Apnea of Prematurity Differential Diagnoses

Updated: Nov 06, 2016
  • Author: Dharmendra J Nimavat, MD, FAAP; Chief Editor: Ted Rosenkrantz, MD  more...
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Diagnostic Considerations

Apnea of prematurity (AOP) is a diagnosis of exclusion. For many diseases in preterm infants, apnea is a presenting symptom. The causes of these diseases are different when the differential diagnosis occurs shortly after birth compared with later in the patient's hospital stay. Other etiologies must be sought before drug and/or ventilatory therapies for apnea of prematurity are started.

Conditions associated with apnea

Shortly after birth, apnea can be a manifestation of several types of conditions. Consider the following:

  • Respiratory distress syndrome and other pulmonary conditions

  • Infections (eg, congenital pneumonia, bacteremia, meningitis, fetal or neonatal inflammatory response syndrome)

  • Hypoglycemia and other metabolic diseases

  • CNS pathology (eg, trauma, intracranial hemorrhage, anoxia and/or ischemia, stroke)

The aforementioned brain insults may be noticed because patients may have seizures and/or associated apnea. [58, 67] Some of the diseases cited above also occur relatively late during the hospitalization of prematurely born infants, but the signs and symptoms may or may not include apnea.

Intraventricular hemorrhage and posthemorrhagic hydrocephalus without seizures increases the frequency of apnea in preterm infants. [57, 68]

Other conditions associated with apnea in preterm infants during their hospitalization

Nosocomial bacterial or fungal infection

Apnea, bradycardia, and desaturations are presenting symptoms of nosocomial infections caused by bacteria and fungi or viral agents. [69, 70]

In a study of 9 infants in an NICU who had respiratory syncytial viral infection, 8 had apnea as a manifestation of disease. [71]

Apnea is also common in preterm infants with Ureaplasma urealyticum infection. [72]

Necrotizing enterocolitis

In addition, apnea is one of several signs and symptoms associated with the onset of necrotizing enterocolitis. [73]

Systemic inflammation

It is well known to the caregivers in the NICU that premature infants who present with a cluster of multiple episodes of apnea, bradycardia, and desaturations could be showing signs of developing sepsis. During the sepsis, the inflammatory mediators and cytokines play a major role in the development of apnea bradycardia and desaturations. Lipopolysaccharide (LPS) attenuates the sensitivity of the carotid body, which leads to the development of apnea, bradycardia, and desaturations. [74]

Exposure to magnesium

The administration of magnesium to prevent seizures in preeclampsia and tocolysis of preterm labor has been associated with hypoventilation, apnea, and other adverse effects in preterm infants. [75] Hypermagnesemia during parenteral nutrition has also been a cause of apnea. [76]


Disagreement exists regarding the role of clinically significant anemia in the development of apnea among convalescing preterm infants. Westkamp and colleagues reported that blood transfusions lowered heart and respiratory rates but had little effect on apnea of prematurity. [77] Bell and associates conversely found that liberal versus restrictive blood transfusion significantly reduced apnea. [78] The recent interest in the adverse neurodevelopmental outcomes observed in preterm infants with anemia and low iron status emphasizes neonatology-related awareness of the problem. [79]

Anemia, apnea of prematurity, and blood transfusion

The etiology of apnea in a premature infant is a multifactorial; however, it is a common practice to transfuse packed red blood cells in an infant who is anemic and having multiple episodes of apnea and bradycardia. Many studies have shown conflicting results, as many variables play a role in the pathogenesis of apnea of prematurity. One retrospective study found that packed red blood cell transfusion reduces the number of apneic events in premature infants, with many limitations. [80] When anemia of prematurity and apnea of prematurity occur in conjunction, clinicians are more inclined to transfuse at higher hematocrit levels in affected infants than in infants without apnea of prematurity. Zagol et al observed more cardiopulmonary events during the 72 hours period prior to the blood transfusion compared to 72 hours after the transfusion. [81] Clinicians should judge the merits of transfusion.


Postoperative apnea occurs in preterm infants, particularly those whose intraoperative pain relief involved general anesthesia. [82, 83]

Additional research is required to determine whether spinal anesthesia, different analgesic agents, or caffeine can mitigate morbidity associated with apnea after surgery in prematurely born infants. [84, 85]


Apnea transiently increases or recurs in hospitalized preterm infants after immunization. The increase in apnea has been attributed to the whole-cell pertussis component. [86] Investigators have observed reduced morbidity with newer vaccines that contain acellular pertussis. [87, 88] Some recent reports still identified clinically significant apnea and other adverse events. [89, 90]

Eye examination

Premature infants routinely undergo screening eye evaluations for retinopathy of prematurity in the NICU. Note that approximately 19% to 25% of infants experience an increased number of apneic spells after these routine eye examinations. [91]

Gastroesophageal reflux

As stated earlier, controversy exists regarding the role of gastroesophageal reflux (GER) as a causative factor in apnea of prematurity. One perspective is that the 2 conditions are related. [51, 92] Laryngeal edema identified during fiberoptic laryngeal endoscopy has been associated with GER, and antireflux surgery has dramatically reduced apnea in preterm infants at highest risk. [93, 94, 95]

Past and recent research failed to reveal a temporal relationship between GER and apnea of prematurity. [46, 47, 96, 97, 98]

Therefore, the NICHD Review Group on Apnea of Prematurity has called for additional investigations with rigorous research designs.

Skin-to-skin contact, or kangaroo care

Skin-to-skin contact, or kangaroo care, for preterm infants has been associated with an increased occurrence of apnea, bradycardia, and desaturation; this appears to be unrelated to hyperthermia. [99, 100] The observation suggests that obstructive events may occur during skin-to-skin contact. These findings call attention to the importance of environmental hyperthermia as a cause of apnea in preterm infants. [101, 102]

No adverse events appear to occur during kangaroo care. [103]

The disparity among the reported studies may be related to the specific practice of skin-to-skin care in a particular NICU or the validity of monitoring during skin-to-skin contact. [104]

Differential Diagnoses