Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis

INTRODUCTION — Meconium aspiration syndrome (MAS) is defined as respiratory distress in newborn infants born through meconium-stained amniotic fluid (MSAF) whose symptoms cannot be otherwise explained [1]. MAS can present with varying degrees of severity from mild respiratory distress to life-threatening respiratory failure.

The pathophysiology, clinical features, and diagnosis of MAS will be discussed here. The management and complications of MAS are discussed elsewhere. (See "Meconium aspiration syndrome: Management and outcome".)

EPIDEMIOLOGY — It is challenging to determine the incidence of MAS as changes in obstetric care during the 1990s have reduced the incidence of MAS [2,3].

In the United States, the reported incidence of MAS varies from 0.1 to 0.4 percent of births [4,5]. In a retrospective study, the incidence of symptomatic MAS was 0.25 percent and asymptomatic MAS was 0.1 percent based on newborn discharge data in 2012 from the Kids Inpatient Database (KID) [4].

MAS occurs in approximately 2 to 10 percent of infants born through meconium-stained amniotic fluid (MSAF) [5,6]. The rates of MSAF vary depending on gestational age (GA). In one large study of approximately 500,000 singleton births, the incidence of MSAF in preterm, term, and postterm infants was 5.1, 16.5, and 27.1 percent, respectively [7]. The reported incidence of MSAF in term infants was similar from a low-resource country [8].

Reported risk factors for MSAF and MAS include:

●Postterm infants (GA >41 weeks) especially those who have intrauterine growth restriction [7,9]

●Vaginal breech delivery [7]

●Caesarean delivery [10]

●Nonreassuring fetal heart rate based on fetal heart monitoring [10] (see "Intrapartum fetal heart rate monitoring: Overview")

●Low Apgar scores and need for resuscitation at the time of delivery [10]

●Black and South Asian ethnicity [7]

●Maternal fever and intraamniotic inflammation and infection [7,10]

PATHOPHYSIOLOGY — The pathophysiology of MAS involves intrauterine passage of meconium into the amniotic fluid, which the infant aspirates. This results in pulmonary disease with associated hypoxemia and respiratory acidosis (algorithm 1). Persistent pulmonary hypertension of the newborn (PPHN) is a complication of severe MAS and contributes to hypoxemia [11]. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Approximately 20 to 33 percent of infants born through meconium-stained amniotic fluid (MSAF) have respiratory and neurologic depression at birth [12-14], suggesting the presence of pathologic intrauterine processes, primarily chronic asphyxia and infection. This intrauterine stress leads to the passage and aspiration of meconium by the fetus.

Meconium composition and passage — Meconium is a sterile, thick, black-green, odorless material first demonstrable in the fetal intestine during the third month of gestation. Meconium results from the accumulation of debris, including desquamated cells from the intestine and skin, gastrointestinal mucin, lanugo hair, fatty material from the vernix caseosa, amniotic fluid, and intestinal secretions. It contains blood group-specific glycoproteins and a small amount of lipid and protein that decreases during gestation [15,16]. The black-green color results from bile pigments.

Fetal defecation with meconium normally begins early in the first trimester, slows after 16 weeks gestation and becomes infrequent by 20 weeks, concurrent with innervation of the anal sphincter [17,18]. From approximately 20 to 34 weeks, fetal passage of meconium remains infrequent [19]. However, fetal stress may result in meconium passage, due to increased peristalsis and relaxation of the anal sphincter from increased vagal outflow associated with umbilical cord compression or increased sympathetic inflow during hypoxia [20-23].

Meconium aspiration — Meconium in amniotic fluid can be aspirated during fetal gasping or in the initial breaths after delivery. Normally, fetal breathing activity results in movement of lung fluid out of the trachea [24]. However, as shown in animals, prolonged hypoxia stimulates fetal breathing and gasping that can lead to inhalation of amniotic fluid [24-28]. Pathologic evidence suggests that this process also occurs in humans. Meconium has been found in the lungs of infants who were stillborn [29] or who died soon after birth without a history of aspiration at delivery [30,31].

Meconium that remains in the hypopharynx or trachea after delivery can be aspirated during the initial breaths. This is more likely to occur in a depressed infant. Meconium, when aspirated into the fetal or neonatal lung, causes pulmonary injury with airway obstruction and inflammation and hypoxemias [32-34].

