology , Virus Diseases/embryology , Virus Diseases/immunologyABSTRACT
Although many pregnant women have been infected by coronavirus, the presence of intrauterine vertical transmission has not been conclusively reported yet. What prevents this highly contagious virus from reaching the fetus? Is it only the presence of a strong placental barrier, or is it the natural absence of the some receptor that the viruses use for transmission? We, therefore, need to comprehensively understand the mechanism of action of the mammalian epithelial barriers located in two different organs with functional similarity. The barriers selected as potential targets by SARS-CoV-2 are the alveolo-capillary barrier (ACB), and the syncytio-capillary barrier (SCB). Caveolae are omega-shaped structures located on the cell membrane. They consist of caveolin-1 protein (Cav-1) and are involved in the internalisation of some viruses. By activating leukocytes and nuclear factor-κB, Cav-1 initiates inflammatory reactions. The presence of more than one Cav-1 binding sites on coronavirus is an important finding supporting the possible relationship between SARS-CoV-2-mediated lung injury. While the ACB cells express Cav-1 there is no caveolin expression in syncytiotrophoblasts. In this short review, we will try to explain our hypothesis that the lack of caveolin expression in the SCB is one of the most important physiological mechanisms that prevents vertical transmission of SARS-CoV-2. Since the physiological Cav-1 deficiency appears to prevent acute cell damage treatment algorithms could potentially be developed to block this pathway in the non-pregnant population affected by SARS-CoV-2.
Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Fetal Diseases/prevention & control , Infectious Disease Transmission, Vertical/prevention & control , Maternal-Fetal Exchange/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Betacoronavirus/immunology , COVID-19 , Caveolin 1/physiology , Coronavirus Infections/immunology , Epithelium/physiology , Epithelium/virology , Female , Fetal Diseases/immunology , Fetal Diseases/virology , Giant Cells/physiology , Giant Cells/virology , Humans , Immunity, Innate/physiology , Pneumonia, Viral/immunology , Pregnancy , Risk Factors , SARS-CoV-2 , Virus InternalizationABSTRACT
Viral infections during pregnancy can have devastating consequences on pregnancy outcomes, fetal development, and maternal health. In this review, we examine fetal and maternal immune defense mechanisms that mediate resistance against viral infections and discuss the range of syndromes that ensue when such mechanisms fail, from fetal developmental defects to establishment of chronic infection. Further, we highlight the role of maternal immune activation, or uncontrolled inflammation triggered by viral infections during pregnancy, and its potential downstream pathological effects, including tissue damage and fetal demise. Insights into the respective contributions of direct viral toxicity versus fetal and maternal immune responses that underlie the pathogenesis of congenital disease will guide future treatment strategies.
Subject(s)
Fetal Diseases/virology , Fetus/abnormalities , Maternal-Fetal Exchange/immunology , Pregnancy Complications, Infectious/virology , Virus Diseases/immunology , Female , Fetal Development/immunology , Fetal Diseases/immunology , Fetus/immunology , Fetus/virology , Humans , Immunity, Innate , Pregnancy , Pregnancy OutcomeABSTRACT
Fetuses exposed to an inflammatory environment are predisposed to long-term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mechanistic target of rapamycin (mTOR) signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well-established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba-1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67-positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2 hr after LPS treatment, declined at 6 hr and showed overall inhibition at 24 hr. In summary, our study revealed that LPS-induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.
Subject(s)
Brain Diseases , Cerebral Cortex , Fetal Development/physiology , Fetal Diseases , Inflammation , Microglia , Signal Transduction/physiology , TOR Serine-Threonine Kinases/metabolism , Animals , Brain Diseases/immunology , Brain Diseases/metabolism , Brain Diseases/pathology , Cerebral Cortex/immunology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Disease Models, Animal , Female , Fetal Development/immunology , Fetal Diseases/immunology , Fetal Diseases/metabolism , Fetal Diseases/pathology , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Lipopolysaccharides/pharmacology , Mice , Microglia/immunology , Microglia/metabolism , Pregnancy , Signal Transduction/immunologyABSTRACT
Fetal inflammatory response syndrome (FIRS) is a condition defined by systemic inflammation in the fetus, a rapid increase of pro-inflammatory cytokines into the fetal circulation (including interleukin-1 and interleukin-6), as well as a cellular response (such as increased neutrophils, monocyte/macrophages, and T cells) and the presence of funisitis. FIRS can lead to death and multisystem organ damage in the fetus and newborn. Brain injuries and subsequent risk of cerebral palsy and cognitive impairments are the most threatening long-term complications. This paper reviews the definition of FIRS, summarizes its associated complications, briefly describes the available methods to study FIRS, and discusses in more detail the potential therapeutic candidates that have been so far studied to protect the fetus/newborn from FIRS and to alleviate its associated complications and sequelae.