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Apnea Prematurity Diagnosis Apnea of prematurity, also known as Apnea-newborns/Apnea-neonatal, is a condition in which preterm (premature) babies experience brief episodes of breathlessness (apnea) that usually last for at least 20 seconds. This scenario arises due to the incomplete development of the respiratory apparatus in infants (less than 37 weeks of gestational age). In most cases, a drop in heart rate, i.e., bradycardia, accompanies the apneic spell.
In a study, the prevalence of apnea of prematurity in preterm newborns was 48%.[1] However, prevalence strongly depends on gestational age: almost all infants born before 28 weeks develop apnea, whereas it is uncommon after 34 weeks. It is one of the most commonly diagnosed diseases in the Neonatal Intensive Care Unit (NICU).[2]
Newborns suffering from the disorder may also have low blood-oxygen levels and a slower-than-normal heart rate. Usually, the condition is diagnosed at the time of birth, and a timely diagnosis can bring significant changes. A few days in the NICU can help your child achieve a normal breathing rhythm.
Apnea Of Prematurity (AOP) Symptoms: Apnea Prematurity Diagnosis
The most common signs and symptoms of apnea of prematurity include:
Apneic Spells:
Infants suffering from the condition display pauses in their breathing. These pauses, known as apneic spells, last for about 15-20 seconds. Studies show that preterm infants experience multiple episodes of apneic periods. In a study, 60% of apneic neonates had more than 3 episodes of apnea, while 40% had 1-2 episodes per day. The two most common causes of apnea were found to be sepsis and apnea of prematurity. Thus, experts suggest that health professionals carefully evaluate all children born before 32 weeks of gestational age with apneic spells, as they may be linked to more serious health issues like sepsis, intracranial hemorrhage, and hypoglycemia.[3]
The disturbance in normal breathing is attributed to multiple issues. Premature babies suffer from periods of apnea due to immature respiratory control. This means that the body is not yet ready to take over the responsibility of breathing. Therefore, apnea arising at this age is more serious and potentially has greater adverse effects than apnea at any other age.[4]
Bradycardia:
A lower-than-normal heart rate, i.e., bradycardia, is often observed in infants with incomplete gestational life. The interplay of apnea, oxygen desaturation, and bradycardia complicates management and can have serious consequences.[5]
In some cases, premature infants with very low birth weight often experience very long periods of apnea. These apneic spells may last for more than 60 seconds and are attributed to an inherent immaturity of the nervous system responsible for breathing control. Researchers found immature brainstem and peripheral chemoreceptors, and other serious conditions like sepsis and hemorrhage to be responsible for the issue. Bradycardia and low oxygen saturation are also present during the spells of apnea.[6]
Hypoxemia:
The main problem in apnea of prematurity is the onset of hypoxemia (low levels of oxygen in the blood). Hypoxemia causes poor perfusion of the organs.
The brief periods of apnea do not cause any significant damage if blood oxygen levels are appropriately managed during those apneic cycles. However, clinical research reveals that chronic intermittent hypoxemia (CIH) in apnea cycles can be problematic. This effect contributes directly to immediate and long-term comorbidities in newborns. Therefore, infants with CIH need prolonged respiratory support.
Unfortunately, patients with more pronounced hypoxemia are at a greater risk of developing poor neurodevelopment and retinopathies. The co-existence of hypoxemia with bradycardia further aggravates the condition.[7] Another study concluded that hypoxemia causes neurological and cognitive ramifications in infants.[8] So, timely treatment is needed.
Cyanosis:
Preterm infants with poor oxygenation due to multiple episodes of apneic spells generally lack oxygen in their blood. This leads to their skin turning blue-purple. The oxygen you inhale binds with the hemoglobin in your blood and turns it into oxyhemoglobin, which imparts the blood its bright red color. However, when less oxygen is present in your blood, the levels of oxyhemoglobin are also low. Thus, instead of the usual red skin color, preterm infants with apnea of prematurity have a bluish skin tone. In a clinical case, a premature infant suffering from apnea of prematurity had 2 apneic events and displayed central cyanosis five hours after birth.[9]
Improper perfusion due to apnea of prematurity can result in cyanosis in babies.