Pulmonary disease — It is likely that the most severe pulmonary manifestations of MAS are a consequence of underlying intrauterine pathologic processes including the following [35,36]:

●Airway obstruction – Airway obstruction by the meconium plug can be complete or partial. Complete obstruction leads to distal atelectasis. Partial airway obstruction occurs when particulate meconium partly occludes the airway. Because the airway diameter is larger in inspiration, gas can enter around the partial obstruction. However, as the airway narrows during exhalation, the meconium plug occludes the airway completely, trapping the gas distally. This process is known as a ball-valve effect and can lead to overdistention of the lung and alveolar rupture, with resulting pneumothorax or other air leak complications [37,38]. (See "Pulmonary air leak in the newborn".)

●Inflammation – Components of meconium cause inflammation of the fetal and postnatal lung [6,35]. Direct injury and inflammation result in an exudative and inflammatory pneumonitis with epithelial disruption, proteinaceous exudation with alveolar collapse, and cellular necrosis [38-42]. Studies in animal models have suggested that MAS is associated with deleterious effects on surfactant activity and synthesis [43-45].

●Infection – Meconium-stained amniotic fluid (MSAF) is a marker for bacterial infection of the amniotic cavity and should alert the clinician to the potential for increased neonatal morbidity [46-48]. Although meconium is sterile, the mucopolysaccharide component provides an excellent growth medium for micro-organisms, especially Escherichia coli [49]. Meconium also may inhibit phagocytosis by polymorphonuclear cells and their oxidative burst [50]. (See "Neonatal pneumonia".)

Hypoxemia — Hypoxemia results from several causes:

●Decreased alveolar ventilation related to lung injury.

●Ventilation-perfusion imbalance with continued perfusion of poorly ventilated lung units, which is often due to associated persistent pulmonary hypertension (PPHN) with right-to-left shunting caused by increased pulmonary vascular resistance. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

CLINICAL MANIFESTATIONS

General findings — In addition to the pulmonary manifestations of MAS, the following features are observed:

●Evidence of meconium-stained amniotic fluid (MSAF) – A history of MSAF or physical evidence of meconium staining on examination of the infant. The vernix, umbilical cord, and nails may be meconium-stained, depending upon how long the infant has been exposed in utero [51]. In general, nails will become stained after six hours and vernix after 12 to 14 hours of exposure.

●Perinatal asphyxia – Perinatal asphyxia occurs in 20 to 33 percent of infants born through MSAF [12-14,52]. These infants have neurologic and/or respiratory depression at birth typically due to hypoxia or shock [52]. (See "Neonatal shock: Etiology, clinical manifestations, and evaluation" and "Perinatal asphyxia in term and late preterm infants" and "Perinatal asphyxia in term and late preterm infants", section on 'Respiratory failure'.)

●Fetal growth restriction and postmaturity – Affected infants are frequently small for gestational age and born postterm (picture 1) [9]. Characteristic findings of postterm infants include peeling skin, long fingernails, and decreased vernix. (See "Postterm infant", section on 'Fetal growth restriction'.)

Pulmonary findings — Pulmonary manifestations usually are seen immediately after birth. However, some patients are asymptomatic at birth and develop worsening signs of pulmonary decompensation as the meconium moves from the large airways into the lower tracheobronchial tree.

●Respiratory distress – Infants with MAS typically have respiratory distress with marked tachypnea and cyanosis immediately after birth [53]. Respiratory distress is indicated with the increased respiratory rate and use of accessory respiratory muscles of respiration demonstrated by intercostal and subxiphoid retractions and abdominal (paradoxical) breathing, often with grunting and nasal flaring.

●Physical findings – Affected infants typically have a barrel-shaped chest with an increased anterior-posterior diameter caused by overinflation. Auscultation reveals rales and rhonchi.

●Pulmonary air leak – In patients with severe MAS, pneumothorax and pneumomediastinum are common findings and other less common air leak syndromes can occur. (See "Pulmonary air leak in the newborn", section on 'Risk factors'.)

