Maternal infections in pregnancy and the risk of sudden unexpected infant death in the offspring in the U.S., 2011-2015.

BACKGROUND: Infection is thought to play a part in some infant deaths. Maternal infection in pregnancy has focused on chlamydia with some reports suggesting an association with sudden unexpected infant death (SUID). OBJECTIVES: We hypothesized that maternal infections in pregnancy are associated with subsequent SUID in their offspring. SETTING: All births in the United States, 2011-2015. DATA SOURCE: Centers for Disease Control and Prevention (CDC) Birth Cohort Linked Birth-Infant Death Data Files. STUDY DESIGN: Cohort study, although the data were analysed as a case control study. Cases were infants that died from SUID. Controls were randomly sampled infants that survived their first year of life; approximately 10 controls per SUID case. EXPOSURES: Chlamydia, gonorrhea and hepatitis C. RESULTS: There were 19,849,690 live births in the U.S. for the period 2011-2015. There were 37,143 infant deaths of which 17,398 were classified as SUID cases (a rate of 0.86/1000 live births). The proportion of the control mothers with chlamydia was 1.7%, gonorrhea 0.2% and hepatitis C was 0.3%. Chlamydia was present in 3.8% of mothers whose infants subsequently died of SUID compared with 1.7% of controls (unadjusted OR = 2.35, 95% CI = 2.15, 2.56; adjusted OR = 1.08, 95% CI = 0.98, 1.19). Gonorrhea was present in 0.7% of mothers of SUID cases compared with 0.2% of mothers of controls (OR = 3.09, (2.50, 3.79); aOR = 1.20(0.95, 1.49)) and hepatitis C was present in 1.3% of mothers of SUID cases compared with 0.3% of mothers of controls (OR = 4.69 (3.97, 5.52): aOR = 1.80 (1.50, 2.15)). CONCLUSIONS: The marked attenuation of SUID risk after adjustment for a wide variety of socioeconomic and demographic factors suggests the small increase in the risk of SUID of the offspring of mothers with infection with hepatitis C in pregnancy is due to residual confounding.

Sudden Unexpected Postnatal Collapse Resulting in Newborn Death in the United States.

BACKGROUND: The sudden collapse of an apparently healthy newborn, or sudden unexpected postnatal collapse (SUPC) is fatal in about half of cases. Epidemiological characteristics of sudden unexpected infant death (SUID) in the first week of life differ from those in the postperinatal age group (7-365 days). AIM: To describe the characteristics of SUPC resulting in neonatal death. METHODS: We analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2003-2013: 41,125,233 births and 37,624 SUIDs). SUPC was defined as infants born ≥35 weeks gestational age, with a 5-minute Apgar score of ≥7, who died suddenly and unexpectedly in the first week of life. RESULTS: Of the 37,624 deaths categorized as SUID during the study period, 616 met the SUPC criteria (1.5/100,000 live births). Eleven percent occurred on the first day of life and nearly three quarters occurred during postnatal days 3-6. SUPC deaths differed statistically from SUID deaths occurring 7-364 days of age, in particular for sex, marital status, and live birth order. IMPLICATIONS: These data support the need for adequate nurse staffing during the immediate recovery period and for the entire postpartum stay as well as nurse rounding for new mothers in the hospital setting.

Altitude and risk of sudden unexpected infant death in the United States.

The effect of altitude on the risk of sudden infant death syndrome (SIDS) has been reported previously, but with conflicting findings. We aimed to examine whether the risk of sudden unexpected infant death (SUID) varies with altitude in the United States. Data from the Centers for Disease Control and Prevention (CDC)'s Cohort Linked Birth/Infant Death Data Set for births between 2005 and 2010 were examined. County of birth was used to estimate altitude. Logistic regression and Generalized Additive Model (GAM) were used, adjusting for year, mother's race, Hispanic origin, marital status, age, education and smoking, father's age and race, number of prenatal visits, plurality, live birth order, and infant's sex, birthweight and gestation. There were 25,305,778 live births over the 6-year study period. The total number of deaths from SUID in this period were 23,673 (rate = 0.94/1000 live births). In the logistic regression model there was a small, but statistically significant, increased risk of SUID associated with birth at > 8000 feet compared with < 6000 feet (aOR = 1.93; 95% CI 1.00-3.71). The GAM showed a similar increased risk over 8000 feet, but this was not statistically significant. Only 9245 (0.037%) of mothers gave birth at > 8000 feet during the study period and 10 deaths (0.042%) were attributed to SUID. The number of SUID deaths at this altitude in the United States is very small (10 deaths in 6 years).

Factors associated with age of death in sudden unexpected infant death.

