GERD in the NICU Infant: Who needs to be treated and what approach is beneficial?

Abstract

In this review, we discuss gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD) as it pertains to the infant in the NICU based on research in this specific population. Specifically, we summarize the developmental biology of the gastroesophageal junction (GEJ), the physiology of GER and the pathophysiology of GERD in the NICU infant setting, and identify risk factors for GER and GERD. We also address the epidemiology, economic burden and controversies surrounding GERD in the NICU infant, and formulate an approach to GER and GERD in his patient population. Finally, we examine the recent advancements in the individual assessment of GER and GERD in the NICU infant, and provide evidence-based guidelines that can be adopted.

Introduction

Definition

Gastroesophageal reflux (GER) is defined as the retrograde passage of gastric contents into the esophagus and possibly the oral cavity, and when ‘troublesome symptoms’ persist due to these events, it is called gastroesophageal reflux disease (GERD).^[1–3] Infants in the neonatal intensive care unit (NICU) present with a multitude of aerodigestive, cardiorespiratory and somatic symptoms; it is often unclear whether these symptoms can be attributed to GER. In infants in the NICU or in non-verbal developmentally challenged patients, it is common to associate the troublesome symptoms/cues that are witnessed by an observer with GERD, however, the definition of ‘troublesome’ can be challenging. Based on subjective definitions, the use of pharmacological and non-pharmacological therapies to mitigate these symptoms has become a common practice, although there is significant practice variation among providers. Many infants in the NICU are prescribed acid suppressive therapies to treat a presumed diagnosis of GERD.^{[4, 5]} These and other pharmacological approaches, including prokinetics, and antacids, have all been associated with serious short-term and long-term consequences.^[5–9] Furthermore, empiric and over-the-counter approved and unapproved therapies are commonly used, adding to the expense and contributing to unintended long-term consequences.^[10]

Epidemiology and burden

The exact burden of GERD in the NICU infant is not known, partly as a result of diverse definitions. To complicate matters, GER is a normal occurrence in the neonate with 2–3 episodes of reflux per hour,^[11] and is related to the infants’ frequent feeding cycles. The composition of gastric contents varies with feeding methods, and therefore the physical and chemical properties of the gastric contents vary within an infant’s feeding cycle.^[12] Symptoms are based on the state of activity of the infant (i.e., sleep-awake-activity states), with infants spending a considerable amount of time sleeping. Interventions that alter the sleep-awake-activity states may include, but are not limited to, routine examination and providing cares, nasogastric tube placement and feeding methods, checking residuals, and suctioning aerodigestive tract secretions in sicker infants. Therefore, changes in sleep patterns and interventions in NICU infants may modify the symptoms and responses to reflux events.^{[13, 14]}

In an attempt to determine the burden of GERD, we studied 33 academic freestanding children’s hospital NICUs in the United States. Using the definition of GERD based on symptoms, we noted a 13-fold variation (2% to 26%) in the diagnosis of GERD and found that infants with a diagnosis of GERD stayed 1 month longer in the NICU.^[15] Preterm infants who are diagnosed with GERD have longer hospital stays and higher hospital costs than infants without this diagnostic label.^[15] It is estimated that the diagnosis of GERD in a NICU infant increases the NICU costs by ~$70,000 US dollars.^[15] Furthermore, many infants continue to be treated after they are discharged from the NICU.^{[5, 16]}

Controversies Surrounding GERD in the NICU infant

Ambiguity in the diagnosis of GER or GERD in the NICU may be related to lack of proper understanding and inability to differentiate normal (physiological) from disease (pathological) processes. In the absence of physiological evidence, the diagnosis and management approaches are often influenced by 4 factors:

1). Symptoms and cues of the patient:

