Editing Meconium aspiration syndrome

{{short description|Medical condition affecting newborn infants}}
{{Infobox medical condition (new)
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| synonym         = Neonatal aspiration of meconium
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| caption         = X-ray showing the extent of lung epithelial damage in response to meconium seen in neonates with meconium aspiration syndrome.
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| specialty       = neonatology
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'''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.<ref name=":0">{{Cite journal|last1=Van Ierland|first1=Y|last2=De Beaufort|first2=AJ|date=2009|title=Why Does Meconium Cause Meconium Aspiration Syndrome? Current Concepts of MAS Pathophysiology|journal=Early Human Development|volume=85|issue=10|pages=617–620|doi=10.1016/j.earlhumdev.2009.09.009|pmid=19833459}}</ref><ref name=":1">{{Cite journal|last1=Vain|first1=NE|last2=Batton|first2=DG|date=2017|title=Meconium "Aspiration" (or Respiratory Distress Associated with Meconium-Stained Amniotic Fluid?)|journal=Seminars in Foetal and Neonatal Medicine|volume=22|issue=4 |pages=214–219|doi=10.1016/j.siny.2017.04.002|pmid=28411000 }}</ref>

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]].<ref name=":2">{{Cite journal|last1=Rahman|first1=S|last2=Unsworth|first2=J|last3=Vause|first3=S|date=2013|title=Meconium in Labour|journal=Obstetrics, Gynaecology and Reproductive Medicine|volume=23|issue=8|pages=247–252|doi=10.1016/j.ogrm.2013.05.007}}</ref>

Meconium is a sticky dark-green substance which contains gastrointestinal secretions, [[amniotic fluid]], [[bile acid]]s, [[bile]], blood, [[mucus]], [[cholesterol]], pancreatic secretions, [[lanugo]], [[vernix caseosa]] and cellular debris.<ref name=":0" /> 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.<ref name=":3">{{Cite journal|last1=Argyridis|first1=S|last2=Arulkumaran|first2=S|date=2016|title=Meconium Stained Amniotic Fluid|journal=Obstetrics, Gynaecology and Reproductive Medicine|volume=26|issue=8|pages=227–230|doi=10.1016/j.ogrm.2016.05.001}}</ref> 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.<ref name=":4">{{Cite journal|last1=Lindenskov|first1=PHH|last2=Castellheim|first2=A|last3=Saugstad|first3=OD|date=2015|title=Meconium Aspiration Syndrome: Possible Pathophysiological Mechanisms and Future Potential Therapies|journal=Neonatology|volume=107|issue=3 |pages=225–230|doi=10.1159/000369373|pmid=25721501 |doi-access=free}}</ref>

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]].<ref name=":0" />

==Causes==
The main theories of meconium passage into amniotic fluid are caused by fetal maturity or from foetal stress as a result of [[hypoxia (medical)|hypoxia]] or infection.<ref name=":2" /> 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]].<ref name=":5" /> 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 (medical)|hypoxia]] with MSAF.<ref name=":1" /> It is believed that foetal distress develops into foetal hypoxia causing the foetus to defecate meconium resulting in MSAF and then perhaps MAS.<ref name=":5" /> Other stressors which causes foetal distress, and therefore meconium passage, includes when umbilical vein oxygen saturation is below 30%.<ref name=":2" />

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 (medical)|hypoxia]].<ref name=":5" /><ref name=":6">{{Cite journal|last=Fanaroff|first=AA|date=2008|title=Meconium Aspiration Syndrome: Historical Aspects|journal=Journal of Perinatology|volume=28|pages=S3–S7|doi=10.1038/jp.2008.162|pmid=19057607 |doi-access=free}}</ref>

The association between foetal distress and meconium passage is not a definite cause-effect relationship as over {{frac|3|4}} of infants with MSAF are vigorous at birth and do not have any distress or hypoxia.<ref name=":1" /> Additionally, foetal distress occurs frequently without the passage of meconium as well.<ref name=":2" />

=== 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]].<ref name=":2" />

[[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.<ref>{{Cite journal|last1=Poggi|first1=SH|last2=Ghidini|first2=A|date=2009|title=Pathophysiology of Meconium Passage into the Amniotic Fluid|journal=Early Human Development|volume=85|issue=10 |pages=607–610|doi=10.1016/j.earlhumdev.2009.09.011|pmid=19836908 }}</ref>