AIM: This study aimed to systematically analyse the pregnancy, birth and demographic-related factors associated with age of death in sudden unexpected infant death (SUID). METHODS: Data were analysed from the Centers for Disease Control and Prevention's Cohort Linked Birth/Infant Death data set (2011-2013; 11 737 930 live births). SUID was defined as deaths from sudden infant death syndrome, ill-defined causes, or accidental suffocation and strangulation in bed. There were 9668 SUID cases (7-364 days; gestation >28 weeks; 0.82/1000 live births). The odds of death at different ages were compared to determine which variables significantly affect the SUID age of death. RESULTS: Forty-three features indicated a significant change in age of death with two main patterns: (a) younger chronologic age at death was associated with maternal smoking and factors associated with lower socio-economic status, and (b) older age was associated with low birthweight, prematurity and admission to the neonatal intensive care unit. However, when age was corrected for gestation, these factors were associated with younger age. CONCLUSION: Factors that varied with age of death are well-documented risk factors for SUID. The majority of these risk factors were associated with younger age at death after allowing for gestational age at birth.

Circadian variation in sudden unexpected infant death in the United States.

AIM: To determine which factors are associated with sudden unexpected infant death (SUID) by time of day. METHODS: Data were analysed from the National Fatality Review Case Reporting System (2006-2015). Out of 20 005 SUID deaths in 37 states, 12 191 (60.9%) deaths had a recorded nearest hour of discovery of the infant. We compared distribution patterns between time of death and 118 variables to determine which were significantly correlated with SUID time of death using advanced statistical modelling techniques. RESULTS: The 12-hour time periods that were most different were 10:00 to 21:00 (daytime) and 22:00 to 09:00 (nighttime). The main 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 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 the infant, smoking and breastfeeding. CONCLUSION: Sudden unexpected infant death deaths that occur at night are associated with a separate set of risk factors compared to deaths that occur during the day. However, to minimise risk, it is important to practice safe sleep guidelines during both nighttime and daytime sleep.

Geographic Variation in Sudden Unexpected Infant Death in the United States.

OBJECTIVES: To assess the geographic variation of sudden unexpected infant death (SUID) and test if variation in geographic factors, such as state, latitude, and longitude, play a role in SUID risk across the US. STUDY DESIGN: We analyzed the Centers for Disease Control and Prevention's Cohort Linked Birth/Infant Death dataset (2005-2010; 22 882 SUID cases, 25 305 837 live births, rate 0.90/1000). SUID was defined as infant deaths (ages 7-364 days) that included sudden infant death syndrome, ill-defined and unknown cause of mortality, and accidental suffocation and strangulation in bed. SUID geographic variation was analyzed using 2 statistical models, logistic regression and generalized additive model (GAM). RESULTS: Both models produced similar results. Without adjustment, there was marked geographic variation in SUID rates, but the variation decreased after adjusting for covariates including known risk factors for SUID. After adjustment, nine states demonstrated significantly higher or lower SUID mortality than the national average. Geographic contribution to SUID risk in terms of latitude and longitude were also attenuated after adjustment for covariates. CONCLUSION: Understanding why some states have lower SUID rates may enhance SUID prevention strategies.

Distinct Populations of Sudden Unexpected Infant Death Based on Age.

OBJECTIVES: In most recent studies, authors combine all cases of sudden infant death syndrome, other deaths from ill-defined or unknown causes, and accidental suffocation and strangulation in bed as a single population to analyze sudden unexpected infant death (SUID). Our aim with this study is to determine if there are statistically different subcategories of SUID that are based on the age of death of an infant. METHODS: In this retrospective, cross-sectional analysis, we analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2003-2013: 41 125 233 births and 37 624 SUIDs). Logistic regression models were developed to identify subpopulations of SUID cases by age of death, and we subsequently analyzed the effects of a set of covariates on each group. RESULTS: Two groups were identified: sudden unexpected early neonatal deaths (SUENDs; days 0-6) and postperinatal SUIDs (days 7-364). These groups significantly differed in the distributions of assigned International Classification of Diseases, 10th Revision code, live birth order, marital status, age of mother, birth weight, and gestational length compared to postperinatal SUIDs (days 7-364). Maternal smoking during pregnancy was not a significant risk factor for deaths that occurred in the first 48 hours. CONCLUSIONS: SUEND should be considered as a discrete entity from postperinatal SUID in future studies. These data could help improve the epidemiological understanding of SUEND and SUID and provide clues to a mechanistic understanding underlying the causes of death.

Maternal Smoking Before and During Pregnancy and the Risk of Sudden Unexpected Infant Death.

