Clin Perinatol 31 (2004) 445–452

Controversies in the treatment of meconium

aspiration syndrome

Steven L. Gelfand, MDa, Jonathan M. Fanaroff, JD, MDa,Michele C. Walsh, MD, MSb,c,*

aDivision of Neonatology, Department of Pediatrics, School of Medicine,

Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-6010, USAbDepartment of Pediatrics, School of Medicine, Case Western Reserve University,

10900 Euclid Avenue, Cleveland, OH 44106-6010, USAcDivision of Neonatology, Rainbow Babies & Children’s Hospital, Mailstop 6010,

Cleveland, OH 44106-6010, USA

Meconium aspiration syndrome (MAS) is a common problem with an es-

timated 25,000 to 30,000 cases and 1000 deaths annually in the United States.

Despite its frequency, management is far from uniform and many controversies

persist. Recently some have questioned whether the incidence of MAS has de-

clined. Approximately 13% of all live births are complicated by meconium-

stained amniotic fluid (MSAF). Fortunately, only 5% of neonates born through

MSAF develop MAS [1,2]. MAS is defined as respiratory distress in an infant

born through MSAF whose symptoms cannot be otherwise explained [2]. Cleary

and Wiswell [2] have proposed severity criteria and have defined mild MAS as

disease requiring less than 40% oxygen for fewer than 48 hours, moderate MAS

as disease requiring greater than 40% oxygen for more than 48 hours with no air

leak, and severe MAS as disease requiring assisted ventilation for more than

48 hours, often associated with persistent pulmonary hypertension (PPHN).

Yoder and colleagues [3] documented a decline in the incidence of MAS from

1990 to 1997 from 5.8% to 1.5%, which they attributed to a 33% reduction in the

incidence of births at more than 41 weeks’ gestation.

0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.clp.2004.03.020

* Corresponding author. Division of Neonatology, Rainbow Babies & Children’s Hospital,

Mailstop 6010, Cleveland, OH 44106-6010.

E-mail address: mcw3@po.cwru.edu (M.C. Walsh).

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452446

Mechanisms of injury

Meconium is toxic to the lungs in many ways and it may be difficult to de-

termine which mechanisms predominate at a given point in time. Some mecha-

nisms of injury are as follows:

� Mechanical obstruction of airways� Chemical pneumonitis� Vasoconstriction of pulmonary vessels� Inactivation of surfactant� Activation of complement

Traditional thinking emphasizes the role of partial obstruction created as viscous

meconium migrates to the distal airways, producing a ‘‘ball-valve’’ effect where

inhaled air is allowed to enter the alveoli but is unable to escape, resulting in air

trapping. The risk for pneumothorax is estimated to be 15% to 33% [2]. More

recent research has elucidated additional deleterious effects that include inflam-

mation, vasoconstriction, and surfactant activation.

Pneumonitis

Meconium seems to have a direct toxic effect mediated by inflammation.

Within hours, neutrophils and macrophages are found in the alveoli, larger air-

ways, and the lung parenchyma. The release of cytokines, such as tumor necrosis

factor-a, interleukin-1b, and interleukin-8, may directly injure lung parenchyma

or lead to vascular leakage causing a toxic pneumonitis with hemorrhagic pul-

monary edema.

Meconium contains many substances, such as bile acids, that, when present

in the amniotic fluid, directly injure the cord vessels and amniotic membranes.

These substances also have a direct vasoconstrictive effect on the placental and

umbilical cord vessels.

Severe MAS may be complicated by PPHN. This pulmonary vasoconstriction

seems to result in part from the underlying in utero stressor. Additionally, the

release of vasoactive mediators, such as eicosanoids, endothelin-1, and prosta-

glandin E2, as a result of injury from meconium seems to play a role in the

development of PPHN [4].

In the early 1990s, it became recognized that meconium inactivates surfactant.

Meconium displaces surfactant from the alveolar surface and inhibits its surface

tension–lowering ability [5]. Studies demonstrate a direct inhibitory effect of

meconium on the function of surfactant in vitro [6] and in animal models in vivo

[7,8]. Lung lavage fluid in infants with MAS has shown evidence of known

surfactant inhibitors [9]. Thus, a full-term baby born with a sufficient quantity of

surfactant may develop surfactant deficiency by inactivation leading to increased

surface tension with atelectasis, decreased lung compliance, decreased lung

volumes, and resultant poor oxygenation [10].

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452 447

Controversies in management

Intrapartum monitoring

The obstetric focus is on interventions to decrease the risk for MAS. Many

authors recommend that, in the case of MSAF, obstetricians carefully monitor the

fetal heart rate tracing and have a low threshold for performing additional testing,

such as fetal scalp pH [11].

