Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Meconium aspiration (or respiratory distress associated

with meconium-stained amniotic uid?)
Nestor E. Vain a, b, c, *, Daniel G. Batton d, 1
a
School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
b
Department of Pediatrics and Neonatology, Hospital Sanatorio de la Trinidad, Buenos Aires, Argentina
c
FUNDASAMIN (Foundation for Maternal Infant Health), Buenos Aires, Argentina
d
Newborn Medicine, Southern Illinois University School of Medicine, Springeld, IL, USA

a b s t r a c t
Keywords: The designation meconium aspiration syndrome (MAS) reects a spectrum of disorders in infants born
Meconium aspiration with meconium-stained amniotic uid, ranging from mild tachypnea to severe respiratory distress and
Persistent pulmonary hypertension of the
signicant mortality. The frequency of MAS is highest among infants with post-term gestation, thick
newborn
Post-term pregnancy
meconium, and birth asphyxia. Pulmonary hypertension is an important component in severe cases.
Neonatal asphyxia Prenatal hypopharyngeal suctioning and postnatal endotracheal intubation and suctioning of vigorous
Surfactant infants are not effective. Intubation and suctioning of non-breathing infants is controversial and needs
Nitric oxide more investigation. Oxygen, mechanical ventilation, and inhaled nitric oxide are the mainstays of
treatment. Surfactant is often used in infants with severe parenchymal involvement. High-frequency
ventilation and extracorporeal membrane oxygenation are usually considered rescue therapies.
2017 Elsevier Ltd. All rights reserved.

1. Introduction
Meconium aspiration syndrome (MAS) is a designation for
the respiratory distress occurring in newborn infants born to
pregnancies complicated by meconium-stained amniotic uid
(MSAF). It is a leading cause of morbidity and mortality in term
infants. MAS is more prevalent in infants born depressed and in
cases with thick meconium. Its association with asphyxia and
pulmonary hypertension is well recognized. However, the syn-
drome may occur in infants vigorous at birth and in the presence
of thin meconium. The incidence of MAS, and its pathophysiology,
prevention, and management have been changing over the last
20 years.
2. Incidence
Historically, the reported frequency of MSAF has ranged be-
tween 4% and 22% of all births [1e5]. Between 3% and 12% of infants
born with MSAF develop MAS. Such a wide variation depends on
various factors including the denition used to report MAS, the
quality of obstetrical care (including the cesarean section rate), and
the population risk [6]. The presence of meconium is related to
gestational age: it is quite unusual in preterm infants in cephalic
presentation, but it may reach 38% at 41 weeks. Accordingly, the
incidence of MAS increases regularly between 38 and 42 weeks,
from 0.24% to 1.42% [7]. MAS is more frequent and more severe in
areas with suboptimal control of pregnancies and a high incidence
of post-term births. The prevalence of MSAF and MAS is decreased
at sites with a high frequency of early medically unjustied cesar-
ean sections, although other maternal and neonatal complications
are increased [8]. Overall the incidence of MAS has decreased in
recent years but the severity has not [9].
3. Pathophysiology
The pathophysiology of MAS is complex and incompletely un-
derstood but only occurs in the presence of MSAF. Other factors
include the following:
3.1. Fetal distress and hypoxia

* Corresponding author. Address: Honduras 4160, Buenos Aires, Argentina.

It has long been observed that there is an important association
E-mail address: nestorvain@gmail.com (N.E. Vain). between fetal distress and hypoxia with MSAF. However, this as-
1
Retired. sociation is not always present and does not demonstrate cause and

http://dx.doi.org/10.1016/j.siny.2017.04.002
1744-165X/ 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
2 N.E. Vain, D.G. Batton / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6

effect, as over three-fourths of infants with MSAF are vigorous at 4. Prevention during pregnancy
birth [6].
4.1. Duration of pregnancy
3.2. Airway obstruction
Since MSAF and MAS are more prevalent when a pregnancy
continues beyond term, an obstetrical approach to prevention
For many years partial and/or complete airway obstruction
could be considered. Elective interruption of pregnancy at term
was considered the primary pathophysiologic mechanism for
could be done, although this introduces the risk of delivering un-
MAS. This was believed also to explain the typical radiologic
diagnosed early term or even late preterm infants, plus the po-
ndings of atelectasis (complete obstruction) and over-expansion
tential increase in the rate of cesarean sections.
