Fetal Brain Injury Research Articles

The Impact of Chronic Intrauterine Inflammation on the Physiologic and Neurodevelopmental Consequences of Intermittent Umbilical Cord Occlusion in Fetal Sheep

To determine the effect of intrauterine inflammation on fetal responses to umbilical cord occlusion (UCO). In pregnant sheep, lipopolysaccharide (LPS) or saline (SAL) was infused intra-amniotically for 4 weeks from 80 days of gestation (d). At 110 d, fetuses were instrumented for UCOs (5 × 2-minutes, 30-minute intervals: LPS + UCO, n = 6; SAL + UCO, n = 8) or no UCO (sham, n = 6) on 117 and 118 d. Tissues were collected at 126 d. Fetal physiological responses to UCO were similar between LPS + UCO and SAL + UCO. Histologic chorioamnionitis and increased amniotic fluid interleukin 8 (IL-8) were observed in LPS + UCO pregnancies (versus SAL + UCO, P < .05). CNPase-positive oligodendrocyte number in the cerebral white matter was lower in LPS + UCO and SAL + UCO than sham (P < .05); there was no effect on astrocytes or activated microglia/macrophages. Two of the SAL + UCO fetuses had white matter lesions; none were observed in LPS + UCO or sham. Chronic pre-existing intrauterine inflammation did not exacerbate fetal brain injury induced by intermittent UCO.

IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of interleukin (IL)-1β in the fetal brain and placenta. In this study, we hypothesized that IL-1 plays a key role in perinatal brain injury. Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation. Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity. Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.

Fetal brain magnetic resonance imaging and long-term neurodevelopmental impairment

ObjectiveTo determine the incidence of fetal brain injury by fetal brain magnetic resonance imaging (MRI) in pregnancies complicated with preterm labor (PL), preterm premature rupture of the membranes (PPROM), and intrauterine growth restriction (IUGR), and to compare fetal brain MRI with prenatal surveillance methods, and with immediate and long-term neurodevelopmental outcome. MethodsBetween February 2007 and January 2009, high-risk pregnancies were analyzed by MRI at 1.5 Tesla after 24weeks of gestation at the Clinical Hospital Center Zagreb, Croatia. Long-term outcome was defined as neurodevelopmental outcome at 24months. ResultsAmong 70 pregnancies analyzed, 40.0% had abnormal fetal brain MRI. The highest incidence occurred in the PL group. There was no correlation between abnormal MRI and fetal surveillance methods (ultrasound, Doppler blood flow analysis, cardiotocography, biophysical profile) or immediate neonatal outcome (1-minute Apgar score, umbilical cord pH). Via MRI, fetal brain injury would have been diagnosed for 45.7% of fetuses with a long-term neurodevelopmental handicap. Binary logistic regression showed that, as compared with other surveillance methods, fetal brain MRI was the best predictor of long-term neurodevelopmental disability. ConclusionPL, IUGR, and PPROM were associated with an early intrauterine CNS insult that was not accurately detected by existing prenatal testing options.

Fetal inflammatory response and brain injury in preterm newborns

The fetal inflammatory response to intrauterine infection plays a crucial role in the pathogenesis of preterm birth and preterm brain injury.The fetal inflammatory response is characterized by elevated levels of proinflammatory cytokines in the fetal circulation.The inflammation signal is likely transmitted across the blood-brain barrier and initiates a neuroinflammatory response and triggers damage in the developing brain.A better understanding of the fetal inflammatory response will help design interventions to improve neurodevelopmental outcomes after preterm birth.This review summarizes researches of fetal inflammatory response and brain injury in the preterm newborn. Key words: Intrauterine infection; Fetal inflammatory response; Preterm birth; Brain injury

Perinatal neuroprotection

Fetal or neonatal brain injury can result in lifelong neurologic disability. The most significant risk factor for perinatal brain injury is prematurity; however, in absolute numbers, full-term infants represent the majority of affected children. Research on strategies to prevent or mitigate the impact of perinatal brain injury (“perinatal neuroprotection”) has established the mitigating roles of magnesium sulfate administration for preterm infants and therapeutic hypothermia for term infants with suspected perinatal brain injury. Banked umbilical cord blood, erythropoietin, and a number of other agents that may improve neuronal repair show promise for improving outcomes following perinatal brain injury in animal models. Other preventative strategies include delayed umbilical cord clamping in preterm infants and progesterone in women with prior preterm birth or short cervix and avoidance of infections. Despite these advances, we have not successfully decreased the rate of preterm birth, nor are we able to predict term infants at risk of hypoxic brain injury in order to intervene prior to the hypoxic event. Further, we lack the ability to modulate the sequelae of neuronal cell insults or the ability to repair brain injury after it has been sustained. As a consequence, despite exciting advances in the field of perinatal neuroprotection, perinatal brain injury still impacts thousands of newborns each year with significant long-term morbidity and mortality.