Hypotonia:
Bradycardia and muscle hypotonia usually accompany unstable breathing patterns in preterm infants. Infants with a shorter intrauterine life have poor development and growth, which contributes not only to breathing problems but also to muscular deficits [10]
Very Low Birth Weight (VLBW):
Almost all infants with a gestational age of less than 28 weeks will experience the episodic cessation of respiration. All such individuals have an incomplete breathing apparatus and present with very low birth weight. Generally, preterm infants weigh less than 1600 grams, which poses significant problems.
Apnea Of Prematurity Causes
Infants do not breathe air during intrauterine life, but they do make fetal breathing movements, which are important for lung development. It is only after delivery that they open up their lungs for respiration, which is why crying immediately after birth is a crucial step (as it marks the beginning of independent breathing). For all of this to happen, there is a need for harmonious collaboration between the neurological system (the brain’s breathing center) and the baby’s breathing organs. Issues in one department or both can contribute to irregular breathing patterns. Based on the region involved, causes of apnea of prematurity are divided into three different types.
Apnea Of Prematurity Types:
Obstructive Apnea
This is similar to obstructive sleep apnea (OSA) in adults, where the airway passages aren’t open enough to allow uninterrupted passage of gases (oxygen and carbon dioxide). This type is characterized by a blockage in the baby’s airways. Obstructive apnea accounts for about 10-25% of all cases of apnea-neonatal.[11] A low pharyngeal tone can also play a role in obstructive apnea.
While the exact mechanisms are not completely understood, experts believe that the poorly developed airway passages of a premature child are unable to stay open all the time. The airway passages (especially in the neck) close, leading to pauses in breathing and associated complications. Studies show that upper airway obstruction is a major contributor to the disease. Some researchers have also found active glottic closure in multiple cases that cause obstructive apnea of prematurity. The glottis is an opening in your vocal cords that opens to allow you to make sounds. Its closure can obstruct breathing and cause apnea.[12]
Central Apnea
Your brainstem houses very important structures like the medulla oblongata and the pons. These structures are responsible for controlling respiration; therefore, they are collectively known as the respiratory or breathing center of the brain. The condition is termed central apnea when there is improper signaling from the breathing center. In a normal scenario, the baby’s brainstem controls the breathing patterns by sending electrical signals to the baby’s respiratory muscles, i.e., the diaphragm and the intercostal muscles of the lungs. The primary function of these muscular contractions is to expel carbon dioxide.
However, apnea can ensue when there are insufficient or irregular signals for the respiratory muscles. This abnormality is attributed to the incomplete development of the brain’s breathing center. The lack of postnatal maturation of the breathing center causes problems. This physiologically immature neural system gives a faulty response to lung stretch receptors and to stimulation from chemoreceptors. Consequently, the brainstem conduction time is also longer in premature infants with apnea than in those without apnea.[13]
Mixed Apnea
The most common type of apnea, present in about 50% of cases, is mixed apnea. It is characterized by a lack of proper functioning of both the brainstem and the respiratory pathways.
Apnea Of Prematurity Diagnosis
Premature babies are prone to developing complications; thus, doctors carefully monitor all such infants at birth. Doctors can diagnose the condition by monitoring the baby’s vital signs, which include heart rate, breathing rate, and blood oxygen levels. Infants in the Neonatal Intensive Care Unit (NICU) are kept under 24-hour monitoring. Any changes in these health signs indicate underlying infirmities and help health professionals diagnose apnea.
Differential Diagnosis (DD):
Different conditions fall under the DD for apnea of prematurity. It is important to know the differences between these conditions.
