RARE DISEASE
Apnea of prematurity
Apnea of prematurity
Apnea of prematurity
Drug discovery
4
drugs
With orphan designations
Overview
Apnea of prematurity (AOP) is a developmental disorder in preterm infants characterized by respiratory pauses (>20 seconds) or shorter pauses with bradycardia (<100 bpm) and/or oxygen desaturation (<85%) [1][2][6]. It stems from immaturity of respiratory control systems, involving central, obstructive, or mixed mechanisms [1][3][8]. Most cases resolve spontaneously by 37–44 weeks postmenstrual age with supportive care, though caffeine therapy and CPAP are widely used to mitigate episodes [1][6][12].
Burden
Associated with intermittent hypoxia, raising risks for retinopathy of prematurity (ROP) and neurodevelopmental delays [7][14][16].
Prolonged hospitalization and monitoring required [1][6][14].
Although not a direct SIDS precursor, preterm infants with AOP share elevated SIDS risk factors [1][2][7].
Clinical management prioritizes minimizing hypoxia and supporting maturation, with caffeine demonstrating long-term safety [12][16]. Persistent apnea beyond 43–44 weeks postmenstrual age warrants evaluation for alternative etiologies [1][2].
Therapies
Methylxanthines: Caffeine citrate (first-line) stimulates respiratory drive via adenosine receptor blockade [1][12][16].
Non-invasive respiratory support: CPAP (4–6 cmH₂O) or NIPPV to maintain airway patency [3][8][14].
Positioning: Prone/side-lying positioning to reduce obstructive episodes [1][3][14].
Categories: rare respiratory diseases
Research Papers
1,210 drug discovery papers about Apnea of prematurity, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,210 drug discovery papers about Apnea of prematurity, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-02 | Hypoxia/reoxygenation cycles, reactive oxygen species and succinate: A mechanistic framework for apnea of prematurity?
We review clinical observations and experimental data to examine the pathophysiological mechanisms by which apnea of prematurity and intermittent hypoxemia destabilizes respiratory control and might lead to neurodevelopmental disorders. Clinically, both apnea and hypoxemia are characterized by marked heterogeneity in definitions, monitoring approaches, and temporal patterns, complicating comparisons across studies. Clinical evidence suggests that cumulative hypoxemic burden, rather than apnea duration alone, is a key determinant of respiratory and neurodevelopmental morbidity in preterm neonates. Repeated hypoxemia-reoxygenation cycles enhance peripheral chemoreceptor sensitivity, narrow the CO₂ reserve, and promote respiratory instability during a critical developmental window. Animal models of intermittent hypoxia demonstrate that this sensitization is mediated by reactive oxygen species (ROS) signaling and a metabolic response involving neuronal adenosine release, activation of xanthine oxidase and NADPH oxidase ultimately converging to inhibition of mitochondrial complex I and metabolic depression during the hypoxic phase. This response is clinically evidenced by a reduction of EEG amplitude occurring during apnea. Recent data suggest that subtle changes in biochemical equilibrium within the Krebs cycle favor succinate accumulation during the hypoxic phase, which is then rapidly oxidized during reoxygenation, leading to enhanced ROS production, as demonstrated in models of ischemia-reperfusion injury and neonatal severe hypoxia. We finally provide preliminary data showing that the succinate dehydrogenase inhibitor dimethyl malonate reduces oxidative phosphorylation in brain sample of mice pups, therefore establishing an experimental framework to address the hypothesis that succinate accumulation contributes to ROS synthesis in a rodent model of apnea of prematurity.
2026-07-14 | The effect of nasal olfactory stimulation on apnea of prematurity: a randomized cross-over trial.
Olfactory stimulation may enhance respiratory drive in preterm infants without respiratory support. The aim of this study was to assess the efficacy of olfactory stimulation on apnea of prematurity (AOP) in preterm infants receiving nasal continuous positive pressure (nCPAP). This randomized, placebo-controlled, double-blind cross-over study enrolled preterm infants born between 23 0/7 and 31 6/7 weeks of gestation receiving nCPAP and treatment with caffeine citrate. Vanilla or strawberry odor, or an odorless placebo solution, was applied to the nCPAP masks with an odor pen. The primary outcome was the number of desaturation and bradycardia episodes. Secondary outcomes included physiological parameters and feeding tolerance. Eighty preterm infants completed the study. The median (interquartile range) number of events during the 12-hour study period was 10 (3-27) in the intervention group and 14 (3-29) in the control group (p = 0.82). No significant differences were observed in any secondary outcome measures with either vanilla or strawberry odor. This study did not demonstrate an effect of olfactory stimulation on the number of desaturation and bradycardia episodes in very preterm infants receiving nCPAP. Future research may focus on optimizing methods for delivering olfactory stimuli to infants on non-invasive respiratory support. Clinical trials have demonstrated that olfactory stimulation, using odors such as vanilla, may reduce the frequency of apnea and desaturation episodes in spontaneously breathing preterm infants. This study evaluates the effect of olfactory stimulation with vanilla and strawberry odor on the respiratory drive of preterm infants receiving nasal continuous positive pressure support - the population most severely affected by the apnea of prematurity. In this population, olfactory stimulation did not significantly reduce the number of desaturations and bradycardia. Future research may focus on optimizing delivery methods to ensure that olfactory stimuli are effectively perceived by infants on non-invasive respiratory support.
2026-06-05 | Developmental age and clinical illness drive in vivo variability of CYP1A2 ontogeny and caffeine metabolism in preterm neonates.
Caffeine is the standard therapy for apnea of prematurity and used near-universally in preterm infants. Interindividual variability in clearance, exposure, and clinical responses persists in neonates. CYP1A2 is the primary enzyme responsible for caffeine metabolism in adults, but the enzyme activity in neonates has historically been considered negligible. Scavenged plasma samples from neonates receiving caffeine therapy in a neonatal intensive care unit were analyzed to quantify caffeine and paraxanthine concentrations. The caffeine metabolic ratio (CMR) was used as a functional biomarker of in vivo CYP1A2 activity. Associations between CMR, postmenstrual age, and clinical covariates were evaluated using univariate analyses, linear mixed-effects modeling, and longitudinal analyses. To compare our data to model predictions, caffeine concentrations were simulated in preterm infants using two previously published physiologically based pharmacokinetic (PBPK) models: the default Simcyp preterm infant model and a 2025 modified model. Thirty-one neonates (186 plasma samples) were recruited for this study. Paraxanthine was detectable in all samples, demonstrating measurable CYP1A2 activity. CMR increased with postmenstrual age even after adjusting for clinical covariates (β = 0.05, p = 0.01). Interindividual variability was observed and longitudinal analyses showed heterogeneous CMR trajectories, indicating modulation by clinical factors beyond age alone. Both PBPK models tested demonstrated systematic overprediction of caffeine exposure, consistent with underestimation of clearance, although the modified model showed better concordance with observed data. These findings provide the first in vivo evidence of quantifiable CYP1A2 activity in neonates and demonstrate the feasibility of using caffeine as a probe drug to study enzyme ontogeny. Current published PBPK models do not accurately capture caffeine concentrations in our cohort, likely reflecting differences between our population and the preterm models. Integrating empirically derived neonatal pharmacokinetic data into PBPK models that more accurately reflect a preterm NICU population may better inform individualized dosing based on developmental age and clinical illness severity. By anchoring neonatal drug dosing in empirically derived physiology rather than adult extrapolation, these models have the potential to transform dosing practice and advance pharmacoequity for one of the most vulnerable and historically understudied populations.
