Perinatal Hypoxia Research Articles

Impact of Hyperthermia on Inflammation-Related Perinatal Brain Injury

In a rat model of perinatal inflammation and hypoxia, we investigated the impact of hyperthermia on the deleterious events which are commonly associated with chorioamnionitis. Late-pregnancy gestational day 20 rats received a single injection of either lipopolysaccharide (LPS) Escherichia coli endotoxin or saline. The offspring were born 24-36 h later at full term. The pups underwent hypoxia on the first postnatal day (PND1) immediately after which they were maintained at a planned target temperature for 2 h, before being returned to the dams. The pups were sacrificed on PND5 and the brain tissue was examined. Results showed that LPS alone or in combination with hypoxia was well tolerated. The additional stress of moderate hyperthermia (39°C for 2 h) on PND1 resulted in (a) a significant increase in brain reactive nitrogen species (RNS), (b) a significant increase in caspase-3 activity, (c) a significant increase in c-jun, bax and bcl-2 gene expression and (d) a significant increase in apoptotic cells in the CA1 region of the hippocampus. Hyperthermia was also associated with reduced growth over the ensuing 4 days in a small number of pups. In this model of perinatal inflammation, we demonstrated that brief hyperthermia when superimposed on a perinatal inflammation stimulus and hypoxia led to brain injury while either inflammation alone, or combined inflammatory stimulus and hypoxia did not cause significant damage.

Study on lipid and protein metabolism status of preterm infants whose mothers suffered from pregnancy induced hypertension

Objective To investigate the lipid and protein metabolism status of preterm infants whose mothers suffered from pregnancy induced hypertension. Methods One hundred and nineteen premature neonates in accordance with inclusion criteria, who were admitted to the Department of Pediatrics, Peking University People's Hospital from Jan.2010 to Dec.2011, were chosen as study samples.The preterm infants were divided into 2 groups, that was mothers with pregnancy induced hypertension group(observation group) and mothers without pregnancy complications group(control group). Then the general condition as well as the lipid and protein levels, which were tested within 24 h after birth, and which of preterm newborns in 2 groups were compared. Results The percent of 26.5 of the preterm infants in observation group were small for gestational age, while the ratio was 11.8% for ones in control group, there was significant difference (P 0.05). Conclusions Mothers with pregnancy induced hypertension can affect the intrauterine growth, levels of lipid and total protein of their offsprings.At the same time, it also increases the possibility of perinatal hypoxia. Key words: Pregnancy induced hypertension; Lipid; Protein; Preterm infant

Examining the role of memory in social cognition

Examining the role of memory in social cognition

Analysis of 58 neonatal cases with cerebral infarction

Cerebral infarction (CI) is one of severe diseases of central nervous system in neonates, and some infants with CI could have poor prognosis in the long term. This study aimed to analyze the clinical data and prognosis of all neonatal cases with cerebral infarction in recent years and to help future clinical work. Totally 58 neonatal cases with CI admitted to NICU of the hospital from January 1999 to December 2010 were included in this study. We analyzed all clinical data and prognosis by retrospective analysis. Fifty-two term babies and six preterm babies were included. There were altogether 51 cases with asphyxia and 7 with hemorrhagic cerebral infarction. Perinatal hypoxia-ischemia was the most common high-risk factor and it accounted for 46.6%. Seizure was the most frequent initial symptom and the most common clinical manifestation (accounted for 77.6%), and it was followed by intermittent cyanosis, apnea and lethargy. Cerebral CT scan and magnetic resonance imaging were major methods to help to make the diagnosis and they also had close relation with prognosis. Diffusion weighted imaging was very helpful to diagnose infarction in early stage. Left middle cerebral artery was the most common artery to be involved. Supportive therapy and symptomatic treatment were the main methods in the acute stage of neonatal cerebral infarction. Those babies with poor prognosis mostly had large infarction involving cerebral hemisphere, thalamus and basal ganglia. Neonatal cerebral infarction was a severe brain injury affecting long tern nervous system prognosis. Perinatal hypoxia was the most common high-risk factor and seizure was the most frequent initial symptom. Diffusion weighted imaging was valuable to diagnose infarction in early stage. Most of infants with poor prognosis had large infarction involving hemisphere, thalamus and basal ganglia. Early diagnosis with brain imaging would be helpful for rehabilitation therapy and improving prognosis.