Periodic Breathing Vs Apnea Of Prematurity
Periodic breathing is a normal phenomenon characterized by brief periods of apnea occurring in short cycles of 5-10 seconds. This is usually seen in clinically stable infants aged 4 weeks to 6 months.[14]
Generally, children gain normal breathing rhythms after this period. However, apnea of prematurity is characterized by a sudden cessation of breathing that lasts for at least 20 seconds. Other issues like cyanosis, bradycardia, and hypotonia accompany this unexplained condition. These symptoms are not present in periodic breathing.
Sepsis Vs. Apnea Of Prematurity
Sometimes, the cause of breathing difficulties is not apnea but a more serious condition in infants, i.e., sepsis. It is a life-threatening infection characterized by tachycardia, fever, and high blood pressure. On the other hand, AOP manifests as low heart rate and hypoxia; and fever and hypertension are absent. Unlike AOP, sepsis is treated with IV antibiotics.
Note: If there is a sudden increase in apneic episodes, the infant likely has sepsis (instead of AOP).
Intracranial Hemorrhage Vs. Apea Of Prematurity
A more serious condition, i.e., brain bleeding (hemorrhage), also has presentations similar to AOP. Infants suffering from a hemorrhage usually have symptoms like muscle weakness and seizures along with apnea. However, such features are not seen in AOP.
Apnea Of Prematurity Treatment
The main aim of the treatment is to minimize the intermittent hypoxia (and hypoxemia) associated with the apneic spells. Management of bradycardia is also a priority because it can lead to long-term morbidities. The following treatment modalities have proven to be beneficial in the management of apnea of prematurity.
Caffeine Citrate:
Using caffeine medications in infants is similar to the morning coffee of adults. The intake of medications containing caffeine citrate stimulates the infant’s nervous system to start and take control of breathing. Clinical research suggests that caffeine is effective in reducing the frequency of apneic spells in preterm infants. However, dose adjustment of caffeine is crucial in maximising outputs and ensuring the safety of the neonates.[15]
Caffeine citrate is regarded as an essential respiratory stimulant for infants suffering from neonatal apnea. It can start to reduce the frequency of apneic spells after one week of administration. As most premature infants are prone to developing AOP, policymakers should ensure the availability of affordable caffeine citrate to all preterm neonates. [16]
Aminophylline:
Sometimes used, but less common today because of side effects and the superiority of caffeine.
Carbon Dioxide Inhalation:
The administration of caffeine is effective in kick-starting the infant’s nervous system. However, these compounds have potential adverse effects. Therefore, in the search for safer alternatives, doctors found other strategies that could work and were safe. Carbon dioxide inhalation is one of the strategies that works by triggering the chemoreceptors in the brain that respond by improving breathing rhythm.[17] There is not much evidence available to support the use of CO2 inhalation. Thus, further research is advised to validate its widespread use.
Positive Airway Pressure:
Nasal continuous positive airway pressure (CPAP) and Nasal intermittent positive pressure ventilation (NIPPV) therapies are effective in alleviating symptoms of AOP. These therapies deliver pressurized air to the patient (via specialized devices) to ease breathing. According to a meta-analysis, both CPAP and NIPPV have similar effects on AOP.[18] CPAP helps keep your upper airway passages open while the infant breathes on its own.
Mechanical Ventilation:
If there is no improvement in apneic spells, your doctor may use mechanical ventilation. It is a life-saving procedure that provides breathing support to infants who can not breathe properly themselves.
The photograph shows an infant on mechanical ventilation (in an incubator) with electrode pads on the chest to monitor heart rate.
Different strategies of mechanical ventilation are adopted in neonates to minimize side effects. Volume-targeted ventilation involves delivering a small volume of gases with advanced technology to prevent ventilator-induced injury.