[[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.<ref name=":2" />

==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.<ref>{{Cite journal|last1=Beligere|first1=N|last2=Rao|first2=R|date=2008|title=Neurodevelopmental Outcome of Infants with Meconium Aspiration Syndrome: Report of a Study and Literature Review|journal=Journal of Perinatology|volume=28|pages=S93–S101|doi=10.1038/jp.2008.154|pmid=19057618|doi-access=free}}</ref>

=== 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]].<ref name=":13" /><ref name=":7" />

=== Foetal hypoxia ===
The lung areas which do not or only partially participate in [[ventilation (physiology)|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.<ref name=":0" />

=== Infection ===
Microorganisms, most commonly [[Gram-negative bacteria|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 [[cytokine]]s (such as [[Interleukin 6|IL-6]]), [[chemokine]]s (such as [[Interleukin 8|IL-8]] and [[monocyte chemoattractant protein-1]]), [[Complement system|complement]], [[Phospholipase A2|phospholipase A<sub>2</sub>]] 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.<ref>{{Cite journal|last1=Romero|first1=R|last2=Yoon|first2=BH|last3=Chaemsaithong|first3=P|last4=Cortez|first4=J|last5=Park|first5=CW|last6=Behnke|first6=RGE|last7=Hassan|first7=SS|last8=Chaiworapongsa|first8=T|last9=Yeo|first9=L|date=2014|title=Bacteria and Endotoxin in Meconium-Stained Amniotic Fluid at Term: Could Intra-amniotic Infection Cause Meconium Passage?|journal=The Journal of Maternal-Fetal and Neonatal Medicine|volume=27|issue=8|pages=775–788|doi=10.3109/14767058.2013.844124|pmc=5881914|pmid=24028637}}</ref>

=== 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 [[Microorganism|microbes]]. Meconium perhaps leads to [[chemical pneumonitis]] as it is a potent activator of inflammatory mediators which include [[cytokine]]s, [[Complement system|complement]], [[prostaglandin]]s and [[reactive oxygen species]].<ref name=":4" />

Meconium is a source of pro-inflammatory [[cytokine]]s, including [[tumour necrosis factor]] (TNF) and [[interleukin]]s ([[Interleukin-1 family|IL-1]], [[Interleukin 6|IL-6]], [[Interleukin 8|IL-8]]), and mediators produced by [[neutrophil]]s, [[macrophage]]s 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 species|reactive nitrogen]] and [[Reactive oxygen species|oxygen species]] which have [[Cytotoxicity|cytotoxic]] effects. [[Oxidative stress]] results in [[vasoconstriction]], [[bronchoconstriction]], [[platelet aggregation]] and accelerated cellular [[apoptosis]].<ref name=":7">{{Cite journal|last1=Mokra|first1=D|last2=Mokry|first2=J|last3=Tonhajzerova|first3=I|date=2013|title=Anti-Inflammatory Treatment of Meconium Aspiration Syndrome: Benefits and Risks|journal=Respiratory Physiology and Neurobiology|volume=187|issue=1|pages=52–57|doi=10.1016/j.resp.2013.02.025|pmid=23466955|s2cid=41008280}}</ref> Recently, it has been hypothesised that meconium is a potent activator of [[toll-like receptor]] (TLRs) and [[Complement system|complement]], key mediators in inflammation, and may thus contribute to the inflammatory response in MAS.<ref name=":0" /><ref name=":4" />

Meconium contains high amounts of [[Phospholipase A2|phospholipase A<sub>2</sub>]] (PLA<sub>2</sub>), 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]].<ref name=":0" /><ref name=":7" /> 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 membrane]]s. Injury to the alveolocapillary membrane results in leakage of liquid, plasma proteins, and cells into the [[interstitium]] and [[Pulmonary alveolus|alveolar]] spaces.<ref name=":7" />