(partial obstruction). For infants with severe MAS requiring me-
A recent meta-analysis evaluated randomized controlled trials
chanical ventilation, meconium is usually suctioned from the
(RCTs) in singleton uncomplicated pregnancies comparing induc-
endotracheal tube during the rst couple of days. Autopsy nd-
tion of labor at term to expectant management. There were no
ings in some infants with fatal MAS demonstrate histologic
differences in cesarean section rates and operative deliveries.
evidence of airway obstruction. These observations led to an
Maternal blood loss was less frequent with induction but the birth
aggressive approach of obstetric and neonatal airway suctioning
weight in the same group was lower. MSAF was less frequent in the
of infants born with MSAF. However, airway obstruction is now
induction group (4.0% vs 13.5%; relative risk: 0.32; 95% condence
considered to be only one component of the multiple factors
interval: 0.18e0.57) [19]. Similarly, a Cochrane review demon-
leading to the clinical picture of MAS. There is little correlation
strated fewer cases of MAS and cesarean deliveries with induction
between the presence of meconium in the trachea and clinical
of labor at 41 completed weeks of gestation [20]. The French Col-
signs of severe MAS [10].
lege of Gynecologists and Obstetricians states that induction of
In addition, suctioning of the fetal airway before delivery of the
labor can be proposed in patients between 41 (0) and 42 (6)
shoulders [3] and neonatal suctioning of the airway of vigorous
weeks, and ACOG suggests that Induction of labor between 41
infants [2] have been shown to be of no value. The role of neonatal
and 42 weeks can be considered but after 42 weeks it is recom-
suctioning of non-vigorous infants born with MSAF remains
mended [7,21].
controversial, as denitive evidence does not exist to support nor to
refute this practice.
4.2. Amnioinfusion

3.3. Inammation
Since some infants with MSAF develop MAS and others do not,
investigators have evaluated the possibility of inammation as a
pathogenic factor. A recent study by Lee and co-workers demon-
strated that histologic signs of funisitis and the presence in amni-
otic uid of an enzyme associated with inammation (matrix
metalloproteinase-8) were associated with the development of
MAS [11]. A comprehensive review suggests that meconium is a
danger signal for the innate immune system and a potent activator
of both complement and Toll-like receptors. [12]. Other inam-
matory mediators such as interleukin-6 and interleukin-8 are
elevated in infants with MAS [13].
3.4. Pulmonary hypertension
Pulmonary hypertension is a major complication in infants with
severe MAS. It is evident by clinical signs and echocardiographic
ndings. Furthermore, autopsy studies demonstrate hypertrophy of
the pulmonary vasculature indicative of longstanding pulmonary
hypertension [10,14,15]. Moreover, many of the infants developing
severe MAS do not show major radiologic signs of parenchymal
lung damage, suggesting that pulmonary hypertension is an
important component of the high oxygen and ventilatory re-
quirements [16].
3.5. Inactivation of surfactant
Meconium appears to affect surfactant function. Some of its
components such as bile salts may inactivate surfactant [17].
Meconium may produce direct toxicity on type II pneumocytes,
displace surfactant from the alveolar surface, and decrease surfac-
tant protein A and B concentrations [1].
A recent review of the mechanisms of surfactant inactivation
suggests that inammation, oxidative stress, and edema may be
causative, but the specic mechanisms are unclear [18].
Since MAS is more prevalent in cases of thick meconium, clini-
cians have attempted to decrease its incidence by diluting meco-
nium through amnioinfusion. Several RCTs have evaluated this
technique. The most recent Cochrane review of women in labor
with moderate or thick meconium staining of the amniotic uid
evaluated 14 trials and included 4435 women. For settings with
adequate peripartum surveillance, there were no differences in the
incidence of MAS, neither in perinatal nor maternal morbidity and
mortality. However, when the three studies performed in settings
with suboptimal perinatal management were evaluated as a sub-
group, there were decreases in the incidence of MAS, in perinatal
mortality, and in other short-term morbidities. The review con-
cludes that it is not clear whether the benets resulted from dilu-
tion of meconium or from relief of oligohydramnios. The studies
were too small to evaluate the potential risks of maternal compli-
cations of the procedure [22].
4.3. Antibiotics
The presence of meconium increases the likelihood of positive
cultures from amniotic uid in preterm and term pregnancies.
However, the association with neonatal sepsis is controversial [23].
Chorioamnionitis, postoperative endometritis, and puerperal in-
fections in term deliveries are more frequent when MSAF is pre-
sent [24e26]. Prophylactic antibiotics administered to the mother
during labor do not reduce the incidence of neonatal sepsis,
neonatal intensive care unit admission, or postpartum endome-
tritis. However, there is a signicant decrease in the risk of cho-
rioamnionitis [27].
5. Prevention of MAS at birth and the peripartum period
5.1. Prenatal suctioning
Since airway obstruction by meconium was long believed to be
the fundamental cause of MAS, a combined obstetrical and pedi-
atric approach to remove meconium from the fetal and newborn

Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
 N.E. Vain, D.G. Batton / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
airway was practised from the mid-1970s to 2005. In the presence
of MSAF, it was recommended to suction the mouth, nose, and
nasopharynx of the fetus before delivery of the shoulders [28].
This recommendation was based on a small, non-randomized,
historically controlled study published by Carson et al., in 1976
[29]. In 273 infants with MSAF, prenatal suction of the mouth and
hypopharynx was performed following delivery of the head.