OBJECTIVES: Maternal smoking during pregnancy is an established risk factor for sudden unexpected infant death (SUID). Here, we aim to investigate the effects of maternal prepregnancy smoking, reduction during pregnancy, and smoking during pregnancy on SUID rates. METHODS: We analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2007-2011: 20 685 463 births and 19 127 SUIDs). SUID was defined as deaths at <1 year of age with International Classification of Diseases, 10th Revision codes R95 (sudden infant death syndrome), R99 (ill-defined or unknown cause), or W75 (accidental suffocation or strangulation in bed). RESULTS: SUID risk more than doubled (adjusted odds ratio [aOR] = 2.44; 95% confidence interval [CI] 2.31-2.57) with any maternal smoking during pregnancy and increased twofold between no smoking and smoking 1 cigarette daily throughout pregnancy. For 1 to 20 cigarettes per day, the probability of SUID increased linearly, with each additional cigarette smoked per day increasing the odds by 0.07 from 1 to 20 cigarettes; beyond 20 cigarettes, the relationship plateaued. Mothers who quit or reduced their smoking decreased their odds compared with those who continued smoking (reduced: aOR = 0.88, 95% CI 0.79-0.98; quit: aOR = 0.77, 95% CI 0.67-0.87). If we assume causality, 22% of SUIDs in the United States can be directly attributed to maternal smoking during pregnancy. CONCLUSIONS: These data support the need for smoking cessation before pregnancy. If no women smoked in pregnancy, SUID rates in the United States could be reduced substantially.

A spatially dynamic network underlies the generation of inspiratory behaviors.

The ability of neuronal networks to reconfigure is a key property underlying behavioral flexibility. Networks with recurrent topology are particularly prone to reconfiguration through changes in synaptic and intrinsic properties. Here, we explore spatial reconfiguration in the reticular networks of the medulla that generate breathing. Combined results from in vitro and in vivo approaches demonstrate that the network architecture underlying generation of the inspiratory phase of breathing is not static but can be spatially redistributed by shifts in the balance of excitatory and inhibitory network influences. These shifts in excitation/inhibition allow the size of the active network to expand and contract along a rostrocaudal medullary column during behavioral or metabolic challenges to breathing, such as changes in sensory feedback, sighing, and gasping. We postulate that the ability of this rhythm-generating network to spatially reconfigure contributes to the remarkable robustness and flexibility of breathing.

Respiratory rhythm generation: triple oscillator hypothesis.

Breathing is vital for survival but also interesting from the perspective of rhythm generation. This rhythmic behavior is generated within the brainstem and is thought to emerge through the interaction between independent oscillatory neuronal networks. In mammals, breathing is composed of three phases - inspiration, post-inspiration, and active expiration - and this article discusses the concept that each phase is generated by anatomically distinct rhythm-generating networks: the preBötzinger complex (preBötC), the post-inspiratory complex (PiCo), and the lateral parafacial nucleus (pF L), respectively. The preBötC was first discovered 25 years ago and was shown to be both necessary and sufficient for the generation of inspiration. More recently, networks have been described that are responsible for post-inspiration and active expiration. Here, we attempt to collate the current knowledge and hypotheses regarding how respiratory rhythms are generated, the role that inhibition plays, and the interactions between the medullary networks. Our considerations may have implications for rhythm generation in general.

A novel excitatory network for the control of breathing.

Breathing must be tightly coordinated with other behaviours such as vocalization, swallowing, and coughing. These behaviours occur after inspiration, during a respiratory phase termed postinspiration. Failure to coordinate postinspiration with inspiration can result in aspiration pneumonia, the leading cause of death in Alzheimer's disease, Parkinson's disease, dementia, and other neurodegenerative diseases. Here we describe an excitatory network that generates the neuronal correlate of postinspiratory activity in mice. Glutamatergic-cholinergic neurons form the basis of this network, and GABA (γ-aminobutyric acid)-mediated inhibition establishes the timing and coordination relative to inspiration. We refer to this network as the postinspiratory complex (PiCo). The PiCo has autonomous rhythm-generating properties and is necessary and sufficient for postinspiratory activity in vivo.The PiCo also shows distinct responses to neuromodulators when compared to other excitatory brainstem networks. On the basis of the discovery of the PiCo, we propose that each of the three phases of breathing is generated by a distinct excitatory network: the pre-Bötzinger complex, which has been linked to inspiration; the PiCo, as described here for the neuronal control of postinspiration; and the lateral parafacial region (pF(L)), which has been associated with active expiration, a respiratory phase that is recruited during high metabolic demand.

The ins and outs of breathing.

Distinct populations of neurons within the brainstem are responsible for generating and coordinating the rhythmic patterns of neural activity that underlie breathing.

Defining modulatory inputs into CNS neuronal subclasses by functional pharmacological profiling.

