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There are multiple causative factors of meconium passage. Meconium passage in utero has been attributed to
a fetal response to intrauterine stress[15] and is often associated with fetal hypoxia, asphyxia, and acidosis.[16-18]
Hypoxia causes increased gastrointestinal peristalsis and relaxed anal sphincter tone. Transient compression
of the umbilical cord or fetal head also causes a vagal response, which can result in meconium passage.[19,20]

Meconium in the amniotic fluid can also simply represent the maturation of fetal intestinal function. Meconium
passage is rare before 34 weeks' gestation, and its incidence increases only slightly through 37 weeks'
gestation. After 37 weeks' gestation, its incidence increases steadily with increasing gestational age.[6,7,9]
Passage of meconium in the mature fetus is facilitated by myelination of nerve fibers, an increase in
parasympathetic tone,[1] and increases in the concentration of motilin (a peptide that stimulates the contraction
of the intestinal muscle).[21-23]An association between fetal distress and elevated levels of motilin has been
reported.[21,22]

  

 



 




The pathophysiology of meconium aspiration and MAS is complex, and the timing of the initial insult resulting in
MAS remains controversial. Intrauterine fetal gasping, mechanical airway obstruction, pneumonitis, surfactant
inactivation, and damage of umbilical vessels all play roles in the pathophysiology of meconium aspiration.
There is also a strong association between MAS and persistent pulmonary hypertension of the newborn
(PPHN).



 

The traditional belief was that meconium aspiration occurs immediately after birth.[12,24,25] When the newborn
exposed to meconium begins respiration outside the womb, aspirated particulate or thick meconium can be
carried rapidly by the first breaths to the distal airways. Studies of neonatal puppies with tantalum-labeled
meconium instilled into the trachea before the first breath have confirmed that the distal migration of particulate
matter can occur within 1 hour of birth.[26]

Several investigators have suggested, however, that most cases of meconium aspiration occur in utero when
fetal gasping is initiated before delivery. Block et al[27] found that hypoxia and hypercarbia in fetal baboons
induced intrauterine gasps and meconium aspiration. Gooding et al,[26] on the other hand, failed to find
intrauterine gasping or meconium aspiration by hypoxic fetal dogs. Retrospective reviews provide indirect
evidence that some cases of meconium aspiration in humans are prenatal rather than postnatal events. For
example, meconium has been found distally as far as the alveoli in some stillborn infants and in some infants
that die within hours of delivery.[28-30] Thus, it is believed that MAS will sometimes occur despite appropriate
airway management at delivery. There is currently no way to distinguish between the infant who has developed
MAS by intrauterine respiration or gasping and the infant who has developed MAS by inhalation of meconium
at the first breaths after delivery.

   






 

It is commonly thought that the initial and most important problem of the infant with MAS is obstruction caused
by meconium in the airways. Complete obstruction of large airways by thick meconium is an uncommon
occurrence. The exact incidence of large-airway obstruction is unknown, though Thureen et al, [28] in an autopsy
study of infants who died of MAS, found no evidence of such obstruction. Usually, small amounts of meconium
migrate slowly to the peripheral airways. This mechanism can create a ball valve phenomenon, in which air
flows past the meconium during inspiration but is trapped distally during expiration, leading to increases in
expiratory lung resistance, functional residual capacity, and anteroposterior diameter of the chest.[1,12] Regional
atelectasis and ventilation-perfusion mismatches develop from total obstruction of the small airways. Adjacent
areas often are partially obstructed and overexpanded, leading to pneumothorax and pneumomediastinum air
leaks.[31,32] Pulmonary air leaks are ten times more likely to develop in infants with meconium aspiration than
those without, and leaks often develop during resuscitation.[1] These obstructive airway phenomena lead to the
classic radiographic findings of MAS shown in Figure 1: atelectasis, pneumothorax, and hyperexpanded areas
of the lung. Consolidation, pleural effusions, and relatively normal radiographic appearances can occur. The
severity of radiographic findings does not accurately predict the severity of illness.[4,33,34]

Chest radiograph of a full-term infant with meconium aspiration showing coarse interstitial
infiltrates and left pneumothorax.

(Enlarge Image)

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Pneumonitis is a usual feature of MAS, occurring in about one half of the cases.[11,35] An intense inflammatory
response in the bronchi and alveoli can occur within hours of aspiration of meconium.[36-40]The airways and lung
parenchyma become infiltrated with large numbers of polymorphonuclear leukocytes and macrophages, which
produce local injury by release of inflammatory mediators and reactive oxygen species.[41,42] Depending upon
the degree of hypoxia, hyaline membranes, pulmonary hemorrhage, and vascular necrosis can occur.[36]

An example of meconium pneumonitis is shown in Figure 2.

Chest radiograph of a full-term infant with coarse interstitial infiltrates of meconium aspiration
pneumonitis.