Cardiac troponin I as an early predictor of perinatal asphyxia

Objective The objective of this study was to test the hypothesis that cardiac troponin I (cTnI), a known marker of myocardial injury, is also an early predictor of both severity and mortality in cases of perinatal hypoxia. Background Delivery is a stressful and risky event that poses a risk to newborns. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply, compromising the survival and development of the central nervous system. The outcomes of perinatal asphyxia are devastating and permanent, making it a major burden for the patient, the family, and society. Thus, there has been considerable focus on the early identification of newborns exposed to perinatal asphyxia and development of therapeutic strategies to reduce long-term morbidity and mortality. Troponin is an inhibitory protein complex located on the actin filament in all striated muscles and consists of three subunits: T, C, and I. cTnI was measured as an indicator of cardiac injury for a long time, but it has been of interest for the prediction of poor neonatal outcome in perinatal asphyxia. Aim of the study The aim of this work was to test the hypothesis that cTnI, a known marker of myocardial injury, is also an early predictor of both morbidity and mortality in cases of perinatal hypoxia. Materials and methods This study was carried out between October 2011 and June 2012. It included 40 neonates with perinatal asphyxia admitted to the neonatal ICU, El-Ahrar Zagazig General Hospital. Twenty healthy neonates matched for both age and sex were selected randomly as a control group. Blood samples were collected from the two study groups. cTnI was measured in relation to neurological sequelae, and deaths in both the groups were also evaluated. Results The mean cTnI of asphyxiated neonates was 4.6 ΁ 4.4 ng/ml, significantly higher than that of the control neonates, which was 0.55 ΁ 0.6 ng/ml. This difference was statistically significant. Conclusion cTnI was markedly increased in perinatal asphyxia. This was related to the severity of perinatal asphyxia. It can also be used as an early predictor of neonatal morbidity and mortality in perinatal asphyxia.

Clinical and etiological correlations in cerebral palsy

Cerebral palsy (CP) is a group of persistent (but not necessarily unchanged), movement, posture, muscle tone, and motor skills disorders, with early onset, due to non-progressive impairments, occurring on an immature brain or a brain under development (prenatal, perinatal, postnatal during the first 3-4 years of life). It is associated to a variable extent with: cognitive disorders, epilepsy, sensory deficits, behaviour disorders. The aim of this study. The study of the correlations between the clinical forms/subtypes of CP and aetiology. Material and method. It is a retrospective trial aimed only at patients with the diagnosis of cerebral palsy admitted at Paediatric Neurology Clinic of the Clinical Hospital “Alexandru Obregia” in 2010. Results and discussions. Patients with cerebral palsy corresponding with the criteria for inclusion: 379 CP was due to prenatal aetiology in 32.45% cases, perinatal aetiology in 60.15% case, postnatal aetiology in 10.8 % cases. Prenatal aetiology was represented mostly by malformations 43.1%. Compared with perinatal or postnatal aetiologies, ataxic forms were more frequently of prenatal cause. The unilateral spastic form was correlated significantly from a statistical point of view with prenatal aetiology – malformations (p0.003) and the dyskinetic form with unknown prenatal aetiology. Mental retardation was present in 86.4% of the cases with assumed prenatal aetiology and was severe in 38.2% of the cases. The perinatal aetiology was represented by PVL 32% haemorrhage 21.1%, hypoxia 18.4%, stroke 14%, the aetiology being unknown in 7% of the cases. The distribution was comparable to that of other causes with a higher frequency of dyskinetic forms. The correlations between the perinatal aetiology and the clinical forms were (p0.000): LPV with spastic diplegia and tetraplegia, perinatal stroke with spastic hemiplegia, perinatal hypoxia with ataxic and dyskinetic forms, peri/intraventricular haemorrhage with spastic triplegia. Perinatal aetiology was correlated significantly with retardation as follows: perinatal stroke with the absence of mental delay, and hypoxia with severe and profound retardation (p0.001) Postnatal aetiology had: infections 36.6%, stroke 17%, stabilized hydrocephaly 17%, cardio- respiratory arrest 9.8%, trauma 7.3%. The number of cases was too small for significant correlations. Conclusions. Aetiology and the time of the occurrence of the lesion are important in cerebral palsy.

