meconium passage in utero

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 2005. Instructions for how CME credits can be earned appear onthe last page of the Table of Contents.

Meconium Passage in Utero:Mechanisms, Consequences,

and ManagementSureshbabu N. Ahanya, MD,* Jayaraman Lakshmanan, PhD,†

Brian L.G. Morgan, MD, PhD,‡ and Michael G. Ross, MD, MPH§*Fellow, †Associate Professor, ‡Assistant Professor, and §Professor, Department of OB/GYN, Harbor UCLA

Medical Center, David Geffen School of Medicine at UCLA, Torrance, California

Meconium passage in newborn infants is a developmentally programmed event normally occur-ring within the first 24 to 48 hours after birth. Intrauterine meconium passage in near-term or termfetuses has been associated with fetomaternal stress factors and/or infection, whereas meconiumpassage in postterm pregnancies has been attributed to gastrointestinal maturation. Despite theseclinical impressions, little information is available on the mechanism(s) underlying the normalmeconium passage that occurs immediately after birth or during the intrauterine period of fetaldevelopment. Birth itself is a stressful process and it is possible that fetal stress-mediated bio-chemical events may regulate the meconium passage occurring either during labor or after birth.Aspiration of meconium during intrauterine life may result in or contribute to meconium aspirationsyndrome (MAS), representing a continued leading cause of perinatal death. This article reviewsaspects of meconium passage in utero, its consequences, and management.

Target Audience: Obstetricians & Gynecologists, Family PhysiciansLearning Objectives: After completion of this article, the reader should be able to describe the composition

of meconium, to outline the timetable of fetal gastrointestinal development, to summarize the theories of fetalmeconium passage, to describe the effects of amniotic fluid meconium, to relate the clinical outcome in thepresence of meconium, to describe the condition of meconium aspiration syndrome, and to review the use ofamnioinfusion for amniotic fluid meconium.

Meconium is derived from the Greek word “meko-nion,” meaning poppy juice or opium. Aristotle iscredited for noting the relationship between the pres-ence of meconium in amniotic fluid and a sleepy fetalstate in utero (1). Meconium-stained amniotic fluid,as a result of the passage of fetal colonic contentsinto the amniotic cavity, is noted in approximately12% of all deliveries. Meconium aspiration syn-

drome (MAS) is noted in 5% of these infants andmore than 4% of MAS infants die (2), accounting for2% of all perinatal deaths (3).

In utero, meconium passage rarely occurs before 32weeks of gestation and most babies with meconium-stained amniotic fluid are 37 weeks or older (4). Theincidence of meconium-stained amniotic fluid increaseswith the gestational age, reaching as high as 30% inpostterm pregnancies. An increased incidence of meco-nium passage into the amniotic cavity is also noted inthe presence of fetomaternal stress factors such as hyp-oxia and infection, independent of fetal maturation.

Meconium itself may have potentially detrimentaleffects on fetal tissues and organs, although fetuses

The authors have disclosed that they have no financial relation-ships with or interests in any commercial companies pertaining tothis educational activity.

Reprint requests to: Michael G. Ross, MD, MPH. Harbor-UCLAMedical Center, Department of Ob/Gyn, 1000 W. Carson St., Box3, Torrance, CA 90509. E-mail: [email protected].

CME REVIEWARTICLEVolume 60, Number 1OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2004by Lippincott Williams & Wilkins 1

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with meconium-stained amniotic fluid born are com-monly born without any adverse sequelae. Amongthe adverse effects, meconium in the amniotic fluidhas been suggested to stimulate umbilical vessel con-striction, vessel necrosis, and production of thrombi,potentially associated with ischemic cerebral palsy(5). Meconium alters the level of zinc in amnioticfluid, which may reduce the antibacterial propertiesand possibly facilitate intraamniotic infection. In thepresence of fetal stress such as hypoxia, the gaspingactions of the fetus may aspirate meconium into itslungs where meconium may neutralize the action ofsurfactant and promote lung tissue inflammation byactivating neutrophils and macrophages. In the pres-ence of continued hypoxia after birth, aspiratedmeconium may contribute to pulmonary vascular hy-pertrophy and possibly pulmonary hypertension. Al-ternatively, Ghidini and Spong (6) have suggestedthat MAS may be a response to previous perinatalasphyxia and associated meconium passage, al-though the pulmonary process may not be dependenton the presence of meconium. Meconium has beenassociated with additional adverse events increasedpreterm labor (7), altered coagulation profile in thefetus, and neonatal seizures (8,9). Although the directand indirect effects remain uncertain, meconium-stained amniotic fluid is consistently identified as apredictor of maternal and perinatal complications.