2026-05-07 | Advancing precision treatment in preterm infants: Population pharmacokinetics of caffeine for apnea of prematurity.
This study aimed to develop a population pharmacokinetic (PopPK) model for caffeine in apnea of prematurity, identify clinically significant covariates that influence pharmacokinetic (PK) parameters, and establish an evidence-based, individualized dosing regimen. The observational cohort comprised 232 serum caffeine concentration measurements from 168 premature infants who received standard caffeine therapy. Data from 136 patients were used for PopPK modeling, while the remaining 32 were reserved for external validation. A 1-compartment model with first-order elimination was developed using NONMEM software. Stepwise selection was used to evaluate the influence of physiological and pathological factors, as well as concomitant medications, on PK parameters in a covariate analysis. The final model was validated using goodness-of-fit plots, bootstrap, and a prediction-corrected visual predictive check. Monte Carlo simulation was further employed to optimize dosing toward a target trough concentration of 14.5 mg/L. The final PopPK model identified current weight (CW) at sampling and sex (male infants had 20% lower clearance than female infants) as significant covariates affecting PK variability. The model was validated internally and externally. Simulations indicated that a 20 mg/kg loading dose followed by CW-stratified maintenance dosing (male infants: 7.5-10 mg/kg/day; female infants: 10-12.5 mg/kg/day across CW 750-2500 g) achieves target concentrations. We established the first PopPK model of caffeine in preterm infants, demonstrating that female sex is an independent predictor of higher clearance. The sex and CW-specific dosing algorithm supports individualized caffeine therapy, reducing apnea episodes and minimizing toxicity. SIGNIFICANCE STATEMENT: In this study, female sex was identified as a novel, independent covariate significantly associated with enhanced caffeine clearance. To translate this finding into clinical practice, we propose a practical dosing regimen to guide personalized caffeine therapy in preterm infants.
2026-05-01 | Investigating inhibitory synaptic transmission in developing Kölliker-Fuse neurons from mu opioid receptor knock-out mice
After nine months in the aqueous uterine environment, a newborn’s first breath of air is a major transition for the respiratory system. Newborn breathing is slow and is often interspersed with apneas. Premature infants can have dangerously impaired breathing with apneas causing oxygen desaturation and death. Administration of the non-selective opioid receptor antagonist naloxone increases breathing rate in neonatal mammals including human infants. Therefore, I hypothesized that endogenous opioid peptides suppress breathing during early life. To test this hypothesis, I measured breathing in mice lacking mu-opioid receptors (MOR-KO) and wild type littermate mice at multiple developmental time points. At P0 and P21, MOR-KO mice breathed faster than wild types. These results suggest that P0 and P21 are critical windows for endogenous opioid regulation of breathing rate in mice. The pontine Kölliker-Fuse (KF) area contains essential breathing control neurons that regulate respiratory rate, in addition to other functions in breathing control. The KF is known to undergo substantial postnatal maturation in rats. Therefore, we hypothesized that the deletion of MORs alters the physiology of developing KF neurons in mice. To test this, we performed brain slice electrophysiology experiments in KF neurons from MOR-KO and wild type mice at different developmental time points. Preliminary data show developmental shifts in the decay kinetics of spontaneous inhibitory postsynaptic currents in wild type mice and MOR-KO mice. Regardless of genotype, spontaneous inhibitory postsynaptic currents recorded from P7-8 mice exhibit slower decay kinetics than those recorded in mice older than P14. These data suggest that the maturational shift in inhibitory synaptic transmission occurs independent of mu opioid receptor expression. Understanding the fundamental role of mu opioid receptors in pontine respiratory neuron development will help determine the physiological mechanisms defining the critical windows of endogenous opioid influence on breathing at birth and weaning. Acknowledgements: This research was supported by K99 HL177177 and T32 DA060142 to JWF and R01 HL174547 to ESL. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
proteins
2026-05-12 | Cortical motor activity modulates respiration and reduces apnoea in neonates.
Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea - the cessation of respiration - is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if there was any evidence for cortical coupling with respiration in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we investigated interactions between cortical and respiratory activity (known as cortico-respiratory coupling) using phase-amplitude coupling. We show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5±2.6 weeks postmenstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. Whilst our study was limited in spatial resolution, and determining causality is challenging, we believe these findings support the notion that the cortico-respiratory coupling observed here constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel insight into this common and potentially life-threatening neonatal pathology.
2025-05-01 | The Role of Pulmonary Vagal Sensory Neurons in the Neural Control of Breathing in Chronic Lung Disease
Infants born extremely prematurely (<28 weeks gestation) are prone to develop chronic lung disease and bronchopulmonary dysplasia (BPD). BPD results from vital respiratory support, like supplemental oxygen (hyperoxia; HX). Over 40% of BPD infants require sustained HX due to poor neural control of breathing (nCOB). However, the underlying mechanisms remain poorly understood. Pulmonary vagal sensory neurons (PSNs) expressing Neuropeptide Y receptor 2 (Npy2r) innervate the alveolar regions of the lungs and express inflammatory receptors. Given the decreased alveolarization, increased presence of proinflammatory markers, and dysfunctional nCOB, which are characteristic features of infants with BPD, we hypothesize that altered Npy2r PSN function contributes to the impaired nCOB in BPD. We exposed Npy2r-Cre driver mice expressing the light-sensitive, excitatory protein Channelrhodopsin (Npy2r-ChR) to either room air (n=13) or chronic neonatal hyperoxia to induce BPD with impaired nCOB (hypoventilation), as we have previously established (n=14). Mice were anesthetized, breathing was recorded via spirometry, and the diaphragm activity was measured by EMG before, during, and after brief light-stimulation epochs (0.625 W/mm 2 ; 5ms on/45ms off for 10 sec), repeated in triplicate but averaged for statistical analyses. While Npy2r stimulation caused a modest (P>0.05) 10% reduction in breathing frequency among NX mice, it caused an exaggerated (30%) reduction among HX mice (p<0.05), which led to significant and similar reductions in minute ventilation among HX but not NX mice. Optogenetic studies demonstrate that hyperoxia animals exhibit a more exaggerated reduction in breathing frequency and minute ventilation. Diaphragm activity was reduced in comparable manners. Histological analysis and whole-body plethysmography of the animal model have validated the reduced alveolarization and hypoventilation characteristic of BPD. To validate the inhibitory effects caused by optogenetics, subsets of NX mice Npy2r Cre+ (n=4) and Cre- (n=2) were intratracheally treated with a retrograde AAV to drive Cre-dependent expression of excitatory DREADS (synthetic receptors activatable by a synthetic ligand, DCZ). Indeed, for up to 100 minutes post-DCZ, breathing frequency was reduced (20-25%), and apneas were increased (500%) relative to pre-DCZ. Effects were minimal among Cre-negative mice. RNA Scope validated the Cre-dependent expression of ChR2 or DREADDs among Npy2r neurons (n=3-5/group) These results support the novel concept that BPD-lung injury may underlie impaired nCOB through impaired Npy2r-PSN signaling. Targeting this signaling pathway may enhance our understanding of mechanisms complicating BPD and potential therapeutic strategies for improving the nCOB in BPD. Neuroscience Research Center, Imagine More Award (3311232); Advancing Healthier Wisconsin REAC Award (5520640) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2019-07-16 | Neuroprotection of the preterm brain
Despite notable advances in the care and survival of preterm infants, a significant proportion of preterm neonates will have life-long cognitive, behavioral, and motor deficits, and robustly effective neuroprotective strategies are still missing. These therapies must target the pathophysiologic mechanisms observed in contemporaneous infants and rely on modern epidemiology, imaging, and experimental models and assessment techniques. Two drugs, magnesium sulfate and caffeine, are already in use in several units, and although their targets are apnea of prematurity and myometrial contractility (respectively), they do offer improved odds of positive outcomes. Nevertheless, these drugs have limited efficacy, and NICU-to-NICU administration varies greatly. As such, there is an obvious need for additional specific neurotherapeutic strategies to further enhance the outcome of this very fragile population of neonates. The chapter reviews these issues, highlights bottlenecks that need to be solved for meaningful progress in the field, and proposes future innovative avenues for intervention, including delayed interventions.