●Respiratory failure – Patients with severe disease are at risk for respiratory failure requiring mechanical ventilation. Severe respiratory disease is often associated with persistent pulmonary hypertension of the newborn (PPHN). Infants with pulmonary hypertension and right-to-left shunting may have a gradient in oxygenation between pre- and postductal arterial blood samples. In addition, echocardiography may demonstrate right-to-left shunting. (See "Meconium aspiration syndrome: Management and outcome", section on 'Respiratory support' and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

EVALUATION AND INITIAL MANAGEMENT — Neonates with respiratory distress require prompt evaluation to determine the etiology and initiate appropriate therapy for the underlying disorder, including MAS (see 'Differential diagnosis' below). In the neonate with suspected MAS, the evaluation includes:

●Chest radiograph – Chest radiography can distinguish MAS from other etiologies of neonatal respiratory distress such as pneumonia, pneumothorax, diaphragmatic hernia, and cyanotic heart disease. In neonates with MAS, there are progressive changes over the course of the disease(image 1). The initial chest film may show streaky, linear densities similar in appearance to transient tachypnea of the newborn. As the disease progresses, the lungs typically appear hyperinflated with flattening of the diaphragms [54-56]. Diffuse patchy densities may alternate with areas of expansion. In infants with severe disease who require high concentrations of supplemental oxygen and mechanical ventilation, the lungs may develop an appearance of homogeneous density similar to respiratory distress syndrome. Radiographic changes resolve over the course of 7 to 10 days but sometimes persist for several weeks. Air leak occurs in 10 to 30 percent of infants with MAS [13,57]. (See "Transient tachypnea of the newborn" and "Pulmonary air leak in the newborn", section on 'Risk factors'.)

●Echocardiography – In neonates with severe respiratory distress, echocardiography is used to distinguish between patients with critical congenital structural heart disease and those with persistent pulmonary hypertension (PPHN), which may be associated with MAS. In PPHN, echocardiography demonstrates normal structural anatomy with evidence of pulmonary hypertension (eg, flattened or displaced ventricular septum) and right-to-left shunting. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis", section on 'Diagnosis' and "Overview of neonatal respiratory distress and disorders of transition", section on 'Echocardiography'.)

●Cultures and empiric antibiotics – Because it is difficult to differentiate MAS from pneumonia, blood cultures and, if possible, tracheal aspirate cultures, are obtained. Empiric antibiotic therapy is started while awaiting culture results. (See "Neonatal pneumonia", section on 'Diagnosis' and "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

●Assessment of oxygenation – Pulse oximetry is initially used to determine adequacy of oxygenation. For infants with a need for supplemental oxygen, an arterial blood gas measurement is obtained and typically demonstrates hypoxemia and hypercarbia. However, these findings are nonspecific and are not used to diagnosis MAS but are used to assess the respiratory status of the infant and whether additional respiratory support, including mechanical ventilation, is needed. Pulse oximetry (pre- and postductal placement) is used to continue to monitor the infant's oxygenation. (See "Meconium aspiration syndrome: Management and outcome", section on 'Respiratory support' and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Pulse oximetry'.)

DIAGNOSIS — The diagnosis of MAS is made in a neonate who presents with respiratory distress at birth or shortly after birth, whose symptoms cannot be otherwise explained, with one or more of the following:

●Evidence of meconium-stained amniotic fluid (MSAF) on the infant. (See 'Clinical manifestations' above.)

●Characteristic radiographic features of MAS with initial streaky, linear densities that progress to hyperinflated lung with flattening of the diaphragms and diffuse patchy densities alternating with areas of expansion. (See 'Evaluation and initial management' above.)

●For the infant that is intubated, the presence of meconium in the trachea. (See "Meconium aspiration syndrome: Management and outcome" and "Meconium aspiration syndrome: Management and outcome", section on 'Neonatal care'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of MAS includes other causes of neonatal respiratory distress [52]. MAS is distinguished from these based on the history, clinical course, and radiographic findings. (See "Overview of neonatal respiratory distress and disorders of transition".)

●Transient tachypnea of the newborn (TTN) is a frequent cause of respiratory distress in late preterm infants (34 to 37 weeks gestation), whereas MAS is most frequently seen in postterm infants (>41 weeks gestation). In addition, patients with TTN improve quickly with resolution of symptoms within 12 to 24 hours after delivery in contrast to those with MAS. (See "Transient tachypnea of the newborn".)

