Olfactory Testing in Perinatal Asphyxia: Enhancing Risk Assessment

Официальное название

Olfactory Memory in Infants With Signs of Asphyxia: An Early Indicator of Neurodevelopmental Outcomes

Обзор

Neonatal asphyxia remains a leading cause of neurodevelopmental disabilities despite advancements in perinatal care. Hypoxic-ischemic encephalopathy (HIE), a severe outcome of asphyxia, impacts 1-3 infants per 1,000 live births annually in industrialized nations, causing long-term neurological impairments such as cognitive dysfunction, motor deficits, and sensory impairments. Early identification of at-risk newborns is critical to initiate timely interventions and improve outcomes. Olfactory perception, crucial for newborns' adaptation to extrauterine life, involves odor identification and memory. Odor perception is known to be impaired in adults with neurological disorders and in animal models of brain injury. However, no clinical studies have assessed olfactory function in newborns with signs of asphyxia. Olfactory memory, which can be evaluated through habituation to repeated odors, may provide insights into early brain function. This study aims to evaluate whether olfactory memory can serve as an early marker of neurodevelopmental outcomes in newborns with signs of asphyxia. By assessing physiological, behavioral, and neurological responses to olfactory stimuli, the study seeks to explore the differences between infants with mild asphyxia and those with moderate-to-severe asphyxia.

Подробное описание

Neonatal asphyxia is the leading cause of neurodevelopmental disability. Despite recent advances in perinatal medicine, which have improved associated mortality, the neurological outcomes of hypoxic-ischemic events in newborns remain significant. The incidence of neonatal asphyxia is estimated to be 1.5 per 100 live births per year in industrialized countries with advanced obstetric-neonatal care. Between 1 and 3 infants per 1,000 live births suffer from severe neurological impairment due to perinatal asphyxia, developing hypoxic-ischemic encephalopathy.

Early identification of newborns with signs of asphyxia who are at high risk for hypoxic-ischemic encephalopathy and brain damage can improve outcomes by enabling the early initiation of rehabilitative interventions. Hypoxic-ischemic injury often results in impairments in audiovisual perception, cerebral palsy, cognitive dysfunction, memory difficulties, and other neurological sequelae.

Olfactory perception (the sense of smell) is one of the most important sensory functions in humans. In newborns, the sense of smell plays a crucial role, allowing them to perceive maternal odors and breast milk, guiding them in adapting to their environment and completing the physiological transition from intrauterine to extrauterine life. Olfactory neurosensory function involves several abilities, particularly odor identification and memory. Olfactory perception is also linked to olfactory memory, which can be tested as a habituation response. Olfactory memory is defined as the recollection of odorants. In recent studies, exposure to pleasant odors, such as breast milk or vanilla, has been shown to reduce perceived pain during invasive procedures in healthy full-term newborns. Olfactory stimuli can generate various physiological changes, regulating heart and respiratory rates, as well as triggering motor responses that guide head movements and initiate orofacial responses.

Some studies have shown that brain injury impairs odor perception: smell is altered in several neurological conditions, including both neurodevelopmental and neurodegenerative disorders. In Alzheimer (AD), Parkinson disease (PD) and in stroke, several cortical and subcortical areas directly involved in olfactory function are damaged or show signs of atrophy, including the olfactory bulb (OB), primary olfactory cortex (POC), hippocampus, orbitofrontal cortex (OFC), amygdala, and olfactory tract. Moreover, reduced odor detection early in life, along with anatomical and functional alterations in olfactory and higher-order cortical networks, has been reported in neurodevelopmental disorders such as Autistic Spectrum Disorder (ASD) and Attention Deficit / Hyperactivity Disorder (ADHD).

Olfactory dysfunction has also been studied and demonstrated in animal models through the induction of brain damage in rabbits. So far, no study has evaluated olfactory function in the clinical setting of brain injury due to neonatal asphyxia.