Severe fetal ischaemic brain injury caused by homozygous protein C deficiency

Severe fetal ischaemic brain injury caused by homozygous protein C deficiency

PSS95 - Critical Oxidative Stress Causes Early Fetal Brain Injury Resulting in Cerebral Palsy

PSS95 - Critical Oxidative Stress Causes Early Fetal Brain Injury Resulting in Cerebral Palsy

Complement inhibition and statins prevent fetal brain cortical abnormalities in a mouse model of preterm birth

Premature babies are particularly vulnerable to brain injury. In this study we focus on cortical brain damage associated with long-term cognitive, behavioral, attentional or socialization deficits in children born preterm. Using a mouse model of preterm birth (PTB), we demonstrated that complement component C5a contributes to fetal cortical brain injury. Disruption of cortical dendritic and axonal cytoarchitecture was observed in PTB-mice. Fetuses deficient in C5aR (−/−) did not show cortical brain damage. Treatment with antibody anti-C5, that prevents generation of C5a, also prevented cortical fetal brain injury in PTB-mice. C5a also showed a detrimental effect on fetal cortical neuron development and survival in vitro. Increased glutamate release was observed in cortical neurons in culture exposed to C5a. Blockade of C5aR prevented glutamate increase and restored neurons dendritic and axonal growth and survival. Similarly, increased glutamate levels – measured by 1HMRS – were observed in vivo in PTB-fetuses compared to age-matched controls. The blockade of glutamate receptors prevented C5a-induced abnormal growth and increased cell death in isolated fetal cortical neurons. Simvastatin and pravastatin prevented cortical fetal brain developmental and metabolic abnormalities -in vivo and in vitro. Neuroprotective effects of statins were mediated by Akt/PKB signaling pathways. This study shows that complement activation plays a crucial role in cortical fetal brain injury in PTL and suggests that complement inhibitors and statins might be good therapeutic options to improve neonatal outcomes in preterm birth.

Fetal intracranial injuries following motor vehicle accidents with airbag deployment

The effects of airbag deployment in motor vehicle accidents (MVA) on the fetus are poorly understood. A 22-year-old woman at 24 weeks of gestation collided with a telephone pole while driving. She was restrained and an airbag deployed. Although she had no major injuries, she experienced decreased fetal movements. Fetal heart rate (FHR) monitoring revealed loss of variability without any evidence of abruptio placentae, and 4 days later, the variability spontaneously recovered. Two weeks after the MVA, ultrasonography showed unilateral ventricular dilatation suggestive of fetal brain injury. Magnetic resonance imaging revealed subdural hematoma, intraventricular hemorrhage and cystic lesions, interpreted as indirect (hypoxic-ischemic) and direct (hemorrhagic) intracranial injuries. After MVA with airbag deployment, FHR monitoring can show a transient loss of variability, which may precede the appearance of fetal brain injury.

Non-visualisation of cavum septi pellucidi: implication in prenatal diagnosis?

ObjectiveThis manuscript reviews congenital anomalies and imaging findings associated with non-visualisation of the cavum septi pellucidi (CSP) found on prenatal sonogram.BackgroundObservation of a normal cavum septi pellucidi (CSP) is an important landmark in the second and third trimester prenatal ultrasound evaluation of the fetal brain, and its visualisation provides reassurance of normal central forebrain development. Non-visualisation of the CSP is a prenatal sonographic finding, which in most cases is associated with neuroanatomical anomalies that include agenesis of the corpus callosum, schizencephaly, septo-optic dysplasia, holoprosencephaly, chronic hydrocephalus and acquired fetal brain injury. Isolated septal deficiency, a rare but controversial entity, is considered a variant of normal. Common pitfalls in the sonographic evaluation of CSP include columns of the fornix that mimic CSP, and prominent cavum vergae that can simulate non-visualisation of the CSP. When non-visualisation of the CSP is suspected, magnetic resonance imaging (MRI) of the fetal brain can confirm and evaluate associated anomalies.ConclusionVisualisation of the CSP is an integral component of the prenatal ultrasound and its non-visualisation is associated with other malformations, diagnosis of which is aided by MRI.Teaching points• Cavum septi pellucidi (CSP) is an important landmark in the prenatal ultrasound evaluation of the fetal brain, and is a marker for normal central forebrain development.• Non-visualisation of the CSP is most commonly associated with other neuroanatomical abnormalities.• Examination of the fetal brain by MRI can confirm the sonographic findings and evaluate for associated anomalies.