The incidence of meconium-stained amniotic fluidhas remained approximately 12% since the last cen-tury. However, the incidence of MAS has decreasedmarkedly during the past 20 years. Yoder et al. (10)reported a nearly 4-fold decrease in the incidence ofMAS from 1990–1992 to 1997–1998 (5.8% to 1.5%of meconium-stained infants more than 37 weeks)possibly as a result of early induction, liberal use ofamnioinfusion, and increased cesarean section rate.Although there are recommended intrapartum andpostpartum clinical strategies for the prevention ofMAS (10,11), autopsy studies suggest that mostmeconium aspiration occurs in utero (12–15). Thus,the prevention of fetal passage of meconium intoamniotic fluid, understanding of the mechanism ofclearance of meconium from amniotic fluid, andknowledge of the multiple factors contributing toMAS are essential to the design of therapeutic ap-proaches for the prevention of MAS.

MECONIUM COMPOSITION

Meconium is primarily composed of 72% to 80%water with additional components of intestinal secre-

tions, desquamated squamous cells, lanugo hair, bilepigments, and blood. Meconium also contains pan-creatic enzymes, free fatty acids, porphyrins (16),interleukin-8, and phospholipase A2 (2). Largeamounts of bile pigments excreted by the biliary tractfrom the fourth month of gestation gives meconiumits green color (1). Meconium contains primary bileacids with a small quantity of secondary bile acids,presumably as a result of transplacental passage fromthe maternal circulation, because there is a lack ofbacterial metabolism in the fetus (1).

FETAL GASTROINTESTINALDEVELOPMENT

In human pregnancies, the fetal gastrointestinaltract originates from endoderm and splanchnic me-soderm by day 14 after fertilization and is lined byundifferentiated cuboidal cells by day 18 (1). Intes-tinal villi appear by the seventh week and activeabsorption of glucose and amino acids occur in the10th and 12th weeks, respectively. The cecum is firstidentified by the fifth week of fetal life (1), teniae andhaustra appear by the 12th week, and peristalticwaves and motility are initiated by the eighth week(17). Meissner’s and Auberbach’s plexuses are re-ported as early as the eighth and 12th weeks ofgestation, respectively (1), whereas Peyer patches arewell developed by the 20th week (1,18).

The first evidence of meconium in the fetal intestineappears at approximately the 10th week to 12th week ofgestation (19). Meconium slowly moves into the colonby the 16th week of gestation (19). The highest levels ofintestinal enzymes (disaccharidases, alkaline phospha-tase) in the amniotic fluid occur between the 14th and22nd weeks of gestation (20–22), suggesting early sec-ond-trimester passage of colonic contents, perhaps con-tributing to the discolored amniotic fluid occasionallynoted with midtrimester amniocentesis. The subsequentdecrease in amniotic fluid gastrointestinal enzyme con-centration coincides with the development of analsphincter function (20th to 22nd week of gestation),suggesting that meconium may be continually clearedfrom the amniotic fluid. Ciftci et al. (23) hypothesizedthat the presence of meconium in the amniotic cavity isthe result of the impaired clearance, rather than in-creased passage, of physiologically produced fecal mat-ter. Accordingly, the relatively clear amniotic fluid inthe majority of pregnancies is either the result of anabsence of meconium passage or perhaps the clearanceof meconium by fetal swallowing (24).

46 Obstetrical and Gynecological Survey

THEORIES OF MECONIUM PASSAGE

In the adult, bowel motor activity is controlled bycomplex local hormonal and myogenic activity. Def-ecation is initiated by reflexes evoked when fecalmatter enters the rectum. Distension of the rectal wallinitiates afferent signals that spread through the my-enteric plexus to initiate peristaltic waves in thedescending colon, sigmoid, and rectum, forcing fecalmatter toward the anus. In the adult, voluntarilyincreased intraabdominal pressure, achieved by clo-sure of the glottis, depression of the diaphragm, andtensing of the abdominal muscles, relaxes the striatedpelvic floor muscles and the anal sphincter, allowingtransanal passage of the contents. When emptying iscomplete, the internal anal sphincter and striatedmuscle contract together, closing the anal canal (25).

Our knowledge of fetal bowel activity and meco-nium passage is limited. It remains to be establishedwhether the mechanisms that regulate fetal bowelactivity and meconium passage are similar to theadult. Although the mechanism(s) contributing di-rectly to meconium passage are unknown, the currentbelief is that fetomaternal stress factors or fetal ma-turity contribute to meconium passage into the am-niotic cavity and perhaps impaired clearance ofmeconium.