2019-05-03 | Respiratory frequency plasticity during development
Respiratory frequency plasticity is a long-lasting increase in breathing frequency due to a perturbation. Mechanisms underlying respiratory frequency are poorly understood, and there is little evidence of frequency plasticity in neonates. This hybrid review/research article discusses available literature regarding frequency plasticity and highlights potential research opportunities. Also, we include data demonstrating a model of frequency plasticity using isolated neonatal rat brainstem-spinal cord preparations. Specifically, substance P (SubP) application induced a long-lasting (>60 min) increase in spontaneous respiratory motor burst frequency, particularly in brainstem-spinal cords with the pons attached; there were no male/female differences. SubP-induced frequency plasticity is dependent on the application pattern, such that intermittent (rather than sustained) SubP applications induce more frequency plasticity. SubP-induced frequency plasticity was blocked by a neurokinin-1 receptor antagonist. Thus, the newborn rat respiratory control system has the capacity to express frequency plasticity. Identifying mechanisms that induce frequency plasticity may lead to novel methods to safely treat breathing disorders in premature and newborn infants.
2007-04-01 | Postnatal maturation of laryngeal chemoreflexes in the preterm lamb
Laryngeal chemoreflexes (LCR) are triggered by the contact of liquids with the laryngeal mucosa. In the mature organism, LCR trigger lower airway protective responses (coughing, effective swallowing, and arousal) to prevent aspiration. General belief holds that LCR are responsible for apnea and bradycardia in the newborn mammal, including humans. Our laboratory has recently shown that LCR in full-term lambs are consistently analogous to the mature LCR reported in adult mammals, without significant apneas and bradycardias (St-Hilaire M, Nsegbe E, Gagnon-Gervais K, Samson N, Moreau-Bussiere F, Fortier PH, and Praud J-P. J Appl Physiol 98: 2197–2203, 2005). The aim of the present study was to assess LCR in nonsedated, newborn preterm lambs born at 132 days of gestation (term = 147 days). The preterm lambs were instrumented for recording glottal adductor electromyogram, electroencephalogram, eye movements, heart rate, respiration, and oximetry. A chronic supraglottal catheter was used for injecting 0.5 ml of saline, distilled water, and HCl (pH 2) during quiet sleep, active sleep, and wakefulness on postnatal days 7 (D7) and 14 (D14). Laryngeal stimulation by water or HCl on D7 induced significant apneas, bradycardia, and desaturation, which, at times, appeared potentially life-threatening. No significant apneas, bradycardias, or desaturation were observed on D14. No consistent effects of sleep state could be shown in the present study. In conclusion, laryngeal stimulation by liquids triggers potentially dangerous LCR in preterm lambs on D7, but not on D14. It is proposed that maturation of the LCR between D7 and D14 is partly involved in the disappearance of apneas/bradycardias of prematurity with postnatal age.
cell therapies
2026-06-23 | Early Surgical Reconstruction of Severe Nasal Interface-Induced Nasal Deformity in a Preterm Infant.
Nasal continuous positive airway pressure (CPAP) is widely used in premature infants but may cause pressure-related nasal injury. Severe deformities involving structural loss can result in significant airway compromise. We report a preterm infant presenting at 3 months of age with progressive nasal deformity, near-complete unilateral nostril occlusion, and features of obstructive sleep apnea complicated by pulmonary hypertension. Early reconstruction was performed at 6 months using autologous conchal cartilage to restore the lateral crus and a helical root composite chondrocutaneous graft for columellar support. Postoperative nasal stenting was utilized. The patient demonstrated marked improvement in airway patency, respiratory function, and tolerance of respiratory support, with stable structural and aesthetic outcomes at 3 months. This case highlights that early airway-directed reconstruction in selected infants is feasible and may prevent progression of functional and cardiopulmonary sequelae.
2018-02-20 | Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies
Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem.
2009-02-26 | Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia
Our aim was to assess the safety and efficacy of transpyloric tube feeding as a therapeutic option to reduce apnea and bradycardia in hospitalized very low birthweight (VLBW) infants with clinical signs suggestive of gastroesophageal reflux (GER). This was a retrospective single-center cohort study of VLBW infants hospitalized from 2001 to 2004 with signs of GER who received transpyloric enteral tube feedings. Apnea (>10 s) and bradycardia (<100 bpm) episodes were compared before and after the initiation of transpyloric feedings. The Wilcoxon signed-rank test was used to compare differences between cardiorespiratory episodes before and after treatment at 1-day and combined 3-day intervals. Events recorded to assess the safety of transpyloric feedings included death, sepsis and necrotizing enterocolitis (NEC). A total of 72 VLBW infants with a median birthweight of 870 g (ranging from 365 to 1435 g) and gestational age of 26 weeks (from 23 to 31 weeks) were identified. The median weight at initiation of transpyloric feedings was 1297 g (from 820 to 3145 g) and infants received transpyloric feeds for a median duration of 18 days (from 1 to 86 days). After the initiation of transpyloric feedings, a reduction in apnea episodes from 4.0 to 2.5 (P=0.02) and a decrease in bradycardia episodes from 7.2 to 4.5 (P<0.001) was observed when comparing the total number of episodes for the 3 days before and after treatment. Five (6.9%) of the infants developed NEC while receiving transpyloric feedings. None of the infants receiving human milk (P=0.07) and 36% of those receiving hydrolysate-based formula (P<0.01) during transpyloric feeds developed NEC. No infants had late-onset culture-proven sepsis. Seven (9.7%) infants died before hospital discharge. Transpyloric feedings, especially when limited to human milk, may safely reduce episodes of apnea and bradycardia in preterm infants with suspected GER. Prospective randomized studies are needed to determine the biological impact of bypassing the stomach, as well as the safety and efficacy of this intervention. The results of such studies could modify the current prevailing safety concerns regarding transpyloric feeding in this population.
antibodies
2025-12-06 | Lung function and sleep-disordered breathing in preschoolers born very preterm.