Human Amnion Epithelial Cells Reduce Fetal Brain Injury in Response to Intrauterine Inflammation

Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause of preterm birth and is a strong risk factor for neurological morbidity and cerebral palsy. This study aims to examine whether human amnion epithelial cells (hAECs) can be used as a potential therapeutic agent to reduce brain injury induced by intra-amniotic administration of lipopolysaccharide (LPS) in preterm fetal sheep. Pregnant ewes underwent surgery at approximately 110 days of gestation (term is approx. 147 days) for implantation of catheters into the amniotic cavity, fetal trachea, carotid artery and jugular vein. LPS was administered at 117 days; hAECs were labeled with carboxyfluorescein succinimidyl ester and administered at 0, 6 and 12 h, relative to LPS administration, into the fetal jugular vein, trachea or both. Control fetuses received an equivalent volume of saline. Brains were collected 7 days later for histological assessment of brain injury. Microglia (Iba-1-positive cells) were present in the brain of all fetuses and were significantly increased in the cortex, subcortical and periventricular white matter in fetuses that received LPS, indicative of inflammation. Inflammation was reduced in fetuses that received hAECs. In LPS fetuses, the number of TUNEL-positive cells was significantly elevated in the cortex, periventricular white matter, subcortical white matter and hippocampus compared with controls, and reduced in fetuses that received hAECs in the cortex and periventricular white matter. Within the fetal brains studied there was a significant positive correlation between the number of Iba-1-immunoreactive cells and the number of TUNEL-positive cells (R² = 0.19, p < 0.001). The administration of hAECs protects the developing brain when administered concurrently with the initiation of intrauterine inflammation.

Peptide Sharing Between Influenza A H1N1 Hemagglutinin and Human Axon Guidance Proteins

Epidemiologic data suggest that maternal microbial infections may cause fetal neurodevelopmental disorders, potentially increasing susceptibility to heavy psychopathologies such as schizophrenia, schizophreniform disorder, autism, pervasive developmental disorders, bipolar disorders, psychosis, epilepsy, language and speech disorders, and cognitive impairment in adult offspring. However, the molecular pathomechanisms underlying such a relationship are not clear. Here we analyze the potential role of the maternal immune response to viral infection in determining fetal brain injuries that increase the risk of neurological disorders in the adult. We use influenza infection as a disease model and human axon guidance pathway, a key process in the formation of neural network during midgestation, as a potential fetal target of immune insults. Specifically, we examined influenza A H1N1 hemagglutinin (HA), an antigenic viral protein, for amino acid sequence similarity to a random library of 188 axon guidance proteins. We obtain the results that (1) contrary to any theoretical expectations, 45 viral pentapeptide matches are distributed throughout a subset of 36 guidance molecules; (2) in 24 guidance proteins, the peptide sharing with HA antigen involves already experimentally validated influenza HA epitopes; and (3) most of the axon guidance vs HA peptide overlap is conserved among influenza A viral strains and subsets. Taken together, our data indicate that immune cross-reactivity between influenza HA and axon guidance molecules is possible and may well represent a pathologic mechanism capable of determining neurodevelopmental disruption in the fetus.