=== Surfactant inactivation ===
[[Surfactant]] is synthesised by [[Alveolar cells|type II alveolar cells]] and is made of a complex of [[phospholipid]]s, proteins and [[saccharides]]. It functions to lower [[surface tension]] (to allow for lung expansion during [[Inhalation|inspiration]]), stabilise [[Pulmonary alveolus|alveoli]] at the end of [[Breathing|expiration]] (to prevent alveolar collapse) and prevents lung [[Edema|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 [[Senescence|senescent]] cells away from the alveolar structure.<ref>{{Cite journal|last1=Dargaville|first1=PA|last2=Mills|first2=JF|date=2005|title=Surfactant therapy for meconium aspiration syndrome: current status|journal=Drugs|volume=65|issue=18|pages=2569–2591|doi=10.2165/00003495-200565180-00003|pmid=16392874 |s2cid=46969843 |doi-access=free}}</ref>

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 ([[Surfactant protein A|SP-A]] and [[Surfactant protein B|SP-B]]), and by changing the viscosity and structure of surfactant.<ref name=":13">{{Cite journal|last1=Mokra|first1=D|last2=Calkovska|first2=A|date=2013|title=How to Overcome Surfactant Dysfunction in Meconium Aspiration Syndrome|journal=Respiratory Physiology and Neurobiology|volume=187|issue=1|pages=58–63|doi=10.1016/j.resp.2013.02.030|pmid=23473924|s2cid=20533996}}</ref> Several morphological changes occur after meconium exposure, the most notable being the detachment of airway epithelium from [[Basement membrane|stroma]] and the shedding of [[Epithelium|epithelial cells]] into the airway. These indicate a direct detrimental effect on lung alveolar cells because of the introduction of meconium into the lungs.<ref name=":0" />

=== 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 (medical)|hypoxia]], pulmonary [[vasoconstriction]] and [[Breathing|ventilation]]/[[perfusion]] mismatch can trigger PPHN, depending on the concentration of meconium within the [[respiratory tract]].<ref>{{Cite journal|last=Brooke-Vincent|first=F|date=2015|title=Meconium Aspiration Syndrome and Persistent Pulmonary Hypertension of the Newborn|journal=Journal of Neonatal Nursing|volume=21|issue=4|pages=161–167|doi=10.1016/j.jnn.2015.05.002}}</ref><ref name=":6" /> PPHN in newborns is the leading cause of death in MAS.<ref name=":4" />

=== 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 [[Autophagy|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%.<ref>{{Cite journal|last1=Zagariya|first1=A|last2=Bhat|first2=R|last3=Chari|first3=G|last4=Uhal|first4=B|last5=Navale|first5=S|last6=Vidyasagar|first6=D|date=2005|title=Apoptosis of Airway Epithelial Cells in Response to Meconium|journal=Life Sciences|volume=76|issue=16|pages=1849–1858|doi=10.1016/j.lfs.2004.10.033|pmid=15698862}}</ref> Therefore, the majority of meconium-induced lung damage may be due to the apoptosis of lung epithelium.<ref name=":0" />

==  Diagnosis ==
[[File:Meconium aspiration syndrome (MAS).png|thumb|Release of meconium into the amniotic cavity and then intrauterine gasping of post-term neonates may cause meconium aspiration syndrome.]]
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.<ref>{{Cite journal|last1=Marco|first1=P|last2=Nadya|first2=Y|last3=Roselyne|first3=B|last4=Paolo|first4=M|last5=Mostafa|first5=M|last6=De Luca|first6=D|date=2014|title=Lung Ultrasound Findings in Meconium Aspiration Syndrome|journal=Early Human Development|volume=90|issue=2|pages=41–43|doi=10.1016/S0378-3782(14)50011-4|pmid=25220126}}</ref>

== 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.<ref name=":10" />

=== Prevention during pregnancy ===
Prevention during pregnancy may include amnioinfusion and antibiotics but the effectiveness of these treatments are questionable.<ref name=":1" />

=== Prevention during parturition ===
As previously mentioned, [[oropharyngeal]] and [[nasopharyngeal]] suctioning is not an ideal preventative treatment for both vigorous and depressed (not breathing) infants.<ref name=":1" />

== Treatment ==
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.<ref name=":0" /> 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 monitoring [[heart rate]], [[respiratory rate]], [[oxygen saturation]] and [[Blood glucose monitoring|blood glucose]] (to detect worsening [[respiratory acidosis]] or the development of [[hypoglycemia]]).<ref name=":8">{{Cite journal|last1=Stenson|first1=BJ|last2=Smith|first2=CL|date=2012|title=Management of Meconium Aspiration Syndrome|journal=Paediatrics and Child Health|volume=22|issue=12|pages=532–535|doi=10.1016/j.paed.2012.08.015}}</ref> In general, treatment of MAS is more supportive in nature.

