Mild Birth AsphyxiaMEMOBRAINNCT06744244
Olfactory Testing in Perinatal Asphyxia: Enhancing Risk Assessment
An observational study of Mild Birth Asphyxia and Moderate Birth Asphyxia, run by University of Parma at 1 site in Italy.
Trial 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… Read more about this study
- Who is it for?
- Ages 6 to 72 hours
- Conditions the study is for
- Mild Birth Asphyxia, Moderate Birth Asphyxia
- What is being tested?
- Olfactory Testing, Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2) and Video-EEG
- How many people
- 30 participants
- Where
- 1 siteItaly
- Study dates
- 10 Sep 2024to 10 Sep 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 72 hours
- All sexes
- No healthy volunteers
- Child
Study population: Newborns with signs of mild asphyxia and newborns with signs of moderate-severe asphyxia at high risk for hypoxic-ischemic encephalopathy and brain damage.
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
Azienda Ospedaliero-Universitaria di Parma
Parma, 43126
Serafina Perrone, MD, PhD, 3388704211 ext. +39, serafina.perrone@unipr.it
Virginia Beretta, PhD Student
About this study
Official title: Olfactory Memory in Infants With Signs of Asphyxia: An Early Indicator of Neurodevelopmental Outcomes
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.
Read the 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.
- Conditions
- Mild Birth Asphyxia, Moderate Birth Asphyxia
- Being tested
- Olfactory Testing, Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2), Video-EEG, fMRI, Neurodevelopment assessment
- Keywords
- Perinatal Asphyxia, Hypoxic-Ischemic Encephalopathy, Biomarkers, Olfactory Function
- Medical subject headings
- Hypoxia-Ischemia, Brain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Olfactory TestingDiagnostic test
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 previous one. The first olfactory test will be conducted during the Video-EEG recording, and the second one will take place during the fMRI acquisition.
Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2)Diagnostic test
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.
Video-EEGDiagnostic test
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).
fMRIDiagnostic test
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.
Neurodevelopment assessmentDiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| Mild Birth Asphyxia | Term newborns (37-41 weeks of gestational age) with signs of moderate asphyxia at birth (cord pH < 7.10 and/or BE > -12), with mild asphyxia at birth. Receives: Diagnostic Test: Olfactory Testing; Diagnostic Test: Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2); Diagnostic Test: Video-EEG; Diagnostic Test: fMRI; Diagnostic Test: Neurodevelopment assessment | |
| Moderate - Severe Birth Asphyxia | Term newborns (37-41 weeks of gestational age) with signs of moderate asphyxia at birth (cord pH < 7.10 and/or BE > -12) with moderate asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy, who don't need hypothermia treatment and with severe asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy who don't need hypothermia treatment. Receives: Diagnostic Test: Olfactory Testing; Diagnostic Test: Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2); Diagnostic Test: Video-EEG; Diagnostic Test: fMRI; Diagnostic Test: Neurodevelopment assessment |
What is being measured
The primary outcome is the main question the study is designed to answer.
Autonomic Responses to Olfactory Stimulation in Asphyxiated Newborns.
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.
Measured: during the Olfactory Testing
Breathing patterns in Asphyxiated Newborns.
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.
Measured: during the Olfactory Testing
Cerebral functioning in Asphyxiated Newborns.
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.
Measured: Within 6 to 72 hours of life
Changes in olfactory evoked potentials (EOPs) in Asphyxiated Newborns.
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.
Measured: during the Olfactory Testing
Spectral analysis of brain oscillatory rhythms to monitor changes in global brain activity.
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.
Measured: Within 6 to 72 hours of life
Changes in behavioral responsens to Olfactory Stimulation in Asphyxiated Newborns.
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.
Measured: Within 6 to 72 hours of life
Highlight a different activation within brain areas involved in olfactory perception, memory, and learning through fMRI.
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.