Immediately after birth laryngoscopy was performed on the
newborn, and, if meconium was visualized, tracheal intubation and
suctioning were performed. The authors compared the incidence of
MAS for this group of patients (0.4%) with that of a historical control
group of 947 patients who were not suctioned (1.9%). Despite the
fact that the difference did not reach statistical signicance
(P 0.071) the authors interpreted the results as being benecial
and this combined approach was widely adopted. In 1988 and 1992
Falciglia and colleagues published two larger non-randomized
studies comparing infants in whom the combined prenatal and
postnatal suction approach had been performed with a control
group who were not suctioned [30,31]. In both studies he found no
differences in the incidence of MAS. Despite these contradictory
results the combined approach was universally accepted. Of note,
the extremely low incidence of MAS among infants with MSAF
(0.4%) in Carson et al.s study was never subsequently reported in
any patient series in the medical literature.
Based on the weak evidence supporting the recommendation
for prenatal suctioning and the lack of a standardized way to
perform this procedure, we undertook a large multicenter RCT to
evaluate the effectiveness of prenatal suctioning to prevent meco-
nium aspiration. We randomized 2514 term infants with MASF to
intrapartum suctioning of the mouth, nose, and hypopharynx
versus no suctioning. There were no differences in the incidence of
MAS (4% vs 4%), mortality, need for mechanical ventilation, or ox-
ygen therapy. There were also no differences when subgroups at
the highest risk of MAS were analyzed (non-vigorous infants, those
born after fetal distress, or those with thick meconium). Our
conclusion was that there are no benets of prenatal suctioning of
the mouth and hypopharynx in infants born with MSAF [3]. Based
on these results the recommendation for prenatal suctioning was
eliminated from international guidelines [32e34]. However,
several authors continued to recommend intrapartum suctioning
for MSAF, especially in areas with suboptimal peripartum care
[35,36]. The reasoning behind this attitude was that the results of
our study could not be extrapolated and that the procedure does
not carry any risks. However, suctioning the mouth and naso-
pharynx of an infant may damage the mucosa and generate
bradycardia through a vagal-mediated reex. More recently, an RCT
by Nangia et al. included 509 infants and was performed in a
community with limited resources. It also demonstrated no
advantage of prenatal suctioning versus expectant management
[37].
5.2. Endotracheal intubation and suctioning of infants vigorous
after birth
The rst description of this procedure appeared in 1960, pub-
lished by James in Abramson's book on resuscitation of the
newborn infant [38]. However, the procedure became popular only
in the 1970s after the study by Gregory et al. [39]. They visualized
the glottis and performed intubation and suctioning in 88 infants
born through MSAF. They noticed that MAS was more severe in
infants in whom meconium had been visualized below the vocal
cords. They reported better outcomes in their patients compared
with 15 outborn infants not suctioned at birth. Based on Gregory's
results and the belief that obstruction was the main pathophysio-
logic mechanism in MAS, this procedure became the standard of
Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
3
care in the ensuing 20 years. The usefulness of endotracheal intu-
bation and suctioning for vigorous infants born with MSAF was rst
challenged by Linder et al. [40]. They compared the outcomes of
308 infants who had been intubated and suctioned by neo-
natologists to 264 in whom the resuscitation team elected not to
intubate. There were no differences in the incidence of MAS.
Furthermore, the authors reported some potential complications of
intubation in vigorous infants. In 2000 the seminal study by Wis-
well et al. was published [2]. They performed a large international
RCT in 2094 vigorous infants with MSAF of any consistency. The
incidences of MAS, the need for mechanical ventilation, mortality,
and any other important clinical outcomes were no different be-
tween the infants randomized to intubation compared with those
in the expectant group. Based on this study, International Liaison
Committee on Resuscitation (ILCOR) modied the guidelines:
postnatal endotracheal intubation and suctioning of vigorous in-
fants was no longer recommended [41]. This change was not fol-
lowed by an increase in the frequency of MAS [42].
Five years after ILCOR no longer recommended prenatal suc-
tioning, we performed a national survey in Argentina to evaluate
compliance with the guidelines. Half of surveyed hospitals still
performed the procedure occasionally and in 7% it was performed
in all infants born with MSAF [43]. More surprising was that in 30%
of hospitals, tracheal intubation and suctioning of vigorous infants
was still a widespread practice. Similarly, Michel et al. evaluated
compliance with regional guidelines for MSAF in France. Prenatal
suctioning and endotracheal intubation and suctioning of vigorous
infants were still widely performed practices [44]. These and other
studies demonstrate the frequent gaps between guidelines and
clinical practices [45].
5.3. Endotracheal intubation and suctioning after birth in depressed
newborns
In 2005 the ILCOR guidelines recommended endotracheal
intubation and suctioning for non-breathing infants with MSAF
[34]. However, at that time there were no RCTs evaluating the
procedure, so the 2010 recommendations stated that The available
evidence does not support or refute the routine endotracheal suc-
tioning of depressed infants born through meconium-stained am-
niotic uid [46]. In 2015 and 2016, two small RCTs evaluated the
impact of immediate endotracheal intubation and suctioning
versus no suctioning in depressed infants born through MSAF
[47,48]. The studies were performed at two different hospitals in
India, in settings with a high incidence of MSAF and MAS, probably
related to limited pregnancy care. Chettri et al.s study included 122
infants and Nangia et al.s trial 175 newborns. Both studies showed
no differences in the incidence of MAS, need for mechanical
ventilation, mortality, or any other clinical variables. However,
these studies were clearly underpowered. Despite a paucity of
sufciently convincing data, ILCOR and the American Academy of
Pediatrics/American College of Obstetricians and Gynecologists
(National Resuscitation Program) modied the 2015 guidelines,
which currently recommend against routine tracheal intubation
and suctioning of non-vigorous infants [49,50]. In the absence of
sufcient evidence, ILCOR utilized common sense: while perform-
ing endotracheal intubation and suctioning of meconium e a pro-
cedure of no proven usefulness e the delay in the institution of
positive pressure ventilation in depressed infants could generate
more harm than benet [49]. Alternatively, doing away with a
procedure that clinicians have considered important for almost fty
years could also do more harm than good.