Gene Expression Profiles in the Fetal Mouse Brain after Etoposide (VP-16) Administration

The aim of this study was to analyze the response of gene expression caused by etoposide (VP-16) in the fetal mouse brain. Four miligrams/kilogram of VP-16 was intraperitoneally injected into pregnant mice on day 12 of gestation (GD 12). Gene expression profiling of the VP-16-treated fetal mouse brain by DNA microarray was performed. The expression changes of the target genes of p53 were also examined by real-time RT-PCR. VP-16 induced S-phase accumulation, G2/M arrest, and eventually apoptosis of neuroepithelial cells in the fetal brain. DNA microarray analysis revealed that 8 of cell cycle control- and apoptosis-related genes were upregulated and that 5 of DNA damage, repair, replication, and transcription genes were also upregulated in the fetal telencephalons at 4 h after VP-16 treatment (HAT). The results of real-time RT-PCR demonstrated that the expression of topoisomerase IIα was increased at 4 and 8 HAT. The expression of pro-apoptotic factors such as puma, noxa, bax, and cyclin G was also increased from 4 to 12 HAT. These results suggest that VP-16 induces DNA damage, DNA repair, cell cycle alternation, and apoptosis in the fetal mouse brain. In addition, VP-16-induced apoptosis is mediated through the mitochondrial pathway in a p53-related manner. The present study will provide a better understanding of the mechanisms of VP-16-induced fetal brain injury.

The Role of Fetal Neurology in the Progress of Perinatal Medicine

The prevalence of cerebral palsy has not decreased despite major improvements in clinical care in antenatal/ neonatal period as well as intrapartum period. In about 70% of cases, cerebral palsy results from events occurring before birth that can disrupt normal development of the brain. The antepartum risk factors should include fetal brain mal development and intrauterine brain injuries, which are unclassifiable into congenital brain anomalies and may exist inconspicuously during pregnancy and even after birth. Especially, neuronal migration disorder and acquired brain damage in utero should be responsible for postnatal neurological impairment. Imaging technologies including three dimensional ultrasound have been remarkably improved and contributed to prenatal evaluation of fetal Central Nervous System (CNS) development and assessment of CNS abnormalities in utero. In this article, objective and precise imaging diagnoses of fetal CNS including migration disorders and acquired brain damages. Furthermore, 3D bidirectional power Doppler angiography has depicted fine cerebral vessels of medullary veins which may relate with timing of insult as well as with postnatal neurological prognosis. It is promising to clarify the developmental mechanism of CNS damages with advanced ultrasound diagnostic techniques in the near future. Postnatal unexplained neurological deficits may strongly relate with intrauterine brain development therefore fetal neurology has great responsibility and an important role in perinatal medicine.

491: Neuronal nitric oxide synthase (nNOS) in human amniotic fluid as a possible indicator of fetal brain injury

rotoxicity. RESULTS: Pretreatment with hASC but not the post-treatment, significantly decreased the rate of preterm birth (p 0.01) by 21%. Pretreatment was associated with increase in IL-10 in MS (p 0.05) and IL-4 in AF (p 0.05); decrease in IL1 cytokine expression in fetal and neonatal brains, and fetal neurotoxicity (p 0.05). CONCLUSION: Maternally administered adipose derived mesenchymal stem cells appear to modulate maternal and fetal response to intrauterine inflammation in a murine model. While further research is needed, this study is the first to demonstrate that autologous hASC harvested from women with history of preterm birth may serve as a cell therapy “vaccine” in their future pregnancy.

White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: Lessons from experimental ovine models

Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is closely related to the development of white matter injury in the fetal brain. Large epidemiological studies support the link between FIRS and fetal brain injury with a clear association between the presence of in utero inflammation and neurodevelopmental complications such as cerebral palsy, autism and cognitive impairments later in life.Translational animal models of chorioamnionitis and fetal sepsis are essential in understanding the underlying pathophysiological mechanisms of fetal brain injury after exposure to intra-uterine inflammation. Concerning this aspect, ovine models have high translational value since neurodevelopment in sheep closely resembles the human situation.In this article, we will review clinical and experimental evidence for the link between FIRS and white matter injury in the fetal brain. With respect to experimental findings, we will particularly focus on the lessons learned from ovine models of chorioamnionitis and fetal sepsis. We also highlight two key players implied in the pathophysiology of white matter injury after in utero exposure to inflammation.