Previously we defined neuronal subclasses within the mouse peripheral nervous system using an experimental strategy called "constellation pharmacology." Here we demonstrate the broad applicability of constellation pharmacology by extending it to the CNS and specifically to the ventral respiratory column (VRC) of mouse brainstem, a region containing the neuronal network controlling respiratory rhythm. Analysis of dissociated cells from this locus revealed three major cell classes, each encompassing multiple subclasses. We broadly analyzed the combinations (constellations) of receptors and ion channels expressed within VRC cell classes and subclasses. These were strikingly different from the constellations of receptors and ion channels found in subclasses of peripheral neurons from mouse dorsal root ganglia. Within the VRC cell population, a subset of dissociated neurons responded to substance P, putatively corresponding to inspiratory pre-Bötzinger complex (preBötC) neurons. Using constellation pharmacology, we found that these substance P-responsive neurons also responded to histamine, and about half responded to bradykinin. Electrophysiological studies conducted in brainstem slices confirmed that preBötC neurons responsive to substance P exhibited similar responsiveness to bradykinin and histamine. The results demonstrate the predictive utility of constellation pharmacology for defining modulatory inputs into specific neuronal subclasses within central neuronal networks.

Central and peripheral factors contributing to obstructive sleep apneas.

Apnea, the cessation of breathing, is a common physiological and pathophysiological phenomenon. Among the different forms of apnea, obstructive sleep apnea (OSA) is clinically the most prominent manifestation. OSA is characterized by repetitive airway occlusions that are typically associated with peripheral airway obstructions. However, it would be an oversimplification to conclude that OSA is caused by peripheral obstructions. OSA is the result of a dynamic interplay between chemo- and mechanosensory reflexes, neuromodulation, behavioral state and the differential activation of the central respiratory network and its motor outputs. This interplay has numerous neuronal and cardiovascular consequences that are initially adaptive but in the long-term become major contributors to morbidity and mortality. Not only OSA, but also central apneas (CA) have multiple, and partly overlapping mechanisms. In OSA and CA the underlying mechanisms are neither "exclusively peripheral" nor "exclusively central" in origin. This review discusses the complex interplay of peripheral and central nervous components that characterizes the cessation of breathing.

Episodic swimming in the larval zebrafish is generated by a spatially distributed spinal network with modular functional organization.

Despite the diverse methods vertebrates use for locomotion, there is evidence that components of the locomotor central pattern generator (CPG) are conserved across species. When zebrafish begin swimming early in development, they perform short episodes of activity separated by periods of inactivity. Within these episodes, the trunk flexes with side-to-side alternation and the traveling body wave progresses rostrocaudally. To characterize the distribution of the swimming CPG along the rostrocaudal axis, we performed transections of the larval zebrafish spinal cord and induced fictive swimming using N-methyl-d-aspartate (NMDA). In both intact and spinalized larvae, bursting is found throughout the rostrocaudal extent of the spinal cord, and the properties of fictive swimming observed were dependent on the concentration of NMDA. We isolated series of contiguous spinal segments by performing multiple spinal transections on the same larvae. Although series from all regions of the spinal cord have the capacity to produce bursts, the capacity to produce organized episodes of fictive swimming has a rostral bias: in the rostral spinal cord, only 12 contiguous body segments are necessary, whereas 23 contiguous body segments are necessary in the caudal spinal cord. Shorter series of segments were often active but produced either continuous rhythmic bursting or sporadic, nonrhythmic bursting. Both episodic and continuous bursting alternated between the left and right sides of the body and showed rostrocaudal progression, demonstrating the functional dissociation of the circuits responsible for episodic structure and fine burst timing. These findings parallel results in mammalian locomotion, and we propose a hierarchical model of the larval zebrafish swimming CPG.

Low-threshold calcium currents contribute to locomotor-like activity in neonatal mice.

In this study, we examined the contribution of a low-threshold calcium current [I(Ca(T))] to locomotor-related activity in the neonatal mouse. Specifically, the role of I(Ca(T)) was studied during chemically induced, locomotor-like activity in the isolated whole cord and in a genetically distinct population of ventromedial spinal interneurons marked by the homeobox gene Hb9. In isolated whole spinal cords, cycle frequency was decreased in the presence of low-threshold calcium channel blockers, which suggests a role for I(Ca(T)) in the network that produces rhythmic, locomotor-like activity. Additionally, we used Hb9 interneurons as a model to study the cellular responses to application of low-threshold calcium channel blockers. In transverse slice preparations from transgenic Hb9::enhanced green fluorescent protein neonatal mice, N-methyl-d-aspartate-induced membrane potential oscillations in identified Hb9 interneurons also slowed in frequency with application of nickel when fast, spike-mediated, synaptic transmission was blocked with TTX. Voltage-clamp and immunolabeling experiments confirmed expression of I(Ca(T)) and channels, respectively, in Hb9 interneurons located in the ventromedial spinal cord. Taken together, these results provide support that T-type calcium currents play an important role in network-wide rhythm generation during chemically evoked, fictive locomotor activity.