Meconium aspiration syndrome (MAS), also known as neonatal aspiration of meconium, is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stained amniotic fluid (MSAF) and have meconium within their lungs. Therefore, MAS has a wide range of severity depending on what conditions and complications develop after parturition. Furthermore, the pathophysiology of MAS is multifactorial and extremely complex which is why it is the leading cause of morbidity and mortality in term infants.
The word meconium is derived from the Greek word mēkōnion meaning juice from the opium poppy as the sedative effects it had on the foetus were observed by Aristotle.
Meconium is a sticky dark-green substance which contains gastrointestinal secretions, amniotic fluid, bile acids, bile, blood, mucus, cholesterol, pancreatic secretions, lanugo, vernix caseosa and cellular debris. Meconium accumulates in the foetal gastrointestinal tract throughout the third trimester of pregnancy and it is the first intestinal discharge released within the first 48 hours after birth. Notably, since meconium and the whole content of the gastrointestinal tract is located 'extracorporeally,' its constituents are hidden and normally not recognised by the foetal immune system.
For the meconium within the amniotic fluid to successfully cause MAS, it has to enter the respiratory system during the period when the fluid-filled lungs transition into an air-filled organ capable of gas exchange.
Causes The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result of hypoxia or infection. Other factors that promote the passage of meconium in utero include placental insufficiency, maternal hypertension, pre-eclampsia and maternal drug use of tobacco and cocaine. However, the exact mechanism for meconium passage into the amniotic fluid is not completely understood and it may be a combination of several factors.
Meconium passage as a result of foetal distress There may be an important association between foetal distress and hypoxia with MSAF. It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS. Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.
Foetal hypoxic stress during parturition can stimulate colonic activity, by enhancing intestinal peristalsis and relaxing the anal sphincter, which results in the passage of meconium. Then, because of intrauterine gasping or from the first few breaths after delivery, MAS may develop. Furthermore, aspiration of thick meconium leads to obstruction of airways resulting in a more severe hypoxia.
The association between foetal distress and meconium passage is not a definite cause-effect relationship as over of infants with MSAF are vigorous at birth and do not have any distress or hypoxia. Additionally, foetal distress occurs frequently without the passage of meconium as well.
Meconium passage as a result of foetal maturity Although meconium is present in the gastrointestinal tract early in development, MSAF rarely occurs before 34 weeks gestation.
Peristalsis of the foetal intestines is present as early as 8 weeks gestation and the anal sphincter develops at about 20–22 weeks. The early control mechanisms of the anal sphincter are not well understood, however there is evidence that the foetus does defecate routinely into the amniotic cavity even in the absence of distress. The presence of fetal intestinal enzymes have been found in the amniotic fluid of women who are as early as 14–22 weeks pregnant. Thus, suggesting there is free passage of the intestinal contents into the amniotic fluid.
Motilin is found in higher concentrations in post-term than pre-term foetal gastrointestinal tracts. Similarly, intestinal parasympathetic innervation and myelination also increases in later gestations. Therefore, the increased incidence of MAS in post-term pregnancies may reflect the maturation and development of the peristalsis within the gastrointestinal tract in the newborn.
Pathophysiology As MAS describes a spectrum of disorders of newborns born through MSAF, without any congenital respiratory disorders or other underlying pathology, there are numerous hypothesised mechanisms and causes for the onset of this syndrome. Long-term consequences may arise from these disorders, for example, infants that develop MAS have higher rates of developing neurodevelopmental defects due to poor respiration.
Airway obstruction In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreased lung compliance, acute hypoxemia, hypercapnia, atelectasis and respiratory acidosis. After 60 minutes of exposure, the meconium travels further down into the smaller airways. Once within the terminal bronchioles and alveoli, the meconium triggers inflammation, pulmonary edema, vasoconstriction, bronchoconstriction, collapse of airways and inactivation of surfactant.
Foetal hypoxia The lung areas which do not or only partially participate in ventilation, because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping and hyperinflation of certain lung areas and pneumothorax may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone and persistent pulmonary hypertension causing respiratory and circulatory failure.
Infection Microorganisms, most commonly Gram-negative rods, and endotoxins are found in samples of MSAF at a higher rate than in clear amniotic fluid, for example 46.9% of patients with MSAF also had endotoxins present. A microbial invasion of the amniotic cavity (MIAC) is more common in patients with MSAF and this could ultimately lead to an intra-amniotic inflammatory response. MIAC is associated with high concentrations of cytokines (such as IL-6), chemokines (such as IL-8 and monocyte chemoattractant protein-1), complement, phospholipase A2 and matrix-degrading enzymes. Therefore, these aforementioned mediators within the amniotic fluid during MIAC and intra-amniotic infection could, when aspirated in utero, induce lung inflammation within the foetus.