MECONIUM PASSAGE

Fetal Stress

The relationship between fetal hypoxia and in-creased intestinal peristalsis has been considered formany years. In earlier human studies, Walker (26)found that meconium was released more frequentlywhen fetal umbilical vein oxygen saturation wasbelow 30%. Furthermore, thick meconium was asso-ciated with lower oxygen saturation more often thanlight meconium. Elevated cord blood erythropoietinlevels have been noted in fetuses with advancedgestation and in fetuses with meconium passage atany gestational age, possibly indicating that an ele-ment of chronic hypoxia contributes to the passage ofmeconium in utero (27,28). In support of a chronicstress mechanism, Manning and coworkers (29) re-ported that amniotic fluid meconium occurs morethan twice as often if the last biophysical profile(BPP) score was �6 as compared with a BPP scoreof �8. Among animal studies, meconium passagecommonly occurs with the occurrence of severewastage syndrome in fetal lambs surviving an exper-imental model of single umbilical artery ligation(30). This finding parallels the increased incidence of

meconium passage observed in severely dysmaturehuman fetuses subjected to chronic stress.

The mechanism of stress or hypoxia-mediatedmeconium passage may include only defecation pro-cesses, rather than intestinal motility, because earlierstudies in guinea pigs and monkeys failed to demon-strate an increase in fetal intestinal peristalsis whenanimals were subjected to hypoxia (31,32). Althoughparasympathetic-mediated gastrointestinal stimula-tion has been postulated to result from umbilical cordcompression (31,32), Krebs et al. (33) found no cor-relation between the frequency of variable heart ratedecelerations and the presence of meconium.

Thus, the relationship between hypoxia and pas-sage of meconium into amniotic fluid remains con-troversial. Ciftci et al. (34) demonstrated spontane-ous in utero defecation in fetal rabbits in the absenceof hypoxia. These authors suggested that rather thana fetal stress-mediated meconium passage, meconi-um-stained amniotic fluid indicates impaired clear-ance of meconium resulting from normal in uterodefecation and decreased swallowing. In support ofthis hypothesis, studies in the ovine fetus demon-strate that acute hypoxia markedly reduces fetalswallowing activity (35). Similarly, Lopez and Mar-tinez (36) sonographically observed spontaneous inutero fetal defecation from the 15th to the 41st weekof gestation.

Alternatively, whereas stimulatory mechanisms forcolon contractility are likely present in the adult,inhibitory mechanisms may be predominant duringfetal life. In the adult rat, the neuropeptides cortico-trophin-releasing factor (CRF) and the CRF analogurocortin have been recently observed to induce def-ecation when animals were subjected to restraintstress (37–40). These neuropeptides induce a patternof cecocolonic myoelectric activity characterized byclustered spike bursts of long duration (41). How-ever, the expression of CRF R1 or R2-type receptorsdetermines whether CRF and urocortin stimulates orsuppresses gastrointestinal motility. Accordingly, theCRF-receptor 1 antagonist, administered centrally orperipherally, was effective in inhibiting stress-in-duced defecation (42,43). Thus, the CRF/urocortin—CRF-R1 system mediates defecation in adult animalsunder stressful conditions. Conversely, urocortin in-hibits adult upper gastrointestinal (ie, gastric) motil-ity through action at the CRF-R2 receptor (44).

Placental or hypothalamic CRF and urocortin arereleased into the fetal circulation under stressful con-ditions. In the rat, stress-induced release of norepi-nephrine and epinephrine mobilizes placental CRFand/or urocortin (45,46). However, because recent

Meconium Passage in Utero Y CME Review Article 47

studies in our laboratory indicate that urocortin in-hibits cholinergic-mediated fetal sigmoid colon con-tractility in an organ bath system (47), we hypothe-size that the preterm fetal colon may predominantlyexpress CRF-R2 receptors. However, stress is aknown inducer of CRF-R1 expression in neural cells(48) and thus fetal stress-mediated CRF-R1 receptorexpression in fetal colonic tissue may ultimately po-tentiate in utero meconium passage. In numerousspecies, including humans, fetal plasma cortisolmarkedly increases at birth (49–53) and in responseto in utero stress. We hypothesize that glucocorti-coid-mediated changes in CRF receptor subtype ex-pression may potentiate colonic motility responses toCRF and/or urocortin. Notably, we recently observedthat intragastric injection of betamethasone, in near-term fetal rabbits, consistently elicits meconium pas-sage in utero; a similar finding was not observed insaline-injected rabbits (54). Further studies are re-quired to confirm these postulated mechanisms offetal colonic motility and meconium passage inutero.