After reviewing these international statements produced by
scientic bodies who carefully analyzed all available studies on this
subject, a question arises: why we do not have one or more
4 N.E. Vain, D.G. Batton / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6

adequately powered large multicenter RCTs to conclusively answer 7.2. Assisted ventilation
the question? The answer, of course, is that doing large studies well
is difcult and expensive. In addition, delivery room studies entail When infants with MAS require increasing oxygen concentra-
problems regarding informed consent. However, the two largest tions the use of ventilatory support is often considered. Other in-
RCTs in infants born with MSAF were performed under a waiver of dications for mechanical ventilation include CO2 retention, apnea,
consent [2,3]. signicant clinical signs of pulmonary hypertension, and the
We and others have discussed this subject previously [51e53]. development of air leaks.
The international neonatology community needs to address this The pulmonary status of patients with severe MAS frequently
important subject. changes because of mobilization of secretions and variable degrees
of pulmonary arterial vasoconstriction. For these reasons, contin-
uous monitoring of oxygenation and ventilation is mandatory. Be-
sides monitoring oxygen saturations by pulse oxymetry,
6. Diagnosis and clinical picture
transcutaneous monitoring of CO2 is an excellent adjunct.
There is no proven optimal method of providing ventilatory
Meconium aspiration syndrome is a clinical diagnosis. Respira-
assistance to infants with severe MAS. CPAP is often considered of
tory distress in an infant born through MSAF with radiographic
limited value in these patients as they tend to ght, increasing the
ndings which do not suggest a different etiology is usually diag-
risks of air leak and hypoxemia [56]. A recent study suggested that
nosed as MAS. It is obvious that there may be overlap with other
high tidal volumes may be necessary [57]. Although clinicians often
entities such as transient tachypnea, pneumonia, and even with
have their own style of managing ventilators in these patients,
respiratory distress syndrome (RDS). This does present a problem
there are no data proving long-term benet of any ventilatory
in comparing different studies. Some studies include infants who
strategy. Before infants with severe MAS appear to be failing con-
were treated with oxygen for more than 12 h, whereas others do
ventional ventilation, they should be transferred to an ECMO center
not require a specic length of treatment. The clinical picture
if at all possible. Many clinicians will use high-frequency ventilation
ranges from mild respiratory distress, with minimal or no supple-
either as a primary or rescue mode of ventilation, although again
mental oxygen requirement and without CO2 retention, to severe
there are no data establishing long-term benets.
respiratory distress requiring mechanical ventilation and/or other
major therapies such as high-frequency ventilation (HFV), inhaled
7.3. Surfactant administration
nitric oxide (iNO), and extracorporeal membrane oxygenation
(ECMO). The severity of the disease is frequently related to the
The various ways in which meconium can inhibit surfactant
degree of associated pulmonary hypertension (PPHN). In many
function prompted clinicians and investigators to administer
cases there is a typical history of perinatal asphyxia, which could be
exogenous surfactant to infants with severe MAS. There are few
responsible for PPHN. In fact, the majority of cases of severe MAS
large, well-designed RCTs. The 2014 Cochrane review included only
(requiring mechanical ventilation) have a background of non-
four trials with an acceptable design (326 infants). Although sur-
reassuring fetal heart rate monitoring, neonatal depression, and
factant decreased the number of infants treated with ECMO by
in many cases thick meconium. Markers of asphyxia are frequently
reducing the severity of MAS, a decrease in mortality could not be
part of the history. However, cases of severe MAS have been re-
demonstrated [58]. Although a recommendation of surfactant
ported in the absence of this background and even with thin MSAF.
cannot be considered the standard of care for infants with MAS, it
An explanation could be the possibility of meconium generating an
may be of benet in selected cases [16,55]. Lung lavage with diluted
inammatory cascade resulting in pulmonary hypertension [12].
surfactant has been attempted based on its potential to remove
Some infants born with MSAF demonstrate radiographic ndings of
meconium debris. However, a 2013 Cochrane review of four very
signicant parenchymal disease even when they have only minimal
small RCTs failed to conclude that the procedure had long-term
or no clinical signs of respiratory distress. Others with minor X-ray
denitive benet and the authors did not recommend it [59].
changes may develop severe MAS. This is an argument for using the
Moreover, introducing and removing large volumes of uid
degree of pulmonary hypertension as a more important prognostic
through the endotracheal tube of severely compromised newborns
nding than the magnitude of radiographic parenchymal involve-
is a risky procedure during which episodes of hypoxia are highly
ment. The outcome of many infants with MAS is dependent upon
likely.
the degree of any associated asphyxia. Neurodevelopmental delay
has been reported in 20% of infants with MAS who responded to
7.4. Inhaled nitric oxideeECMO
therapy with conventional mechanical ventilation [54].