A newer modality for monitoring the fetus is fetal pulse oximetry. Fetal pulse

oximetry was approved for use by the US Food and Drug Administration (FDA)

in May 2000 and is finding increased acceptance among obstetricians [12]. In the

case of nonreassuring fetal heart rate patterns, studies have shown a high

correlation between fetal oxygen saturation below 30% and a scalp pH value

of 7.20 [13]. There are some limitations, however. In addition to the membranes

having to be ruptured, the probe cannot be placed until the cervix is dilated at

least 2 to 3 cm. Additionally, with current technology, an adequate signal can be

obtained only approximately 70% of the time [14]. As technology improves and

experience widens, fetal pulse oximetry may improve greatly our abilities to

monitor the at-risk fetus, including those exposed to MSAF.

Amnioinfusion

Amnioinfusion is the primary obstetrical intervention aimed at reducing the

incidence of MAS. During this procedure a sterile isotonic solution (either normal

saline or ringers lactate) is infused into the amniotic cavity through a catheter. By

adding volume into the cavity, not only is the meconium diluted, but the cord

compression may be decreased, relieving hypoxia and therefore decreasing fetal

gasping [15]. There is evidence that amnioinfusion reduces the consistency of

meconium [16]. It is less clear whether amnioinfusion prevents MAS, a difficult

issue to study because of the low incidence of this condition.

Nevertheless, in a prospective, randomized study in pregnancies complicated

by thick meconium and oligohydramnios, amnioinfusion significantly reduced

the rates of fetal distress and MAS [17]. A metanalysis of 13 studies demon-

strated that prophylactic intrapartum amnioinfusion for moderate or thick MSAF

significantly reduced the frequency of MAS (odds ratio [OR] 0.30; 95% con-

fidence interval [CI] 0.19, 0.46), caesarian section rate (OR 0.74; 95% CI 0.59,

0.93), meconium below the vocal cords (OR 0.18; 95% CI 0.11, 0.27), and

neonatal acidemia (OR 0.42; 95% CI 0.28, 0.62) with no increase in the rate of

chorioamnionitis (OR 0.47; 95% CI 0.31, 0.72) [18]. The greatest benefits were

seen in facilities where perinatal surveillance was limited. There was, however,

significant heterogeneity between study results.

There are several reports of relatively common adverse events associated with

amnioinfusion, including increased basal uterine tone, uterine hypertonus, and

fetal bradycardia that may be mitigated by adustment of infusion rate. Although

the procedure seems to be relatively safe, rare complications reported included

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452448

uterine rupture, cord prolapse, abruption, amniotic fluid embolus, and maternal

morbidity or death [18–20]. Because of the potential for complications, many

authors recommend reserving amnioinfusion for patients with signs of cord com-

pression or other fetal distress together with MSAF rather than in cases with

MSAF without distress. There have been case reports of amniotic fluid embolus

and pulmonary edema in mothers treated with amnioinfusion. There seems to be

no significant effect on infants’ electrolyte profile. An international, multicenter,

randomized controlled trial is underway and may define further the role of

prophylactic amnioinfusion in the presence of thick meconium without other

evidence of fetal distress.

When there is moderate to thick meconium accompanied by evidence of fetal

compromise, such as variable fetal heart rate decelerations, however, therapeutic

amnioinfusion may be considered as a potential method to decrease the risk

for MAS.

Intrapartum suctioning

Intrapartum suctioning has been considered standard for over 25 years based

on the seminal work of Carson and colleagues [21]. Wiswell and colleagues [22]

confirmed the effectiveness of intrapartum suctioning in a randomized trial that

evaluated delivery-room management of the vigorous infant. Two thousand

ninety-four neonates were studied at 12 participating centers. Infants were ran-

domized to receive intubation and tracheal suctioning in the delivery room or

were managed expectantly and treated only if they developed symptoms of

respiratory distress. One hundred forty-nine (7.1%) of enrolled infants subse-

quently developed respiratory distress, 62 (3%) of whom were diagnosed with

MAS and 87 (4.2%) of whom were diagnosed with other respiratory disorders

(including transient tachypnea, delayed transition from fetal circulation, sepsis,

and PPHN of the newborn). There was no difference in the rate of MAS in those

intubated (3.2%) and those not intubated (2.7%). In addition, there was no

difference between the groups in subanalyses that adjusted for the thickness of

the meconium in the amniotic fluid. The study found a difference in the rate of

MAS in those who did not receive intrapartum oropharyngeal suction before

delivery of the shoulders compared with those who received suctioning (8.5%

versus 2.7%; OR 3.35; CI 1.55, 7.27) [22].

Ventilatory strategies

The optimal ventilatory modes in MAS are not known. The underlying

pathology predisposes affected infants to air trapping and air-leak syndromes.

Thus, ventilatory strategies that rely on high rates with limited expiratory time

may aggravate this tendency. No randomized trials have compared different forms

of ventilation in MAS. A strategy that emphasizes alveolar recruitment with either

conventional or high frequency ventilation resulted in improved oxygenation and

less ventilator-induced lung injury in an experimental piglet model [23].