Generation of striatal projection neurons extends into the neonatal period in the rat brain

Substantial advances have been made in the last decade on our understanding of the basic physiology underlying neurogenesis in the postnatal mammalian brain. The bulk of the work in this area has been based on analysis of the adult brain. Relatively less is known about the capacity for neurogenesis in specific structures within the neonatal brain. Here we report that the production of medium spiny striatal projection neurons extends into the early neonatal period under normal physiological conditions in the rat brain. Birth-dating of newborn cells with bromodeoxyuridine at postnatal days 0, 2 and 5 showed a peak production close to birth, which sharply declined at the later time-points. Additionally, there was a low-level but stable contribution of neurons with interneuron identity over the same time-period. Importantly, retroviral labelling of new striatal projection neurons with green fluorescent protein showed long-term survival and terminal differentiation with characteristic morphology, including highly elaborated spiny dendrites, and appropriate axonal targeting of the globus pallidus and midbrain. This latent period of striatal neurogenesis in the early neonatal brain represents an interesting target for regenerative approaches aimed at restoring striatal circuitry in perinatal pathologies, such as hypoxic and ischaemic damage associated with cerebral palsy.

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

Antiepileptic effects of levetiracetam in a rodent neonatal seizure model

Neonatal seizures can result in chronic epilepsy and long-term behavioral and cognitive deficits. Levetiracetam (LEV), an antiepileptic drug that binds to the synaptic vesicle protein 2A (SV2A), has been increasingly used off-label for the therapy of neonatal seizures. Preclinical data regarding the acute or long-term efficacy of LEV are lacking. We tested the anticonvulsant efficacy of LEV in a rat model of hypoxia-induced neonatal seizures. In addition, we evaluated the protective effects of postnatal day (P)10 LEV treatment on later-life kainic acid (KA)-induced seizure susceptibility and seizure-induced neuronal injury. Western blot and immunohistochemistry were used to assess the developmental regulation of SV2A in the rat and human brain. LEV pretreatment at P10 significantly decreased the cumulative duration of behavioral and electrographic seizures at both 25 and 50 mg/kg. At P40, KA-induced seizures and neuronal loss were significantly diminished in rats previously treated with LEV. LEV target SV2A is present in both neonatal rat and human brain and increases steadily to adulthood. LEV suppressed acute seizures induced by perinatal hypoxia and diminished later-life seizure susceptibility and seizure-induced neuronal injury, providing evidence for disease modification. These results support consideration of a clinical trial of LEV in neonatal seizures.

Hypothermia and erythropoietin for neuroprotection after neonatal brain damage

Both hypothermia and erythropoietin (EPO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (HI). We investigated a possible additive effect of the use of a combination of hypothermia-EPO in a rat model of neonatal HI. At postnatal day 7, rats were subjected to HI and then randomized to 3 h of hypothermia, EPO, or both. Sensorimotor function was assessed by the cylinder-rearing test (CRT) at 2 and 5 wk after HI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. Multivariable analysis using general linear modeling showed that hypothermia, EPO, and the interaction hypothermia × gender were determinants of sensorimotor function, both at 2 and 5 wk after HI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the CRT. Maximal improvement in males was 26% after combined treatment with hypothermia and EPO. Histological outcome was improved by hypothermia only with no additional effect of EPO or gender. Hypothermia after HI improved sensorimotor function in females more than in males. There was a borderline additive effect of EPO when combined with hypothermia. Histology of brain lesion volume and white matter damage was improved only by hypothermia.