Pulmonary hypertension may be a critical component of severe
MAS. Therefore, in infants requiring intubation, iNO is frequently
7. Treatment of MAS used. Although iNO was not specically designed for use in MAS,
many of the patients included in studies of iNO for PPHN were
7.1. Oxygen infants with MAS. Those trials demonstrated a decrease in death
and the need for ECMO.
Supplemental oxygen is frequently required by infants with In the developed world, ECMO is the standard of care for infants
MAS. Although appropriate targets for oxygen use have been more with MAS who fail to respond to maximum ventilation therapy
thoroughly investigated for preterm infants with RDS, most clini- including HFV and the administration of iNO. Excellent survival
cians accept 90e95% saturation by pulse oxymetry or an arterial rates in infants with MAS have been reported [60].
PaO2 50e90 mmHg as adequate [16]. Higher levels may lead to
oxygen free radical damage, and lower levels may worsen pulmo- 7.5. Antibiotics
nary hypertension. Because of the high frequency of right-to-left
shunting and pulmonary vascular reactivity associated with MAS, The presence of meconium in the amniotic uid can increase the
some authors recommend higher targets for O2 saturation risk of infection. However, a recent RCT evaluating routine antibi-
(94e98%) and pre-ductal PaO2 (60e100 mmHg) [55]. otics in infants born with MSAF showed no advantages [61], and a

Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
 N.E. Vain, D.G. Batton / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
systematic review on the administration of antibiotics to infants
with MAS demonstrated that their use did not reduce mortality,
sepsis, or any other important clinical variable [62]. Nevertheless,
since the denition of MAS is vague, and there are no denitive
radiographic ndings to rule out pneumonia, antibiotic treatment
of patients with MAS is considered reasonable. Care should be
taken to discontinue their use after 48 h if cultures are negative and
there is no clinical and laboratory evidence to conrm infection.
7.6. Corticosteroids
Since inammation may be part of the pathogenesis of MAS,
steroids have been tried with variable success. A review of animal
and small clinical studies suggests that they may be benecial for
patients with lung edema and inammation [63].
A recent clinical trial reports some improvement in infants with
MAS after the early administration of nebulized budesonide but
with no impact on the nal outcome [64]. Recent publications on
the instillation of budesonide in suspension with surfactant in
animal models of MAS and one clinical trial in infants suggest some
positive benets [65e67]. However, at this juncture, glucocorti-
coids cannot be recommended for infants with MAS routinely.
7.7. Bedside care and decision-making
The mortality rate for severe MAS has declined signicantly in
developed countries over the last forty years. Why? The individual
therapies routinely used for MAS either show no or only a modest
impact on mortality. This suggests there is some contribution of
supportive care and bedside decision-making in improving the
outcome but which cannot be quantied. Any experienced clinician
recognizes that an infant with severe MAS and labile pulmonary
hypertension is among the sickest patients in the NICU; yet, they
now rarely die. Continuous bedside observations and attention to
detail by both the nursing staff and the most experienced physi-
cians are necessary to optimize outcomes. The condition of these
infants is extremely labile and their management requires a dy-
namic approach. These are not patients who can be optimally
managed by twice-a-day rounds or by inexperienced personnel.
8. Conclusions
The designation MAS reects a spectrum of disorders occur-
ring in newborn infants born with MSAF, ranging from mild and
short-term tachypnea to severe respiratory distress requiring
maximum therapies and implying potential mortality. Because of
the lack of a universally accepted denition it is difcult to deter-
mine the exact incidence. The frequency of MAS increases with the
length of gestation and is elevated in post-term pregnancies. The
risk and severity of the disease are highest when asphyxia is also
present. Pulmonary hypertension plays a signicant role in the
severity and outcome. Prevention with prenatal suctioning of the
nose, mouth, and hypopharynx is ineffective, as is endotracheal
intubation and suctioning of vigorous infants. Intubation and suc-
tioning of non-breathing infants with MSAF may also be ineffective,
but larger RCTs are needed to conrm the results. Therapy for MAS
is primarily directed to managing hypoxemia and respiratory fail-
ure. Oxygen, mechanical ventilation, and iNO (for PPHN) are the
mainstays of treatment. Surfactant may be tried in infants with
severe parenchymal involvement. Bronchoalveolar lavage with
dilute surfactant is a risky procedure that needs further research.
HFV is effective as a rescue therapy in some infants but has not
demonstrated advantages as the primary strategy. ECMO is often
the ultimate rescue therapy. Antibiotics and steroids have not
demonstrated effectiveness but are selectively used. New therapies
Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
5
including anti-inammatory drugs are currently under investiga-
tion. MAS continues to be a serious threat to newborn infants,
especially in areas of the world with poor obstetrical surveillance, a
high rate of post-term pregnancy, and frequent birth asphyxia.