Fetal Maturation

Meconium passage is a developmentally pro-grammed postnatal event, because 98% of healthynewborns pass meconium in the first 24 to 48 hoursafter birth (55). Greater than 98% of cases of meco-nium-stained amniotic fluid are noted in fetuses at orfollowing 37 weeks gestation (56). Meconium-stained amniotic fluid commonly occurs in posttermpregnancies and is relatively rare in preterm deliver-ies (57,58). Because approximately 25% of meconi-um-stained amniotic fluid cases are not associatedwith demonstrable hypoxia (57,59), meconium pas-sage thus may represent a normal event associatedwith fetal maturation.

Animal studies have demonstrated the maturationof intestinal motility and colonic-emptying functionwith advancing gestation. Studies in guinea pig tae-nia coli indicate that the motility inhibitory (adren-ergic) system arises before and matures more quicklythan the cholinergic system. Excitatory cholinergictransmission was not seen until birth, indicating thatthe colonic innervation does not achieve maturityuntil birth (60). These mechanisms likely mediate anincrease in gastrointestinal motility at term. In earlierstudies, Becker and associates (31) injected ra-dioopaque thorium salts into the amniotic sac ofguinea pigs and followed the course of thoriumthrough the intestine by radiographs. There was amore rapid transit from amniotic fluid to the stomach

and increased subsequent excretion of dye into theamniotic cavity in the last week of gestation. Simi-larly, Speert in 1943 (32) demonstrated an increase ingastrointestinal motility and rate of propagation ofgastrointestinal contents with increasing gestation inRhesus monkeys. In 1994, Kizilcan et al. (61) dem-onstrated that unstressed fetal goats defecate in uteroat 110 to 114 days of gestation (term � 147–155days). Fetal goats passed contrast into the amnioticcavity in 16 to 24 hours after nasogastric contrastinjection without any signs of hypoxia. Similarly,unstressed fetal rabbits (34) and guinea pigs (31)defecate in utero, although this is uncommon inmonkeys (32).

In human fetuses, amniographic studies demon-strated more rapid gastrointestinal transit with in-creasing gestational age (62). Hormonal and neuralmaturation in the human fetal colon does not occuruntil 38 weeks of gestation (1). Studies in our labo-ratory have indicated that the colonic smooth musclecontractile response to bethanechol, a cholinergicagonist, is greatly augmented by fetal administrationof glucocorticoid and thyroxine (63), suggesting theendocrine-mediated maturation of cholinergic co-lonic contractile machinery. In this connection, it isinteresting to note that the intraamniotic injection ofglucocorticoid and thyroxin in the fetal rhesus mon-key induces meconium passage in utero (64). Itshould be noted here that in most species, includinghumans, a surge in plasma glucocorticoid and thyroidhormones occurs at birth (49–53,65,66). A signifi-cant time delay in meconium passage and subsequentconstipation has been reported in infants born withhypothyroidism (67).

EFFECTS OF AMNIOTICFLUID MECONIUM

Amniotic fluid meconium may act both directlyand indirectly on the exposed tissue, with effectsdependent on the concentration of meconium, dura-tion of exposure, and the presence of associatedstress factors (eg, hypoxia and infection). Meconiumcan stain fetal tissues after sufficient exposure, withstaining of vernix requiring 12 to 14 hours, newbornfingers 4 to 6 hours, and pigment accumulation inmacrophages occurring in only 3 hours (68). Thetime course of staining of fetal tissues is dependenton the meconium concentration in amniotic fluid.Thus, 5% meconium may stain the umbilical cord in1 hour, and placental and umbilical cord tissues inless than 3 hours (69–71). In addition, exposure tomeconium for more than 16 hours may induce um-


bilical cord ulceration and vascular necrosis, poten-tially compromising fetal oxygenation (5). These ef-fects may be the result of bile acids present inmeconium, although the complex composition ofmeconium makes identification of a precise agentdifficult. Meconium may have a vasoconstrictive ef-fect on the umbilical vein that has been postulated toinduce vasospasm and impaired fetal–placental bloodflow (5,72), although this effect has not been dem-onstrated in vivo. In vitro placental studies with oxy-tocin perfusion demonstrate increased vasoconstric-tive effects in meconium-impregnated placenta (73).

