What are the other Names for this Condition? (Also known as/Synonyms)

• AOP (Apnea of Prematurity)
• Apnea - Newborns
• As and Bs

What is Apnea of Prematurity? (Definition/Background Information)

• Apnea of Prematurity (AOP) is a disorder where there is stoppage (cessation) of breathing for more than 20 seconds in a premature/preterm infant, born before 34 weeks of gestation. Occasionally, this stoppage is less than 20 seconds. In normal cases, a baby is born at around 40 weeks of gestation
• If cessation of breathing is less than 20 seconds, then in order to diagnose the condition as AOP, it has to be accompanied with a low heart rate, or low O2 saturation in blood (below 85%). A low heart rate is defined as heart rate that is more than 30 beats below the baseline heart rate of the infant. The normal saturation of O2 in the blood is over 98%
• The exact cause of AOP is unknown. However, there are a variety of hypothesis proposed, such as:
  • Central respiratory regulation theory
  • Paradoxical chest movement theory
  • Upper airway instability theory
  • Association with gastro-esophageal reflux theory
• The prognosis depends on severity of Apnea of Prematurity. In mild cases, the prognosis is excellent even without treatment, since the condition gets better as the baby gets older. In severe cases, the infant has to be monitored very closely, since AOP can result in sudden death

Apnea is of two types: Central Apnea and Obstructive Apnea, depending on the cause of AOP

• Central Apnea is caused due to inhibition of the respiratory response from the brain, which means that the brain does not send adequate signals for a normal breathing pattern. This leads to a poor breathing process
• Obstructive Apnea occurs when there is a stoppage of breathing, in spite of continuous respiratory effort. In this type, the brain sends the correct signals for breathing, but the breathing organs, such as wind pipe, chest muscles, and lungs, do not function well

Who gets Apnea of Prematurity? (Age and Sex Distribution)

• The incidence of Apnea of Prematurity is more common in premature infants born before 34 weeks of gestation (infants, who are born before the normal 40 weeks of development in the mother’s womb) and having a low birth weight, below 1000 gm (2.2 lbs). Normally, the baby weight at birth, is over 2500-2700 gm (5.5-6 lbs)
• There is no sexual predilection for development of AOP. Both male and female babies are affected equally
• Babies of all races and ethnic backgrounds may be affected

What are the Risk Factors for Apnea of Prematurity? (Predisposing Factors)

Following are the risk factors of Apnea of Prematurity:

• Preterm delivery, before 34 weeks (in normal cases, a baby is born at around 40 weeks of gestation)
• A history of ‘sudden infant deaths’ in siblings of the baby, increases the risk of development of AOP
• Presence of GERD (gastroesophageal reflux disease) in the baby increases the chances of development of the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Apnea of Prematurity? (Etiology)

• The exact cause of Apnea of Prematurity is unknown
• Scientists have proposed a few possible causes and potential hypotheses

The proposed mechanisms are the following (termed hypothesis for Apnea of Prematurity):

Central respiratory regulation theory:

• In premature infants the ventral part of the brain, called medulla oblongata, is under developed. This is the area is responsible for regulating respiration
• This region of the brain operates based on the inputs from specialized parts of the body, called chemoreceptors (CO2 sensors that monitor the CO2 levels in the blood) and mechanoreceptors (that senses the mechanical changes in the chest wall)
• When there is underdevelopment of this area of the brain, the response to increased CO2 concentrations in the blood is abnormal, which causes a decreased response
• This abnormal diminished response may partly be due to a decreased response of the brain cells (also called decreased central chemosensitivity response), or abnormal mechanical factors that prevent an adequate ventilatory response

Paradoxical chest movement theory:

• In premature infants, the chest wall and the rib-cage are very tender and soft. When an infant breathes, the chest wall and rib-cage moves abnormally inwards, instead of normally moving upwards or outwards
• Such a movement pattern is not normal. This kind of paradoxical movement reduces the lung volume and prevents adequate oxygenation of the blood
• However, the reason for such an abnormal movement of chest wall is unknown

Upper airway instability theory:

• Normally, premature infants have weak upper airways and they tend to collapse, when the infant puts an effort to breath. This collapse is caused by a negative pressure created in the hollow airways, during the effort of breathing-in
• Generally, this tendency to collapse is overcome by the upper airway muscles, called genioglossus muscle, which contracts and stretches the airway and keeps it open (patent)
• In premature infants, the response of these muscles is delayed a bit after the effort of breathing, resulting in collapse and blockage of airways

Association with gastro-esophageal reflux (GERD) theory:

• There is an association between Apnea of Prematurity and GERD
• In AOP, there are poor signals that originate in the brain, from the respiratory centre
• Similarly, it is thought that even the region in the brain, which is responsible for the signals to the lower esophageal sphincter (food-pipe), also sends poor signal output
• These poor signals results in improper closure of food-pipe which causes the development of GERD. Hence, it is common to notice the presence of GERD in infants, who have AOP

In summary, the proposed causes of Apnea of Prematurity include: 

• Immature neural connections and insensitive chemoreceptors in the brain, due to improper brain development
• Weak and collapsible upper airway, causing closure of the airway during breathing-in effort
• Abnormal movement of the chest wall tissue, which makes the chest wall move inwards (paradoxical) as opposed to outwards, thus reducing the lung volume

What are the Signs and Symptoms of Apnea of Prematurity?

Overall, the signs and symptoms of Apnea of Prematurity include:

A sudden stoppage of breathing in a premature infant (born within 34 weeks of gestation) associated with lowering of heart beat (below 30 beats from the baseline heart rate) and oxygen (O2) desaturation, below 85% in the blood.