Pulmonary inflammation Meconium has a complex chemical composition, so it is difficult to identify a single agent responsible for the several diseases that arise. As meconium is stored inside the intestines, and is partly unexposed to the immune system, when it becomes aspirated the innate immune system recognises as a foreign and dangerous substance. The immune system, which is present at birth, responds within minutes with a low specificity and no memory in order to try to eliminate microbes. Meconium perhaps leads to chemical pneumonitis as it is a potent activator of inflammatory mediators which include cytokines, complement, prostaglandins and reactive oxygen species.
Meconium is a source of pro-inflammatory cytokines, including tumour necrosis factor (TNF) and interleukins (IL-1, IL-6, IL-8), and mediators produced by neutrophils, macrophages and epithelial cells that may injure the lung tissue directly or indirectly. For example, proteolytic enzymes are released from neutrophilic granules and these may damage the lung membrane and surfactant proteins. Additionally, activated leukocytes and cytokines generate reactive nitrogen and oxygen species which have cytotoxic effects. Oxidative stress results in vasoconstriction, bronchoconstriction, platelet aggregation and accelerated cellular apoptosis. Recently, it has been hypothesised that meconium is a potent activator of toll-like receptor (TLRs) and complement, key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.
Meconium contains high amounts of phospholipase A2 (PLA2), a potent proinflammatory enzyme, which may directly (or through the stimulation of arachidonic acid) lead to surfactant dysfunction, lung epithelium destruction, tissue necrosis and an increase in apoptosis. Meconium can also activate the coagulation cascade, production of platelet-activating factor (PAF) and other vasoactive substances that may lead to destruction of capillary endothelium and basement membranes. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the interstitium and alveolar spaces.
Surfactant inactivation Surfactant is synthesised by type II alveolar cells and is made of a complex of phospholipids, proteins and saccharides. It functions to lower surface tension (to allow for lung expansion during inspiration), stabilise alveoli at the end of expiration (to prevent alveolar collapse) and prevents lung oedema. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles and senescent cells away from the alveolar structure.
The extent of surfactant inhibition depends on both the concentration of surfactant and meconium. If the surfactant concentration is low, even very highly diluted meconium can inhibit surfactant function whereas, in high surfactant concentrations, the effects of meconium are limited. Meconium may impact surfactant mechanisms by preventing surfactant from spreading over the alveolar surface, decreasing the concentration of surfactant proteins (SP-A and SP-B), and by changing the viscosity and structure of surfactant. Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from stroma and the shedding of epithelial cells into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.
Persistent Pulmonary Hypertension Persistent pulmonary hypertension (PPHN) is the failure of the foetal circulation to adapt to extra-uterine conditions after birth. PPHN is associated with various respiratory diseases, including MAS (as 15-20% of infants with MAS develop PPHN), but also pneumonia and sepsis. A combination of hypoxia, pulmonary vasoconstriction and ventilation/perfusion mismatch can trigger PPHN, depending on the concentration of meconium within the respiratory tract. PPHN in newborns is the leading cause of death in MAS.
Apoptosis Apoptosis is an important mechanism in the clearance of injured cells and in tissue repair, however too much apoptosis may cause harm, such as acute lung injury. Meconium induces apoptosis and DNA cleavage of lung airway epithelial cells, this is detected by the presence of fragmented DNA within the airways and in alveolar epithelial nuclei. Meconium induces an inflammatory reaction within the lungs as there is an increase of autophagocytic cells and levels of caspase 3 after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%. Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.
Diagnosis
Respiratory distress in an infant born through the darkly coloured MSAF as well as meconium obstructing the airways is usually sufficient to diagnose MAS. Additionally, newborns with MAS can have other types of respiratory distress such as tachypnea and hypercapnia. Sometimes it is hard to diagnose MAS as it can be confused with other diseases that also cause respiratory distress, such as pneumonia. Additionally, X-rays and lung ultrasounds can be quick, easy and cheap imaging techniques to diagnose lung diseases like MAS.
Prevention In general, the incidence of MAS has been significantly reduced over the past two decades as the number of post-term deliveries has minimized.
Prevention during pregnancy