In general, NICU infants have many types of presenting symptoms/cues; these can be classified into 4 groups: a) gastrointestinal (regurgitation, emesis, abdominal distention), b) cardiorespiratory (spells characterized with bradycardia, tachycardia, apnea, periodic breathing, tachypnea, increased respiratory effort, desaturations), c) somatosensory (irritability and back arching, crying and grimace) and d) aerodigestive (swallowing and feeding difficulties, sneezing, coughing and choking, breathing disturbances) systems. Attributing such troublesome symptoms to reflux events in the absence of evidence remains controversial. Often there is more than one category of presenting symptoms and cues, which can occur with any provocation from within the airway, pulmonary, digestive, cardiac or neurologic systems. However, the vagal response is a common attribute that can possibly link all of these 4 categories with nerve-mediated aggravating and ameliorating sensory-motor mechanisms that involve sympathetic and parasympathetic responses.

2). Perceptions of parents and providers:

Parents and bedside care providers are often the first responders to symptoms and clinical signs, and an initial work-up for GERD is often based on their reports. Parental perception of GERD may be influenced by individual experiences or readings from older literature. The presence or magnitude of symptoms as a significant predictor of GERD has been evaluated in a survey, the Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R).^[17] The I-GERQ-R is a brief, 12-item validated questionnaire completed by parents and physician providers to measure GERD symptoms in infants. This questionnaire validates the diagnosis of GERD in children ages 1–14 months by using abnormal pH-probe studies and/or abnormal esophageal biopsies as gold standards. An IGERQ-R score greater than 16 is suggestive of acid-GERD. However, Salvatore et al found that the I-GERQ-R questionnaire is not reliable for predicting the severity of GERD. The questionnaire had no correlation with esophageal acid exposure as measured by pH-metry and with esophagitis as evaluated by histology of esophageal biopsies.^[18] The questionnaire also does not assess the anticipated response to therapeutic interventions.^[18]

3). NICU operational systems-processes:

The NICU operating systems also play an important role in the supply chain of diet and/or feeding methods provided to hospitalized infants. For example, the processes involving infant diet, volume intake, milk type, position during feeding, caloric density, osmolality of feedings, use of feeding pumps and gavage tube, or transitional and/or oral feeding methods can influence GER.^{[12, 19]}

4). Physician’s role in the definition of the GERD:

Responsibility ultimately rests with the physician as to whether to treat GERD empirically or wait, or to consider tests for persistent feeding difficulties or troublesome symptoms, and seek alternate diagnoses. Such a determination can be challenging when several factors, as described earlier, are at play. The absence of a highly sensitive and specific, easily available crib-side test makes it more difficult to make a diagnosis based on objective criteria.

Developmental Anatomy and Physiology of the Gastro Esophageal Junction (GEJ)

The neonatal period is the only time when anatomical development and functional physiological maturation of individual systems are rapidly evolving ex-utero. This process is further dependent on the birth gestation, efficient nutrition and feeding methods, and interventions associated with coexisting morbidities. For the purpose of delineating the pathophysiological basis of GERD as related to NICU infant, it is important to understand the development and maturation of GEJ in early infancy, as structural and functional abnormalities can influence the GERD diagnosis particularly in the NICU setting.