Several authors have reported increased rates ofchorioamnionitis with meconium-stained amnioticfluid (74–76), although it is unclear whether this is acause or effect phenomenon. Exposure to meconiumcan alter the bactericidal properties of amniotic fluidand increase the growth of Escherichia coli, Staph-ylococcus aureus, and Listeria monocytogenes sig-nificantly earlier than in exposed controls (77,78).Inhibition of amniotic fluid antibacterial activity (79)may occur through inhibition of neutrophil phago-cytic activity (80) and alterations in zinc concentra-tion (81). Fetal microbial invasion has been proposedto cause inflammatory brain damage through theeffects of elevated cytokines (eg, TNF alpha, IL-1beta, IL-6), and it could be postulated that the meco-nium contributes to this effect by its inhibition ofantibacterial effects of amniotic fluid (81,82).

MECONIUM ASPIRATION SYNDROME

At the pulmonary level, MAS is believed to becaused by a combination of mechanical blockage ofsmall airways and production of chemical pneumo-nitis by the meconium particles inhaled by the infant(83–85). The resulting vasospasm, hypertrophy ofthe pulmonary musculature, and pulmonary hyper-tension lead to right-to-left shunting through the fo-ramen ovale or ductus arteriosus. Meconium directlyinhibits pulmonary function by displacing surfactantwith its free fatty acid content (86) and by directinhibition of surfactant function (87–90). Meconiumcan cause a dose-dependent oxidative burst in neu-trophils with increased levels of leukotrienes, endo-thelin-1, and big ET and ET-1 (vasoactive peptides).Big ET and ET-1 are vasoconstrictors that stimulateNO production and expression of iNOS in the alve-olar macrophages by activation of nuclear factorkappa B, COX2, and NOS2 gene expression. This inturn increases stimulation of macrophages leading tolocal tissue damage in the target organs exposed tomeconium (91–97). Further, interleukin 8 and phos-

pholipase A2 present in the meconium can lead todamage of lung tissue by activation of neutrophilicchemotaxis and neutralization of surfactant, respec-tively. In the murine model, meconium aspirationproduces airway hyperresponsiveness and eosinophilinflammation along with elevated IL-5, IL-13,BALF, lymphocytic inflammation, and goblet cellmetaplasia leading to airway dysfunction (98).

MAS appears dependent on both meconium and fetalhypoxia. In humans, fetal inhalation of the amnioticfluid was demonstrated by injections of chromium-labeled red blood cells into the amniotic fluid (99). Thefetal gasping movements noted with hypoxia increasemeconium aspiration into the lungs and hence the pos-sibility of MAS (100). Ramin et al. reported that 68% ofMAS neonates showed fetal heart rate abnormalities(101). Other studies have demonstrated fetal tachycar-dia (102,103), increased incidence of late decelerations(104,105), and the presence of acidosis in approxi-mately 50% of MAS newborns (101,106,107). Simi-larly, animal studies have demonstrated that fetal meco-nium aspiration is promoted by fetal hypoxia (term fetalsheep) (108), fetal hypoxia or acidosis (monkeys)(12,109), and by acidosis with or without hypoxia (ba-boons) (110). However, Cornish et al. (111) demon-strated that meconium aspiration alone does not lead topulmonary hypertension in term baboons. In this study,the presence of meconium in the lungs significantlyimpaired fetal oxygenation and increased the need forventilatory support. Concurrent asphyxia further poten-tiated this effect, although acute meconium aspirationdid not result in systemic or pulmonary hypertension, orabnormal pulmonary arteriolar muscularization. Evi-dence from animal models in which pulmonary instil-lation of meconium was done before the first breathdemonstrate lung injury reversible with surfactant ad-ministration with symptoms similar to that of mild andmoderate human MAS (88).

Despite the commonly assumed association of fetalstress, meconium passage, and MAS, Ghidini andSpong (6) questioned the role of acute and chronichypoxia, and infection in the development of MAS.These authors suggested that mild and moderateMAS results from in utero inhalation of meconium(consistent with animal studies discussed here),whereas severe MAS is a multifactorial disease re-quiring the presence of hypoxia along with otherfactors, as yet poorly understood. This hypothesis issupported by the lack of studies that directly correlatethe severity of MAS with the amount of meconiumaspirated, the duration of exposure to meconium, orthe “thickness” of meconium. Similarly, studies havebeen unable to correlate the presence of meconium in


the trachea with clinical MAS symptoms. In addition,chest radiographs have not been able to predict theseverity of MAS, implying that additional factors areresponsible for pulmonary symptoms. Thus, the di-agnosis of MAS should be made only after ruling outall other causes for neonatal respiratory compromise.Ghidini and Spong further postulated that severeMAS results from either chronic asphyxia or intra-uterine infection: Chronic hypoxia induces a fetalwasting syndrome, associated with placental isch-emic changes, pulmonary vascular hypertrophy, andpossibly stimulation of hypoxia-sensitive genes. Al-ternatively, intrauterine infection may induce fetalinflammation syndrome, which consists of activationof neutrophils, macrophages, cytokines, and the com-plement system resulting in tissue destruction.