8.1. Practice points
 The lack of a standardized denition hinders interpretation of
the medical literature.
 The frequency of MAS increases with the length of gestation and
is elevated in post-term pregnancies.
 The risk and severity are highest when asphyxia is also present.
 Pulmonary hypertension plays a signicant role in the severity
and outcome.
 Prevention with prenatal suctioning of the nose, mouth, and
hypopharynx is ineffective, as is endotracheal intubation and
suctioning of vigorous infants.
8.2. Research directions
 Evaluation of intubation and suctioning in non-vigorous infants.
 Role of antibiotic therapy.
 Use of surfactant replacement therapy.
 Investigation of anti-inammatory agents in MAS.
Funding sources
None.
Conict of interest statement
None declared.
Acknowledgements
We are grateful to all those who give good care to our patients at
the bedside and allow us time for research, teaching, and writing.
References
[1] Cleary GM, Wiswell TE. Meconium-stained amniotic uid and the meconium
aspiration syndrome. An update Pediatr Clin North Am 1998;45:511e29.
[2] Wiswell TE, Gannon CM, Jacob J, et al. Delivery room management of the
apparently vigorous meconium-stained neonate: results of the multicenter,
international collaborative trial. Pediatrics 2000;105(1 Pt 1):1e7.
[3] Vain NE, Szyld EG, Prudent LM, Wiswell TE, Aguilar AM, Vivas NI. Oropha-
ryngeal and nasopharyngeal suctioning of meconium-stained neonates before
delivery of their shoulders: multicentre, randomised controlled trial. Lancet
2004;364:597e602.
[4] Oyelese Y, Culin A, Ananth CV, Kaminsky LM, Vintzileos A, Smulian JC.
Meconium stained amniotic uid across gestation and neonatal acidebase
status. Obstet Gynecol 2006;108:345e9.
[5] Fischer C, Rybakowski C, Ferdynus C, Sagot P, Gouyon JB. A population-based
study of meconium aspiration syndrome in neonates born between 37 and 43
weeks of gestation. Int J Pediatr 2012;2012:321545.
[6] Aguilar AM, Vain NE. The suctioning in the delivery room debate. Early Hum
Dev 2011;87(Suppl 1):S13e5.
[7] Vayssiere C, Haumonte JB, Chantry A, et al. Prolonged and post-term preg-
nancies: guidelines for clinical practice from the French College of Gynecol-
ogists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2013;169:
10e6.
[8] Saleh AM, Dudenhausen JW, Ahmed B. Increased rates of cesarean sections
and large families: a potentially dangerous combination. J Perinat Med 2016
Nov 8. http://dx.doi.org/10.1515/jpm-2016-0242. pii: /j/jpme.ahead-of-print/
jpm-2016-0242/jpm-2016-0242.xml, [Epub ahead of print].
[9] Hofer N, Jank K, Resch E, Urlesberger B, Reiterer F, Resch B. Meconium aspi-
ration syndrome e a 21-years' experience from a tertiary care center and
analysis of risk factors for predicting disease severity. Klin Padiatr 2013;225:
383e8.
[10] Ghidini A, Spong CY. Severe meconium aspiration syndrome is not caused by
aspiration of meconium. Am J Obstet Gynecol 2001;185:931e8.
6 N.E. Vain, D.G. Batton / Seminars in Fetal & Neonatal Medicine xxx (2017) 1e6
[11] Lee J, Romero R, Lee KA, Kim EN, Korzeniewski SJ, Chaemsaithong P, et al.
Meconium aspiration syndrome: a role for fetal systemic inammation. Am J
Obstet Gynecol 2016;214(366):e1e9.
[12] Lindenskov PH, Castellheim A, Saugstad OD, Mollnes TE. Meconium aspiration
syndrome: possible pathophysiological mechanisms and future potential
therapies. Neonatology 2015;107:225e30.
[13] Okazaki K, Kondo M, Kato M, et al. Serum cytokine and chemokine proles in
neonates with meconium aspiration syndrome. Pediatrics 2008;121:e748e53.
[14] Brown BL, Gleicher N. Intrauterine meconium aspiration. Obstet Gynecol
1981;57:26e9.
[15] Murphy JD, Vawter GF, Reid LM. Pulmonary vascular disease in fatal meco-
nium aspiration. J Pediatr 1984;104:758e62.
[16] Vain NE, Szyld EG, Prudent LM, Aguilar AM. What (not) to do at and after
delivery? Prevention and management of meconium aspiration syndrome.
Early Hum Dev 2009;85:621e6.
[17] Donn SM, Dalton J. Surfactant replacement therapy in the neonate: beyond
respiratory distress syndrome. Respir Care 2009;54:1203e8.
[18] Kopincova J, Calkovska A. Meconium-induced inammation and surfactant
inactivation: specics of molecular mechanisms. Pediatr Res 2016;79:514e21.
[19] Saccone G, Berghella V. Induction of labor at full term in uncomplicated
singleton gestations: a systematic review and metaanalysis of randomized
controlled trials. Am J Obstet Gynecol 2015;213:629e36.