Embryology and clinical implications

The neuroanatomic relationship between the airway and foregut can be explained by their embryologic origins from adjacent segments of the primitive foregut.^[20–23] The tracheobronchial diverticulum, the pharynx, the esophagus, the stomach, and the diaphragm are all derived from the primitive foregut and/or its mesenchyme and share similar control systems. By 4 weeks’ gestation, the tracheobronchial diverticulum appears at the ventral wall of the foregut, with the left vagus located anterior and the right vagus located posterior. The stomach is a fusiform tube with a growth rate of the dorsal side that is greater than the ventral side, thus creating greater and lesser curvatures. At 7 weeks’ gestation, the stomach also rotates 90° clockwise, with the greater curvature displaced to the left. By the sixth or seventh week of gestation, a structure superior to the true vocal cords evolves to protect the vocal cords and lower airway. This superior structure consists of the epiglottis, aryepiglottic folds, false vocal cords, and the laryngeal ventricles. The epiglottis starts as a hypo-branchial eminence behind the future tongue. By week 7, the epiglottis is separated from the tongue and two lateral folds are connected to the base of the epiglottis and the distal end of the lateral folds develops into the arytenoids cartilages. The larynx begins as a groove in the primitive foregut, which folds upon itself to become the laryngo-tracheal bud, the subsequent divisions of which form the bronchopulmonary segments. From this phase, 20 generations of conducting airways form. The first 8 generations constitute bronchi and acquire cartilaginous walls; the next 9 to 20 generations comprise the non-respiratory bronchioles, which are not cartilaginous and contain smooth muscle. Subsequent divisions form the bronchopulmonary segments. At 10 weeks’ gestation, the esophagus and the stomach are properly positioned; the circular and longitudinal muscle layers and the ganglion cells are in place. The true vocal cords begin as glottal folds.

Thus, from 4 weeks to 24 weeks of intra-uterine growth, rapid changes in development, maturation and functioning of the organs related to the pharyngo-esophageal and cardio-respiratory apparatus occur. In the premature infant developing ex-utero, further development and maturation of these inadequately developed organ systems can influence the overlapping reflexes involving the 4 categories of symptoms described earlier. Therefore, the structural maldevelopment of the aerodigestive tract and GEJ can result in situations predisposing to GER. Such predisposing conditions for a causal increase in GER events or maladaptive presenting symptoms, may include, but are not limited to: craniofacial anomalies, airway anomalies, esophageal atresia and tracheoesophageal fistula, congenital diaphragmatic hernia, hiatal hernia, abdominal wall defects, malrotation, pyloric stenosis, atresia and stricture, and duplication of the small intestine.

Neuromuscular physiology of GEJ and clinical implications

The pharynx, upper esophageal sphincter (UES), and proximal esophagus are composed of striated muscle. The UES is a high pressure zone generated by the cricopharyngeus, proximal cervical esophagus, and inferior pharyngeal constrictor, and is located between the pharynx and the esophagus.^[24] The UES is innervated by the vagus nerve via the branches of the pharyngo-esophageal, superior laryngeal, and recurrent laryngeal nerve, the glossopharyngeal nerve, and the sympathetic nerve fibers via the cranial nerve ganglia. The distal esophagus and the lower esophageal sphincter (LES) are composed of smooth muscle with an inner layer consisting of circular muscle cells and an outer layer consisting of longitudinal muscle cells with a myenteric plexus in between. The LES is an autonomous contractile apparatus that is tonically active and relaxes periodically to facilitate bolus transit. The integrity of the GEJ is augmented by the LES, diaphragmatic crural fibers, intra-abdominal esophagus, and sling fibers of the stomach.^[2]

The high pressure zone at the GEJ relaxes via inhibitory neural pathways to allow the passage of contents into the stomach during swallowing or into the proximal esophagus and higher structures, as in GER. As shown in the high resolution impedance manometry recording (Figure 1), the high-pressure zone at the LES abruptly drops and this reflex is the TLESR. This is the most common mechanism of GER.^[25–27] The LES relaxes during basal swallowing, pharyngeal stimulation, esophageal distention, abdominal strain, and GER.^[28] In general, the clearance of the refluxate occurs via peristaltic reflexes, and retrograde movement is abruptly halted through the contraction of the UES (Figure 1); this barrier function matures with postnatal development. The retrograde movement and clearance of refluxate is captured on the pH-impedance recording (Figure 2A and 2B).

Figure 1: GER event in a neonate recorded by high resolution manometry capturing the actual occurrence of GER event in a neonate.