Ischemia–reperfusion impairs blood–brain barrier function and alters tight junction protein expression in the ovine fetus

The blood–brain barrier is a restrictive interface between the brain parenchyma and the intravascular compartment. Tight junctions contribute to the integrity of the blood–brain barrier. Hypoxic–ischemic damage to the blood–brain barrier could be an important component of fetal brain injury. We hypothesized that increases in blood–brain barrier permeability after ischemia depend upon the duration of reperfusion and that decreases in tight junction proteins are associated with the ischemia-related impairment in blood–brain barrier function in the fetus. Blood–brain barrier function was quantified with the blood-to-brain transfer constant (Ki) and tight junction proteins by Western immunoblot in fetal sheep at 127days of gestation without ischemia, and 4, 24, or 48h after ischemia. The largest increase in Ki (P<0.05) was 4h after ischemia. Occludin and claudin-5 expressions decreased at 4h, but returned toward control levels 24 and 48h after ischemia. Zonula occludens-1 and -2 decreased after ischemia. Inverse correlations between Ki and tight junction proteins suggest that the decreases in tight junction proteins contribute to impaired blood–brain barrier function after ischemia. We conclude that impaired blood–brain barrier function is an important component of hypoxic–ischemic brain injury in the fetus, and that increases in quantitatively measured barrier permeability (Ki) change as a function of the duration of reperfusion after ischemia. The largest increase in permeability occurs 4h after ischemia and blood–brain barrier function improves early after injury because the blood–brain barrier is less permeable 24 and 48 than 4h after ischemia. Changes in the tight junction molecular composition are associated with increases in blood–brain barrier permeability after ischemia.

OP16.06: Assessing acute fetal brain injury with US and MRI: antenatal imaging and associated risk factors

To identify patterns offetal brain injury with US and MRI, and to correlate findings with antenatal risk factors and postnatal outcome. Institutional ethical approval was obtained in order to review records to identify fetuses with evidence of brain injury. Postnatal imaging and postmortem findings were correlated with prenatal sonographic findings. Sonographic evidence of brain injury was documented antenatally in 54 fetuses and confirmed on fetal or postnatal MRI or at autopsy. There was intracranial hemorrhage in 24 (44%), hypoxia-ischemia in 9 (17%), fetal infection in 6 (11%), schizencephaly/stroke in 5 (9%), teratogen exposure in 5 (9%), and periventricular pseudocysts in 5 (9%) associated with other non-CNS anomalies. Aneuploidy was found in 2 fetuses (3.7%). Antenatal risk factors included multiple gestation in 26% of cases (3 dichorionic, 11 monochorionic gestation). Among monochorionic gestations, 3 were related to twin transfusion syndrome and 8 to IUFD. Intracranial hemorrhage was seen in 6 twins, 2 of which were dichorionic. Singletons with hemorrhage (18 cases) were associated with alloimmune thrombocytopenia in 4, metabolic disorder in 2, and CMV in 1; in the remainder, etiology was undetermined. A spectrum of imaging findings in brain hemorrhage included Grade 4 ICH in 6 fetuses, Grade 3 ICH in 7 including one with Dandy-Walker malformation, Grade 2 hemorrhage in 2, Grade 1 ICH in 3; and 3 fetuses with posterior fossa hemorrhage. Two fetuses had focal white matter hemorrhage. Fetal brain injury can be detected sonographically and confirmed with fetal MRI, postnatally, or at autopsy. Knowledge of risk factors and the spectrum of imaging findings can improve antenatal detection of prenatal insults. Specific maternal, fetal, or placental conditions are associated with a higher risk of fetal brain injury and a spectrum of causative pathological entities are involved (ischemia/infarction, hemorrhage, teratogens, infection).

TLR-4-Dependent and -Independent Mechanisms of Fetal Brain Injury in the Setting of Preterm Birth

In this study, we sought to assess how essential activation of toll-like receptor 4 (TLR-4) is to fetal brain injury from intrauterine inflammation. Both wild-type and TLR-4 mutant fetal central nervous system cells were exposed to inflammation using lipopolysaccharide in vivo or in vitro. Inflammation could not induce neuronal injury in the absence of glial cells, in either wild-type or TLR-4 mutant neurons. However, injured neurons could induce injury in other neurons regardless of TLR-4 competency. Our results indicate that initiation of neuronal injury is a TLR-4-dependent event, while propagation is a TLR-4-independent event.

Epigenetic regulation of fetal brain development and neurocognitive outcome

Twenty-five years ago, the neurodevelopmental hypothesis of schizophrenia opened the way for analyzing potential prenatal influences on late postnatal pathogenetic events (1). Since that time, it has been well-established that hypoxia, infection, and other noxious factors can cause fetal brain injury and intrauterine growth restriction and that prenatal brain lesions can cause alterations in the postnatal brain development (2). A study in PNAS (3) suggests that even the subtle normal variations of intrauterine environment may lead to recognizable differences in postnatal brain structure and cognitive functions.