| Meconium aspiration syndrome | |
|---|---|
| Other names | Neonatal aspiration of meconium |
 | |
| X-ray showing the extent of lung epithelial damage in response to meconium seen in neonates with meconium aspiration syndrome. | |
| Specialty | Neonatology |
Meconium aspiration syndrome (MAS), also known asneonatal aspiration of meconium, is a medical condition affecting newborn infants. It describes the spectrum of disorders and pathophysiology of newborns born in meconium-stainedamniotic fluid (MSAF) and havemeconium 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.[1][2]
The wordmeconium is derived from the Greek wordmēkōnion meaningjuice from the opium poppy as the sedative effects it had on the foetus were observed byAristotle.[3]
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.[1] Meconium accumulates in the foetalgastrointestinal tract throughout the third trimester of pregnancy and it is the first intestinal discharge released within the first 48 hours after birth.[4] 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.[5]
For the meconium within the amniotic fluid to successfully cause MAS, it has to enter therespiratory system during the period when the fluid-filled lungs transition into an air-filled organ capable ofgas exchange.[1]
The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result ofhypoxia or infection.[3] Other factors that promote the passage of meconiumin utero include placental insufficiency, maternal hypertension,pre-eclampsia and maternal drug use oftobacco andcocaine.[6] However, the exact mechanism for meconium passage into the amniotic fluid is not completely understood and it may be a combination of several factors.
There may be an important association between foetal distress andhypoxia with MSAF.[2] It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS.[6] Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.[3]
Foetal hypoxic stress during parturition can stimulate colonic activity, by enhancing intestinalperistalsis 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 severehypoxia.[6][7]
The association between foetal distress and meconium passage is not a definite cause-effect relationship as over3⁄4 of infants with MSAF are vigorous at birth and do not have any distress or hypoxia.[2] Additionally, foetal distress occurs frequently without the passage of meconium as well.[3]
Although meconium is present in thegastrointestinal tract early in development, MSAF rarely occurs before 34 weeksgestation.[3]
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 theamniotic 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.[8]
Motilin is found in higher concentrations in post-term than pre-term foetal gastrointestinal tracts. Similarly, intestinal parasympathetic innervation andmyelination 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.[3]
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.[9]
In the first 15 minutes of meconium aspiration, there is obstruction of larger airways which causes increased lung resistance, decreasedlung compliance, acutehypoxemia,hypercapnia,atelectasis andrespiratory 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 ofsurfactant.[10][11]
The lung areas which do not or only partially participate inventilation, because of obstruction and/or destruction, will become hypoxic and an inflammatory response may consequently occur. Partial obstruction will lead to air trapping andhyperinflation of certain lung areas andpneumothorax may follow. Chronic hypoxia will lead to an increase in pulmonary vascular smooth muscle tone andpersistent pulmonary hypertension causing respiratory and circulatory failure.[1]
Microorganisms, most commonlyGram-negative rods, andendotoxins 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 ofcytokines (such asIL-6),chemokines (such asIL-8 andmonocyte 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 aspiratedinutero, induce lung inflammation within the foetus.[12]
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 theintestines, and is partly unexposed to theimmune system, when it becomes aspirated theinnate 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 eliminatemicrobes. Meconium perhaps leads tochemical pneumonitis as it is a potent activator of inflammatory mediators which includecytokines,complement,prostaglandins andreactive oxygen species.[5]
Meconium is a source of pro-inflammatorycytokines, includingtumour necrosis factor (TNF) andinterleukins (IL-1,IL-6,IL-8), and mediators produced byneutrophils,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, activatedleukocytes and cytokines generatereactive nitrogen andoxygen species which havecytotoxic effects.Oxidative stress results invasoconstriction,bronchoconstriction,platelet aggregation and accelerated cellularapoptosis.[11] Recently, it has been hypothesised that meconium is a potent activator oftoll-like receptor (TLRs) andcomplement, key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.[1][5]
Meconium contains high amounts ofphospholipase A2 (PLA2), a potent proinflammatory enzyme, which may directly (or through the stimulation ofarachidonic acid) lead to surfactant dysfunction, lung epithelium destruction, tissuenecrosis and an increase inapoptosis.[1][11] Meconium can also activate thecoagulation cascade, production ofplatelet-activating factor (PAF) and other vasoactive substances that may lead to destruction of capillaryendothelium andbasement membranes. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into theinterstitium andalveolar spaces.[11]
