What are the causes of recurrent apnea in preterm neonates?

Causes of Recurrent Apnea in Preterm Neonates

Recurrent apnea in preterm neonates is primarily caused by physiologic immaturity of respiratory control centers in the brainstem, but must be distinguished from secondary causes including infection, metabolic disturbances, central nervous system pathology, anemia, cardiovascular abnormalities, and obstructive airway problems. 1, 2

Primary Cause: Apnea of Prematurity

Apnea of prematurity is fundamentally a diagnosis of exclusion caused by developmental immaturity of the central nervous system and respiratory musculature. 1, 3

Pathophysiologic Mechanisms

The immature respiratory control system in preterm infants manifests through several specific mechanisms:

• Altered ventilatory responses to hypoxia and hypercapnia, with preterm infants showing ventilatory depression rather than stimulation when exposed to hypoxia (persistence of fetal response) 2, 4
• Narrow margin between eupneic and apneic CO2 thresholds, making infants vulnerable to apnea with minimal changes in blood gases 4
• Increased sensitivity to inhibitory neurotransmitters in the immature brainstem 2
• Diaphragmatic fatigue, particularly evident by the increased occurrence of apnea during the second and third weeks of life rather than the first week 4
• Low expiratory lung volume that falls even further during apnea, leading to rapid hypoxemia 4

Sleep State Effects

• Altered sleep state transitions contribute significantly to apnea episodes, with immature sleep architecture increasing vulnerability 2

Secondary Causes That Must Be Excluded

Before diagnosing apnea of prematurity, systematically rule out the following conditions: 1, 5

Infectious Causes

• Sepsis (bacterial or viral) 1, 5
• Meningitis or other central nervous system infections 1
• Pneumonia 1

Central Nervous System Disorders

• Intraventricular hemorrhage 1, 5
• Periventricular leukomalacia 1
• Seizures (apnea may be the only manifestation) 1, 5
• Intracranial pathology including hydrocephalus 3

Metabolic Disturbances

• Hypoglycemia 1, 5
• Hypocalcemia 5
• Hyponatremia or hypernatremia 5
• Metabolic acidosis 5

Cardiovascular Abnormalities

• Patent ductus arteriosus with significant shunting 1, 5
• Congenital heart disease 1
• Persistent pulmonary hypertension of the newborn 6

Respiratory/Airway Causes

• Primary lung disease including respiratory distress syndrome 1, 3
• Upper airway obstruction (obstructive apnea subtype) 2, 4
• Laryngeal chemoreflex activation (particularly triggered by feeding) 2, 4
• Subglottic stenosis from prolonged intubation 6
• Tracheomalacia 6

Hematologic Causes

• Anemia (though the role remains somewhat controversial, severe anemia can contribute) 2, 5

Gastrointestinal Factors

• Feeding-related triggers: Hypoxemia during feeding due to immature coordination between sucking, swallowing, and breathing 4
• Post-feeding hypoxemia from diaphragmatic fatigue 4
• Gastroesophageal reflux: The role is controversial and it only rarely plays a significant role 2, 4

Medication-Related

• Caffeine toxicity when serum levels exceed 50 mg/L, which can paradoxically worsen apnea or cause seizures 1
• Inadequate caffeine levels (therapeutic range 5-20 mg/L) in infants on treatment 7, 8

Obstructive vs Central vs Mixed Apnea

Understanding the subtype helps identify the underlying cause:

• Central apnea: Cessation of respiratory effort due to brainstem immaturity 2, 3
• Obstructive apnea: Pharyngeal collapse or upper airway obstruction despite continued respiratory effort 2, 3
• Mixed apnea: Combination of both central and obstructive components (most common in preterm infants) 2

Risk Factors for More Severe or Prolonged Apnea

• Gestational age <28 weeks: The smaller the gestational age, the higher the risk of apnea 9
• Prolonged mechanical ventilation: Increases risk of extubation failure and recurrent apnea 9
• Severe/moderate bronchopulmonary dysplasia: Associated with persistent apnea 9
• Perioperative period: Postoperative apnea risk is particularly high in former preterm infants <46 weeks corrected gestational age undergoing general anesthesia 6

Clinical Pitfalls to Avoid

• Do not assume apnea is benign "apnea of prematurity" without systematically excluding secondary causes, as this can delay treatment of serious underlying conditions 1, 5
• Do not rely solely on brief oxygen saturation spot checks; continuous monitoring and sleep studies may be necessary to capture intermittent hypoxic episodes 6
• Recognize that apnea can be the sole manifestation of seizures in preterm infants, requiring EEG evaluation when other causes are excluded 1, 5
• Understand that gastroesophageal reflux is overdiagnosed as a cause of apnea; it rarely plays a significant role 2, 4