1156 Hypoxic Perinatal Cardiomyopathy-Diagnosis and Evolution

PurposeTo present the main aspects of myocardial injury secondary to perinatal hypoxia.Methods/patients88 newborns aged 0–14 days, normal birth weight, with perinatal hypoxia (Apgar score 3–7), receveing resuscitation, without major congenital...

Acute Encephalopathy With Pandemic (H1N1) 2009 Virus Infection

In April 2009, a novel influenza A (H1N1) pdm virus was identified in Mexico and spread quickly around the world. However, the clinical features of acute encephalopathy associated with 2009 pandemic influenza have not yet been elucidated. We treated 8 patients (3 boys and 5 girls) aged 4 to 11 years (average age, 8 y 3 months) with influenza virus-associated encephalopathy, who presented at our 2 hospitals between July 2009 and March 2010. We investigated the clinical characteristics, treatments, and outcomes in the patients. In all patients, brain computed tomography showed mild to severe diffuse cerebral edema, and electroencephalography revealed diffuse high-voltage slow waves. They were all treated with oseltamivir and methylprednisolone pulse therapy. Six patients recovered without any sequelae; however, the remaining 2 had residual neurological sequelae. These 2 patients presented with severe disturbance of consciousness, and their central nervous system symptoms appeared within 12 hours after the onset of fever. One patient had periventricular leukomalacia and symptomatic epilepsy by perinatal brain hypoxia, and the other patient had 1 complex febrile and 2 febrile seizures. This study showed that patients with influenza-associated encephalopathy caused by influenza A (H1N1) pdm infection were all older than those with seasonal influenza. Underlying neurological disease or history may be associated with poor prognosis.

788 Fetal Hypoxia-Ischemia is Related to Circulatory Compromise in Preterm Infants

Background and AimsImpairment of gas exchange and blood flow through the placenta leads to hypoxia and hypercapnia. This causes increased systemic vascular resistance and tachycardia, thus compromising the cardiovascular system...

1706 Value of Echocardiography for the Diagnosis and Monitoring of Evolution of Persistent Pulmonary Hypertension In Newborn

PurposeTo evaluate the value of the echocardiographic exam for the diagnosis of the persistent pulmonary hypertension (PPHN) in the newborn infant.MethodsPatients, 41 newborns (aged 0–8 days) with PPHN induced by...

Nonadditive Neuroprotection With Early Glutamate Receptor Blockade and Delayed Hypothermia After Asphyxia in Preterm Fetal Sheep

Hypothermia induced after perinatal hypoxia-ischemia is partially protective. This study examined whether early treatment with the noncompetitive N-methyl-d-aspartate receptor antagonist, dizocilpine, can augment neuroprotection with delayed hypothermia after severe asphyxia in preterm fetal sheep at 0.7 weeks gestation (equivalent to 28-32 weeks in humans). Fifty minutes after umbilical cord occlusion for 25 minutes, fetuses were randomized to either dizocilpine (2 mg/kg estimated fetal weight intravenously, then 0.07 mg/kg/h for 4 hours) and then after 5.5 hours to whole-body cooling to 3°C below baseline, or sham cooling, until 72 hours, and euthanized 7 days after umbilical cord occlusion. Delayed hypothermia was associated with improved neuronal survival (P<0.02) and reduced microglia (P=0.004) and caspase-3-positive cells (P<0.01) compared with umbilical cord occlusion. Dizocilpine was associated with reduced microglia (P<0.05) but no effect on caspase-3 induction and improved survival only in CA1/2 (P<0.05) with no apparent additive effect with delayed hypothermia. Early N-methyl-d-aspartate blockade and a clinical regime of delayed whole-body hypothermia provide nonadditive neuroprotection in the preterm brain.

