Olfactory Testing in Perinatal Asphyxia: Enhancing Risk Assessment

Recruiting

• Conditions: Mild Birth Asphyxia; Moderate Birth Asphyxia

• Registration Number: NCT06744244
• Lead Sponsor: University of Parma

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 2024-09-10
• Status Verified: 2024-12
• Study First Submitted: 2024-12-06
• Study First Submitted QC: 2024-12-16
• Study First Posted: 2024-12-20
• Last Update Submitted: 2024-12-30
• Last Update Posted: 2024-12-31
• Primary Completion: 2025-01
• Study Completion: 2026-09-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Autonomic Responses to Olfactory Stimulation in Asphyxiated Newborns.	during the Olfactory Testing	Heart Rate (HR) and Heart Rate Variability (HRV) will be continuously monitored via electrocardiography throughout the procedure and compared between the two groups. Data will be analyzed using software such as Kubios.; For HRV, the following metrics will be extracted: SDNN (Standard Deviation of NN Intervals): Reflects overall HRV. RMSSD (Root Mean Square of Successive Differences): Reflects parasympathetic (vagal) activity.; LF Power (Low-Frequency): Reflects both sympathetic and parasympathetic activity (0.04 - 0.15 Hz).; HF Power (High-Frequency): Primarily reflects parasympathetic activity (0.15 - 0.4 Hz).; LF/HF Ratio: Assesses the balance between sympathetic and parasympathetic activity, with a higher ratio indicating sympathetic dominance.
Breathing patterns in Asphyxiated Newborns.	during the Olfactory Testing	Variations in breathing patterns are assessed by the pulse oximeter that operates on the principle of light absorption, emitting red and infrared light through the skin. A photodetector measures the light absorbed by the blood, with oxygenated hemoglobin absorbing more infrared light and deoxygenated hemoglobin absorbing more red light. The ratio of light absorption at these wavelengths is used to estimate the percentage of oxygenated hemoglobin (Peripheral Oxygen Saturation - SpO2), displayed as a percentage on the device's screen. This metric provides insight into oxygenation levels in the bloodstream, which may improve due to enhanced respiratory efficiency triggered by olfactory exposure. The pulse oximeter also features a respiratory rate (RR) measurement, estimating RR by detecting changes in blood flow or pulse linked to breathing patterns.
Cerebral functioning in Asphyxiated Newborns.	Within 6 to 72 hours of life	Amplitude EEG (aEEG) provides a continuous, real-time overview of cerebral function by measuring the brain's electrical activity. In the context of perinatal asphyxia, aEEG is used to detect abnormal brain patterns, such as reduced or absent brain activity. These patterns are reflected in the amplitude of the signal (measured in microvolts), which can indicate the severity of brain injury and help clinicians assess the extent of neurological damage.
Changes in olfactory evoked potentials (EOPs) in Asphyxiated Newborns.	during the Olfactory Testing	The analysis of EOPs in response to olfactory stimuli, such as rose, vanilla, and breast milk, will be conducted using dedicated software like EEGLAB and ERPLAB (MATLAB). The analysis parameters for EOPs will include latency, amplitude, wave components, spatial distribution, duration, topography and localization, as well as habituation and adaptation. These parameters will be compared between the two groups.
Spectral analysis of brain oscillatory rhythms to monitor changes in global brain activity.	Within 6 to 72 hours of life	Brain activity will be continuously monitored with electroencephalography (EEG) throughout the procedure using a 12-channel system and oscillatory activity across brain rhythm bands (Delta: 0.5 - 4 Hz, Theta: 4 - 8 Hz, Alpha: 8 - 12 Hz, Beta: 12 - 30 Hz, Gamma: 30 - 100 Hz) will be analyzed with dedicated software such as EEGLAB (MATLAB) in both groups.
Changes in behavioral responsens to Olfactory Stimulation in Asphyxiated Newborns.	Within 6 to 72 hours of life	Facial expressions obtained from video-recordings will be assessed by two neonatologists, who will be blinded to the odor used to obtain insight into changes in behavioral responsens.; A score will be assigned on a scale of 0 to 100 (0 = extremely disgusted; 100 = extremely pleased).; The neonatologists will view the video as many times as necessary to ensure the highest accuracy inscoring. The videos will be destroyed after 5 years.
Highlight a different activation within brain areas involved in olfactory perception, memory, and learning through fMRI.	Within 6 to 72 hours of life	Data from functional magnetic resonance imaging (fMRI) will be analyzed to compare the activation of regions of interest (ROIs), especially in regions such as the olfactory bulb, entorhinal cortex, hippocampus, and amygdala, between the two groups of patients during the execution of olfactory test. The parameters that will be evalueted and compared between the two groups will be: BOLD Signal (Blood Oxygenation Level Dependent), Activation Intensity (Signal Strength), Peak Activation, Time Course of Activation, Functional Connectivity and Effect Size.

Secondary Outcome Measures

Name	Time	Method
Neurodevelopmental follow-up	Between 12 and 18 months	The Bayley III assessment will be administered in both groups. It provides a comprehensive overview of a child's cognitive, motor, and socio-emotional abilities. The measures obtained from the Bayley-III include cognitive, motor, language, social-emotional and adaptive behavior scales. Scores from the different scales are converted into standard scores (mean of 100, standard deviation of 15), which help compare the child to the general population.

Trial Locations

Locations (1)

Azienda Ospedaliero-Universitaria di Parma; 🇮🇹 Parma, Italy