In cases of perinatal asphyxia, early identification of hypoxic-ischemic encephalopathy is achieved through continuous video-electroencephalographic monitoring, which is currently considered the gold standard for evaluating brain functions and detecting subclinical seizures. Although EEG does not directly assess olfactory function, certain electroencephalographic alterations may suggest impairment in brain regions involved in olfactory perception (piriform cortex, insular cortex, and amygdala).There are numerous studies in the literature that adopt various methods of olfactory testing in healthy newborns, but no validated tool or test exists to evaluate olfactory memory in newborns.

This study aims to assess olfactory function in newborns exhibiting signs of asphyxia at birth and to investigate whether infants with mild asphyxia differ from those with moderate to severe asphyxia.

The hypotheses of this study is that olfactory stimulation with odors such as rose, vanilla, and breast milk induces changes in heart rate, respiratory rate, peripheral oxygen saturation, EEG activity, and neuroimaging measures in asphyxiated newborns. These changes also occur following repeated olfactory stimuli. Olfactory memory, or habituation to odors, is delayed or absent in newborns with moderate-severe asphyxia.

Вмешательства

• Диагностический тест Olfactory Testing
  Olfactory Test: Odor stimuli will be administered using a custom-designed olfactometer, developed by engineers specifically for this study. The olfactometer will release different odorants (maternal breast milk, vanilla essential oil, rose essential oil, and water as a control) in a controlled way. Each odor will be presented between 6 and 72 hours of life for 10 seconds (On), followed by a 50-second pause (Off) for a total of 15 cycles (On-Off). A new odor will be presented 5 minutes after the
• Диагностический тест Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2)
  Simultaneously with the presentation of odors, heart rate (HR), heart rate variability (HRV), respiratory rate (RR), and peripheral oxygen saturation (SpO2) will be monitored and recorded. The onset of the odor will be recorded using a manual timer.
• Диагностический тест Video-EEG
  The infant's Video-EEG, as per guidelines following perinatal asphyxia, will be recorded for approximately 2 hours, including the period preceding odor administration (baseline).
• Диагностический тест fMRI
  Newborns will undergo an fMRI, as part of routine clinical practice, to identify any brain injury, its extent, and the structures involved. The use of a custom-built fMRI compatible olfactometer will facilitate these studies.
• Диагностический тест Neurodevelopment assessment
  Between 12 and 18 months, the infants will undergo neurodevelopmental follow-up, during which the Bayley III assessment will be administered to evaluate any potential neurocognitive deficits.

Первичные конечные точки

• Autonomic Responses to Olfactory Stimulation in Asphyxiated Newborns. [Срок оценки: during the Olfactory Testing]
• Breathing patterns in Asphyxiated Newborns. [Срок оценки: during the Olfactory Testing]
• Cerebral functioning in Asphyxiated Newborns. [Срок оценки: Within 6 to 72 hours of life]
• Changes in olfactory evoked potentials (EOPs) in Asphyxiated Newborns. [Срок оценки: during the Olfactory Testing]
• Spectral analysis of brain oscillatory rhythms to monitor changes in global brain activity. [Срок оценки: Within 6 to 72 hours of life]
• Changes in behavioral responsens to Olfactory Stimulation in Asphyxiated Newborns. [Срок оценки: Within 6 to 72 hours of life]
• Highlight a different activation within brain areas involved in olfactory perception, memory, and learning through fMRI. [Срок оценки: Within 6 to 72 hours of life]

Вторичные конечные точки (1)

• Neurodevelopmental follow-up [Срок оценки: Between 12 and 18 months]

Критерии участия

Критерии включения

• Term newborns (37-41 weeks of gestational age) with signs of asphyxia at birth (cord pH < 7.10 and/or BE > -12).
• Maternal age > 18 years.
• No medication use during pregnancy (e.g., antipsychotics, antidepressants, sedatives, anticonvulsants, anxiolytics).
• Absence of maternal infections.
• Apgar score < 5 at 10 minutes of life.
• Newborns with mild asphyxia at birth.
• Newborns with moderate asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy, who don't need hypothermia treatment.
• Newborns with severe asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy who don't need hypothermia treatment.