●Pneumonia may be difficult to differentiate from MAS. As a result, infants with presumed MAS are treated with antibiotics while awaiting the results of cultures. (See "Neonatal pneumonia" and "Meconium aspiration syndrome: Management and outcome" and "Meconium aspiration syndrome: Management and outcome", section on 'Antibiotics'.)

●Congenital cyanotic heart disease is differentiated from MAS by physical examination, chest radiography, and echocardiography. (See "Diagnosis and initial management of cyanotic heart disease in the newborn".)

●Respiratory distress syndrome (RDS) generally occurs in very preterm infants (gestational age [GA] <32 weeks), whereas MAS usually occurs in postterm infants. (See "Respiratory distress syndrome (RDS) in the newborn: Clinical features and diagnosis", section on 'Clinical manifestations'.)

●Persistent pulmonary hypertension of the newborn (PPHN) is an associated complication of MAS. However, PPHN is also associated with other conditions, including perinatal asphyxia, RDS, congenital diaphragmatic hernia, and pneumonia. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

●Congenital diaphragmatic hernia is differentiated from MAS by physical examination (barrel-shaped chest, a scaphoid-appearing abdomen, and absence of breath sounds on the ipsilateral side) and chest radiography showing herniation of abdominal contents into the hemithorax. (See "Congenital diaphragmatic hernia in the neonate", section on 'Diagnosis'.)

●Pulmonary air leak such as pneumothorax is differentiated from MAS by history (absence of meconium-stained amniotic fluid) and chest radiography. (See "Pulmonary air leak in the newborn", section on 'Risk factors'.)

SUMMARY AND RECOMMENDATIONS

●Definition – Meconium aspiration syndrome (MAS) is defined as respiratory distress in an infant born through meconium-stained amniotic fluid (MSAF) whose symptoms cannot be otherwise explained. (See 'Introduction' above.)

●Incidence and risk factors – With changes in obstetric care, the incidence of MAS has declined to approximately 0.1 to 0.4 percent of live births in developed countries. Risk factors for MAS include postterm birth and being small for gestational age. (See 'Epidemiology' above.)

●Pathophysiology – The pathophysiology of MAS involves intrauterine passage of meconium, aspiration, and pulmonary disease resulting in hypoxemia, acidosis, and potentially pulmonary hypertension (algorithm 1). Pulmonary disease is a result of aspirated meconium interfering with normal lung function due to airway obstruction, chemical irritation and inflammation, and deleterious effects on surfactant metabolism (ie, inactivation and reduced production). (See 'Pathophysiology' above.)

●Clinical features of affected infants – Infants with MAS typically have a history of MSAF or evidence of meconium staining on physical examination. They are frequently small for gestational age and/or postterm. Many infants with MAS also have neurologic or respiratory depression due to perinatal asphyxia. (See 'Clinical manifestations' above.)

●Presenting pulmonary features – MAS can present with varying degrees of severity from mild respiratory distress to life-threatening disease with respiratory failure. Patients present with marked tachypnea, cyanosis, intercostal and subxiphoid retractions, abdominal breathing, grunting, and nasal flaring. The chest appears barrel-shaped (increased anterior-posterior diameter) due to overinflation. In patients with severe MAS, complications include air leaks (eg, pneumothorax) and persistent pulmonary hypertension of the newborn (PPHN). (See 'Pulmonary disease' above and "Pulmonary air leak in the newborn" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

●Evaluation – The initial evaluation and management of suspected MAS includes chest radiography, blood cultures and, if possible, tracheal aspirate cultures, and the administration of empiric antibiotics. In patients with more severe disease, echocardiography may be indicated to exclude structural heart disease and detect persistent PPHN, an associated complication of MAS. Pulse oximetry and arterial blood gas are obtained to assess the respiratory status and determine if respiratory support is needed. (See 'Evaluation and initial management' above.)

●Diagnosis – The diagnosis of MAS is based on the clinical findings of MSAF or meconium-stained infant, respiratory distress, and characteristic radiographic features. In patients who require intubation, the diagnosis is established by the presence of meconium in the trachea. (See 'Diagnosis' above.)

●Differential diagnosis – MAS is differentiated from other causes of neonatal respiratory distress (eg, transient tachypnea of the newborn, neonatal pneumonia, respiratory distress syndrome, and congenital cyanotic heart disease) based upon the patient's history, physical examination, clinical course, and radiographic findings. (See 'Differential diagnosis' above.)