PP138. Human fetal malformations associated with the use of angiotensin II receptor antagonist

antagonists of angiotensin II receptor (AAR) are commonly used for the treatment of chronic hypertension in the general population. Some of these pharmacological agents are losartan, candesartan, valsartan and tasosartan. Despite the good response achieved with these drugs in the control of hypertension, all medications that act directly on the renin-angiotensin system should be contraindicated during pregnancy. These drugs have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death.Here we report a case of fetal malformations and death associated with the use of losartan. describing the association of fetal malformations and the use of losartan during first and second trimester of pregnancy. this is a case report involving a 37-year-old pregnant woman at 26 gestational weeks. This patient had history of chronic hypertension for more than five years that was being regularly treated with Losartan 50mg/day. After her first consultation losartan was promptly discontinued and substituted for methyldopa. However, scan evaluation demonstrated severe oligohydramnios associated with altered fetal biophysical profile and altered Doppler fluxometry (absent diastolic flow at umbilical arteries). Therefore, a cesarean-section was performed after corticoid administration for fetal lung maturation. At first moment some characteristic alterations as fetal limb contractures and craniofacial deformation were detected at the 1007g new-born. This baby went to death 36h after delivery due to severe lung hypoplasia. the autopsy examination revealed renal tubular dysgenesis associated with changes secondary to nephropathy, probably induced by drug (Fig. 1). Associated findings were underdevelopment of bones of the skull with large fontanelles, thymus atrophy and signs of perinatal hypoxia. the difficulty of attending basic health assistance was attributed to be associated with this case, as this patient did not have opportunity and sufficient information about the necessity of changing her medication during pregnancy. Apart from this situation, this case report brings good information about the association between antagonists of angiotensin II receptor and human fetal malformations.

Feeding and communication impairments in infants with central grey matter lesions following perinatal hypoxic–ischaemic injury

BackgroundBasal ganglia and thalamic (BGT) injury is common after acute perinatal hypoxia–ischaemia. Cerebral palsy is the most obvious consequence of BGT injury affecting 70–75% of survivors and is predictable from neonatal magnetic resonance imaging (MRI). However there is no equivalent predictive data for other specific outcomes. Feeding and communication impairments are also common in children following hypoxic–ischaemic encephalopathy (HIE) and BGT injury. AimsTo describe, in infants with HIE and BGT injury, the prevalence of feeding and communication impairments; and to evaluate the accuracy of early MRI for predicting these outcomes. Methods175 term infants with HIE and BGT injury were studied. Brain lesions were classified by site and severity from the MRI scans. Motor, feeding and communication impairments were documented at 2 years. ResultsFeeding and communication impairments occurred in 65% and 82% of 126 survivors respectively and related strongly to the severity of motor impairment. Forty-one children had a gastrostomy or long-term nasogastric tube. Injury severity in all brain regions was significantly associated with feeding and communication impairment on univariate analysis. On logistic regression analysis BGT (OR 10.9) and mesencephalic lesions (OR 3.7) were independently associated with feeding impairment; BGT (OR 10.5) and pontine lesions (OR 3.8) were associated with gastrostomy; the severity of BGT lesions (OR 20.1) was related to the severity of communication impairment. ConclusionsFeeding and communication impairment are very common in children with BGT and brainstem injury of neonatal origin and can be well predicted from early MRI scans.