=== Assisted ventilation techniques ===
To clear the airways of meconium, [[trachea]]l suctioning can be used however, the efficacy of this method is in question and it can cause harm.<ref name=":9">{{Cite journal|last1=Aguilar|first1=AM|last2=Vain|first2=NE|date=2011|title=The Suctioning in the Delivery Room Debate|journal=Early Human Development|volume=87S|pages=S13–S15|doi=10.1016/j.earlhumdev.2011.01.003|pmid=21277716 }}</ref>

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.<ref>{{Cite journal|last1=Vain|first1=NE|last2=Szyld|first2=EG|last3=Prudent|first3=LM|last4=Wiswell|first4=TE|last5=Aguilar|first5=AM|last6=Vivas|first6=NI|date=2004|title=Oropharyngeal and Nasopharyngeal Suctioning of Meconium-Stained Neonates Before Delivery of their Shoulders: Multicentre, Randomised Controlled Trial|journal=Lancet|volume=364|issue=9434 |pages=597–602|doi=10.1016/S0140-6736(04)16852-9|pmid=15313360 |s2cid=29268118 }}</ref><ref name=":1" /> The desired oxygen saturation is between 90 and 95% and [[PaO2|PaO<sub>2</sub>]] may be as high as 90mmHg.<ref name=":10">{{Cite journal|last1=Chettri|first1=S|last2=Bhat|first2=BV|last3=Adhisivam|first3=B|date=2016|title=Current Concepts in the Management of Meconium Aspiration Syndrome|journal=Indian J Paediatr|volume=83|issue=10|pages=1125–1130|doi=10.1007/s12098-016-2128-9|pmid=27206687|s2cid=4723566}}</ref> 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.<ref name=":1" /> 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%.<ref>{{Cite journal|last=Short|first=BL|date=2008|title=Extracorporeal Membrane Oxygenation: Use in Meconium Aspiration Syndrome|journal=Journal of Perinatology|volume=28|pages=S79–S83|doi=10.1038/jp.2008.152|pmid=19057615|doi-access=free}}</ref>

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 of [[pneumothorax]] associated with dyssynchronous breathing.<ref name=":8" />

=== Inhaled nitric oxide ===
Inhaled [[nitric oxide]] (iNO) acts on [[vascular smooth muscle]] causing selective pulmonary [[vasodilation]]. This is ideal in the treatment of [[Persistent pulmonary hypertension|PPHN]] 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 for [[Extracorporeal membrane oxygenation|ECMO]] 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.<ref name=":10" />

=== Antiinflammatories ===
As inflammation is such a huge issue in MAS, treatment has consisted of anti-inflammatories.

==== Glucocorticoids ====
[[Glucocorticoid]]s have a strong anti-inflammatory activity and works to reduce the migration and activation of [[neutrophil]]s, [[eosinophil]]s, [[Monocyte|mononuclear]] cells, and other cells. They reduce the migration of neutrophils into the lungs ergo, decreasing their adherence to the [[endothelium]]. Thus, there is a reduction in the action of mediators released from these cells and therefore, a reduced inflammatory response.<ref name=":11">{{Cite journal|last1=Mokra|first1=D|last2=Mokry|first2=J|date=2011|title=Glucocorticoids in the Treatment of Neonatal Meconium Aspiration Syndrome|journal=Eur J Pediatr|volume=170|issue=12|pages=1495–1505|doi=10.1007/s00431-011-1453-2|pmc=3221844|pmid=21465122}}</ref><ref name=":7" />