The blue zone reflects 0 mmHg, whereas the purple color zone reflects 100 mmHg (designated on the left). The white horizontal lines represent impedance lines that detect bolus presence, directionality, and characteristic of the bolus (air, liquid, and mixed). As the liquid refluxate moves retrograde (drop in impedance), it drags air with it (shown as rise in impedance). Note that the most proximal extent of reflux stops at the upper esophageal sphincter (UES). At that point, there is an increase in UES contractility (protective UES contractile reflex) that is immediately followed by a relaxation of UES associated with swallowing and the peristaltic reflex. Also note that the UES barrier maintains the integrity after swallowing (UES relaxation). PX stands for pharynx. The peristaltic reflex is the mechanism for the clearance of the bolus. TLESR is the transient relaxation of lower esophageal sphincter wherein the LES resting pressure drops abruptly (relaxes), during which the ascent of the reflux material occurs. TLESR is the most common mechanism for GER event. The burdensome symptoms that result as a consequence of GER events constitute towards GERD diagnosis.

Figure 2: Example of pH-impedance recordings.

There are 6 impedance (Imp) channels, and 1 and 6 refers to the proximal channel and the distal channel, respectively. During this measurement, the pH sensor records the degree of acid exposure over a period of time. Figure 2A: During an acid-related GER event, the acid exposure at the distal channel is shown by a drop in pH at the acid sensor, and a fall in impedance is also associated with retrograde migration of acid reflux material. This is followed by clearance of the refluxate, which is mediated via anterograde peristalsis, as evidenced by the return of the impedance to baseline. Also noted is that that this infant presented with arching and irritability during the GER event. Figure 2B: During a non-acid GER event, the pH is not in the acidic range and liquid material is moving retrograde and is followed by anterograde clearance and peristalsis.

In summary, the high-pressure zone at the GEJ depends on the tone generated by the intrinsic LES and also on the magnitude of crural diaphragmatic contraction. Transit of material through the GEJ is most likely to occur during simultaneous relaxation of the LES and inhibition of the crural diaphragm and is also dependent on the pressure gradients across the stomach and esophageal lumen.

Physiology of GER in NICU Infants

TLESR (Figure 1) remains the most common mechanism of GER in neonates and infants.^{[26, 29, 30]} Regurgitation is very common in this age group; 40% to 60% of normal 0- to 4-month-old infants regurgitate some amount of their feedings. Basic mechanical considerations provide some explanation for the high frequency of regurgitation in infants.^{[1, 31–35]} Newborns sleep or spend most of their time in the supine position, a position that is protective against sudden infant death syndrome (SIDS). Supine and right lateral positions increase the risk for GER, whereas prone and left lateral positions are associated with less GER but an increased rate of SIDS.^{[1, 36–38]} Preterm infants are noted to have GER immediately following their feeding, which is most likely due to gastric distension rather than delayed gastric emptying. Studies have shown a normal gastric emptying pattern, in both infants with symptomatic GER and those without symptoms.^{[26, 39]} Preterm infants who receive tube feedings may have increased episodes of GER due to the incomplete closure of the LES secondary to the presence of a feeding tube.^[40] However, on the contrary, in symptomatic dysphagic neonates evaluated for suspected GERD using pH-impedance methods, we showed that tube-fed infants had fewer GER events than the exclusively oral-fed group.^[12] The length of the infant’s esophagus and LES are short and increase with maturation.^[41] A term infant’s esophagus may be only 8 to 10 cm; the intra-abdominal esophagus develops during the first 6 months of life after full term birth. Thus, refluxed material has a greater chance of extending to a more proximal extent in preterm infants who are at 6 months corrected age.

