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Apnea of Prematurity Differential Diagnoses

  • Author: Dharmendra J Nimavat, MD, FAAP; Chief Editor: Ted Rosenkrantz, MD  more...
Updated: May 29, 2014

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:

  • 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.[64, 53] 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.[52, 65]

Other Conditions Associated with Apnea in Preterm Infants During Hospitalization

Other conditions associated with apnea in preterm infants during their hospitalization are summarized below.

Nosocomial bacterial or fungal infection

Apnea, bradycardia, and desaturations are presenting symptoms of nosocomial infections caused by bacteria and fungi or viral agents.[66, 67]

In a study of 9 infants in an NICU who had respiratory syncytial viral infection, 8 had apnea as a manifestation of disease.[68]

Apnea is also common in preterm infants with Ureaplasma urealyticum infection.[69]

Necrotizing enterocolitis

In addition, apnea is one of several signs and symptoms associated with the onset of necrotizing enterocolitis.[70]

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.[71]

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.[72] Hypermagnesemia during parenteral nutrition has also been a cause of apnea.[73]


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.[74] Bell and associates conversely found that liberal versus restrictive blood transfusion significantly reduced apnea.[75] 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.[76]

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.[77] Clinicians should judge the merits of transfusion.


Postoperative apnea occurs in preterm infants, particularly those whose intraoperative pain relief involved general anesthesia.[78, 79]

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.[80, 81]


Apnea transiently increases or recurs in hospitalized preterm infants after immunization. The increase in apnea has been attributed to the whole-cell pertussis component.[82] Investigators have observed reduced morbidity with newer vaccines that contain acellular pertussis.[83, 84] Some recent reports still identified clinically significant apnea and other adverse events.[85, 86]

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.[62, 87] 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.[88, 89, 90]

Past and recent research failed to reveal a temporal relationship between GER and apnea of prematurity.[46, 91, 92, 93, 47]

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.[94, 95] 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.[96, 97]

Recent investigators found no adverse events during kangaroo care.[98]

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.[99]

Differential Diagnoses

Contributor Information and Disclosures

Dharmendra J Nimavat, MD, FAAP Associate Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Southern Illinois University School of Medicine

Dharmendra J Nimavat, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association of Physicians of Indian Origin

Disclosure: Nothing to disclose.


Michael P Sherman, MD, FAAP Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Neonatologist, Women’s and Children’s Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine

Michael P Sherman, MD, FAAP is a member of the following medical societies: American Pediatric Society, American Society for Microbiology, American Thoracic Society, Pediatric Infectious Diseases Society, American Association for the Advancement of Science, European Society for Paediatric Research, Western Society for Pediatric Research, Perinatal Research Society, American Academy of Pediatrics, American Association of Immunologists, Society for Pediatric Research

Disclosure: Nothing to disclose.

Rene L Santin, MD 

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Arun K Pramanik, MD, MBBS Professor of Pediatrics, Louisiana State University Health Sciences Center

Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.


Rachel Porat, MD Director, Neonatal Apnea Monitoring Program, Assistant Director, Division of Neonatology, Albert Einstein Medical Center; Associate Professor, Department of Pediatrics, Thomas Jefferson University

Rachel Porat, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

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Central apnea is defined as the cessation of both airflow and respiratory effort. ECG = electrocardiogram; HR = heart rate; THO = thoracic impedance; FLOW = air flow; ACT = ; SpO2 = peripheral oxygen saturation; STAGE = sleep stage.
Polysomnogram. Mixed apnea contains elements of both central and obstructive apnea. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement; SpO2 = peripheral oxygen saturation (%); STAGE = sleep stage, where AT = active sleep.
Polysomnogram. Periodic breathing is defined as periods of regular respiration for as long as 20 seconds followed by apneic periods no longer than 10 seconds that occur at least 3 times in succession. ECG = electrocardiogram; HR = heart rate (bpm); THO = thoracic movement; FLOW = flow the from nose and mouth; ACT = gross body movement.
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