To determine the prevalence of abnormalities in small airway function and sleep-disordered breathing in preschoolers born very preterm and with very low birth weight, and their association with bronchopulmonary dysplasia and other neonatal risk factors. Cross-sectional study of children aged 3 to 6 years born before 32 weeks of gestation with a birth weight of less than 1500 g. Respiratory oscillometry was performed, determining the resistance and reactance at 5 Hz (R5 and X5), the difference in resistance at 5 and 19 Hz (R5-19), area under the reactance curve (AX), and the resonant frequency (fres). Nocturnal oximetry was also performed, determining the oxygen desaturation indices at thresholds of 3% (ODI3) and 4% (ODI4). We analyzed the association of the results with bronchopulmonary dysplasia and other neonatal risk factors with the χ2 test or the Mann-Whitney U test. The sample included 22 children with a median (IQR) age of 4.9 (3.7-5.4) years, of who 54.5% had bronchopulmonary dysplasia. There was a high prevalence of abnormal results for all oscillometry parameters (R5-19, 10.0%; X5, 21.1%; R5, 25.0%; fres, 40.0%; AX, 45.0%) and oximetry parameters (ODI3, 38.1%; ODI4, 33.3%). None of these results were associated with bronchopulmonary dysplasia or other neonatal risk factors. Preschoolers born very preterm and with very low birth weight have a high prevalence of abnormal small airway function and, probably, sleep-disordered breathing, unrelated to bronchopulmonary dysplasia.
2025-12-06 | Nonlinear Analysis of Neonatal Breathing Dynamics – A Case Study
The premature infant is prone to respiratory issues due to poor development of the regulatory system as well as mechanical issues with the lung itself. These problems often lead to apnea, the cessation of breathing. Until the respiratory system develops, the infant must be kept in critical care.
2025-08-17 | Safety of timely immunization with nirsevimab in hospitalized preterm infants.
We aimed to assess the safety profile of nirsevimab in hospitalized preterm infants (PT). We conducted an observational, uncontrolled, prospective study in clinically stable PT admitted to the neonatal unit. One hundred and ten PT were eligible for immunization; uptake was 93.5 % (n = 103) (median GA and BW of 33 weeks and 1892 g, respectively), and a median age at immunization of 3 days. No anaphylaxis, seizures or local AE were reported. 16.5 % (n = 16) reported systemic AEs. Fever (n = 8) was mild (median of 38 °C). 8.7 % (n = 9) experienced apneas (median of 26 h post-immunization), mainly in PT with lower GA. Eight recovered with tactile stimulation, and one required intubation which was unrelated to nirsevimab injection. Bradycardia occurred only in two PT during apneic episodes, being both fully recovered with tactile stimulation. Nirsevimab administration was safe regardless GA or BW, with apnea reported mainly in those <32 weeks. Therefore, we recommend early and monitored administration of nirsevimab in hospitalized PT during RSV season.
2025-07-10 | Long Term Developmental Consequences of Short Apneas and Periodic Breathing in Preterm Infants.
Preterm infants frequently experience short apneas which can occur in isolation or in a repetitive pattern termed periodic breathing. We assessed the consequences of the amount of time spent with short apneas on developmental outcomes at 2 years of age. Preterm infants (N = 23) born between 28 and 32 weeks gestational age were studied during daytime sleep in the supine position at 32-36 weeks post menstrual age (PMA), 36-40 weeks PMA, 3 months and 6 months corrected age. The percentage of total sleep time (TST) spent with apneas at each study was calculated. Infants were divided into those below and above the median cumulative time spent with apneas over the 4 studies (28.4% TST) and developmental assessments (Bayley Scales of Infant Development III, Early Childhood Behavior Questionnaire, Child Behavior Check List) at 2 years of age were compared with ANCOVA. The above median group tended to have lower unadjusted scores for motor composite, social emotional composite and adaptive behavior composite on the Bayley's. After adjusting for confounders and %TST spent with apneas, the motor composite score was significantly lower in the above median group (p < 0.05). Perceptual Sensitivity was lower in the above median group (p < 0.05). In clinically stable very preterm infants, who had been discharged home with no concerns of respiratory instability, those infants who spent more time with short apneas, particularly periodic breathing, had reduced motor outcomes at 2 years of age. Our findings add to a growing literature suggesting that short apneas and periodic breathing are not benign.
2025-04-08 | Clinical Characteristics of Apnea in Full-Term Infants: Compared to Late Preterm Infants
Objective: Apnea in newborns is defined as a respiratory pause of 20 seconds or longer, or apnea accompanied by bradycardia or cyanosis.To date, research on neonatal apnea has focused on premature infants born within 34 weeks of gestation.The aim of this study is to present clinical significance of apnea in full-term infants compared with late premature infants born over 34 weeks of gestation.Methods: In a retrospective study, we reviewed medical records of neonates born over 34 weeks of gestation hospitalized for apnea and their mothers from November 2020 to May 2024.A total of 124 neonates were collected and divided into full-term infants (n=54) and late preterm infants (n=70) groups. Results:The mean gestational age of full-term and late preterm infants was 38 +5 weeks and 35 +2 weeks, and the mean birth weight was 3.16 kg and 2.14 kg.Apnea was associated with diseases in 44.4% of full-term infants and 38.6% of late preterm infants.The rates of multiple births, small for gestational age, and cesarean section deliveries were significantly higher in late preterm infants.Apnea occurred significantly earlier and recovered faster in full-term infants.Neurologic disease was significantly more occurred in full-term infants (P=0.021).Especially, cerebral infarction and seizure were diagnosed only in full-term infants. Conclusion:Apnea occurred earlier in full-term infants and severe neurologic diseases were significantly more found in full-term infants compared with late preterm infants.A close examination is needed in full-term infants with apnea.
small molecules
2026-08-02 | Hypoxia/reoxygenation cycles, reactive oxygen species and succinate: A mechanistic framework for apnea of prematurity?
