Neonatal Monitoring: Prediction of Autonomic Regulation at 1 Month from Newborn Assessments

Excerpt

It has been nearly 30 years since the publication of a seminal book that defined the state of knowledge related to the epidemiology of, and mechanisms underlying, sudden infant death syndrome (SIDS) (1). Despite decades of subsequent research, much of which is summarized in other chapters in this book, we must acknowledge that SIDS remains an enigma. Indeed, two longstanding definitions of SIDS (2, 3) are testament to our lack of understanding of why infants die of SIDS — that is, these deaths remain unexplained after thorough investigation. Although infrequent, SIDS remains the most common cause of infant death between 1 month and 1 year of age, and the deaths of 2,000 infants annually in the United States (US) alone are unimaginable tragedies for these 2,000 families. At the heart of the reason why we have such an incomplete understanding of SIDS is, fortunately, its rarity. In the US, the 2014 estimates suggest that SIDS is the cause of death for about 3.9 of every 10,000 infants born each year (4). Over the past few decades, our understanding of the external factors that contribute to why infants die of SIDS has come from numerous, worldwide, epidemiological studies. Associations gleaned from these studies have led to recommendations including strong discouragement for mothers not to smoke during pregnancy paired with specific guidance for safe sleeping practices. Subsequent to these recommendations, the rate of SIDS was reduced in many countries (5). However, the physiological mechanisms that underlie SIDS remain unknown.

By definition, SIDS deaths are unexpected. While there may be evidence of low-grade infection prior to the time of death (6) in general, there are no overt, chronic signs of the impending demise. These deaths do not seem to be “programmed”, in the sense that they are inevitable; rather, they appear to be due to suboptimal physiological regulatory responses to what may be rather common challenges faced by infants during the first year of life. Nonetheless, these deaths are not random. Some infants are more likely to experience the failure of adequate physiological responses to environmental challenges than others, hence the concept of the vulnerable infant. Infants born prematurely are at greater risk for SIDS (7), as are infants of mothers who smoked or drank during pregnancy (8, 9). Yet we still do not understand how such factors create physiological vulnerability, and investigations of risk factor mechanisms remain a mainstay of SIDS research.

An extremely important area of SIDS research that reinforces the non-random nature of SIDS deaths is based on anatomical and biochemical differences between SIDS infants and infants dying of known causes (10). Results from post-mortem studies, reviewed in other chapters of this book, provide compelling evidence for differences in brain structure and function that are linked to vulnerability for SIDS. These studies have largely focused on brainstem anomalies, with many revealing differences in serotonergic systems within brainstem areas associated with the regulation of breathing, the cardiovascular system, temperature regulation, and sleep-wake cycles (11). These findings strongly support the hypothesis that SIDS is the result of dysregulation of the autonomic nervous system (ANS). However, it is important to note that anomalies also are found in other regions of the brain, including the forebrain, suggesting deficits in brain development of SIDS infants that may be quite widespread (12).

The major function of the ANS is to provide organisms with integrated physiological responses to a wide variety of environmental challenges, requiring adjustments to body temperature, blood pressure, and respiratory activity. These challenges frequently occur during sleep and the transitions between sleep states. While population-based research strategies have sought to identify specific environmental factors that place infants at greater risk, other researchers have worked to identify physiological markers linked to the vulnerability to SIDS. In general, it is believed that SIDS infants appear to have increased vulnerability to triggering events which ordinarily should not be life-threatening (13). During specific critical periods of development, characterized by major changes in sleep organization and autonomic balance, all infants, particularly those with adverse prenatal histories, may have a diminished capacity to adequately respond to autonomic challenges (14). As examples, physiologic deficits associated with this risk status may be the inability to mount adequate cardiovascular responses to hypotensive and thermal challenges during the vulnerable period for SIDS (15-17), adequate respiratory activation in response to hypoxic and/or hypercarbic challenges (18, 19), and appropriate cortical arousals from sleep to a variety of physiologic challenges (20, 21). Thus, many SIDS researchers have proposed that the maturation of brainstem regions involved in the integration of cardiac and respiratory functions underlies these vulnerabilities.

The overall premise of our own research is that at least some SIDS victims are unable to mount rescue responses to homeostatic challenges in the extrauterine environment, and that assessments of ANS activity will reveal vulnerabilities in this system prior to death. Our working model is that many SIDS cases, and infants at the greatest risk, will exhibit altered baseline autonomic activity and atypical responses to cardiorespiratory challenges. Several years ago we published the case of a SIDS infant with abnormalities in the brainstem serotonergic system who also exhibited extreme values for cardiorespiratory variables measured on the second day of life (22). This was the first reported case of a SIDS infant with a documented brainstem abnormality and clear evidence of neonatal dysfunction in cardiorespiratory respiratory control. Consistent with this finding, infants who subsequently die of SIDS have been shown to have higher heart rates, reduced heart rate variability, disturbed co-ordination between cardiac and respiratory measures, increased variability and rate of breathing during quiet sleep, fewer short respiratory pauses, and abnormalities in the beat-to-beat dynamics of cardiac control (23-29). Several studies have assessed the ability of infants to respond to respiratory, thermal, and autonomic challenges (30-32). Based on studies demonstrating the presence of functioning baroreceptor reflexes during the neonatal period in many species (33), we and others have studied heart rate and electrocortical responses associated with blood pressure changes following postural adjustment and have shown that these baroreceptor-mediated reflexes are present in newborn infants within the first few days after birth (32, 34-40). These homeostatic responses, which can be assessed in the neonate, provide measures of the competence of neural mechanisms to process, and respond to, a frequently encountered stimulus.

Unfortunately, there are still no widely accepted animal models with the determining characteristics of SIDS. Nonetheless, as reviewed in other chapters of this volume, animal model studies can provide important information about mechanisms and risk factors that influence cardiorespiratory control during early development. As examples, much has been learned from animal models about how cardiorespiratory control mechanisms are affected by nicotine exposure (41, 42), various neurotransmitter systems (including serotonin and gamma-aminobutyric acid [GABA]) (43-49), repeated hypoxic experiences (50), chemo- and baroreceptor feedback (51, 52), and interactions with endotoxins (53, 54). Despite the impressive advances in understanding that animal models have provided about cardiorespiratory control during early development, we still do not know exactly how these mechanisms are related to SIDS. However, as noted previously, there is wide agreement that deficits in regulation of these systems underlie the vulnerability to SIDS.

Dysfunction in autonomic control may underlie SIDS, with a window of increased risk starting as early as 1 month of age (1). A central question is, however, whether measurements of autonomic function, including heart rate and heart rate variability at an age prior to the age of increased risk for SIDS, can be used to predict possible deficits in autonomic function and response to environmental challenge during the high-risk period. As mentioned above, in a report of a single case of SIDS, we found evidence of parasympathetic/sympathetic imbalance during sleep, as well as several cardiorespiratory variables with extreme values (22). The remainder of this chapter focuses on results of a study where we explored data from a set of infants collected over the past few years in which such measurements were made in newborns and again at 1-month postnatal age. These new longitudinal analyses suggest that extremes in certain measures of ANS function at the beginning of the high-risk window for SIDS (1 month) may be predicted by the same measurements in the neonatal period, prior to the time of increased risk for SIDS.