Measured: Within 6 to 72 hours of life
Secondary outcomes (1)
Neurodevelopmental follow-up
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.
Measured: Between 12 and 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Dec 2024
- Study start10 Sep 2024
- Primary completionJan 2025 (estimated)
- Study completion10 Sep 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for Mild Birth AsphyxiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Parma
- Sponsor type
- University, hospital or other
- Collaborators
- Azienda Ospedaliero-Universitaria di Parma
- Responsible party
- Principal investigator, Serafina Perrone, University of Parma
- Investigators
- Serafina Perrone, MD, PhD, Principal investigator, Università di Parma
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06744244
- Sponsor's protocol ID
- 27408
- Acronym
- MEMOBRAIN
- Status last verified
- Dec 2024
- First submitted
- 6 Dec 2024
- Last updated
- 31 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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.
PubMed 34795631Finder 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.
PubMed 31710357Ambalavanan 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.
PubMed 33986149Disdier 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.
PubMed 32060970Drobyshevsky 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.
PubMed 16861007Juliano 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.
PubMed 25476492Schaal 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.
PubMed 32306879Tristao 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.
PubMed 34674234Chen X, Gao F, Lin C, Chen A, Deng J, Chen P, Lin M, Xie B, Liao Y, Gong C, Zheng X. mTOR-mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats. CNS Neurosci Ther. 2022 Apr;28(4):540-553. doi: 10.1111/cns.13762. Epub 2021 Nov 16.
PubMed 34784444Lan HY, Yang L, Lin CH, Hsieh KH, Chang YC, Yin T. Breastmilk as a Multisensory Intervention for Relieving Pain during Newborn Screening Procedures: A Randomized Control Trial. Int J Environ Res Public Health. 2021 Dec 10;18(24):13023. doi: 10.3390/ijerph182413023.
PubMed 34948633Baudesson de Chanville A, Brevaut-Malaty V, Garbi A, Tosello B, Baumstarck K, Gire C. Analgesic Effect of Maternal Human Milk Odor on Premature Neonates: A Randomized Controlled Trial. J Hum Lact. 2017 May;33(2):300-308. doi: 10.1177/0890334417693225. Epub 2017 Mar 27.
PubMed 28346843Zhang S, Su F, Li J, Chen W. The Analgesic Effects of Maternal Milk Odor on Newborns: A Meta-Analysis. Breastfeed Med. 2018 Jun;13(5):327-334. doi: 10.1089/bfm.2017.0226. Epub 2018 May 7.
PubMed 29733222Doucet S, Soussignan R, Sagot P, Schaal B. The "smellscape" of mother's breast: effects of odor masking and selective unmasking on neonatal arousal, oral, and visual responses. Dev Psychobiol. 2007 Mar;49(2):129-38. doi: 10.1002/dev.20210.
PubMed 17299785Schaal B, Marlier L, Soussignan R. Responsiveness to the odour of amniotic fluid in the human neonate. Biol Neonate. 1995;67(6):397-406. doi: 10.1159/000244192.
PubMed 7578623Schaal B, Marlier L, Soussignan R. Olfactory function in the human fetus: evidence from selective neonatal responsiveness to the odor of amniotic fluid. Behav Neurosci. 1998 Dec;112(6):1438-49. doi: 10.1037//0735-7044.112.6.1438.