We review clinical observations and experimental data to examine the pathophysiological mechanisms by which apnea of prematurity and intermittent hypoxemia destabilizes respiratory control and might lead to neurodevelopmental disorders. Clinically, both apnea and hypoxemia are characterized by marked heterogeneity in definitions, monitoring approaches, and temporal patterns, complicating comparisons across studies. Clinical evidence suggests that cumulative hypoxemic burden, rather than apnea duration alone, is a key determinant of respiratory and neurodevelopmental morbidity in preterm neonates. Repeated hypoxemia-reoxygenation cycles enhance peripheral chemoreceptor sensitivity, narrow the CO₂ reserve, and promote respiratory instability during a critical developmental window. Animal models of intermittent hypoxia demonstrate that this sensitization is mediated by reactive oxygen species (ROS) signaling and a metabolic response involving neuronal adenosine release, activation of xanthine oxidase and NADPH oxidase ultimately converging to inhibition of mitochondrial complex I and metabolic depression during the hypoxic phase. This response is clinically evidenced by a reduction of EEG amplitude occurring during apnea. Recent data suggest that subtle changes in biochemical equilibrium within the Krebs cycle favor succinate accumulation during the hypoxic phase, which is then rapidly oxidized during reoxygenation, leading to enhanced ROS production, as demonstrated in models of ischemia-reperfusion injury and neonatal severe hypoxia. We finally provide preliminary data showing that the succinate dehydrogenase inhibitor dimethyl malonate reduces oxidative phosphorylation in brain sample of mice pups, therefore establishing an experimental framework to address the hypothesis that succinate accumulation contributes to ROS synthesis in a rodent model of apnea of prematurity.
2026-07-14 | The effect of nasal olfactory stimulation on apnea of prematurity: a randomized cross-over trial.
Olfactory stimulation may enhance respiratory drive in preterm infants without respiratory support. The aim of this study was to assess the efficacy of olfactory stimulation on apnea of prematurity (AOP) in preterm infants receiving nasal continuous positive pressure (nCPAP). This randomized, placebo-controlled, double-blind cross-over study enrolled preterm infants born between 23 0/7 and 31 6/7 weeks of gestation receiving nCPAP and treatment with caffeine citrate. Vanilla or strawberry odor, or an odorless placebo solution, was applied to the nCPAP masks with an odor pen. The primary outcome was the number of desaturation and bradycardia episodes. Secondary outcomes included physiological parameters and feeding tolerance. Eighty preterm infants completed the study. The median (interquartile range) number of events during the 12-hour study period was 10 (3-27) in the intervention group and 14 (3-29) in the control group (p = 0.82). No significant differences were observed in any secondary outcome measures with either vanilla or strawberry odor. This study did not demonstrate an effect of olfactory stimulation on the number of desaturation and bradycardia episodes in very preterm infants receiving nCPAP. Future research may focus on optimizing methods for delivering olfactory stimuli to infants on non-invasive respiratory support. Clinical trials have demonstrated that olfactory stimulation, using odors such as vanilla, may reduce the frequency of apnea and desaturation episodes in spontaneously breathing preterm infants. This study evaluates the effect of olfactory stimulation with vanilla and strawberry odor on the respiratory drive of preterm infants receiving nasal continuous positive pressure support - the population most severely affected by the apnea of prematurity. In this population, olfactory stimulation did not significantly reduce the number of desaturations and bradycardia. Future research may focus on optimizing delivery methods to ensure that olfactory stimuli are effectively perceived by infants on non-invasive respiratory support.
2026-06-05 | Developmental age and clinical illness drive in vivo variability of CYP1A2 ontogeny and caffeine metabolism in preterm neonates.
Caffeine is the standard therapy for apnea of prematurity and used near-universally in preterm infants. Interindividual variability in clearance, exposure, and clinical responses persists in neonates. CYP1A2 is the primary enzyme responsible for caffeine metabolism in adults, but the enzyme activity in neonates has historically been considered negligible. Scavenged plasma samples from neonates receiving caffeine therapy in a neonatal intensive care unit were analyzed to quantify caffeine and paraxanthine concentrations. The caffeine metabolic ratio (CMR) was used as a functional biomarker of in vivo CYP1A2 activity. Associations between CMR, postmenstrual age, and clinical covariates were evaluated using univariate analyses, linear mixed-effects modeling, and longitudinal analyses. To compare our data to model predictions, caffeine concentrations were simulated in preterm infants using two previously published physiologically based pharmacokinetic (PBPK) models: the default Simcyp preterm infant model and a 2025 modified model. Thirty-one neonates (186 plasma samples) were recruited for this study. Paraxanthine was detectable in all samples, demonstrating measurable CYP1A2 activity. CMR increased with postmenstrual age even after adjusting for clinical covariates (β = 0.05, p = 0.01). Interindividual variability was observed and longitudinal analyses showed heterogeneous CMR trajectories, indicating modulation by clinical factors beyond age alone. Both PBPK models tested demonstrated systematic overprediction of caffeine exposure, consistent with underestimation of clearance, although the modified model showed better concordance with observed data. These findings provide the first in vivo evidence of quantifiable CYP1A2 activity in neonates and demonstrate the feasibility of using caffeine as a probe drug to study enzyme ontogeny. Current published PBPK models do not accurately capture caffeine concentrations in our cohort, likely reflecting differences between our population and the preterm models. Integrating empirically derived neonatal pharmacokinetic data into PBPK models that more accurately reflect a preterm NICU population may better inform individualized dosing based on developmental age and clinical illness severity. By anchoring neonatal drug dosing in empirically derived physiology rather than adult extrapolation, these models have the potential to transform dosing practice and advance pharmacoequity for one of the most vulnerable and historically understudied populations.
2026-05-07 | Advancing precision treatment in preterm infants: Population pharmacokinetics of caffeine for apnea of prematurity.
This study aimed to develop a population pharmacokinetic (PopPK) model for caffeine in apnea of prematurity, identify clinically significant covariates that influence pharmacokinetic (PK) parameters, and establish an evidence-based, individualized dosing regimen. The observational cohort comprised 232 serum caffeine concentration measurements from 168 premature infants who received standard caffeine therapy. Data from 136 patients were used for PopPK modeling, while the remaining 32 were reserved for external validation. A 1-compartment model with first-order elimination was developed using NONMEM software. Stepwise selection was used to evaluate the influence of physiological and pathological factors, as well as concomitant medications, on PK parameters in a covariate analysis. The final model was validated using goodness-of-fit plots, bootstrap, and a prediction-corrected visual predictive check. Monte Carlo simulation was further employed to optimize dosing toward a target trough concentration of 14.5 mg/L. The final PopPK model identified current weight (CW) at sampling and sex (male infants had 20% lower clearance than female infants) as significant covariates affecting PK variability. The model was validated internally and externally. Simulations indicated that a 20 mg/kg loading dose followed by CW-stratified maintenance dosing (male infants: 7.5-10 mg/kg/day; female infants: 10-12.5 mg/kg/day across CW 750-2500 g) achieves target concentrations. We established the first PopPK model of caffeine in preterm infants, demonstrating that female sex is an independent predictor of higher clearance. The sex and CW-specific dosing algorithm supports individualized caffeine therapy, reducing apnea episodes and minimizing toxicity. SIGNIFICANCE STATEMENT: In this study, female sex was identified as a novel, independent covariate significantly associated with enhanced caffeine clearance. To translate this finding into clinical practice, we propose a practical dosing regimen to guide personalized caffeine therapy in preterm infants.
