Long-Term Effects Of Respiratory Distress In Newborns

Introduction 

In 1963, Jacqueline Kennedy experienced a heart-wrenching tragedy with the premature birth of her son, Patrick Bouvier Kennedy, nearly six weeks before his due date. Shortly after his birth, Patrick struggled to breathe due to hyaline membrane disease, now recognised as neonatal respiratory distress syndrome (NRDS). In a pioneering effort to save the newborn's life, Dr. William F. Bernhard, a cardiovascular surgeon at Boston Children's Hospital, utilised a hyperbaric chamber—a groundbreaking treatment.

Despite these efforts, Patrick succumbed to the challenges posed by his premature birth just two days after his arrival. This poignant event heightened public awareness of the complexities associated with premature birth and spurred increased research into the understanding and treatment of neonatal respiratory distress.

Neonate respiratory distress syndrome (NRDS) is a respiratory condition that typically presents itself hours after the birth of premature babies or in exceptionally rare cases, full-term infants.¹ While the condition only affects 7% of newborn infants,² NRDS has been shown to cause several long-term physiological and psychological effects ranging from lung scarring to brain damage.³ This article outlines the causes, effects, symptoms and strategies to effectively treat and compassionately care for infants who suffer from NRDS. 

Causes, risk factors and symptoms

Vast improvements in medicine and healthcare have made the survival of extremely preterm infants not just a possibility, but a strong probability. However, this has also caused the emergence of respiratory complications associated with the underdeveloped infant due to a variety of causes and risk factors. A fundamental understanding of the normal lung development in infants is essential to understanding the bodily mechanisms that cause NRDS. The five major stages of normal lung development are shown in the table below:⁴

Within 24 weeks of gestation (canalicular and saccular stages), a primitive form of gas exchange is observed within the foetus with the detectable presence of a complex compound (surfactant) made up of protein and fat.⁵ The surfactants, secreted by a specialised group of cells in the developing lung (type II pneumocytes), are responsible for maintaining the structural integrity of the lungs and preventing it from collapsing inwards.

However, breathing efficiency is vastly improved and adapted to the environment outside the womb during the alveolar stage. Therefore, a premature delivery results in underdeveloped lungs with approximately ten times lower amounts of surfactants and immature pulmonary cells. Since the baby and the mother have so much in common, it is useful to think of the risk factors labelled “infant” and “maternal” as being closely related rather than distinct.^6,7 

A multitude of risk factors could lead to NRDS including sex, race, family history, and other medical conditions with non-caucasian male babies having a comorbidity of other medical conditions such as infections and pulmonary haemorrhage at a relatively higher risk of the condition.⁸ However, prematurity is the greatest risk factor for NRDS with research indicating that the risk of developing respiratory distress is inversely related to gestational age.⁹

That is, the earlier the baby is born, the more likely it is that the infant experiences respiratory distress. Over 50% of babies born before a gestation period of 30 weeks develop NRDS due to surfactant deficiency and immaturity of the infant’s lung structure.¹⁰

Over the last six decades, clinical research has identified three possible genes whose malfunctioning in the developing infant could lead to respiratory distress (SFTPB, SFTPC and ABCA3) with over 60% of the cases occurring due to a faulty SFTPB gene.¹¹ The precise mechanisms through which these genes bring about different variations of respiratory distress is however a topic of ongoing scientific investigation.

Besides the infant-related and incidental risk factors, several maternal factors have been reported to increase the risk of the infant suffering from NRDS. For instance, infants born to diabetic mothers are 23.7 times more likely to develop NRDS than those born to non-diabetic mothers.¹²

Further, elective caesarean section also has an influential impact on the risk of NRDS even in full-term infants since the foetal absorption of lung fluid and maturation of the foetal pneumocytes is only adequately achieved through vaginal delivery.¹³ Hypertension has also been indirectly associated with incidents of NRDS with a hypothesis indicating an increased incidence of caesarean section in hypertensive mothers.¹⁴ 

The symptoms of NRDS are typically apparent immediately after the delivery and worsen to varying degrees over time. The symptoms include blue colouration in the lips, fingers and toes, an increase in breathing rate, nostril flaring and a distinct grunting sound during respiration. 