In modern times, Neurally adjusted ventilatory assist (NAVA) is safe and effective in premature infants with apnea. It works by giving electrical stimulation to the diaphragm muscle. Studies show that preterm neonates on NAVA-PAP had minimal time spent in backup ventilation and consequently had fewer adverse events.[19]
Kangaroo Mother Care:
KMC, Kangaroo care, or Kangaroo mother care, is a strategy to support weak infants (premature or having low birth weight). As the name indicates, it involves a caregiver giving prolonged skin-to-skin contact, just like a kangaroo mother. Clinicians believe that exclusive breastfeeding and skin contact of the mother with the baby can improve the infant’s breathing and promote healthy growth while keeping infections at bay. This method of apnea management has been shown to improve the electrical activity of the diaphragm, but clinical evidence to explain its benefits is low.[20]
It was concluded in a study that kangaroo mother care shortens ventilation duration (and supplemental oxygen support) in extremely low birth weight infants. This love-based therapy also reduces the frequency of apneas.[21]
Postural Changes:
Doctors may also adopt simple procedures like placing the neonate in a prone position to reduce AOP. However, it must be carefully adopted as it is linked to an increased risk of sudden infant death syndrome.
Sensory Stimulation:
It is a conventional method of treating apnea of prematurity. It involves giving different types of sensory stimuli to the patient to reduce apnea intensity. Doctors use olfactory (smell), auditory (sound), and tactile (touch) stimuli to activate the neuronal activity. Research shows that sensory stimulation paired with respiratory care helps decrease the frequency of AOP.[22] Therapists perform gentle stroking/rubbing on the infant’s skin to stimulate the skin nerves. Moreover, gentle pressure on the joints stimulates proprioception.
Most patients recover within a few days if proper breathing help and neonatal care are provided. However, the outcome of AOP management depends on multiple factors, such as the severity of apnea and the birth weight of the child.
Final Word
Apnea of prematurity is a condition in which preterm infants (with less than 37 weeks of gestational age) experience episodes of apnea that last for at least 20 seconds. The premature infants generally have very low birth weight. The disorder arises due to poor neuronal development of the brain’s breathing center (central apnea), incomplete opening of airway passages (obstructive apnea), or a combination of both (mixed apnea). These abnormalities are attributed to incomplete intrauterine life.
In the vast majority of cases, hypoxia/hypoxemia (lack of oxygen in the body/blood) and bradycardia accompany the apneic spells. These children generally have muscle hypotonia and are cyanosed due to oxygen deficiency. Doctors diagnose the condition early and treat the infants in the NICU. Clinicians adopt different strategies to treat AOP. Methylxanthine medications (caffeine and aminophylline) stimulate the nervous system, and positive airway pressure therapy (CPAP and NIPPV) opens up the breathing passages. Neurally adjusted ventilatory assist (NAVA) is the latest and most effective way to stimulate breathing muscles like the diaphragm.
Strategies like prone positioning, kangaroo mother care, and sensory stimulation can potentially benefit premature infants, but evidence to support their role is scarce.
References
[1] Aslamzai, M., Froogh, B. A., & Faizi, O. (2022). Prevalence and Risk Factors of Apnea in Preterm Neonates Admitted to the French Medical Institute for Mothers and Children Hospital in Kabul City: An Analytic Cross-Sectional Study.J Pediatr Neonatal,4(2), 1-5.
[2] Eichenwald, E. C., Watterberg, K. L., Aucott, S., Benitz, W. E., Cummings, J. J., Goldsmith, J., … & Wang, K. S. (2016). Apnea of prematurity.Pediatrics,137(1).
[3] Pal, A. C., Jha, R. K., Bandyopadhyay, S., Chakraborti, S., Mandal, R. K., & Ali, S. A study on neonatal apnea in relation to etiopathogenesis and their outcome in a rural-based Medical College Hospital; West Bengal; India.
[4] Martin, R. J., Mitchell, L. J., & MacFarlane, P. M. (2022). Apnea of prematurity and sudden infant death syndrome.Handbook of clinical neurology,189, 43-52.