Glucocorticoids also possess a genomic mechanism of action in which, once bound to a [[glucocorticoid receptor]], the activated complex moves into the [[Cell nucleus|nucleus]] and inhibits [[Transcription (biology)|transcription]] of [[Messenger RNA|mRNA]]. Ultimately, effecting whether various proteins get produced or not. Inhibiting the transcription of nuclear factor ([[NF-κB]]) and protein activator ([[AP-1 transcription factor|AP-1]]) attenuates the expression of pro-inflammatory cytokines ([[Interleukin-1 family|IL-1]], [[Interleukin 6|IL-6]], [[Interleukin 8|IL-8]] and [[Tumor necrosis factor superfamily|TNF]] etc.), enzymes ([[Phospholipase A2|PLA<sub>2</sub>]], [[Cyclooxygenase-2|COX-2]], [[Nitric oxide|iNOs]] etc.) and other biologically active substances.<ref name=":12">{{Cite journal|last1=Czock|first1=D|last2=Keller|first2=F|last3=Rasche|first3=FM|last4=Haussler|first4=U|date=2005|title=Pharmacokinetics and Pharmacodynamics of Systemically Administered Glucocorticoids|journal=Clinical Pharmacokinetics|volume=44|issue=1|pages=61–98|doi=10.2165/00003088-200544010-00003|pmid=15634032|s2cid=24458998}}</ref><ref name=":11" /><ref name=":7" /> The anti-inflammatory effect of glucocorticoids is also demonstrated by enhancing the activity of lipocortines which inhibit the activity of PLA<sub>2</sub> and therefore, decrease the production of [[arachidonic acid]] and mediators of [[lipoxygenase]] and [[cyclooxygenase]] pathways.<ref name=":11" />

[[Anti-inflammatory|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 of [[dexamethasone]] significantly enhanced [[gas exchange]], reduced ventilatory pressures, decreased the number of [[neutrophil]]s in the bronchoalveolar area, reduced [[Edema|oedema]] formation and oxidative lung injury.<ref name=":7" /> 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 of [[diabetes mellitus]], [[osteoporosis]], skin [[atrophy]] and [[growth retardation]] in children.<ref name=":12" />

==== Inhibitors of phosphodiesterase ====
[[Phosphodiesterase]]s (PDE) degrades [[Cyclic adenosine monophosphate|cAMP]] and [[Cyclic guanosine monophosphate|cGMP]] and, within the [[respiratory system]] of a newborn with MAS, various isoforms of PDE may be involved due to their pro-inflammatory and [[Smooth muscle tissue|smooth 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 cause [[cardiovascular]] side effects. Non-selective PDE inhibitors, such as [[methylxanthines]], increase concentrations of cAMP and cGMP in the cells leading to [[Bronchodilator|bronchodilation]] and [[vasodilation]]. Additionally, methylxanthines decreases the concentrations of calcium, [[acetylcholine]] and [[monoamines]], this controls the release of various mediators of inflammation and [[bronchoconstriction]], including [[prostaglandin]]s. Selective PDE inhibitors target one subtype of [[phosphodiesterase]] and in MAS the activities of [[Phosphodiesterase 3|PDE-3]], [[Phosphodiesterase 4|PDE-4]], [[Phosphodiesterase 5|PDE-5]] and PDE-7 may become enhanced.<ref name=":7" /> For example, [[Milrinone]] (a selective PDE3 inhibitor) improved oxygenation and survival of neonates with MAS.<ref>{{Cite journal|last1=Bassler|first1=D|last2=Choong|first2=K|last3=McNamara|first3=P|last4=Kirpalani|first4=H|date=2006|title=Neonatal Persistent Pulmonary Hypertension Treated with Milrinone: Four Case Report|journal=Biology of the Neonate|volume=89|issue=1|pages=1–5|doi=10.1159/000088192|pmid=16155380|s2cid=38587541}}</ref>

==== Inhibitors of cyclooxygenase ====
[[Arachidonic acid]] is metabolised, via [[cyclooxygenase]] (COX) and [[lipoxygenase]], to various substances including [[prostaglandin]]s and [[leukotriene]]s, which exhibit potent pro-inflammatory and [[Vasoactivity|vasoactive]] effects. By inhibiting COX, and more specifically [[COX-2]], (either through selective or non-selective drugs) inflammation and oedema can be reduced. However, COX inhibitors may induce [[Peptic ulcer disease|peptic ulcers]] and cause [[hyperkalemia]] and [[hypernatremia]]. Additionally, COX inhibitors have not shown any great response in the treatment of MAS.<ref name=":7" />

=== Antibiotics ===
Meconium is typically sterile however, it can contain various cultures of bacteria so appropriate antibiotics may need to be prescribed.<ref name=":10" />