Long-term consequences 

Respiratory implications

Lung scarring, chronic lung disease or bronchopulmonary dysplasia (BPD) is one of the most common and long-term effects of NRDS due to the immediate mechanical ventilation and the nature of the surfactants used to treat it. BPD is characterised by abnormal lung development and structural changes which lead to respiratory symptoms such as shortness of breath and wheezing. Infants with NRDS have been reported to be more susceptible to infections like pneumonia and bronchiolitis while asthma has also been hypothesised to be a possible clinical manifestation in children who have severe lung damage while on mechanical ventilation.^15,16,17

Preterm newborns, particularly those born before 28 weeks gestation, are predisposed to apnea due to inadequate development of respiratory control mechanisms, resulting in apnea of prematurity. Apnea can occur shortly after delivery as a result of birth asphyxia, maternal medication usage, infections, metabolic disorders, or congenital defects. The majority of preterm infants develop a mature breathing pattern and recover from the initial lung disease.

However, in rare cases, respiratory difficulties continue, possibly due to insufficient maturation of respiratory control, obstructive breathing habits, or the development of chronic lung disease. Furthermore, preterm newborns have a higher risk of experiencing apparent life-threatening events (ALTE) or brief resolved unexplained events (BRUE). These respiratory issues primarily manifest during sleep. When breathing issues or unexpected events occur, hospitalisation is frequently required until the newborn regains normal respiratory control during sleep.^18,19

Neurodevelopmental and cognitive implications

Neurodevelopment refers to the development of the brain’s neural pathways and networks essential for our normal functioning. Neuroscientific research has shown that not only does NRDS lead to an increased risk of brain disorders such as cerebral palsy, but the development of strong neuronal connections is significantly delayed in infants who suffer from NRDS as opposed to those who don’t.

Furthermore, on evaluation of “school-readiness” of infants who experienced NRDS two years on, 11% of the children were found to be disabled and 23% to be delayed in their brain’s development strongly suggesting the need for specialised education and care to these children especially if they belong to underprivileged backgrounds.

Recent studies point towards possible alterations to existing therapeutic methods that could significantly reduce adverse neurodevelopmental effects such as restricted ventilation. However, substantially more research needs to be done to optimise these techniques into a coherent and effective clinical strategy.^20,21,22,23

Treatment options

Since the initial identification of the link between respiratory distress syndrome and surfactant deficiency more than six decades ago²⁴, substantial progress has been achieved in comprehending the pathophysiology and addressing the treatment of this condition. The vulnerability of the lungs in very preterm infants stems from their distinctive susceptibility to injury due to structural immaturity, surfactant deficiency, fluid-filled state, and lack of support from a rigid chest wall.

Particularly, infants with birth weights below 1250 grams face a significant risk of developing BPD linked to the initiation and prolonged use of mechanical ventilation, resulting in lung injuries.²⁵ Therefore, managing this condition necessitates a multidisciplinary approach to achieve optimal outcomes. Adhering to fundamental neonatal care principles, including thermoregulation, providing cardiovascular and nutritional support, addressing early neonatal infections, and preventing hospital-acquired infections, is essential in reaching therapeutic objectives.²⁶

Consequently, contemporary foundational respiratory support approaches such as surfactant replacement therapy, continuous positive airway pressure (CPAP), and diverse mechanical ventilation modalities are currently undergoing refinement to enhance their safety profile and minimise potential side effects.

nCPAP

Nasal continuous positive airway pressure (nCPAP) is a non-invasive, safe, and effective respiratory method for providing positive end-expiratory pressure in neonates. nCPAP maintains a consistent inspiratory and expiratory pressure above ambient levels for spontaneously breathing neonates. Resulting in improved respiratory function, and reduced upper airway resistance, it stabilises the chest wall, regulates respiratory rate, promotes surfactant production, reduces alveolar oedema, and supports lung growth.²⁷ Many studies show nCPAP improving respiratory outcomes with preterm neonates with reduced incidences of BPD.^28,29 

In light of mounting empirical evidence supporting the efficacy of nCPAP, various non-invasive positive end-expiratory pressure (PEEP) delivery modalities have been investigated such as machine-derived CPAP, bubble CPAP, non-invasive ventilation (NIV), high-frequency nasal breathing, and devices that provide unquantified PEEP, such as the high-flow nasal cannula (HFNC).³⁰