Thus, in utero events other than meconium passagelikely contribute to the complex findings of MAS.Animal models such as the null mutant mice ofactivating transcription factor 2 (ATF-2) may ulti-mately aid in our understanding of MAS pathogen-esis. Null ATF-2 mice develop MAS at delivery anddie with similar features as those exhibited by hu-mans with MAS (112). Activating transcription fac-tor 2 is known to induce a number of genes, includ-ing the hypoxia-inducible genes and platelet-derivedgrowth factor receptors (112). Because the latter isknown to mediate trophoblast mitogenesis, the pla-centa of these mutant mice contained a reduced num-ber of cytotrophoblast. Whether hypoxia alone, orsecondary effects from upregulation of genes andproteins associated with ATF-2 mutations (eg, glu-cose transporter-3, epidermal growth factor-likegrowth factor, GADD45, and insulin growth factor-II), contribute to meconium passage and the pulmo-nary findings of MAS remain to be determined.

CLINICAL OUTCOME IN THE PRESENCEOF MECONIUM

Second-Trimester Passage of Meconium

The incidence of meconium-stained amniotic fluidobtained from second-trimester amniocentesis ap-proximates 1 in 40–55, although various nonstand-ardized methods have been used to identify meco-nium (113–115). Some studies used visual inspectionor spectrophotometry (81,116–119), although it isnot possible to distinguish between blood and meco-nium content by either means. Zorn et al. (119)recommended electrophoresis and gel chromatogra-phy to differentiate meconium from blood pigment inthe amniotic fluid. These authors reported hemoglo-

bin to be the major coloring agent in 33 of 34specimens of stained amniotic fluid, with only 3 ofthe 34 specimens reported to have a pigment consis-tent with meconium. Although fetal loss rates vary-ing from 5% to 30% have been associated with thepresence of second-trimester meconium-stained am-niotic fluid, this staining likely represents hemoglo-bin because there was a further increase in fetal lossrates in patients with a history of first-trimesterbleeding (116,119). No difference in the outcomewas noted between patients with thick or thin meco-nium-stained amniotic fluid derived from midtrimes-ter genetic amniocentesis (115). These authors sim-ilarly reported increased perinatal complications inthe presence of stained amniotic fluid, regardless ofmeconium or hemoglobin, with a 9% loss rate inpatients with discolored amniotic fluid as comparedwith 1.6% among all amniocentesis patients. Basedon these studies, it remains uncertain whether meco-nium contributes significantly to stained amnioticfluid or, more importantly, to fetal loss after second-trimester amniocentesis.

Third-Trimester Passage of Meconium

Using an amnioscope, Lee (120) noted the pres-ence of meconium in amniotic fluid in 67 of 681high-risk patients (10%), with a perinatal mortalityrate of 4 of 1000 in these patients. Similarly, Man-delbaum (121) detected meconium-stained amnioticfluid in 11.3% of patients having serial amniocente-sis beginning at 30 to 32 weeks gestation. Of thesepatients, 26% experienced fetal demise and 41% hadneonatal complications. Based on these observations,the author recommended active intervention in pa-tients with meconium-stained amniotic fluid in thethird trimester. Similarly, Kasper et al. (122) notedcomparatively worse outcomes in fetuses exposed tomeconium chronically as opposed to acutely. Con-versely, Saldana et al. (123) performed weekly am-nioscopy, detecting meconium-stained amniotic fluidin only 2.2% of the 508 patients. No adverse effectswere found when these patients were managed eitherconservatively or actively (ie, induction of labor).These authors concluded that meconium-stained am-niotic fluid by itself is not an indication for interven-tion, although patients with this finding should besubjected to further fetal evaluation/surveillance.

Intrapartum Meconium

The incidence of the passage of meconium at thetime of delivery ranges from 7% to 22% for term


fetuses and increases up to 40% in postterm fetuses(124,125). Initial studies observed that meconiumpassage in conjunction with an abnormal fetal hearttracing increased perinatal morbidity and mortalityrates (33,126–128) with an increased incidence oflow 1-minute and 5-minute Apgar scores (33,129–133), although additional studies have not demon-strated these findings (28,107,134,135). Similarly,the association between fetal acidosis and meconiumpassage during labor is controversial, being observedby some authors (124,129,132,133) and not others(27,28,33,135,136). Meconium appears to not be anindependent predictor of acidosis (131,137). Thus, inthe absence of fetal heart rate abnormalities, thepresence of meconium does not indicate fetal com-promise and no intervention is necessary other thanclose monitoring (128,137,138). Similarly, amongpostterm patients with normal antepartum testing,women with heavy meconium in early labor have nogreater risk for fetal distress or perinatal morbiditythan women with clear amniotic fluid. These findingssuggest that postterm patients with heavy meconiumin early labor and normal antepartum testing can bemanaged in labor in the same manner as low-riskpatients without meconium (138).