[5] Martin, R. J., & Wilson, C. G. (2012). Apnea of prematurity.Comprehensive Physiology,2(4), 2923-2931.
[6] Mohr, M. A., Vergales, B. D., Lee, H., Clark, M. T., Lake, D. E., Mennen, A. C., … & Delos, J. B. (2015). Very long apnea events in preterm infants.Journal of Applied Physiology,118(5), 558-568.
[7] Di Fiore, J. M., Martin, R. J., & Gauda, E. B. (2013). Apnea of prematurity–perfect storm.Respiratory physiology & neurobiology,189(2), 213-222.
[8] Picone, S., Aufieri, R., & Paolillo, P. (2014). Apnea of prematurity: challenges and solutions.Research and Reports in Neonatology, 101-109.
[9] Ness, T. E., King, B. C., Kukreja, M., & Sundgren, N. C. (2021). Apnea Spells in a Term Neonate.Pediatrics In Review,42(11), 616-618.
[10] Alvaro, R. E. (2018). Control of breathing and apnea of prematurity.NeoReviews,19(4), e224-e234.
[11] Zhao, J., Gonzalez, F., & Mu, D. (2011). Apnea of prematurity: from cause to treatment.European journal of pediatrics,170(9), 1097-1105.
[12] Poets, C. F. (2010). Apnea of prematurity: What can observational studies tell us about pathophysiology?.Sleep medicine,11(7), 701-707.
[13] MacFarlane, P. M., Ribeiro, A. P., & Martin, R. J. (2013). Carotid chemoreceptor development and neonatal apnea.Respiratory physiology & neurobiology,185(1), 170-176.
[14] Yee, A. K., Siriwardhana, L. S., Nixon, G. M., Walter, L. M., Wong, F. Y., & Horne, R. S. (2023). Periodic breathing in clinically stable very preterm infants.Pediatric Pulmonology,58(3), 887-898.
[15] Long, J. Y., Guo, H. L., He, X., Hu, Y. H., Xia, Y., Cheng, R., … & Xu, J. (2021). Caffeine for the pharmacological treatment of apnea of prematurity in the NICU: dose selection conundrum, therapeutic drug monitoring and genetic factors.Frontiers in Pharmacology,12, 681842.
[16] Schmidt, B. (2023). Caffeine for apnea of prematurity: too much or too little of a good thing.The journal of pediatrics,259, 113488.
[17] Kocjan, A., Papachristoforou, N., Michałka, D., Gałuszka, Z., Makar, M., Bartuś, T., … & Chmiel, R. (2025). The Innovative Approaches to Treating Apnea of Prematurity: From Sensory Stimulation to Aromatherapy.Quality in Sport,37, 57616-57616.
[18] Sabsabi, B., Harrison, A., Banfield, L., & Mukerji, A. (2022). Nasal intermittent positive pressure ventilation versus continuous positive airway pressure and apnea of prematurity: a systematic review and meta-analysis.American Journal of Perinatology,39(12), 1314-1320.
[19] Protain, A., Firestone, K., Hussain, S., Lubarsky, D., & Stein, H. (2023). Evaluation of NAVA-PAP in premature neonates with apnea of prematurity: minimal backup ventilation and clinically significant events.Frontiers in Pediatrics,11, 1234964.
[20] Thompson, M. T. (2024). Kangaroo care to improve respiratory function in preterm infants: a literature review.Journal of Neonatal Nursing,30(2), 109-118.
[21] Xie, X., Chen, X., Sun, P., Cao, A., Zhuang, Y., Xiong, X., & Yang, C. (2021). Kangaroo mother care reduces noninvasive ventilation and total oxygen support duration in extremely low birth weight infants.American Journal of Perinatology,38(08), 791-795.
[22] Mageed, A. S. A., Olama, K. A., Rahman, S. A. A., & El-Gazzar, H. E. (2022). The effect of sensory stimulation on apnea of prematurity. Journal of Taibah University Medical Sciences, 17(2), 311-319.