Volume 60, Number 1 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright 2004 by Lippincott Williams & Wilkins

CME REVIEWARTICLE

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

Meconium Passage in Utero: Mechanisms, Consequences, and Management

Sureshbabu 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 occurring within the first 24 to 48 hours after birth. Intrauterine meconium passage in near-term or term fetuses has been associated with fetomaternal stress factors and/or infection, whereas meconium passage in postterm pregnancies has been attributed to gastrointestinal maturation. Despite these clinical impressions, little information is available on the mechanism(s) underlying the normal meconium passage that occurs immediately after birth or during the intrauterine period of fetal development. Birth itself is a stressful process and it is possible that fetal stress-mediated biochemical 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 aspiration syndrome (MAS), representing a continued leading cause of perinatal death. This article reviews aspects of meconium passage in utero, its consequences, and management. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning 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 fetal meconium passage, to describe the effects of amniotic fluid meconium, to relate the clinical outcome in the presence of meconium, to describe the condition of meconium aspiration syndrome, and to review the use of amnioinfusion for amniotic fluid meconium.

Meconium is derived from the Greek word mekonion, meaning poppy juice or opium. Aristotle is credited for noting the relationship between the presence of meconium in amniotic fluid and a sleepy fetal state in utero (1). Meconium-stained amniotic fluid, as a result of the passage of fetal colonic contents into the amniotic cavity, is noted in approximately 12% of all deliveries. Meconium aspiration synThe authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to this educational activity. Reprint requests to: Michael G. Ross, MD, MPH. Harbor-UCLA Medical Center, Department of Ob/Gyn, 1000 W. Carson St., Box 3, Torrance, CA 90509. E-mail: mikeross@ucla.edu. 45

drome (MAS) is noted in 5% of these infants and more than 4% of MAS infants die (2), accounting for 2% of all perinatal deaths (3). In utero, meconium passage rarely occurs before 32 weeks of gestation and most babies with meconiumstained amniotic fluid are 37 weeks or older (4). The incidence of meconium-stained amniotic fluid increases with the gestational age, reaching as high as 30% in postterm pregnancies. An increased incidence of meconium passage into the amniotic cavity is also noted in the presence of fetomaternal stress factors such as hypoxia and infection, independent of fetal maturation. Meconium itself may have potentially detrimental effects on fetal tissues and organs, although fetuses

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with meconium-stained amniotic fluid born are commonly born without any adverse sequelae. Among the adverse effects, meconium in the amniotic fluid has been suggested to stimulate umbilical vessel constriction, vessel necrosis, and production of thrombi, potentially associated with ischemic cerebral palsy (5). Meconium alters the level of zinc in amniotic fluid, which may reduce the antibacterial properties and possibly facilitate intraamniotic infection. In the presence of fetal stress such as hypoxia, the gasping actions of the fetus may aspirate meconium into its lungs where meconium may neutralize the action of surfactant and promote lung tissue inflammation by activating neutrophils and macrophages. In the presence of continued hypoxia after birth, aspirated meconium may contribute to pulmonary vascular hypertrophy and possibly pulmonary hypertension. Alternatively, Ghidini and Spong (6) have suggested that MAS may be a response to previous perinatal asphyxia and associated meconium passage, although the pulmonary process may not be dependent on the presence of meconium. Meconium has been associated with additional adverse events increased preterm labor (7), altered coagulation profile in the fetus, and neonatal seizures (8,9). Although the direct and indirect effects remain uncertain, meconiumstained amniotic fluid is consistently identified as a predictor of maternal and perinatal complications. The incidence of meconium-stained amniotic fluid has remained approximately 12% since the last century. However, the incidence of MAS has decreased markedly during the past 20 years. Yoder et al. (10) reported a nearly 4-fold decrease in the incidence of MAS from 19901992 to 19971998 (5.8% to 1.5% of meconium-stained infants more than 37 weeks) possibly as a result of early induction, liberal use of amnioinfusion, and increased cesarean section rate. Although there are recommended intrapartum and postpartum clinical strategies for the prevention of MAS (10,11), autopsy studies suggest that most meconium aspiration occurs in utero (1215). Thus, the prevention of fetal passage of meconium into amniotic fluid, understanding of the mechanism of clearance of meconium from amniotic fluid, and knowledge of the multiple factors contributing to MAS are essential to the design of therapeutic approaches 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, bile pigments, and blood. Meconium also contains pancreatic enzymes, free fatty acids, porphyrins (16), interleukin-8, and phospholipase A2 (2). Large amounts of bile pigments excreted by the biliary tract from the fourth month of gestation gives meconium its green color (1). Meconium contains primary bile acids with a small quantity of secondary bile acids, presumably as a result of transplacental passage from the maternal circulation, because there is a lack of bacterial metabolism in the fetus (1).