2026-05-01 | Investigating inhibitory synaptic transmission in developing Kölliker-Fuse neurons from mu opioid receptor knock-out mice
After nine months in the aqueous uterine environment, a newborn’s first breath of air is a major transition for the respiratory system. Newborn breathing is slow and is often interspersed with apneas. Premature infants can have dangerously impaired breathing with apneas causing oxygen desaturation and death. Administration of the non-selective opioid receptor antagonist naloxone increases breathing rate in neonatal mammals including human infants. Therefore, I hypothesized that endogenous opioid peptides suppress breathing during early life. To test this hypothesis, I measured breathing in mice lacking mu-opioid receptors (MOR-KO) and wild type littermate mice at multiple developmental time points. At P0 and P21, MOR-KO mice breathed faster than wild types. These results suggest that P0 and P21 are critical windows for endogenous opioid regulation of breathing rate in mice. The pontine Kölliker-Fuse (KF) area contains essential breathing control neurons that regulate respiratory rate, in addition to other functions in breathing control. The KF is known to undergo substantial postnatal maturation in rats. Therefore, we hypothesized that the deletion of MORs alters the physiology of developing KF neurons in mice. To test this, we performed brain slice electrophysiology experiments in KF neurons from MOR-KO and wild type mice at different developmental time points. Preliminary data show developmental shifts in the decay kinetics of spontaneous inhibitory postsynaptic currents in wild type mice and MOR-KO mice. Regardless of genotype, spontaneous inhibitory postsynaptic currents recorded from P7-8 mice exhibit slower decay kinetics than those recorded in mice older than P14. These data suggest that the maturational shift in inhibitory synaptic transmission occurs independent of mu opioid receptor expression. Understanding the fundamental role of mu opioid receptors in pontine respiratory neuron development will help determine the physiological mechanisms defining the critical windows of endogenous opioid influence on breathing at birth and weaning. Acknowledgements: This research was supported by K99 HL177177 and T32 DA060142 to JWF and R01 HL174547 to ESL. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
proteins
2026-05-12 | Cortical motor activity modulates respiration and reduces apnoea in neonates.
Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea - the cessation of respiration - is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if there was any evidence for cortical coupling with respiration in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we investigated interactions between cortical and respiratory activity (known as cortico-respiratory coupling) using phase-amplitude coupling. We show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5±2.6 weeks postmenstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. Whilst our study was limited in spatial resolution, and determining causality is challenging, we believe these findings support the notion that the cortico-respiratory coupling observed here constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel insight into this common and potentially life-threatening neonatal pathology.
2025-05-01 | The Role of Pulmonary Vagal Sensory Neurons in the Neural Control of Breathing in Chronic Lung Disease
Infants born extremely prematurely (<28 weeks gestation) are prone to develop chronic lung disease and bronchopulmonary dysplasia (BPD). BPD results from vital respiratory support, like supplemental oxygen (hyperoxia; HX). Over 40% of BPD infants require sustained HX due to poor neural control of breathing (nCOB). However, the underlying mechanisms remain poorly understood. Pulmonary vagal sensory neurons (PSNs) expressing Neuropeptide Y receptor 2 (Npy2r) innervate the alveolar regions of the lungs and express inflammatory receptors. Given the decreased alveolarization, increased presence of proinflammatory markers, and dysfunctional nCOB, which are characteristic features of infants with BPD, we hypothesize that altered Npy2r PSN function contributes to the impaired nCOB in BPD. We exposed Npy2r-Cre driver mice expressing the light-sensitive, excitatory protein Channelrhodopsin (Npy2r-ChR) to either room air (n=13) or chronic neonatal hyperoxia to induce BPD with impaired nCOB (hypoventilation), as we have previously established (n=14). Mice were anesthetized, breathing was recorded via spirometry, and the diaphragm activity was measured by EMG before, during, and after brief light-stimulation epochs (0.625 W/mm 2 ; 5ms on/45ms off for 10 sec), repeated in triplicate but averaged for statistical analyses. While Npy2r stimulation caused a modest (P>0.05) 10% reduction in breathing frequency among NX mice, it caused an exaggerated (30%) reduction among HX mice (p<0.05), which led to significant and similar reductions in minute ventilation among HX but not NX mice. Optogenetic studies demonstrate that hyperoxia animals exhibit a more exaggerated reduction in breathing frequency and minute ventilation. Diaphragm activity was reduced in comparable manners. Histological analysis and whole-body plethysmography of the animal model have validated the reduced alveolarization and hypoventilation characteristic of BPD. To validate the inhibitory effects caused by optogenetics, subsets of NX mice Npy2r Cre+ (n=4) and Cre- (n=2) were intratracheally treated with a retrograde AAV to drive Cre-dependent expression of excitatory DREADS (synthetic receptors activatable by a synthetic ligand, DCZ). Indeed, for up to 100 minutes post-DCZ, breathing frequency was reduced (20-25%), and apneas were increased (500%) relative to pre-DCZ. Effects were minimal among Cre-negative mice. RNA Scope validated the Cre-dependent expression of ChR2 or DREADDs among Npy2r neurons (n=3-5/group) These results support the novel concept that BPD-lung injury may underlie impaired nCOB through impaired Npy2r-PSN signaling. Targeting this signaling pathway may enhance our understanding of mechanisms complicating BPD and potential therapeutic strategies for improving the nCOB in BPD. Neuroscience Research Center, Imagine More Award (3311232); Advancing Healthier Wisconsin REAC Award (5520640) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2019-07-16 | Neuroprotection of the preterm brain
Despite notable advances in the care and survival of preterm infants, a significant proportion of preterm neonates will have life-long cognitive, behavioral, and motor deficits, and robustly effective neuroprotective strategies are still missing. These therapies must target the pathophysiologic mechanisms observed in contemporaneous infants and rely on modern epidemiology, imaging, and experimental models and assessment techniques. Two drugs, magnesium sulfate and caffeine, are already in use in several units, and although their targets are apnea of prematurity and myometrial contractility (respectively), they do offer improved odds of positive outcomes. Nevertheless, these drugs have limited efficacy, and NICU-to-NICU administration varies greatly. As such, there is an obvious need for additional specific neurotherapeutic strategies to further enhance the outcome of this very fragile population of neonates. The chapter reviews these issues, highlights bottlenecks that need to be solved for meaningful progress in the field, and proposes future innovative avenues for intervention, including delayed interventions.