[20] Glmezoglu AM, Crowther CA, Middleton P, Heatley E. Induction of labour for
improving birth outcomes for women at or beyond term. Cochrane Database
Syst Rev 2012;(6):CD004945.
[21] American College of Obstetricians and Gynecologists. Practice bulletin no.
146: management of late-term and postterm pregnancies. Obstet Gynecol
2014;124(2 Pt 1):390e6.
[22] Hofmeyr GJ, Xu H, Eke AC. Amnioinfusion for meconium-stained liquor in
labour. Cochrane Database Syst Rev 2014;(1):CD000014.
[23] Romero R, Hanaoka S, Mazor M, et al. Meconium-stained amniotic uid: a risk
factor for microbial invasion of the amniotic cavity. Am J Obstet Gynecol
1991;164:859e62.
[24] Josephson A. An epidemiologic study of postcesarean infection. Am J Infect
Control 1984;12:19e25.
[25] Piper JM, Newton ER, Berkus MD, Peairs WA. Meconium: a marker for peri-
partum infection. Obstet Gynecol 1998;91(5 Pt 1):741e5.
[26] Tran SH, Caughey AB, Musci TJ. Meconium-stained amniotic uid is associated
with puerperal infections. Am J Obstet Gynecol 2003;189:746e50.
[27] Siriwachirachai T, Sangkomkamhang US, Lumbiganon P, Laopaiboon M. An-
tibiotics for meconium-stained amniotic uid in labour for preventing
maternal and neonatal infections. Cochrane Database Syst Rev 2014;(11):
CD007772.
[28] American Academy of Pediatrics and the American College of Obstetricians
and Gynecologists. Guidelines for perinatal care. fourth ed. Elk Grove Village,
IL: AAP/ACOG; 1997. p. 117e8.
[29] Carson BS, Losey RW, Bowes Jr WA, Simmons MA. Combined obstetric and
pediatric approach to prevent meconium aspiration syndrome. Am J Obstet
Gynecol 1976;15(126):712e5.
[30] Falciglia HS. Failure to prevent meconium aspiration syndrome. Obstet
Gynecol 1988;71:349e53.
[31] Falciglia HS, Henderschott C, Potter P, Helmchen R. Does DeLee suction at the
perineum prevent meconium aspiration syndrome? Am J Obstet Gynecol
1992;167:1243e9.
[32] Kattwinkel J. Textbook of neonatal resuscitation. 5 ed. American Academy of
Pediatrics and American Heart Association; 2006.
[33] International Liaison Committee on Resuscitation (ILCOR) consensus on sci-
ence with treatment recommendations for pediatric and neonatal patients:
neonatal resuscitation. Pediatrics 2006;17:e978e88.
[34] American College of Obstetrics and Gynecology. Committee Opinion No. 379.
Management of delivery of a newborn with meconium-stained amniotic uid.
Obstet Gynecol 2007;110:739.
[35] Lin HC, Wu SY, Wu JM, Yeh TF. Meconium aspiration syndrome: experiences
in Taiwan. J Perinatol 2008;28:S43e8.
[36] Bhutani VK. Developing a systems approach to prevent meconium aspiration
syndrome: lessons learned from multinational studies. J Perinatol 2008;28:
S30e5.
[37] Nangia S, Pal MM, Saili A, Gupta U. Effect of intrapartum oropharyngeal (IP-
OP) suction on meconium aspiration syndrome (MAS) in developing country:
a RCT. Resuscitation 2015;97:83e7.
[38] James LS. Resuscitation procedures in the delivery room. In: Abramson H,
editor. Resuscitation of newborn infant. St Louis: CV Mosby; 1960. p. 141e61.
[39] Gregory GA, Gooding CA, Phibbs RH, Tooley WH. Meconium aspiration in
infants e a prospective study. J Pediatr 1974;85:848e52.
[40] Linder N, Aranda JV, Tsur M, et al. Need for endotracheal intubation and
suction in meconium-stained neonates. J Pediatr 1988;112:613e5.
[41] Kattwinkel J, Niermeyer S, Nadkarni V, et al. An advisory statement from the
pediatric working group of the international Liaison committee on
Please cite this article in press as: Vain NE, Batton DG, Meconium aspiration (or respiratory distress associated with meconium-stained
amniotic uid?), Seminars in Fetal & Neonatal Medicine (2017), http://dx.doi.org/10.1016/j.siny.2017.04.002
resuscitation. Pediatrics 1999;103:e56.
[42] Kabbur PM, Herson VC, Zaremba S, Lerer T. Have the year 2000 neonatal
resuscitation program guidelines changed the delivery room management or
outcome of meconium stained infants? J Perinatol 2005;25:694e7.
[43] Aguilar AM, Satragno DS, Vain NE, Szyld EG, Prudent LM. Delivery room
practices in infants born through meconium stained amniotic uid: a national
survey. Archs Argent Pediatr 2010;108:31e9.
[44] Michel F, Nicaise C, Camus T, et al. Management of newborns with meconium-
stained amniotic uid: prospective evaluation of practice. Ann Fr Anesth
Reanim 2010;29:605e9.