=== Surfactant treatment ===
[[Lung lavage]] with diluted [[surfactant]] 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 for [[Extracorporeal membrane oxygenation|ECMO]] 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 with [[pulmonary hypertension]]) as it can exacerbate [[Hypoxia (medical)|hypoxia]] and lead to mortality.<ref>{{Cite journal|last1=Choi|first1=HJ|last2=Hahn|first2=S|last3=Lee|first3=J|last4=Park|first4=BJ|last5=Lee|first5=SM|last6=Kin|first6=HS|last7=Bae|first7=CW|date=2012|title=Surfactant Lavage Therapy for Meconium Aspiration Syndrome: A Systematic Review and Meta-Analysis|journal=Neonatology|volume=101|issue=3|pages=183–191|doi=10.1159/000329822|pmid=22067375 |doi-access=free}}</ref>

=== Previous treatments ===
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 the [[oropharyngeal]] and [[nasopharyngeal]] area before delivery of the shoulders followed by [[trachea]]l 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.<ref>{{Cite journal|last1=Carson|first1=BS|last2=Losey|first2=RW|last3=Bowes Jr|first3=WA|last4=Simmons|first4=MA|date=1976|title=Combined Obstetric and Pediatric Approach to Prevent Meconium Aspiration Syndrome|journal=Am J Obstet Gynecol|volume=15|issue=126|pages=172–175|doi=10.1016/0002-9378(76)90525-1|pmid=984149 }}</ref> 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.<ref name=":1" /> In fact, it can cause more issues and damage (e.g. [[Mucous membrane|mucosal]] damage), thus it is not a recommended preventative treatment.<ref name=":9" /> Suctioning may not significantly reduce the incidence of MAS as meconium passage and aspiration may occur ''in-utero.'' Thereby making the suctioning redundant and useless as the meconium may already be deep within the lungs at the time of birth.<ref name=":10" />

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.<ref name=":1" /> However, there are associated risks, such as [[umbilical 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.<ref name=":8" />

== Prevalence ==

1 in every 7 pregnancies have MSAF and, of these cases, approximately 5% of these infants develop MAS.<ref name=":0" /> MSAF is observed 23-52% in pregnancies at 42 weeks. Therefore, the frequency of MAS increases as the length of [[gestation]] increases, such that the prevalence is greatest in post-term pregnancies. Conversely, [[preterm birth]]s 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.<ref name=":3" /> 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.<ref>{{Cite journal|last1=Sehaghatian|first1=MR|last2=Othman|first2=I|last3=Hossain|first3=MM|last4=Vidyasagar|first4=D|date=2000|title=Risk of Meconium-Stained Amniotic Fluid in Different Ethnic Groups|journal=J Perinatol|volume=20|issue=4 |pages=257–261|doi=10.1038/sj.jp.7200367|pmid=10879341 |doi-access=free}}</ref><ref name=":5">{{Cite journal|last1=Swarnam|first1=K|last2=Soraisham|first2=AS|last3=Sivanandan|first3=S|date=2012|title=Advances in the Management of Meconium Aspiration Syndrome|journal=International Journal of Pediatrics|volume=2012|page=359571|doi=10.1155/2012/359571|pmc=3228378|pmid=22164183|doi-access=free}}</ref>

== Future research ==
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 of [[anti-inflammatory]] agents, surfactant replacement therapy and [[Antibiotics|antibiotic]] therapy. More research needs to be conducted on the pharmacological properties of, for example, [[glucocorticoid]]s, including dosages, administration, timing or any drug interactions.<ref name=":11" /> 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.

==See also==
{{Portal|Medicine}}
* [[Aspiration pneumonia]]

==References==
{{Reflist}}

== External links ==
* [http://www.emedicine.com/ped/topic768.htm eMedicine's article about meconium aspiration syndrome]
{{Medical resources
| ICD11           = {{ICD11|KB26.0}}
| ICD10           = {{ICD10|P24.0}}
| ICD9            = {{ICD9|770.11}}, {{ICD9|770.12}}
| ICDO            = 
| OMIM            = 
| MedlinePlus     = 001596
| eMedicineSubj   = ped
| eMedicineTopic  = 768
| DiseasesDB      = 7907
| MeshID          = D008471
| Orphanet        = 70588
}}

{{Certain conditions originating in the perinatal period}}

{{DEFAULTSORT:Meconium Aspiration Syndrome}}
[[Category:Neonatology]]
[[Category:Syndromes]]