Diagnosing Cerebral Visual Impairment in Children with Good Visual Acuity

Purpose: To identify elements that could facilitate the diagnosis of cerebral visual impairment (CVI) in children with good visual acuity in the general ophthalmic clinic.Methods: We retrospectively investigated the clinical characteristics of 30 children with good visual acuity and CVI and compared them with those of 23 children who were referred with a suspicion of CVI, but proved to have a different diagnosis. Clinical characteristics included medical history, MRI findings, visual acuity, crowding ratio (CR), visual field assessment, and the results of ophthalmologic and orthoptic examination. We also evaluated the additional value of a short CVI questionnaire.Results: Eighty-three percent of the children with an abnormal medical history (mainly prematurity and perinatal hypoxia) had CVI, in contrast with none of the children with a normal medical history. Cerebral palsy, visual field defects, and partial optic atrophy only occurred in the CVI group. 41% of the children with CVI had a CR ≥2.0, which may be related to dorsal stream dysfunction. All children with CVI, but also 91% of the children without CVI gave ≥3 affirmative answers on the CVI questionnaire.Conclusion: An abnormal pre- or perinatal medical history is the most important risk factor for CVI in children, and therefore in deciding which children should be referred for further multidisciplinary assessment. Additional symptoms of cerebral damage, i.e., cerebral palsy, visual field defects, partial optic atrophy, and a CR ≥2 may support the diagnosis. CVI questionnaires should not be used for screening purposes as they yield too many false positives.

Umbilical activin A concentration as an early marker of perinatal hypoxia

Objective: To evaluate activin A as a potential, early marker of perinatal hypoxia and to analyze factors, other than hypoxia, which influence on activin A concentration. Methods: Umbilical cord blood samples were collected from 86 newborns with gestational age 30–41. Of the 86 newborns, 26 were regarded as hypoxic. Activin A concentrations were measured by means of specific two-site enzyme immunoassays. Activin A concentrations were correlated with newborns’ gender, week gestation, mode of delivery and blood gas measurements. Results: Activin A levels were significantly higher in hypoxic than nonhypoxic newborns (medians, minimum and maximum values: 1.516; 0.149 –1.974 versus 0.368; 0.054 – 1.041 ng/mL, p = 0.0452). Activin A concentration was significantly higher in male newborns (p = 0.0074). Activin A levels were lower in term than preterm babies but the differences were not statistically significant (p = 0.2368 in hypoxic, p = 0.2487 nonhypoxic). Mode of delivery did not influence on activin A concentration (p = 0.8293 hypoxic, p = 0.9458 nonhypoxic). The differences of occurrence of intraventricular hemorrhage (IVH) in both group was not statistically significant (p = 0.61). Conclusions: Umbilical artery activin A combined with other markers of hypoxia could be a useful marker of perinatal hypoxia. Concentration of activin A is significantly higher in male newborns. The mode and time of delivery have no influence on activin A concentration.

Impact of prenatal ischemia on behavior, cognitive abilities and neuroanatomy in adult rats with white matter damage

Early brain damage, such as white matter damage (WMD), resulting from perinatal hypoxia–ischemia in preterm and low birth weight infants represents a high risk factor for mortality and chronic disabilities, including sensory, motor, behavioral and cognitive disorders. In previous studies, we developed a model of WMD based on prenatal ischemia (PI), induced by unilateral ligation of uterine artery at E17 in pregnant rats. We have shown that PI reproduced some of the main deficits observed in preterm infants, such as white and gray matter damage, myelination deficits, locomotor, sensorimotor, and short-term memory impairments, as well as related musculoskeletal and neuroanatomical histopathologies [1–3]. Here, we determined the deleterious impact of PI on several behavioral and cognitive abilities in adult rats, as well as on the neuroanatomical substratum in various related brain areas. Adult PI rats exhibited spontaneous exploratory and motor hyperactivity, deficits in information encoding, and deficits in short- and long-term object memory tasks, but no impairments in spatial learning or working memory in watermaze tasks. These results were in accordance with white matter injury and damage in the medial and lateral entorhinal cortices, as detected by axonal degeneration, astrogliosis and neuronal density. Although there was astrogliosis and axonal degeneration in the fornix, hippocampus and cingulate cortex, neuronal density in the hippocampus and cingulate cortex was not affected by PI. Levels of spontaneous hyperactivity, deficits in object memory tasks, neuronal density in the medial and lateral entorhinal cortices, and astrogliosis in the fornix correlated with birth weight in PI rats. Thus, this rodent model of WMD based on PI appears to recapitulate the main neurobehavioral and neuroanatomical human deficits often observed in preterm children with a perinatal history of ischemia.