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452 449

In the past, hyperventilation was used in cases of MAS associated with PPHN,

but concern for increased barotrauma and adverse impacts on hearing have led

many to question its role [24–26]. Wung and colleagues [27] have advocated a

gentle ventilation strategy for various respiratory disorders, including MAS, with

reported favorable results.

Experimental studies in animals have evaluated the ability of high-frequency

ventilation to facilitate the removal of meconium aspirated into the airways. Se-

vecova and colleagues [28] compared removal of meconium by conventional

and high-frequency ventilation. Compared with conventional ventilation, high-

frequency jet ventilation (HFJV) enhanced carbon-dioxide elimination, increased

lung compliance, and diminished right-to-left shunts. Elimination of meconium,

however, was no different with HFJV than with conventional ventilation.

Surfactant treatment and surfactant lavage

One of the mechanisms of injury in MAS is surfactant inhibition. This ob-

servation has led to the investigation of exogenous surfactant administration [9].

Two randomized, controlled trials have evaluated the efficacy of exogenous

surfactant therapy in MAS. The results have been promising, with a decrease in

the number of infants requiring extracorporeal membrane oxygenation (ECMO),

and a possible reduction in the risk for pneumothorax [10,29]. There was, how-

ever, no difference in mortality.

In an attempt to remove meconium from the lungs, minimize obstruction, and

simultaneously offset inactivation of surfactant, some investigators have exam-

ined lung lavage with dilute surfactant [30,31]. The benefits seem to be an

increase in oxygenation and shortened duration of mechanical ventilation. The

procedure may require sedation, and may be complicated by hypotension or

transient hypoxemia. Nonetheless, this is an exciting area of investigation and

additional trials are warranted.

Surfactants differ in their resistance to the surfactant inhibitors seen in

MAS [32]. The production of new synthetic surfactant preparations highly re-

sistant to inactivation by meconium or other forms of toxic pneumonitis would

be advantageous.

Inhaled nitric oxide and extracorporeal membrane oxygenation

The use of inhaled nitric oxide (iNO) increases oxygenation in neonates with

hypoxic respiratory failure produced by many diseases, including MAS [33–36].

What has remained controversial is the optimal time to begin iNO. Konduuri and

colleagues [37] studied conventional iNO begun at an oxygenation index (OI) of

25 or more versus early iNO begun at an OI of 15 or more. Two hundred ninety-

nine infants were randomized to the two treatment strategies in this trial, which

was terminated early at 75% of the initial sample size because of slow re-

cruitment. Early initiation of iNO improved oxygenation compared with placebo.

Early initiation of iNO compared with standard iNO did not change the incidence

0

200

400

600

800

1000

1200

1400

1600

1986 1988 1990 1992 1994 1996 1998 2000 2002

Neo

nata

l Cas

es

Fig. 1. The frequency of neonatal hypoxic respiratory failure treated with ECMO has steadily declined

since the introduction and licensing of iNO in the mid-1990s.

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452450

of the combined endpoint ECMO or death (16.7% versus 19.5%, P = 0.53),

ECMO (10.7% versus 12.1%, P = 0.385), or death (6.7% versus 9.4%, P = 0.70).

Infants in the two groups also did not differ in length of hospital stay, duration of

ventilation, or incidence of chronic lung disease. Thus, initiation of iNO at this

earlier disease severity did not improve patient outcomes. Another striking find-

ing in this study is the substantial decrease in ECMO/death (18.1%) in this cohort

compared with that in previous trials of iNO (35%). Although the reasons for this

difference are not clear, the investigators speculated that close tracking of OI

early in the disease course might have led to expeditious implementation of iNO

when the OI exceeded 25. The lack of efficacy of early iNO is accompanied by

increased expense, as has been shown in several analyses of the cost-effective-

ness of iNO. This multicenter trial answers the question of the optimal time for

initiation of iNO.

The approval of iNO by the FDA in 2001 has had a substantial impact on the

use of ECMO as a last-resort treatment for neonatal hypoxic respiratory failure

[38]. As shown in Fig. 1, use of ECMO has continued to fall in the registry of the

Extracorporeal Life Support Organization. Despite selection of only the sickest

infants for treatment with ECMO, survival among neonates treated with ECMO

for MAS remains high at 88% [39].

Summary

MAS remains an infrequent but challenging condition confronting neonatolo-

gists. Avoidance of postterm pregnancies, improved intrapartum monitoring,

and amnioinfusion have been beneficial. Studies have not demonstrated con-

clusively that any form of ventilation is superior to others, but strategies that

recruit alveoli are desirable. Surfactant lavage or replacement may be beneficial.

S.L. Gelfand et al / Clin Perinatol 31 (2004) 445–452 451

When hypoxic respiratory failure progresses, iNO may improve oxygenation and

avoid ECMO.

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