PubMed 9926826
Study at a glance
From the registry record, last updated by the sponsor on 31 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Olfactory Memory in Infants With Signs of Asphyxia: An Early Indicator of Neurodevelopmental Outcomes
- ClinicalTrials.gov ID
- NCT06744244
- Acronym / sponsor ID
- MEMOBRAIN / 27408
- Conditions
- Mild Birth Asphyxia, Moderate Birth Asphyxia
- Keywords
- Perinatal Asphyxia, Hypoxic-Ischemic Encephalopathy, Biomarkers, Olfactory Function
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- University of ParmaUniversity, hospital or other
- Collaborators
- Azienda Ospedaliero-Universitaria di Parma
- Study start
- 10 Sep 2024 (actual)
- Primary completion
- Jan 2025 (estimated)
- Study completion
- 10 Sep 2026 (estimated)
- First posted
- 20 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mild Birth Asphyxia | – | Diagnostic Test: Olfactory Testing, Diagnostic Test: Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2), Diagnostic Test: Video-EEG, Diagnostic Test: fMRI, Diagnostic Test: Neurodevelopment assessmentTerm newborns (37-41 weeks of gestational age) with signs of moderate asphyxia at birth (cord pH < 7.10 and/or BE > -12), with mild asphyxia at birth. |
| Moderate - Severe Birth Asphyxia | – | Diagnostic Test: Olfactory Testing, Diagnostic Test: Heart rate (HR), Heart Rate Variability (HRV), Respiratory Rate (RR), peripheral oxygen saturation (SpO2), Diagnostic Test: Video-EEG, Diagnostic Test: fMRI, Diagnostic Test: Neurodevelopment assessmentTerm newborns (37-41 weeks of gestational age) with signs of moderate asphyxia at birth (cord pH < 7.10 and/or BE > -12) with moderate asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy, who don't need hypothermia treatment and with severe asphyxia at birth, at risk of developing hypoxic-ischemic encephalopathy who don't need hypothermia treatment. |
Who may qualify
- Ages
- 6 to 72 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
- Study population
- Newborns with signs of mild asphyxia and newborns with signs of moderate-severe asphyxia at high risk for hypoxic-ischemic encephalopathy and brain damage.
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Olfactory TestingOlfactory 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 previous one. The first olfactory test will be conducted during the Video-EEG recording, and the second one will take place during the fMRI acquisition. | Diagnostic test | Mild Birth Asphyxia, Moderate - Severe Birth Asphyxia |
| 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. | Diagnostic test | Mild Birth Asphyxia, Moderate - Severe Birth Asphyxia |
| Video-EEGThe infant's Video-EEG, as per guidelines following perinatal asphyxia, will be recorded for approximately 2 hours, including the period preceding odor administration (baseline). | Diagnostic test | Mild Birth Asphyxia, Moderate - Severe Birth Asphyxia |
| fMRINewborns 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. | Diagnostic test | Mild Birth Asphyxia, Moderate - Severe Birth Asphyxia |
| Neurodevelopment assessmentBetween 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. | Diagnostic test | Mild Birth Asphyxia, Moderate - Severe Birth Asphyxia |
Primary outcome
Autonomic Responses to Olfactory Stimulation in Asphyxiated Newborns.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
1 secondary outcome
Neurodevelopmental follow-up
Time frame: Between 12 and 18 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Dec 2024.
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- Background: PubMed 34784444Chen X, Gao F, Lin C, Chen A, Deng J, Chen P, Lin M, Xie B, Liao Y, Gong C, Zheng X. mTOR-mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats. CNS Neurosci Ther. 2022 Apr;28(4):540-553. doi: 10.1111/cns.13762. Epub 2021 Nov 16.
- Background: PubMed 34948633Lan HY, Yang L, Lin CH, Hsieh KH, Chang YC, Yin T. Breastmilk as a Multisensory Intervention for Relieving Pain during Newborn Screening Procedures: A Randomized Control Trial. Int J Environ Res Public Health. 2021 Dec 10;18(24):13023. doi: 10.3390/ijerph182413023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Serafina Perrone, MD, PhD principal investigator
Università di Parma
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Mild Birth Asphyxia and Moderate Birth Asphyxia, run by University of Parma at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 31 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Serafina Perrone, MD, PhD (3388704211 ext. +39, serafina.perrone@unipr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Autonomic Responses to Olfactory Stimulation in Asphyxiated Newborns. (time frame: during the Olfactory Testing). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06744244, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Dec 2024.