Manometric studies in both premature and term neonates have confirmed normal primary esophageal peristalsis. However, premature infants at 30 to 34 weeks’ gestational age have lower esophageal peristaltic velocity and amplitude than term infants,^{[42, 43]} and preterm infants as young as 33 weeks’ postmenstrual age have a reduced esophageal high-pressure zone, which increases with age.^[44–46] In response to mid-esophageal liquid stimulus provocations, premature infants have a longer delay to LES relaxation, but once the relaxation occurs, it is of a longer duration than that found in term infants.^[28] Premature infants have an elevated frequency of non-peristaltic esophageal contractions in the absence of a swallow, and this lack of coordination may lead to inadequate clearance of refluxed material.^{[44, 46]} As in adults, it appears that transient relaxations of the high-pressure zone are the primary mechanism of GER in neonates.^{[44, 46, 47]}

In summary, the most frequent mechanism for GER is TLESR, a common mechanism in neonates and adults. Factors unique to neonates include anatomic factors, position, feeding methods, immaturity, esophageal clearance mechanisms, and presence of inflammation or anomalies.

Pathophysiology of GERD

The esophageal and laryngeal reflexes that protect the esophagus and airway from damages due to GER appear to be present in healthy preterm infants. Esophageal distension from the reflux of gastric contents activates anterograde peristalsis reflex of the esophagus along with closure of the UES. This prevents the refluxate from reaching the pharynx. However, if the UES relaxes to allow the refluxate to reach the pharynx, the laryngeal chemo-sensitive receptors trigger the initiation of the laryngeal chemoreflex to prevent aspiration of gastric contents by glottis closure, which is always accompanied by a period of apnea (glottal closure reflex), although the duration of pause in breathing varies. In addition, primary peristalsis is triggered when the refluxate is present in the pharynx. Theoretically, GERD and retrograde aspiration could result from the failure of these mechanisms. Abnormalities of all of these reflexes are unlikely in physiologically healthy infants, which is why most healthy infants are asymptomatic despite having frequent episodes of GER.^[48–50]

Risk Factors for GERD

Several risk factors for GERD have been identified in infants, and the most common causes are listed in Figure 3. Apart from the congenital causes and physiological consequences of prematurity, it is important to analyze the causes of GER events that arise due to complications of prematurity. Bronchopulmonary dysplasia is a major complication of prematurity that affects 30% of extremely low birth weight infants.^[51] These infants have increased risk of GER events secondary to increased respiratory effort and transient increase in intra-abdominal pressure due to coughing, airflow obstruction, and crying. This causes the LES tone to decrease and in turn, contributes to TLESR.^{[1, 47, 52]} In addition, these infants are usually treated with respiratory stimulants such as caffeine, which may exacerbate GER events due to an increase in secretion of gastric acid and lowering of LES pressure.^{[53, 54]} Neuropathology such as intraventricular hemorrhage (IVH) noted in 30% to 40% of preterm infants,^{[55, 56]} and hypoxic-ischemic encephalopathy^[57] are some of the common risk factors likely to alter the causal or ameliorating mechanisms for reflux events and resulting troublesome symptoms. The incidence of GERD is about 15% to 75% in children with neurological impairment, and the prevalence of GERD in the presence of neuropathology is estimated to be 50%.^[58] Neuropathology contributes to GERD through dysregulation of aerodigestive reflexes. There are several other causes that may contribute to GERD, and these include metabolic disorders, body positioning, milk protein allergy, and infections, to name a few. These conditions must be investigated in preterm infants who present with signs concerning of GERD.

Figure 3: Risk factors for GERD in the NICU infant.

Owing to embryological and neuroanatomical considerations on the aerodigestive functions, the neonate in the NICU is in a much more vulnerable state than at any other periods of life. The risk factors are classified into 4 domains as stated in the text.

