Research Postings
Research Postings
Published Manuscripts
Results from our ongoing studies are published in prestigious peer-reviewed medical journals. Whenever possible these articles have been made open access for parents and clinicians so that they can learn and reference the content.
Five complimentary approaches are at the center of our comprehensive research plan to unravel the causes of SIDS and SUID.
Research pillars:
- Epidemiology
- Genetics
- Physiology
- Pathology
- Parental education
Together they form a solid science-based foundation that guides our strategies to prevent further deaths.
A selection of our recent papers are listed below, and organized by these categories.
Epidemiology
Weatherly M, Trivedi A, Chembrolu R, Gupta S, Ramirez JM, Lavista Ferres JM, Anderson TM, Mitchell EA (2023). PLoS One
Maternal infections, particularly chlamydia and hepatitis C, are associated with an increased risk of sudden unexpected infant death (SUID) in the offspring.
Risk factors for late (28+ weeks’ gestation) stillbirth in the United States, 2014–2015
Tanner D, Murthy S, Lavista Ferres JM, Ramirez JM, Mitchell EA. (2023). PLoS One
High Maternal BMI increases the risk of late stillbirth by 15%. Small for Gestational Age accounted for 38% of late stillbirths. Black and Native Hawaiian and Other Pacific Islander mothers were at higher risks compared to White mothers, as well as for mothers with low educational attainment and older mothers. Participation in the supplemental nutrition for women, infants, and children program was associated with a 28% reduction in the overall stillbirth burden
Tanner D, Lavista Ferres JM, Mitchell EA. Scientific Reports
High-Risk Infants: Infants in the lowest Gestation Related Optimal Weight (GROW) centile had a stillbirth rate of 39.8 per 1000 births, compared to a predicted rate of 11.7 per 1000 births. The study provides stillbirth risk estimates for each GROW centile which helps clinicians to better manage obstetric care and potentially reduce the incidence of late stillbirths.
Maternal Obesity and Risk of Sudden Unexpected Infant Death
Tanner D, Ramirez JM, Weeks WB, Lavista Ferres JM, Mitchell EA. (2024). JAMA Network
Infants born to mothers with obesity have a higher risk of SUID. The SUID risk increases as maternal BMI increases.Approximately 5.4% of SUID cases are attributable to maternal obesity. Maternal obesity should be added to the list of known risk factors for SUID, and further research is needed to investigate the specific causal mechanisms for this association.
Sudden Unexpected Postnatal Collapse Resulting in Newborn Death in the United States
Tatiana M Anderson, Juan M Lavista Ferres, Jan-Marino Ramirez, Edwin A Mitchell. February 2021. (Online ahead of print) MCN: The American Journal of Maternal/Child Nursing.
As a follow up to the ‘Distinct Populations of SUID Based on Age’ (see Ferres et al. 2020 below) study, we applied the same methodology, but narrowed the focus on sudden unexpected postnatal collapse (SUPC) cases that resulted in death (defined as infants born ≥35 weeks gestational age with a 5-minute APGAR score of ≥7). SUPC deaths in the first week were still significantly different from SUID deaths that occurred between 7-364 days with the same inclusion criteria. These data support the need for adequate nurse staffing during the entire postpartum stay for new mothers in the hospital setting.
Altitude and Risk of Sudden Unexpected Infant Death in the United States
Richard Johnston, Xiaohan Yan, Tatiana M Anderson, Edwin A Mitchell. January 2021. Scientific Reports.
We aimed to examine whether the risk of sudden unexpected infant death (SUID) varies with altitude in the United States. Two different models indicated an increased risk of SUID at elevations >8000 feet. However, the number of cases were very small at 10 deaths over 6 years. Thus, we concluded that future research and educational resources should focus on SUID risk factors with higher prevalence in the United States. The findings may be relevant, however, to other countries with larger populations residing at high altitude.
Factors Associated with Age of Death in Sudden Unexpected Infant Death
Kelty Allen, Tatiana M Anderson, Urszula Chajewska, Jan-Marino Ramirez, Edwin A Mitchell. January 2021. Acta Paediatrica.
Here we found that younger chronologic age at death was associated with maternal smoking and factors associated with lower socio-economic status, and older age was associated with low birthweight, prematurity, and admission to the neonatal intensive care unit.