2019-05-03 | Respiratory frequency plasticity during development
Respiratory frequency plasticity is a long-lasting increase in breathing frequency due to a perturbation. Mechanisms underlying respiratory frequency are poorly understood, and there is little evidence of frequency plasticity in neonates. This hybrid review/research article discusses available literature regarding frequency plasticity and highlights potential research opportunities. Also, we include data demonstrating a model of frequency plasticity using isolated neonatal rat brainstem-spinal cord preparations. Specifically, substance P (SubP) application induced a long-lasting (>60 min) increase in spontaneous respiratory motor burst frequency, particularly in brainstem-spinal cords with the pons attached; there were no male/female differences. SubP-induced frequency plasticity is dependent on the application pattern, such that intermittent (rather than sustained) SubP applications induce more frequency plasticity. SubP-induced frequency plasticity was blocked by a neurokinin-1 receptor antagonist. Thus, the newborn rat respiratory control system has the capacity to express frequency plasticity. Identifying mechanisms that induce frequency plasticity may lead to novel methods to safely treat breathing disorders in premature and newborn infants.
2007-04-01 | Postnatal maturation of laryngeal chemoreflexes in the preterm lamb
Laryngeal chemoreflexes (LCR) are triggered by the contact of liquids with the laryngeal mucosa. In the mature organism, LCR trigger lower airway protective responses (coughing, effective swallowing, and arousal) to prevent aspiration. General belief holds that LCR are responsible for apnea and bradycardia in the newborn mammal, including humans. Our laboratory has recently shown that LCR in full-term lambs are consistently analogous to the mature LCR reported in adult mammals, without significant apneas and bradycardias (St-Hilaire M, Nsegbe E, Gagnon-Gervais K, Samson N, Moreau-Bussiere F, Fortier PH, and Praud J-P. J Appl Physiol 98: 2197–2203, 2005). The aim of the present study was to assess LCR in nonsedated, newborn preterm lambs born at 132 days of gestation (term = 147 days). The preterm lambs were instrumented for recording glottal adductor electromyogram, electroencephalogram, eye movements, heart rate, respiration, and oximetry. A chronic supraglottal catheter was used for injecting 0.5 ml of saline, distilled water, and HCl (pH 2) during quiet sleep, active sleep, and wakefulness on postnatal days 7 (D7) and 14 (D14). Laryngeal stimulation by water or HCl on D7 induced significant apneas, bradycardia, and desaturation, which, at times, appeared potentially life-threatening. No significant apneas, bradycardias, or desaturation were observed on D14. No consistent effects of sleep state could be shown in the present study. In conclusion, laryngeal stimulation by liquids triggers potentially dangerous LCR in preterm lambs on D7, but not on D14. It is proposed that maturation of the LCR between D7 and D14 is partly involved in the disappearance of apneas/bradycardias of prematurity with postnatal age.
cell therapies
2026-06-23 | Early Surgical Reconstruction of Severe Nasal Interface-Induced Nasal Deformity in a Preterm Infant.
Nasal continuous positive airway pressure (CPAP) is widely used in premature infants but may cause pressure-related nasal injury. Severe deformities involving structural loss can result in significant airway compromise. We report a preterm infant presenting at 3 months of age with progressive nasal deformity, near-complete unilateral nostril occlusion, and features of obstructive sleep apnea complicated by pulmonary hypertension. Early reconstruction was performed at 6 months using autologous conchal cartilage to restore the lateral crus and a helical root composite chondrocutaneous graft for columellar support. Postoperative nasal stenting was utilized. The patient demonstrated marked improvement in airway patency, respiratory function, and tolerance of respiratory support, with stable structural and aesthetic outcomes at 3 months. This case highlights that early airway-directed reconstruction in selected infants is feasible and may prevent progression of functional and cardiopulmonary sequelae.
2018-02-20 | Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies
Bronchopulmonary dysplasia (BPD) is the result of a complex process in which several prenatal and/or postnatal factors interfere with lower respiratory tract development, leading to a severe, lifelong disease. In this review, what is presently known regarding BPD pathogenesis, its impact on long-term pulmonary morbidity and mortality and the available preventive and therapeutic strategies are discussed. Bronchopulmonary dysplasia is associated with persistent lung impairment later in life, significantly impacting health services because subjects with BPD have, in most cases, frequent respiratory diseases and reductions in quality of life and life expectancy. Prematurity per se is associated with an increased risk of long-term lung problems. However, in children with BPD, impairment of pulmonary structures and function is even greater, although the characterization of long-term outcomes of BPD is difficult because the adults presently available to study have received outdated treatment. Prenatal and postnatal preventive measures are extremely important to reduce the risk of BPD. Bronchopulmonary dysplasia is a respiratory condition that presently occurs in preterm neonates and can lead to chronic respiratory problems. Although knowledge about BPD pathogenesis has significantly increased in recent years, not all of the mechanisms that lead to lung damage are completely understood, which explains why therapeutic approaches that are theoretically effective have been only partly satisfactory or useless and, in some cases, potentially negative. However, prevention of prematurity, systematic use of nonaggressive ventilator measures, avoiding supraphysiologic oxygen exposure and administration of surfactant, caffeine and vitamin A can significantly reduce the risk of BPD development. Cell therapy is the most fascinating new measure to address the lung damage due to BPD. It is desirable that ongoing studies yield positive results to definitively solve a major clinical, social and economic problem.
2009-02-26 | Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia
Our aim was to assess the safety and efficacy of transpyloric tube feeding as a therapeutic option to reduce apnea and bradycardia in hospitalized very low birthweight (VLBW) infants with clinical signs suggestive of gastroesophageal reflux (GER). This was a retrospective single-center cohort study of VLBW infants hospitalized from 2001 to 2004 with signs of GER who received transpyloric enteral tube feedings. Apnea (>10 s) and bradycardia (<100 bpm) episodes were compared before and after the initiation of transpyloric feedings. The Wilcoxon signed-rank test was used to compare differences between cardiorespiratory episodes before and after treatment at 1-day and combined 3-day intervals. Events recorded to assess the safety of transpyloric feedings included death, sepsis and necrotizing enterocolitis (NEC). A total of 72 VLBW infants with a median birthweight of 870 g (ranging from 365 to 1435 g) and gestational age of 26 weeks (from 23 to 31 weeks) were identified. The median weight at initiation of transpyloric feedings was 1297 g (from 820 to 3145 g) and infants received transpyloric feeds for a median duration of 18 days (from 1 to 86 days). After the initiation of transpyloric feedings, a reduction in apnea episodes from 4.0 to 2.5 (P=0.02) and a decrease in bradycardia episodes from 7.2 to 4.5 (P<0.001) was observed when comparing the total number of episodes for the 3 days before and after treatment. Five (6.9%) of the infants developed NEC while receiving transpyloric feedings. None of the infants receiving human milk (P=0.07) and 36% of those receiving hydrolysate-based formula (P<0.01) during transpyloric feeds developed NEC. No infants had late-onset culture-proven sepsis. Seven (9.7%) infants died before hospital discharge. Transpyloric feedings, especially when limited to human milk, may safely reduce episodes of apnea and bradycardia in preterm infants with suspected GER. Prospective randomized studies are needed to determine the biological impact of bypassing the stomach, as well as the safety and efficacy of this intervention. The results of such studies could modify the current prevailing safety concerns regarding transpyloric feeding in this population.
antibodies
2025-12-06 | Lung function and sleep-disordered breathing in preschoolers born very preterm.