Approach to the Problem thought to be due to GERD in Infants in the NICU

In 2018, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) ^[1] published guidelines on the approach to children presenting with GER or GERD. However, further research is needed as these guidelines are not entirely clear about applicability to infants in the NICU. Infants in the NICU presenting with troublesome signs and symptoms suspected to be due to GERD should be evaluated thoroughly for any findings suggestive of disorders other than GERD. A wide range of clinical symptoms are attributed to GERD in NICU infants, however, the reliability of these symptoms as a manifestation of GERD is not clear. The evaluation of a neonate with a suspicion for GERD begins with a thorough focused history (Table 1) and physical examination while paying attention to the pharyngo-esophageal, cardio-respiratory and neurological systems, nutrition, feeding methods and growth characteristics. In particular, the evaluation should pay attention to signs and symptoms of aero-digestive problems, nonspecific behavioral signs including arching and irritability, and feeding problems that may be associated with GERD (Table 2). Additionally, it is imperative to exclude any symptoms and signs that masquerade as GERD. Relevant risk factors (Figure 3) must be addressed. Initial management should include paying attention to optimal nutrition and feeding methods, and continued breastfeeding. However, if there are no improvements, a trial of protein hydrolysate or amino-acid based formula or, in breastfed infants, elimination of cow’s milk in the maternal diet should be considered for 2–4 weeks. If there are no improvements despite these interventions, GI specialty testing using pH-Impedance with symptom correlation methods, and or manometry for pharyngo-esophageal functional abnormalities may be considered where available to ascertain the causal and ameliorating mechanisms. In such situations, or if a referral for specialty testing is not possible, 4–8 weeks’ trial of acid suppression using proton pump inhibitors may be considered with extreme caution, while weighing the benefits versus risks, and this can only be considered when infants are at and beyond full term age.^[10] There are no safe prokinetic agents for use in premature infants. The role of antacids remains uncertain in the premature infant population.

Table 1.

Screening history for GERD in NICU infants

Age at symptom onset Length of feeding periods Volume of each feeding Type of milk Methods of mixing the formula Additives to the feedings Attention to food allergens Time interval between feeding Pattern of regurgitation/spitting/vomiting Family medical history Environmental triggers-position Infant’s growth trajectory Prior pharmacological and dietary interventions Presence of warning signs such as, failure to thrive, back arching and irritability, airway signs, poor oral intake, coughing and choking spells

Table 2.

Signs and symptoms that may be associated with GERD in NICU infants

Symptoms
Gastrointestinal Regurgitation Spitting Emesis Abdominal distension	Cardiorespiratory Spells Bradycardia Tachycardia Apneas Periodic breathing Tachypnea Increased respiratory effort Desaturations
Aerodigestive Swallowing problems Feeding problems Sneezing Coughing Choking Wheezing Stridor	Somatosensorv Irritability Back arching Crying Grimace
Signs
Aerodiqestive Esophagitis Recurrent pneumonia with aspiration Recurrent otitis media	General Anemia Failure to thrive

Summary

Diagnosis and management considerations for GER and GERD in the NICU infant can be challenging. Neonatal presentations are not typical as that seen in older infants and children with GERD. Symptom-based diagnosis and empiric pharmacological therapies are not appropriate. Developmental pathologies and maturational deficits in the causal and ameliorating mechanisms of GER may be associated with GERD risks. Where relevant, structural anomalies and risk factors of GERD must be addressed. Emphasis must first be placed on optimal nutrition, feeding methods, growth, conservative management and reassurance. As symptoms are non-specific, other etiologies and diagnoses that masquerade as GERD must be considered. Minimizing the use and duration of acid-suppressive therapies is appropriate while weighing benefits and risks. Further research is critically needed in this high-risk population of NICU infants, with relevance to screening, diagnostic algorithms, objective criteria, and non-pharmacological and pharmacological approaches to manage objectively determined acid- or non-acid GERD or of their consequences.

Key Points:

1. Gastroesophageal reflux (GER) is defined as the retrograde passage of gastric contents into the esophagus and possibly the oral cavity, and when ‘troublesome symptoms’ persist due to these events, it is called gastroesophageal reflux disease (GERD)

2. Transient lower esophageal sphincter relaxation (TLESR) remains the most common mechanism of GER in neonates and infants

3. Neonatal presentations are distinct from clinical findings in older infants and children with GERD.

4. Symptom-based diagnosis and empiric pharmacological therapies are not appropriate in the management of neonates with GERD.