Circadian Variation in Sudden Unexpected Infant Death in the United States
Tatiana M Anderson, Kelty Allen, Jan-Marino Ramirez, Edwin A Mitchell. November 2020. Acta Paediatrica.
This study identified features that are associated with SUID by time of day. Features that were associated with nighttime SUID were bed sharing, younger infants, non-white infants, placed supine to sleep and found supine, and caregiver was the parent. Daytime SUID death was associated with older infants, day care, white infants, sleeping in an adult bed, and prone sleep position. Factors not associated with time of death were sex of infant, smoking, and breastfeeding.
Geographic Variation in Sudden Unexpected Infant Death in the United States
Edwin A Mitchell, Xiaohan Yan, Shirley You Ren, Tatiana M Anderson, Jan-Marino Ramirez, Juan M Lavista Ferres, Richard Johnston. May 2020. The Journal of Pediatrics.
Here we addressed the question whether geographic factors play a role in SUID risk across the United States. We found that there was marked geographic variation in SUID rates across the country, but the variation decreased after adjusting for known risk factors. After adjustment, nine states were found to have significantly higher or lower SUID mortality compared to the national average.
Distinct Populations of Sudden Unexpected Infant Death Based on Age
Juan M Lavista Ferres, Tatiana M Anderson, Richard Johnston, Jan-Marino Ramirez, Edwin A Mitchell. January 2020. Pediatrics.
This study found that SUID deaths that occur in the first week of life (days 0-6) are statistically different from deaths that occur between days 7-364. The groups differed in assigned cause of death code, live birth order, marital status, age of mother, birth weight, and gestational length.
Maternal Smoking Before and During Pregnancy and the Risk of Sudden Unexpected Infant Death
Tatiana M Anderson, Juan M Lavista Ferres, Shirley You Ren, Rachel Y Moon, Richard D Goldstein, Jan-Marino Ramirez, Edwin A Mitchell. April 2019. Pediatrics
Study found that SUID risk more than doubled with any maternal smoking during pregnancy and increased twofold between no smoking and smoking a single cigarette daily throughout pregnancy. Assuming causality, we estimate 22% of SUID cases in the US can be directly attributed to maternal smoking during pregnancy.
Genetics
All five research pillars combined indicate that a vulnerable child succumbs to SIDS/SUID during their first year of life when exposed to external stressors such as lack of oxygen, a condition that is for example encountered when children sleep on their stomach.
Developmental factors that contribute to a child’s vulnerability such as maternal smoking have been confirmed by our epidemiological studies. Such scientific research has led to campaigns to reduce smoking and prone sleeping which has saved thousands of lives.
One important, yet still little understood, factor that renders a child vulnerable is genetic disposition. Recent advances in whole-genome and RNA-sequencing opened up the opportunity to genetically screen every child that succumbs to SUID in order to determine whether an underlying genetic vulnerability contributed to their death.
In the future, this evolving research area will allow us to develop effective strategies to prevent further deaths, such as newborn screening which can identify genetic risk factors.
The majority of our resources are invested in building the world’s largest SIDS-focused whole-genome database. Like the CDC data base, which has been instrumental for our published epidemiological research, we expect that this genetic data base will lead to many scientific manuscripts that will inform parents, researchers and clinicians, and will safe future lives.
Bard AM, Clark LV, Cosgun E, Aldinger KA, Timms A, Quina LA, Lavista Ferres JM, Jardine D, Haas EA, Becker TM, Pagan CM, Santani A, Martinez D, Barua S, McNutt Z, Nesbitt A, Ramirez JM. (2024). Wiley Online Library
Identified many new genetic factors that might help explain why some infants die suddenly and unexpectedly, particularly highlighting the role of heart disease genes and the body’s response to low oxygen levels. Genetic Insights: The study identified significant genetic variants in 86 genes, highlighting their roles in heart and brain functions and expanding the understanding of SUID causes. New Genetic Factors: Newly discovered variants related to the body’s response to low oxygen levels were highlighted, supporting the triple risk hypothesis and shedding light on SUID’s complex pathophysiology.