Surfactant is synthesised bytype II alveolar cells and is made of a complex ofphospholipids, proteins andsaccharides. It functions to lowersurface tension (to allow for lung expansion duringinspiration), stabilisealveoli at the end ofexpiration (to prevent alveolar collapse) and prevents lungoedema. Surfactant also contributes to lung protection and defence as it is also an anti-inflammatory agent. Surfactant enhances the removal of inhaled particles andsenescent cells away from the alveolar structure.[13]
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 andSP-B), and by changing the viscosity and structure of surfactant.[10] Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium fromstroma and the shedding ofepithelial cells into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.[1]
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 alsopneumonia andsepsis. A combination ofhypoxia, pulmonaryvasoconstriction andventilation/perfusion mismatch can trigger PPHN, depending on the concentration of meconium within therespiratory tract.[14][7] PPHN in newborns is the leading cause of death in MAS.[5]
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 andDNA 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 ofautophagocytic cells and levels ofcaspase 3 after exposure. After 8 hours of meconium exposure, in rabbit foetuses, the total amount of apoptotic cells is 54%.[15] Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.[1]
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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 astachypnea andhypercapnia. Sometimes it is hard to diagnose MAS as it can be confused with other diseases that also cause respiratory distress, such aspneumonia. Additionally, X-rays and lung ultrasounds can be quick, easy and cheap imaging techniques to diagnose lung diseases like MAS.[16]
In general, the incidence of MAS has been significantly reduced over the past two decades as the number of post-term deliveries has minimized.[17]
Prevention during pregnancy may include amnioinfusion and antibiotics but the effectiveness of these treatments are questionable.[2]
As previously mentioned,oropharyngeal andnasopharyngeal suctioning is not an ideal preventative treatment for both vigorous and depressed (not breathing) infants.[2]
Most infants born through MSAF do not require any treatments (other than routine postnatal care) as they show no signs of respiratory distress, as only approximately 5% of infants born through MSAF develop MAS.[1] However, infants which do develop MAS need to be admitted to a neonatal unit where they will be closely observed and provided any treatments needed. Observations include monitoringheart rate,respiratory rate,oxygen saturation andblood glucose (to detect worseningrespiratory acidosis or the development ofhypoglycemia).[18] In general, treatment of MAS is more supportive in nature.
To clear the airways of meconium,tracheal suctioning can be used however, the efficacy of this method is in question and it can cause harm.[19]
In cases of MAS, there is a need for supplemental oxygen for at least 12 hours in order to maintain oxygen saturation of haemoglobin at 92% or more. The severity of respiratory distress can vary significantly between newborns with MAS, as some require minimal or no supplemental oxygen requirement and, in severe cases, mechanical ventilation may be needed.[20][2] The desired oxygen saturation is between 90 and 95% andPaO2 may be as high as 90mmHg.[17] In cases where there is thick meconium deep within the lungs,mechanical ventilation may be required. In extreme cases,extracorporeal membrane oxygenation (ECMO) may be utilised in infants who fail to respond to ventilation therapy.[2] While on ECMO, the body can have time to absorb the meconium and for all the associated disorders to resolve. There has been an excellent response to this treatment, as the survival rate of MAS while on ECMO is more than 94%.[21]
Ventilation of infants with MAS can be challenging and, as MAS can affect each individual differently, ventilation administration may need to be customised. Some newborns with MAS can have homogenous lung changes and others can have inconsistent and patchy changes to their lungs. It is common for sedation and muscle relaxants to be used to optimise ventilation and minimise the risk ofpneumothorax associated with dyssynchronous breathing.[18]
Inhalednitric oxide (iNO) acts onvascular smooth muscle causing selective pulmonaryvasodilation. This is ideal in the treatment ofPPHN as it causes vasodilation within ventilated areas of the lung thus, decreasing the ventilation-perfusion mismatch and thereby, improves oxygenation. Treatment utilising iNO decreases the need forECMO and mortality in newborns with hypoxic respiratory failure and PPHN as a result of MAS. However, approximately 30-50% of infants with PPHN do not respond to iNO therapy.[17]
As inflammation is such a huge issue in MAS, treatment has consisted of anti-inflammatories.