AMNIOINFUSION FOR AMNIOTICFLUID MECONIUM

The association between oligohydramnios and fetalheart tracing abnormalities, particularly variable de-celerations, is well known. Amnioinfusion to correctoligohydramnios acts by decreasing umbilical cordcompression, which potentially improves fetal oxy-genation. Although the majority of meconium aspi-ration likely occurs before labor (discussed previ-ously in this article), it has been hypothesized thatamnioinfusion for meconium-stained amniotic fluidis a result of a reduction in fetal hypoxia-inducedgasping and subsequent meconium aspiration. Be-cause thick meconium generally occurs in the pres-ence of oligohydramnios, a more likely explanationfor the beneficial effects of amnioinfusion for meco-nium is the prevention of variable fetal heart ratedecelerations by amelioration of oligohydramnios.Because hypoxia may aggravate the effects of previ-ously aspirated meconium, prevention of fetal hyp-oxia by amnioinfusion may reduce the incidence ofMAS.

The prophylactic use of amnioinfusion for meco-nium in the absence of fetal heart rate decelerationshas been a controversial topic, in part as a result ofthe limited studies specifically addressing the ques-

tion. As discussed subsequently, the vast majority ofstudies have compared outcomes among patients re-ceiving prophylactic amnioinfusion for meconium(and often oligohydramnios) with patients who werenot provided amnioinfusion, regardless of subse-quent fetal heart rate patterns or the development ofoligohydramnios-associated fetal heart rate deceler-ations. For example, although Wenstrom and Parsons(139) used a randomized design to examine the ef-fects of prophylactic amnioinfusion in laboring pa-tients with thick meconium-stained amniotic fluidand no fetal heart rate abnormalities, the controlgroup was not provided amnioinfusion despite theappearance of variable heart rate decelerations. Inthis study, mothers who received amnioinfusion hadsignificantly fewer operative deliveries and had in-fants with higher 1-minute Apgar scores and lessmeconium below the vocal cords than patients whowere not provided amnioinfusion. Three cases ofMAS were noted in the control group compared withnone in the amnioinfused group (not statisticallysignificant). In a randomized study of laboring pa-tients with moderate to thick meconium-stained am-niotic fluid, Sadovsky et al. (140) reported that am-nioinfusion reduced the concentration of meconiumfrom 79% to 5% and decreased the rate of variablefetal heart rate decelerations and rate of neonatalacidemia, although there was no change in Apgarscores. There was no evidence of meconium belowthe vocal cords in the amnioinfusion group, as com-pared with 29% incidence in the control group. Sim-ilar observations were noted by others (141–144).

Although these studies may initially suggest thatamnioinfusion is beneficial for patients with meco-nium, one needs to determine if there is a benefit tothe use of amnioinfusion prophylactically for meco-nium alone or therapeutically if fetal heart rate de-celerations occur. In a randomized, prospective studyof patients with moderate to thick meconium, Sponget al. (145) compared prophylactic amnioinfusionwith “standard obstetric care,” which included ther-apeutic amnioinfusion only if fetal heart rate decel-erations occurred. There were no significant differ-ences in the incidence of operative delivery, fetaldistress, or meconium below the cords or in newbornApgar scores and umbilical artery gas values be-tween the prophylactic amnioinfusion and controlpatients. There were 4 cases of meconium aspiration,3 in the amnioinfusion group and 1 in the standardcare group. Furthermore, the rate of endometritis–chorioamnionitis was significantly higher in the am-nioinfusion (16%) than in the control group (8%).These results suggest that the benefit of amnioinfu-


sion for meconium-stained amniotic fluid is a resultof the alleviation of variable fetal heart rate deceler-ations rather than meconium dilution. Thus, for pa-tients with moderate to thick meconium and no fetalheart rate abnormalities, physicians may elect eitherto use prophylactic amnioinfusion or therapeutic am-nioinfusion (should variable fetal heart rate deceler-ations occur).