AAV-mediated interneuron-specific gene replacement for Dravet syndrome
Mich JK, Ryu J, Wei AD, Gore BB, Guo R, Bard AM, Martinez RA, BishawY, Luber E, Oliveira Santos LM, Miranda N, Ramirez JM, Ting JT, Lein ES, Levi BP, Kalume FK. (2024). Cold Spring Harbor Laboratory bioRxiv
Targeted Gene Therapy: The study demonstrated that AAV-mediated gene therapy can specifically target interneurons to replace defective genes in a mouse model of Dravet syndrome. Positive Outcomes: This targeted gene replacement approach significantly reduced seizure activity and improved survival rates in the treated mice, showing promise for future therapeutic applications. Safety: No mortality or toxicity was observed in wild-type mice, indicating the therapy’s safety and potential for future therapeutic applications.
Physiology
Garcia III, AJ, DashevskiyT, Khuu MA, Ramirez JM (2017). Frontiers in Physiology
Chronic intermittent hypoxia (CIH) is a major risk factor for SIDS: CIH affects key brain centers that control breathing and the response to hypoxia and arousal. The persistent sodium current is needed for successful autoresuscitation, gasping and arousal response. This molecular mechanisms is altered by CIH
Chapter 13 – The sigh and related behaviors
Ramirez JM, Vlemincx E, Baertsch NA, Severs LJ. The Science Direct.
The number of sighs and the number of arousals are reduced in SIDS. This study describes that the Pre-Bötzinger Complex (preBötC) is crucial for generating both sighing and normal rhythmic breathing and discusses also new insights that have been gained into the pathways and mechanisms that control yawning, sneezing, and hiccupping
Ramirez JM, Carroll MS, Burgraff N, Rand CM, WeeseMayer DE (2023). Springer Nature Link
This review discusses how intermittent hypoxia can trigger a cascade of molecular, cellular, and network events that lead to the dysregulation of multiple organ systems. Intermittent Hypoxia is associated with disturbances in autonomic functions, that are exacerbated in SIDS, epilepsy, sleep apnea, Rett syndrome, congenital heart disease, and mitochondrial diseases. We also discuss advanced techniques for analyzing the progression of autonomic disorders.
Purinergic signaling mediates neuroglial interactions to modulate sighs
Severs LJ, Bush NE, Quina LA, Hidalgo-Andrade S, Burgraff NJ, DashevskiyT, Shih AY, Baertsch NA, Ramirez JM. (2023). Nature Communications
It is known that sigh generation is reduced in SIDS. Here we identify the brain center and cellular mechanisms generating sighs through neuron-glia coupling and purinergic signaling.
Bush N and Ramirez JM (2024). Nature Neuroscience
SIDS is caused by the failure of the cardiorespiratory network to respond to hypoxia. Here we show that breathing is generated through population dynamics distributed along the ventrolateral medulla. Our computational and experimental approach shows how these dynamics are fundamentally altered in hypoxia, which provides critical insights to explain failed arousal in SIDS.
Huff A, Karlen-Amarante M, Oliveira LM, Ramirez JM. (2024). eLife
Laryngeal spasms and swallowing disturbances are implicated in SIDS. We identified a critical brain region that controls laryngeal and swallowing functions and coordinates these function with breathing (PiCo). PiCo’s function is compromised by Chronic Intermittent Hypoxia (CIH) which could explain these disturbances in SIDS. This finding has also important implications for Obstructive Sleep Apnea.
Karlen-Amarante M, Glovak ZT, Huff A, Oliveira LM, Ramirez JM (2024). Frontiers
Dysautonomia and disturbances in cardiorespiratory coupling are associated with SIDS. Here we identify the brain centers (PiCo & preBötC) that are critical for coordinating and coupling respiratory and sympathetic control. Chronic Intermittent Hypoxia (CIH) alters this coupling which could explain the dysautonomia in SIDS. The study has also important implications for Hypertension
Advances in Cellular and Integrative Control of Oxygen Homeostasis within the Central Nervous System
Jan-Marino Ramirez, Liza J Severs, Sanja C Ramirez, Ibis M Agosto-Marlin. June 2018. The Journal of Physiology.
Failure to adequately regulate levels of oxygen and carbon dioxide in the brain has been associated with many disorders including sudden infant death syndrome. This review explores questions surrounding how the brain senses and regulates oxygen, carbon dioxide, and changes in pH.
Jan-Marino Ramirez, Sanja C. Ramirez, Tatiana M Anderson. SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future. Adelaide (AU): University of Adelaide Press; 2018 May. Chapter 27.