[45] Iriondo M, Thio  M, Buro n E, Salguero E, Aguayo J, Vento M. A survey of
neonatal resuscitation in Spain: gaps between guidelines and practice. Acta
Paediatr 2009;98:786e91.
[46] Perlman JM, Wyllie J, Kattwinkel J, et al. Part 11: neonatal resuscitation: 2010
international consensus on cardiopulmonary resuscitation and emergency
cardiovascular care science with treatment recommendations. Circulation
2010;122:S516e38.
[47] Chettri S, Adhisivam B, Bhat BV. Endotracheal suction for nonvigorous neo-
nates born through meconium stained amniotic uid: a randomized
controlled trial. J Pediatr 2015;166:1208e13.
[48] Nangia S, Sunder S, Biswas R, Saili A. Endotracheal suction in term non
vigorous meconium stained neonates e a pilot study. Resuscitation 2016;105:
79e84.
[49] Wyllie J, Perlman JM, Kattwinkel J, et al. Part 7: neonatal resuscitation: 2015
international consensus on cardiopulmonary resuscitation and emergency
cardiovascular care science with treatment recommendations. Resuscitation
2015;95:e169e201.
[50] Wyckoff MH, Aziz K, Escobedo MB, et al. Part 13: neonatal Resuscitation: 2015
American heart association guidelines update for cardiopulmonary resusci-
tation and emergency cardiovascular care. Circulation 2015;132:S543e60.
[51] Schreiner MS, Feltman D, Wiswell T, et al. When is waiver of consent
appropriate in a neonatal clinical trial? Pediatrics 2014;134:1006e12.
[52] Vain NE, Barrington KJ. Feasibility of evaluating treatment of early hypoten-
sion in extremely low birth weight infants. J Pediatr 2012;161:4e7.
[53] Vain NE, Musante GA, Mariani GL. Meconium stained newborns: ethics for
evidence in resuscitation. J Pediatr 2015;166:1109e12.
[54] Beligere N, Rao R. Neurodevelopmental outcome of infants with meconium
aspiration syndrome: report of a study and literature review. J Perinatol
2008;28:S93e101.
[55] Dargaville PA. Respiratory support in meconium aspiration syndrome: a
practical guide. Int J Pediatr 2012;2012:965159.
[56] Goldsmith JP. Continuous positive airway pressure and conventional me-
chanical ventilation in the treatment of meconium aspiration syndrome.
J Perinatol 2008;28:S49e55.
[57] Sharma S, Clark S, Abubakar K, Keszler M. Tidal volume requirement in me-
chanically ventilated infants with meconium aspiration syndrome. Am J
Perinatol 2015;32:916e9.
[58] El Shahed AI, Dargaville PA, Ohlsson A, Soll R. Surfactant for meconium
aspiration syndrome in term and late preterm infants. Cochrane Database Syst
Rev 2014;(12):CD002054.
[59] Hahn S, Choi HJ, Soll R, Dargaville PA. Lung lavage for meconium aspiration
syndrome in newborn infants. Cochrane Database Syst Rev 2013;(4):
CD003486.
[60] Short BL. Extracorporeal membrane oxygenation: use in meconium aspiration
syndrome. J Perinatol 2008;28:S79e83.
[61] Goel A, Nangia S, Saili A, Garg A, Sharma S, Randhawa VS. Role of prophylactic
antibiotics in neonates born through meconium-stained amniotic uid
(MSAF) e a randomized controlled trial. Eur J Pediatr 2015;174:237e43.
[62] Natarajan CK, Sankar MJ, Jain K, Agarwal R, Paul VK. Surfactant therapy and
antibiotics in neonates with meconium aspiration syndrome: a systematic
review and meta-analysis. J Perinatol 2016;36:S49e54.
[63] Mokra D, Mokry J. Glucocorticoids in the treatment of neonatal meconium
aspiration syndrome. Eur J Pediatr 2011;170:1495e505.
[64] Garg N, Choudhary M, Sharma D, Dabi D, Choudhary JS, Choudhary SK. The
role of early inhaled budesonide therapy in meconium aspiration in term
newborns: a randomized control study. J Matern Fetal Neonatal Med 2016;29:
36e40.
[65] Mikolka P, Kopincova  J, Kostov 
a P, Cierny 
D, Calkovsk 
a A, Mokr a D. Lung
inammatory and oxidative alterations after exogenous surfactant therapy
fortied with budesonide in rabbit model of meconium aspiration syndrome.
Physiol Res 2016;65:S653e62.
[66] Lin CH, Jeng MJ, Kuo BI, Kou YR. Effects of surfactant lavage combined with
intratracheal budesonide instillation on meconium-injured piglet lungs.
Pediatr Crit Care Med 2016;17:e287e95.
[67] Tan XZ, Wu SG, Zhang JH, Li XF, Gao PM, Wang Y. Clinical efcacy of porcine
pulmonary surfactant combined with budesonide suspension intratracheal
instillation in the treatment of neonatal meconium aspiration syndrome.
Zhongguo Dang Dai Er Ke Za Zhi 2016;18:1237e41.