Glucocorticoids have a strong anti-inflammatory activity and works to reduce the migration and activation ofneutrophils,eosinophils,mononuclear cells, and other cells. They reduce the migration of neutrophils into the lungs ergo, decreasing their adherence to theendothelium. Thus, there is a reduction in the action of mediators released from these cells and therefore, a reduced inflammatory response.[22][11]
Glucocorticoids also possess a genomic mechanism of action in which, once bound to aglucocorticoid receptor, the activated complex moves into thenucleus and inhibitstranscription ofmRNA. Ultimately, effecting whether various proteins get produced or not. Inhibiting the transcription of nuclear factor (NF-κB) and protein activator (AP-1) attenuates the expression of pro-inflammatory cytokines (IL-1,IL-6,IL-8 andTNF etc.), enzymes (PLA2,COX-2,iNOs etc.) and other biologically active substances.[23][22][11] The anti-inflammatory effect of glucocorticoids is also demonstrated by enhancing the activity of lipocortines which inhibit the activity of PLA2 and therefore, decrease the production ofarachidonic acid and mediators oflipoxygenase andcyclooxygenase pathways.[22]
Anti-inflammatories need to be administered as quickly as possible as the effect of these drugs can diminish even just an hour after meconium aspiration. For example, early administration ofdexamethasone significantly enhancedgas exchange, reduced ventilatory pressures, decreased the number ofneutrophils in the bronchoalveolar area, reducedoedema formation and oxidative lung injury.[11] However, glucocorticoids may increase the risk of infection and this risk increases with the dose and duration of glucocorticoid treatment. Other issues can arise, such as aggravation ofdiabetes mellitus,osteoporosis, skinatrophy andgrowth retardation in children.[23]
Phosphodiesterases (PDE) degradescAMP andcGMP and, within therespiratory system of a newborn with MAS, various isoforms of PDE may be involved due to their pro-inflammatory andsmooth muscle contractile activity. Therefore, non-selective and selective inhibitors of PDE could potentially be used in MAS therapy. However, the use of PDE inhibitors can causecardiovascular side effects. Non-selective PDE inhibitors, such asmethylxanthines, increase concentrations of cAMP and cGMP in the cells leading tobronchodilation andvasodilation. Additionally, methylxanthines decreases the concentrations of calcium,acetylcholine andmonoamines, this controls the release of various mediators of inflammation andbronchoconstriction, includingprostaglandins. Selective PDE inhibitors target one subtype ofphosphodiesterase and in MAS the activities ofPDE-3,PDE-4,PDE-5 and PDE-7 may become enhanced.[11] For example,Milrinone (a selective PDE3 inhibitor) improved oxygenation and survival of neonates with MAS.[24]
Arachidonic acid is metabolised, viacyclooxygenase (COX) andlipoxygenase, to various substances includingprostaglandins andleukotrienes, which exhibit potent pro-inflammatory andvasoactive effects. By inhibiting COX, and more specificallyCOX-2, (either through selective or non-selective drugs) inflammation and oedema can be reduced. However, COX inhibitors may inducepeptic ulcers and causehyperkalemia andhypernatremia. Additionally, COX inhibitors have not shown any great response in the treatment of MAS.[11]
Meconium is typically sterile however, it can contain various cultures of bacteria so appropriate antibiotics may need to be prescribed.[17]
Lung lavage with dilutedsurfactant has potential benefits depending on how early it is given in newborns with MAS. This treatment shows promise as it has an effect on air leaks,pneumothorax, the need forECMO and death. Early intervention and using it on newborns with mild MAS is more effective. However, there are risks as a large volume of fluid instillation to the lung of a newborn can be dangerous (particularly in cases of severe MAS withpulmonary hypertension) as it can exacerbatehypoxia and lead to mortality.[25]
Originally, it was believed that MAS developed as a result of the meconium being a physical blockage of the airways. Thus, to prevent newborns, who were born through MSAF, from developing MAS, suctioning of theoropharyngeal andnasopharyngeal area before delivery of the shoulders followed bytracheal aspiration was utilised for 20 years. This treatment was believed to be effective as it was reported to significantly decrease the incidence of MAS compared to those newborns born through MSAF who were not treated.[26] This claim was later disproved and future studies concluded that oropharyngeal and nasopharyngeal suctioning, before delivery of the shoulders in infants born through MSAF, does not prevent MAS or its complications.[2] In fact, it can cause more issues and damage (e.g.mucosal damage), thus it is not a recommended preventative treatment.[19] Suctioning may not significantly reduce the incidence of MAS as meconium passage and aspiration may occurin-utero. Thereby making the suctioning redundant and useless as the meconium may already be deep within the lungs at the time of birth.[17]
Historically,amnioinfusion has been used when MSAF was present, which involves a transcervical infusion of fluid during labour. The idea was to dilute the thick meconium to reduce its potential pathophysiology and reduce cases of MAS, since MAS is more prevalent in cases of thick meconium.[2] However, there are associated risks, such asumbilical cord prolapse and prolongation of labour. The UK National Institute of Health and Clinical Excellence (NICE) Guidelines recommend against the use of amnioinfusion in women with MSAF.[18]
1 in every 7 pregnancies have MSAF and, of these cases, approximately 5% of these infants develop MAS.[1] MSAF is observed 23-52% in pregnancies at 42 weeks. Therefore, the frequency of MAS increases as the length ofgestation increases, such that the prevalence is greatest in post-term pregnancies. Conversely,preterm births are not frequently associated with MSAF (only approximately 5% in total contain MSAF). The rate of MAS declines in populations where labour is induced in women that have pregnancies exceeding 41 weeks.[4] There are many suspected pre-disposing factors that are thought to increase the risk of MAS. For example, the risk of MSAF is higher in African American, African and Pacific Islander mothers, compared to mothers from other ethnic groups.[27][6]
Research is being focused on developing both a successful method for preventing MAS as well as an effective treatment. For example, investigations are being made in the efficiency ofanti-inflammatory agents, surfactant replacement therapy andantibiotic therapy. More research needs to be conducted on the pharmacological properties of, for example,glucocorticoids, including dosages, administration, timing or any drug interactions.[22] Additionally, there is still research being conducted on whether intubation and suctioning of meconium in newborns with MAS is beneficial, harmful or is simply a redundant and outdated treatment. In general, there is still no generally accepted therapeutic protocol and effective treatment plan for MAS.