(Enlarge Image)

The inflammatory response is caused by chemotactic cytokines (such as interleukin 8) in meconium.[42] The
inflammatory response itself leads to high levels of vasoactive mediators (eg, thromboxanes, leukotrienes, and
prostaglandins).[43,44] Such vasoactive mediators play a role in the development of PPHN.[45-47]Antiinflammatory
treatments, such as systemic steroids, can become important in the prevention of serious lung injury in cases
of meconium aspiration.[48,49]

 


 



Proteins and fatty acids in aspirated meconium can interfere with surfactant function. Meconium aspiration
syndrome in humans is mediated, in part, by inactivation of endogenous surfactant.[50-52] Atelectasis, decreased
lung compliance, intrapulmonary shunting, and hypoventilation are aggravated by inhibition of surfactant
function.
Moses and colleagues[50] found that surfactant inhibition is related both to the consistency (thickness) of the
meconium and the concentration of the surfactant itself. At low concentrations of surfactant, very dilute
meconium inhibited surfactant function, whereas thick meconium was unable to affect surfactant function at
high concentrations of surfactant.[50] This information suggested that preterm infants or those with thick
meconium might benefit from treatment with exogenous surfactant. One small randomized trial (n = 40) of
infants with MAS who were given intermittent boluses of high-dose surfactant found improvement in all
parameters measured (oxygenation, resolution of PPHN, number of air leaks, need for extracorporal
membrane oxygenation and duration of mechanical ventilation).[53] Other observational studies have provided
conflicting results concerning the efficacy and proper administration of surfactant for MAS.[54-57] Cleary and
Wiswell[4] suggest that the optimal dose, type, concentration, and method of administration (bolus, infusion, or
lavage) of surfactant for MAS have yet to be determined, and that more rigorous investigation is needed before
widespread use of such therapy.

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The effect of meconium on the various fetal tissues differs greatly. Meconium exposure to the placental
membranes and chorionic plate results in only slight inflammation. Inflammation and focal injury of the umbilical
vessels, however, may be quite severe.[35] Meconium-induced cord vessel wall injury adversely affects vessel
function by inducing spasm and necrosis, with potential fetal hypoperfusion.[58,59]Altshuler et al[59] found
meconium-induced umbilical vascular necrosis in 1% of meconium-stained placentas. Cesarean delivery for
fetal distress was needed in 60% of the cases with umbilical vascular necrosis.

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PPHN is common in neonates with fatal MAS. Indeed, a majority of cases of PPHN are associated with MAS,[60]
and this condition could be the final common pathway for the severe morbidity and mortality seen in infants with
MAS. Both acute pulmonary arterial vasoconstriction and abnormally thick muscularization of the intraacinous
arteries are important elements in the pathophysiology of PPHN.

Vasoconstriction of the pulmonary arteries can be caused by hypoxia as a result of any of the mechanisms
discussed above (mechanical obstruction, chemical inflammation, or inactivation of surfactant). Chronic
hypoxia caused by other factors can also lead to PPHN through the development of abnormal pulmonary
arterial muscularization. This histologic finding reflects a chronic change that likely develops before birth, not as
a response to acute meconium aspiration. Thus, meconium passage associated with PPHN can be both a
direct pathogenic cause of lung damage and a simple marker of chronic intrauterine hypoxia. The difficulty in
managing PPHN and MAS is addressed by Wiswell and Bent,[12] who write: "whatever the cause of PPHN,
which is concomitant with MAS, the vicious cycle of shunting, hypoxemia, and acidosis can lead to further
pulmonary hypertension that may be difficult or impossible to successfully treat."

" 




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The information presented in the previous section raises the question of the relative importance of the various
pathophysiologic mechanisms of meconium passage and aspiration. Is meconium itself a direct primary cause
of neonatal morbidity and mortality? Or is meconium harmless itself and merely a marker of fetal maturation or
of chronic fetal hypoxia?

Recent studies of small groups of patients have attempted to delineate the relative importance of the
pathophysiologic mechanisms. Carbonne and colleagues,[61] in their study of fetal pulse oximetry in labors
complicated by meconium passage, found evidence that MAS was primarily associated with acute hypoxic
events late in labor. In contrast, Thureen et al[28] found that meconium aspiration is often a chronic prenatal
disease rather than a condition related to acute events that occur late in labor or after birth.

Ramin et al[62] studied umbilical cord blood gases of more than 7000 term infants with meconium-stained
amniotic fluid. Less than 1% of these infants developed MAS, and of these, about one half had an associated
acute acidemia at birth. Because most acidemic fetuses had abnormally increased Pco2 levels (rather than
pure metabolic acidemia) the authors concluded that many of the cases of fetal compromise associated with
MAS were acute events. They hypothesized that "the pathophysiology of MAS includes, but is not limited to,
fetal hypercarbia, which stimulates fetal respiration leading to intrauterine aspiration of meconium into the
alveoli, and lung parenchymal damage secondary to acidemia induced alveolar cell damage in the presence of
meconium." They further noted that this pathophysiologic sequence did not account for the other half of cases
of MAS because these neonates were not acidemic at birth, and other unidentified (potentially chronic) factors
were responsible for these other cases of MAS.

The current understanding of the complex pathophysiologic mechanisms of MAS and associated PPHN is
summarized in Figure 3. Though the relative importance of each mechanism is not completely understood, it is
apparent from the studies previously reviewed that many cases of MAS are related only to chronic hypoxia and
its sequelae and cannot be prevented by efforts to clear the fetal nasopharynx of meconium. It is likewise
apparent that a substantial proportion of MAS is directly caused by the meconium itself, and recommended
measures to clear meconium from the fetal nasopharynx should not be abandoned on the basis of
pathophysiologic considerations.