Based on severity, Apnea of Prematurity is categorized into 3 types:

• Mild: In mild type, there is a spontaneous recovery within a few seconds, during each episode. These episodes may occur less than twice in 24 hours. Heart rate and O2 saturation remains normal and does not reduce, or go down. Breathing recovers spontaneously, without any intervention/assistance
• Moderate: In moderate type, there is no spontaneous recovery. Recovery occurs with medical help within few seconds, during each episode. Heart rate and O2 saturation are abnormal and their levels go down moderately. Breathing recovers spontaneously, with minimal medical intervention
• Severe: In severe type, there is no spontaneous recovery. Recovery occurs with intensive medical help, during each episode. Heart rate and O2 saturation are abnormal and are markedly reduced. Breathing recovers spontaneously, only with intensive medical intervention, often requiring vigorous stimulation and assisted ventilation (with bag and mask)

Signs and symptoms of AOP include:

• Bluish discoloration of skin, in the face and the extremities
• Swallowing during apnea episodes (stoppage of breathing). Sometimes, it is normal in newborns to have periodic breathing spells, where there might be a very brief stoppage of breathing. It is important to keep in mind that swallowing is not seen in periodic breathing (a normal phenomenon in newborns)
• The presence of congenital anomalies, such as choanal atresia, cleft palate, neck masses, and other medical conditions, like seizures, bleeding in the brain, biochemical abnormalities

How is Apnea of Prematurity Diagnosed?

Apnea caused by other conditions, such as bacterial, fungal, or viral infections, and metabolic disorders, should be ruled out before diagnosing Apnea of Prematurity.

• Complete blood investigations, cerebrospinal fluid (CSF) and urine exam, to rule out bacterial and fungal infections
• C-reactive protein level measured at 36-48 hours after birth, may be useful for excluding infections
• Pyruvate and lactate levels in blood and CSF, are essential to rule out metabolic disorders
• Urine ketones to rule out organic acidemia
• Serum electrolytes, like calcium, magnesium, glucose
• Stool examination for botulism-related toxins

Imaging studies:

• X-ray of chest, if there is persistent and unexplained lower airway symptoms
• CT scan and lateral view neck x-ray are useful, to rule out any obstructive causes of apnea
• Barium swallow is used, if esophageal web or tracheo-esophageal fistula are suspected
• CT  scan of brain, to check intracranial bleeding

Other tests:

• Polysomnographic multichannel recording - to measure the chest wall movement, airflow, O2 saturation, and heart rate trend
  • Central apnea - there is absence of nasal airflow and wall movement
  • Obstructive apnea - there is a lack of airflow, despite chest wall movement
  • Mixed apnea - combined results of central and obstructive apnea
• ECG (electrocardiogram), if heart rates are abnormal
• EEG (electroencephalogram), if there is seizure and unidentifiable cause for central apnea
• Passing small diameter nasogastric tube in both the nostrils, to rule out choanal atresia

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Apnea of Prematurity?

Premature infants, who are diagnosed with Apnea of Prematurity, are more prone to:

• Apnea (stoppage of breathing)
• Decreased heart rates (bradycardia)
• Decreased oxygen in the blood (oxygen desaturation)

These changes are more readily seen, when the infants are administered general anesthesia and ketamine sedation. Such a response makes them vulnerable to side effects of anesthesia medications. Hence, it is recommended to postpone any elective surgeries in infants diagnosed with AOP, until the baby is at least 52-60 weeks old.

How is Apnea of Prematurity Treated?

Treatment of Apnea of Prematurity starts with eliminating all medical causes of apnea. AOP can be treated according to the severity of apnea, bradycardia, and oxygen saturation. The various treatments options for AOP include:

Stimulation and relieving upper airway obstruction:

• For an isolated event of central apnea, stroking of the bottom of the foot, can end the episode
• If any obstructive symptoms are present, repositioning of head and neck and elevating (raising) the jaw, can relieve obstruction
• If the obstruction is not relieved by any of the above methods, then high-flow oxygen through the nasal cannula may be attempted. Nasal irritation due to the cannula may prevent central apnea, by causing arousal of the brain areas responsible for sending breathing signals

Oxygen administration:

• Supplemental oxygenation and bag-mask ventilation may be required, if there is bradycardia and oxygen desaturation. Medical treatment is required, if there is severe bradycardia, desaturation, and apnoeic episode, more than 6-10 times per day
• Excessive oxygenation should be avoided to prevent retinopathy of prematurity

Continuous positive airway pressure (CPAP):

• CPAP is used, if the oxygen saturation is low, despite high methyl-xanthine (a drug used to stimulate the airway) concentration in blood
• A positive pressure of 3-5cm of water is given through the nasal prongs of the face mask. This is effective in alleviating apnea, due to obstruction and mixed types

Drugs used in treatment of Apnea of Prematurity:

• Methyl-xanthines are the commonly used drug group; of which, caffeine and aminophylline are the two drugs used in this group
• When infants are discharged on methyl-xanthines, they should be continuously monitored. This is because the dosage of the drugs may have to be altered periodically, if the symptoms recur

How can Apnea of Prematurity be Prevented?

Currently, there are no effective ways to prevent Apnea of Prematurity occurrence.

What is the Prognosis of Apnea of Prematurity? (Outcomes/Resolutions)

• The prognosis depends on the severity of AOP and frequency of apnea
• In most cases, apnea frequency gradually decreases during the first few months of life
• Proper home-monitoring is required to prevent sudden infant death, due to Apnea of Prematurity. The family members should also be informed/educated on AOP and maintain a constant vigilance

Additional and Relevant Useful Information for Apnea of Prematurity:

Apnea of Prematurityis also called as “As and Bs”, which respectively stand for ‘Apnea’ and ‘Bradycardia’.