Критерии исключения

• Post-term infants (gestational age > 42 weeks).
• Preterm infants (gestational age < 37 weeks).
• Infants with genetic syndromes or congenital anomalies.
• Infants from mothers using drugs of abuse.
• Infants with scalp injuries or lesions.
• Infants with microcephaly.
• Infants who underwent therapeutic hypothermia.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Случай-контроль

Центры проведения

Италия · 1 центр

• Azienda Ospedaliero-Universitaria di Parma — Parma

Публикации

• Chavez-Valdez R, Miller S, Spahic H, Vaidya D, Parkinson C, Dietrick B, Brooks S, Gerner GJ, Tekes A, Graham EM, Northington FJ, Everett AD. Therapeutic Hypothermia Modulates the Relationships Between Indicators of Severity of Neonatal Hypoxic Ischemic Encephalopathy and Serum Biomarkers. Front Neurol. 2021 Nov 2;12:748150. doi: 10.3389/fneur.2021.748150. eCollection 2021. PMID 34795631
• Finder M, Boylan GB, Twomey D, Ahearne C, Murray DM, Hallberg B. Two-Year Neurodevelopmental Outcomes After Mild Hypoxic Ischemic Encephalopathy in the Era of Therapeutic Hypothermia. JAMA Pediatr. 2020 Jan 1;174(1):48-55. doi: 10.1001/jamapediatrics.2019.4011. PMID 31710357
• Ambalavanan N, Shankaran S, Laptook AR, Carper BA, Das A, Carlo WA, Cotten CM, Duncan AF, Higgins RD; EUNICE KENNEDY SHRIVER NICHD NEONATAL RESEARCH NETWORK. Early Determination of Prognosis in Neonatal Moderate or Severe Hypoxic-Ischemic Encephalopathy. Pediatrics. 2021 Jun;147(6):e2020048678. doi: 10.1542/peds.2020-048678. Epub 2021 May 13. PMID 33986149
• Disdier C, Stonestreet BS. Hypoxic-ischemic-related cerebrovascular changes and potential therapeutic strategies in the neonatal brain. J Neurosci Res. 2020 Jul;98(7):1468-1484. doi: 10.1002/jnr.24590. Epub 2020 Feb 14. PMID 32060970
• Drobyshevsky A, Robinson AM, Derrick M, Wyrwicz AM, Ji X, Englof I, Tan S. Sensory deficits and olfactory system injury detected by novel application of MEMRI in newborn rabbit after antenatal hypoxia-ischemia. Neuroimage. 2006 Sep;32(3):1106-12. doi: 10.1016/j.neuroimage.2006.06.002. Epub 2006 Jul 24. PMID 16861007
• Juliano C, Sosunov S, Niatsetskaya Z, Isler JA, Utkina-Sosunova I, Jang I, Ratner V, Ten V. Mild intermittent hypoxemia in neonatal mice causes permanent neurofunctional deficit and white matter hypomyelination. Exp Neurol. 2015 Feb;264:33-42. doi: 10.1016/j.expneurol.2014.11.010. Epub 2014 Dec 2. PMID 25476492
• Schaal B, Saxton TK, Loos H, Soussignan R, Durand K. Olfaction scaffolds the developing human from neonate to adolescent and beyond. Philos Trans R Soc Lond B Biol Sci. 2020 Jun 8;375(1800):20190261. doi: 10.1098/rstb.2019.0261. Epub 2020 Apr 20. PMID 32306879
• Tristao RM, Lauand L, Costa KSF, Brant LA, Fernandes GM, Costa KN, Spilski J, Lachmann T. Olfactory sensory and perceptual evaluation in newborn infants: A systematic review. Dev Psychobiol. 2021 Nov;63(7):e22201. doi: 10.1002/dev.22201. PMID 34674234

Идентификаторы

NCT: NCT06744244 · 27408

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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