NEONATAL INTERVENTIONS

Management

Although the current definition of MAS suggests aneonatal syndrome, it has its pathophysiological or-igin in intrauterine events. Initially, it was believedthat MAS was caused by inhalation of meconium atthe time of the first breath, because meconium wasnoted in the trachea of infants that developed severerespiratory distress and MAS (11,58,105). Conse-quently, much of the focus was placed on clearingmeconium out of the infant’s pharynx and trachea toprevent MAS. Carson et al. (146) were the first todemonstrate that DeLee suctioning of the pharynxbefore birth with selective intubation reduced theincidence as well as the severity of the MAS. Othersnoted similar results by aggressive tracheal suction-ing (58,147). Controversies have continued regardingoral, nasal, and tracheal suctioning. In fetal kittens,catheter suctioning removed larger quantities ofmeconium than bulb suctioning (148). Pfenninger etal. (149) demonstrated that oral suctioning is betterthan nasal suctioning, although they recommendedthat both should be used in clinical practice together.Several authors have demonstrated similar efficacyof bulb or DeLee suctioning (11), as well as similaroutcomes with DeLee suctioning before the firstbreath as compared with after complete delivery.

Despite the apparent progress in suctioning formeconium, several retrospective studies did not noteany difference in the incidence of meconium belowthe vocal cords or the incidence of MAS with orwithout routine suctioning (150,151) or with vigor-ous suctioning before birth (3,152–154). The lack ofimpact of these interventions may be a result of inutero meconium aspiration, as demonstrated in ani-mal models of fetal hypoxia or acidosis (110). Stud-ies of infants who underwent vigorous suctioningbefore the first breath and studies of autopsies ofstillbirths, which found meconium in alveolar spaces,similarly suggest that the incidence of MAS is notaffected by routine suctioning of the newborn (12–14). Under the present clinical conditions, we recom-

mend nasal or oral suctioning of the meconium-stained fetus on delivery of the head. Pediatricintubation and suctioning is often dependent on thenewborn respiratory condition, with suctioning oftennot performed in the presence of spontaneous new-born breathing.

These results further emphasize the importance ofthe intrauterine and prelabor process for meconiumaspiration. However, because the combination ofhypoxia and meconium passage may potentiateMAS, delivery of the newborn without severe acido-sis may be the primary action that prevents MAS.

SUMMARY

Passage of meconium is a highly regulated postna-tal event. The majority of newborns pass meconiumwithin 48 hours after birth, and 10% to 12% offetuses pass meconium prematurely in utero. Themechanism of regulation of meconium passage isunknown, although fetal stress and maturity maycontribute to gastrointestinal motility. Prolonged ex-posure of meconium to the fetal and placental tissuemay potentially contribute to adverse effects, al-though there are limited in vivo studies. Currently,there is no known way to precisely ascertain thetiming of meconium passage. Importantly, the pres-ence of meconium alone may not lead to MAS.

The majority of the patients with stained amnioticfluid identified during genetic amniocentesis ulti-mately have clear amniotic fluid at delivery. Whetherthis staining represents hemoglobin from the amni-otic environment or colonic meconium is unknown.However, these patients demonstrate an increasedrisk of adverse outcomes if accompanied by first-trimester bleeding. At present, no intervention isrecommended for these patients other than surveil-lance during pregnancy.

Patients with meconium-stained amniotic fluidnoted during the third trimester may need additionalmaternal and fetal surveillance, although there is noconsensus regarding management or prognosis. Pa-tients with moderate or thick meconium-stained am-niotic fluid during the intrapartum period requirecontinuous fetal monitoring throughout labor anddelivery. In laboring patients with thin or thick meco-nium, in the absence of fetal heart rate decelerations,there appears to be no benefit of prophylactic am-nioinfusion versus therapeutic amnioinfusion (per-formed if fetal heart rate decelerations occurred).Alternatively, there are minimal risks of amnioinfu-sion, such that prophylactic amnioinfusion for mod-erate or thick meconium, in the absence of fetal heart


rate decelerations, may be a therapeutic option.Clearly, amnioinfusion efficacy has been demon-strated for patients with moderate or thick meco-nium, together with fetal heart rate variable deceler-ations.

Further research is required to understand the roleof chronic hypoxia, infection, and other fetomaternalstress factors in the development of MAS. Researchinto the understanding of intestinal maturation andthe mechanism of meconium passage may aid inreducing the incidence of meconium passage in uteroand improving perinatal outcome. With understand-ing of the in utero fetal and maternal stress factorsresponsible for meconium passage, we may be betterable to prevent the severe complications of MAS.

ACKNOWLEDGMENTS

This work has been supported by a grant from theMarch of Dimes (MGR).

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