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:
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.
2026-06-23 | 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.
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.
2026-05-12 | 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.
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.
2026-06-23 | 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.
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.
2026-05-12 | 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.
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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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