Antepartum and Intrapartum Factors Preceding Neonatal Hypoxic-Ischemic Encephalopathy

Martinez‐Biarge, Miriam; Díez‐Sebastián, Jesús; Wusthoff, Courtney J.; Mercuri, Eugenio; Cowan, Frances

doi:10.1542/peds.2013-0511

Cited by 142 publications

(97 citation statements)

References 46 publications

(58 reference statements)

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“…We have to take into consideration the difficulty of applying a preventative measure at the exact time of injury in a clinical setting. Nevertheless, although formal randomized clinical trials have not been performed on this drug, its safety profile is high (5, 26), so we can envision a scenario where MB is used as a therapeutic option in cases with a high risk of developing perinatal asphyxia (6,33).…”

Section: Discussionmentioning

confidence: 99%

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Rey-Funes

Larráyoz

Fernández

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-Perinatal asphyxia induces retinal lesions, generating ischemic proliferative retinopathy, which may result in blindness. Previously, we showed that the nitrergic system was involved in the physiopathology of perinatal asphyxia. Here we analyze the application of methylene blue, a well-known soluble guanylate cyclase inhibitor, as a therapeutic strategy to prevent retinopathy. Male rats (n ϭ 28 per group) were treated in different ways: 1) control group comprised born-to-term animals; 2) methylene blue group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery; 3) perinatal asphyxia (PA) group comprised rats exposed to perinatal asphyxia (20 min at 37°C); and 4) methylene blue-PA group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery, and then the pups were subjected to PA as above. For molecular studies, mRNA was obtained at different times after asphyxia, and tissue was collected at 30 days for morphological and biochemical analysis. Perinatal asphyxia produced significant gliosis, angiogenesis, and thickening of the inner retina. Methylene blue treatment reduced these parameters. Perinatal asphyxia resulted in a significant elevation of the nitrergic system as shown by NO synthase (NOS) activity assays, Western blotting, and (immuno)histochemistry for the neuronal isoform of NOS and NADPH-diaphorase activity. All these parameters were also normalized by the treatment. In addition, methylene blue induced the upregulation of the anti-angiogenic peptide, pigment epithelium-derived factor. Application of methylene blue reduced morphological and biochemical parameters of retinopathy. This finding suggests the use of methylene blue as a new treatment to prevent or decrease retinal damage in the context of ischemic proliferative retinopathy. retina; nitric oxide; ischemic proliferative retinopathy; methylene blue; angiogenesis PERINATAL ASPHYXIA (PA) is one of the most severe problems in perinatology services across the world (9,15,23,27). PA generates a transient global hypoxia-ischemia status that damages the brain, spinal cord, and retina (14, 17, 39, 52). The degree and the length of perinatal asphyxia are decisive for the development of injury sequelae, such as attention-deficit hyperactivity disorder (1), epilepsy, mental retardation, spasticity, and visual or hearing alterations (61). One third of asphyctic neonates develop serious long-term neurological injuries including several degrees of ischemic proliferative retinopathy (IPR) and even blindness (20).In rats, the retina is particularly sensitive to oxygen alterations (56), and the morphological changes observed in its inner layers are compatible with some alterations observed in human diseases such as retinopathy in diabetes, retinal vein occlusion, and retinopathy of prematurity (ROP), an avoidable cause of visual impairment and blindness in children (20, 61). The changes observed in asphyctic animals include ganglion cell degeneration, n...

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Section: Discussionmentioning

confidence: 99%

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Rey-Funes

Larráyoz

Fernández

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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“…4 Despite this significant association between fetal Doppler and the need for neonatal unit admission at term, its predictive accuracy as an isolated marker is likely to be poor because of the confounding effect of the process of labor and birth. 27 Whether fetal Doppler assessment in AGA pregnancies is predictive of perinatal morbidity or neurodevelopmental delay is unknown. The extent to which fetal hemodynamic assessment could be used to optimize the timing of delivery and reduce neurodevelopmental impairment merits further investigation.…”

Section: Strengths and Limitationsmentioning

confidence: 99%

The association between fetal Doppler and admission to neonatal unit at term

Khalil

Elsaddig

Khan

et al. 2015

American Journal of Obstetrics and Gynecology

110

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“…Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased. 2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes.…”

Section: Perinatal Brain Injury In the Term-born Infantmentioning

confidence: 99%

Inflammation‐induced sensitization of the brain in term infants

Fleiss

Tann

Degos

et al. 2015

Develop Med Child Neuro

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COXPerinatal insults are a leading cause of infant mortality and amongst survivors are frequently associated with neurocognitive impairment, cerebral palsy (CP), and seizure disorders. The events leading to perinatal brain injury are multifactorial. This review describes how one subinjurious factor affecting the brain sensitizes it to a second injurious factor, causing an exacerbated injurious cascade. We will review the clinical and experimental evidence, including observations of high rates of maternal and fetal infections in term-born infants with neonatal encephalopathy and cerebral palsy. In addition, we will discuss preclinical evidence for the sensitizing effects of inflammation on injuries, such as hypoxia-ischaemia, our current understanding of the mechanisms underpinning the sensitization process, and the possibility for neuroprotection. PERINATAL BRAIN INJURY IN THE TERM-BORN INFANTIntrapartum neonatal deaths are the third leading cause of global childhood mortality. 1 In addition, each year perinatal insults are estimated to be responsible for more than one million new cases of neonatal encephalopathy, and nearly half a million infants with impairments such as cerebral palsy (CP).2 Infants exposed to a perinatal insult typically present with encephalopathy, a descriptive term for a clinical constellation of neurological dysfunctions in the term-born that includes difficulty with initiating and maintaining respiration; depression of tone and reflexes; subnormal levels of consciousness; and seizures.3 Whilst often assumed to result solely from acute intrapartum hypoxic-ischaemia, the precise contribution of hypoxia is likely to vary according to the definition of encephalopathy used, the range of competing risks, and the care setting. 3,4 Presumed hypoxia-ischaemia is diagnosed based on reduced Apgar scores and acidosis, 5 and the combination of progressive hypoxia, hypercarbia, and acidosis is often referred to as asphyxia. 6 Encephalopathy resulting from hypoxia-ischaemia can be clearly diagnosed only in a small number of cases in which a sentinel event, such as placental abruption, uterine rupture, cord prolapse, or shoulder dystocia, is clearly present. Clinical studies have identified a number of other important antepartum and intrapartum risk factors for neonatal encephalopathy. [7][8][9][10] In low-income settings, where access to skilled birth attendants and emergency obstetric intervention is often limited, the probability of intrapartum hypoxic events contributing to neonatal encephalopathy is increased.2,9,11 However, in general, neonatal encephalopathy is likely to be a multifactorial condition with complex aetiology, encompassing several causal events, with strong evidence that fetal exposure to infection contributes. 12 CONCEPT OF INFLAMMATION-INDUCED SENSITIZATIONAn increasingly common model for the complex and multifactorial process of perinatal brain injury involves sensitization, 13-15 whereby factors not severe enough by themselves to induce significant brain damage make the developi...

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Antepartum and Intrapartum Factors Preceding Neonatal Hypoxic-Ischemic Encephalopathy

Cited by 142 publications

References 46 publications

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

The association between fetal Doppler and admission to neonatal unit at term

Inflammation‐induced sensitization of the brain in term infants

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