However, the use of nasal continuous positive airway pressure (nCPAP) has been linked to operator-dependent complications such as nasal injury, air leak syndromes, heat and chemical burns, and ingestion or aspiration of nasal interface components. In tackling these challenges, it is imperative to institute continuous quality improvement practices through a collaborative approach that engages neonatologists, nurses, and respiratory therapists. Additionally, the integration of a regular checklist is of paramount importance.³¹

Surfactant therapy

Surfactant replacement therapy has been used for the treatment of NRDS for decades. Naturally available surfactants are acquired from bovine/porcine lungs, although the research for synthetic surfactants has been ongoing. A combination of nCPAP with surfactant therapy aims to avoid mechanical ventilation completely, reducing the probability of infections and injuries.

Emerging evidence advocates for a paradigm shift in surfactant administration, favouring a selective approach over prophylactic use to mitigate BPD and mortality. The use of nebulized surfactant is also being explored for its potential to diminish intubation requirements in preterm infants subjected to nasal CPAP.

Early identification of surfactant-requiring infants, mitigating drawbacks associated with delayed surfactant administration, and discerning the potential advantages of prophylactic surfactant with less invasive surfactant administration (LISA) in comparison to CPAP with rescue surfactant administration among extremely preterm infants are some of the key features being explored.^32,33,34

Mechanical ventilation 

While nCPAP is advocated as the preferred initial form of respiratory support, the failure rate of nCPAP and the necessity for intubation and invasive mechanical ventilation (IMV) remain elevated, particularly among extremely preterm infants. Given that all forms of invasive mechanical ventilation for immature lungs are believed to contribute to some extent to ventilator-induced lung injury, there is a hypothesis suggesting that minimising the use of ventilation could potentially lead to a decrease in BPD.

Therefore, the primary objectives in ventilatory management during the initial phases of respiratory distress syndrome are to ensure adequate oxygenation and ventilation while minimising the risk of ventilator-induced lung injury. In the context of NRDS, the neonate's pulmonary anatomy is characterised by a deficiency in surfactant, resulting in diminished compliance and reduced lung volume.

The expeditious administration of exogenous surfactant improves oxygenation in the lungs. Despite the swift improvement in oxygen saturation, the restoration of lung elasticity occurs gradually. Therefore, the medical team must discern this critical juncture and systematically taper the administered oxygen and ventilatory support, mitigating the risk of potential pulmonary harm.^26,35,36

Future directions 

Current research efforts have resulted in considerable advances in neonatal care for respiratory distress syndrome, including the development of numerous viable therapies that are noninvasive and targeted. Protocols governing mechanical ventilation and oxygenation are under review, with findings highlighting the inflammatory ramifications of short-term exposure to higher oxygen levels during invasive mechanical ventilation. Emerging evidence advocates for a paradigm shift in surfactant administration, favouring a selective approach over prophylactic use to mitigate BPD and mortality.

The use of nebulized surfactant is also being explored for its potential to diminish intubation requirements in preterm infants subjected to nasal CPAP. Early identification of surfactant-requiring infants, mitigating drawbacks associated with delayed surfactant administration, and discerning the potential advantages of prophylactic surfactant with less invasive surfactant administration (LISA) in comparison to CPAP with rescue surfactant administration among extremely preterm infants are some of the key features being explored.

Along with the respiratory interventions, some research is also investigating the potential of nutrition as therapy. Notably, vitamin D and vitamin A supplementation, are subject to ongoing scrutiny for their roles in foetal lung maturation and BPD reduction, respectively.^{32,34,37,38,39}

Summary

Heartbreaking deaths and ground-breaking discoveries have underscored the history of newborn respiratory distress syndrome. We have come a long way from the preterm birth of Jacqueline Kennedy's son due to the unwavering efforts of researchers and medical professionals like Dr. William F. Bernhard. This article has examined the long-term effects, risk factors, symptoms, and causes of non-radiative diabetes syndrome (NRDS), exploring the importance of a multidisciplinary approach to treatment.

A variety of treatment options have been discussed, including non-invasive respiratory support such as nasal continuous positive airway pressure (nCPAP) and surfactant replacement therapy, while also looking ahead to potential future directions, including nebulized surfactant therapy and selective surfactant administration. It is of paramount importance that we combine sustained research, patient-centred care, and unwavering innovation to fight against NRDS and ensure that every newborn has the chance to have a good start in life.