This book chapter describes how different risk factors can contribute to the sudden death, the failure to arouse, the specific conditions associated with sleep, and the neuronal networks controlling cardiorespiratory functions and how they contribute to the events leading to sudden death.
Having a better understanding of brainstem mechanics and how systems react to other influences (i.e. risk factors) can help us understand the significance of known risk factors that contribute to SIDS.
Sanja Ramirez, Travis Allen, Lindsay Villagracia, Yooree Chae, Jan-Marino Ramirez, Daniel D Rubens. November 2016. Neuroscience.
Infants that succumb to SIDS have been identified with inner ear dysfunction at birth and on autopsy. This study sought to investigate the individual roles of hypercarbia (increased carbon dioxide) and hypoxia (decreased oxygen) in eliciting movement during natural sleep in mice with inner ear damage compared to control mice with no ear damage. Hypoxia is the trigger for the movement response while carbon dioxide suppresses it. Carbon dioxide does not trigger active movements under natural sleep conditions.
The Integrative Role of the Sigh in Psychology, Physiology, Pathology, and Neurobiology
Jan-Marino Ramirez. 2014. Progress in Brain Research.
Hypoarousal and failure to sigh have been associated with sudden infant death syndrome. This book chapter delves into the neuroscience behind the sigh and its relationship with psychology, physiology, and pathology. In a state of decreased oxygen (hypoxia) a sigh is generated which evokes an arousal.
The Physiological Determinants of Sudden Infant Death Syndrome
Alfredo J Garcia 3rd, Jenna E Koschnitzky, Jan-Marino Ramirez June 2013. Respiratory Physiology and Neurobiology.
This review aims to explore the physiological determinants (cardiac and respiratory) that actually cause the sudden death of an infant, to figure out how the determinants are affected by known risk factors, and to propose new ideas for SIDS prevention. Epidemiological, pathological, and experimental data are used together to examine current and emerging perspectives.
Pathology
Bhagavan H, Wei AD, Oliveira LM, Aldinger KA, Ramirez JM (2024). American Journal of Physiology-Lung Cellular and Molecular Physiology
Understanding how Chronic Intermittent hypoxia alters gene expression is important to understand how this risk factor leads to sudden death and SIDS. This study describes distinct Transcriptomic Responses: Chronic intermittent hypoxia (CIH) induces different gene expression changes in neurons and oligodendrocytes within the brainstem. Neurons: Neurons showed transcriptional dysregulation of genes associated with synaptic transmission, structural remodeling, ion channels, and inflammatory responses. Oligodendrocytes: Oligodendrocytes exhibited dysregulated genes related to myelin production and maintenance, as well as inflammatory processes. Implications for Neurological Health: These findings suggest that CIH can lead to significant alterations in brainstem function, potentially impacting respiratory and autonomic control which ultimately can lead to sudden death.
Fu Chuen Kon, Rita Zapata Vazquez, Andrew Lang, Marta C Cohen. September 2020, Forensic Science, Medicine, and Pathology.
Hippocampal abnormalites have been previously described in SUDEP (sudden unexpected death in epilepsy). The aim of this study was to determine the prevalence of abnormalities in the hippocampus, history of seizures, and demographic features in SUDC (sudden unexpected death in childhood), SUDEP, and SIDS cases.
Nailyam Nasirova, Lely A Quina, Ibis M Agosto‐Marlin, Jan‐Marino Ramirez, Evelyn K Lambe, Eric E Turner. August 2019. The Journal of Comparative Neurology.
Maternal smoking is a known risk factor for SUID. It is generally assumed that nicotine contained in cigarettes acts specifically on cholinergic neurons in the brain.
This study made the unexpected discovery that some neurons in the brain, including those implicated in the arousal response are transiently cholinergic at a critical developmental time window. Thus, these important brain networks become vulnerable to exposure to nicotine in utero which may explain the association between maternal smoking during pregnancy and sudden infant death syndrome.
Parental Education
In October of 2020, Microsoft hosted ‘Project Dream Catcher’ that used crowd-sourcing to label safe and unsafe sleep positions and environments. The goals in the short-term were to raise SIDS awareness and educate parents on safe sleep practices, and in the long term, to build machine learning algorithms to automatically detect and alert parents to unsafe sleep conditions.