To determine the prevalence of abnormalities in small airway function and sleep-disordered breathing in preschoolers born very preterm and with very low birth weight, and their association with bronchopulmonary dysplasia and other neonatal risk factors. Cross-sectional study of children aged 3 to 6 years born before 32 weeks of gestation with a birth weight of less than 1500 g. Respiratory oscillometry was performed, determining the resistance and reactance at 5 Hz (R5 and X5), the difference in resistance at 5 and 19 Hz (R5-19), area under the reactance curve (AX), and the resonant frequency (fres). Nocturnal oximetry was also performed, determining the oxygen desaturation indices at thresholds of 3% (ODI3) and 4% (ODI4). We analyzed the association of the results with bronchopulmonary dysplasia and other neonatal risk factors with the χ2 test or the Mann-Whitney U test. The sample included 22 children with a median (IQR) age of 4.9 (3.7-5.4) years, of who 54.5% had bronchopulmonary dysplasia. There was a high prevalence of abnormal results for all oscillometry parameters (R5-19, 10.0%; X5, 21.1%; R5, 25.0%; fres, 40.0%; AX, 45.0%) and oximetry parameters (ODI3, 38.1%; ODI4, 33.3%). None of these results were associated with bronchopulmonary dysplasia or other neonatal risk factors. Preschoolers born very preterm and with very low birth weight have a high prevalence of abnormal small airway function and, probably, sleep-disordered breathing, unrelated to bronchopulmonary dysplasia.
2025-12-06 | Nonlinear Analysis of Neonatal Breathing Dynamics – A Case Study
The premature infant is prone to respiratory issues due to poor development of the regulatory system as well as mechanical issues with the lung itself. These problems often lead to apnea, the cessation of breathing. Until the respiratory system develops, the infant must be kept in critical care.
2025-08-17 | Safety of timely immunization with nirsevimab in hospitalized preterm infants.
We aimed to assess the safety profile of nirsevimab in hospitalized preterm infants (PT). We conducted an observational, uncontrolled, prospective study in clinically stable PT admitted to the neonatal unit. One hundred and ten PT were eligible for immunization; uptake was 93.5 % (n = 103) (median GA and BW of 33 weeks and 1892 g, respectively), and a median age at immunization of 3 days. No anaphylaxis, seizures or local AE were reported. 16.5 % (n = 16) reported systemic AEs. Fever (n = 8) was mild (median of 38 °C). 8.7 % (n = 9) experienced apneas (median of 26 h post-immunization), mainly in PT with lower GA. Eight recovered with tactile stimulation, and one required intubation which was unrelated to nirsevimab injection. Bradycardia occurred only in two PT during apneic episodes, being both fully recovered with tactile stimulation. Nirsevimab administration was safe regardless GA or BW, with apnea reported mainly in those <32 weeks. Therefore, we recommend early and monitored administration of nirsevimab in hospitalized PT during RSV season.
2025-07-10 | Long Term Developmental Consequences of Short Apneas and Periodic Breathing in Preterm Infants.
Preterm infants frequently experience short apneas which can occur in isolation or in a repetitive pattern termed periodic breathing. We assessed the consequences of the amount of time spent with short apneas on developmental outcomes at 2 years of age. Preterm infants (N = 23) born between 28 and 32 weeks gestational age were studied during daytime sleep in the supine position at 32-36 weeks post menstrual age (PMA), 36-40 weeks PMA, 3 months and 6 months corrected age. The percentage of total sleep time (TST) spent with apneas at each study was calculated. Infants were divided into those below and above the median cumulative time spent with apneas over the 4 studies (28.4% TST) and developmental assessments (Bayley Scales of Infant Development III, Early Childhood Behavior Questionnaire, Child Behavior Check List) at 2 years of age were compared with ANCOVA. The above median group tended to have lower unadjusted scores for motor composite, social emotional composite and adaptive behavior composite on the Bayley's. After adjusting for confounders and %TST spent with apneas, the motor composite score was significantly lower in the above median group (p < 0.05). Perceptual Sensitivity was lower in the above median group (p < 0.05). In clinically stable very preterm infants, who had been discharged home with no concerns of respiratory instability, those infants who spent more time with short apneas, particularly periodic breathing, had reduced motor outcomes at 2 years of age. Our findings add to a growing literature suggesting that short apneas and periodic breathing are not benign.
2025-04-08 | Clinical Characteristics of Apnea in Full-Term Infants: Compared to Late Preterm Infants
Objective: Apnea in newborns is defined as a respiratory pause of 20 seconds or longer, or apnea accompanied by bradycardia or cyanosis.To date, research on neonatal apnea has focused on premature infants born within 34 weeks of gestation.The aim of this study is to present clinical significance of apnea in full-term infants compared with late premature infants born over 34 weeks of gestation.Methods: In a retrospective study, we reviewed medical records of neonates born over 34 weeks of gestation hospitalized for apnea and their mothers from November 2020 to May 2024.A total of 124 neonates were collected and divided into full-term infants (n=54) and late preterm infants (n=70) groups. Results:The mean gestational age of full-term and late preterm infants was 38 +5 weeks and 35 +2 weeks, and the mean birth weight was 3.16 kg and 2.14 kg.Apnea was associated with diseases in 44.4% of full-term infants and 38.6% of late preterm infants.The rates of multiple births, small for gestational age, and cesarean section deliveries were significantly higher in late preterm infants.Apnea occurred significantly earlier and recovered faster in full-term infants.Neurologic disease was significantly more occurred in full-term infants (P=0.021).Especially, cerebral infarction and seizure were diagnosed only in full-term infants. Conclusion:Apnea occurred earlier in full-term infants and severe neurologic diseases were significantly more found in full-term infants compared with late preterm infants.A close examination is needed in full-term infants with apnea.
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Drug Discovery Landscape
4 orphan drug designations for Apnea of prematurity, including 1 approved therapy.
4 orphan drug designations for Apnea of prematurity, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
hydrogen sulfate salt is a white or off white crystalline powder with a molecular weight of 352.42 Da [C11H24N6O5S], prepared in a 1:1 ratio of sulfuric acid (MW 98.06 DA) and ENA-001 (free base; MW 254.36 Da [C11H22N6O]. | small molecules | FDA | 2022-09-28 | — | Enalare Therapeutics Inc. |
N-acetylcysteine | small molecules | FDA | 2010-10-21 | — | Galleon Pharmaceuticals |
Caffeine citrate [Peyona] | small molecules | EMA | 2003-02-17 | — | Chiesi Farmaceutici S.p.A. |
Caffeine [Cafcit] | small molecules | FDA | 1988-09-20 | 1999-09-21 | O.P.R. Development, L.P. |
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