FETAL GASTROINTESTINAL DEVELOPMENT In human pregnancies, the fetal gastrointestinal tract originates from endoderm and splanchnic mesoderm by day 14 after fertilization and is lined by undifferentiated cuboidal cells by day 18 (1). Intestinal villi appear by the seventh week and active absorption of glucose and amino acids occur in the 10th and 12th weeks, respectively. The cecum is first identified by the fifth week of fetal life (1), teniae and haustra appear by the 12th week, and peristaltic waves and motility are initiated by the eighth week (17). Meissners and Auberbachs plexuses are reported as early as the eighth and 12th weeks of gestation, respectively (1), whereas Peyer patches are well developed by the 20th week (1,18). The first evidence of meconium in the fetal intestine appears at approximately the 10th week to 12th week of gestation (19). Meconium slowly moves into the colon by the 16th week of gestation (19). The highest levels of intestinal enzymes (disaccharidases, alkaline phosphatase) in the amniotic fluid occur between the 14th and 22nd weeks of gestation (2022), suggesting early second-trimester passage of colonic contents, perhaps contributing to the discolored amniotic fluid occasionally noted with midtrimester amniocentesis. The subsequent decrease in amniotic fluid gastrointestinal enzyme concentration coincides with the development of anal sphincter function (20th to 22nd week of gestation), suggesting that meconium may be continually cleared from the amniotic fluid. Ciftci et al. (23) hypothesized that the presence of meconium in the amniotic cavity is the result of the impaired clearance, rather than increased passage, of physiologically produced fecal matter. Accordingly, the relatively clear amniotic fluid in the majority of pregnancies is either the result of an absence of meconium passage or perhaps the clearance of meconium by fetal swallowing (24).

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THEORIES OF MECONIUM PASSAGE In the adult, bowel motor activity is controlled by complex local hormonal and myogenic activity. Defecation is initiated by reflexes evoked when fecal matter enters the rectum. Distension of the rectal wall initiates afferent signals that spread through the myenteric plexus to initiate peristaltic waves in the descending colon, sigmoid, and rectum, forcing fecal matter toward the anus. In the adult, voluntarily increased intraabdominal pressure, achieved by closure of the glottis, depression of the diaphragm, and tensing of the abdominal muscles, relaxes the striated pelvic floor muscles and the anal sphincter, allowing transanal passage of the contents. When emptying is complete, the internal anal sphincter and striated muscle contract together, closing the anal canal (25). Our knowledge of fetal bowel activity and meconium passage is limited. It remains to be established whether the mechanisms that regulate fetal bowel activity and meconium passage are similar to the adult. Although the mechanism(s) contributing directly to meconium passage are unknown, the current belief is that fetomaternal stress factors or fetal maturity contribute to meconium passage into the amniotic cavity and perhaps impaired clearance of meconium. MECONIUM PASSAGE Fetal Stress The relationship between fetal hypoxia and increased intestinal peristalsis has been considered for many years. In earlier human studies, Walker (26) found that meconium was released more frequently when fetal umbilical vein oxygen saturation was below 30%. Furthermore, thick meconium was associated with lower oxygen saturation more often than light meconium. Elevated cord blood erythropoietin levels have been noted in fetuses with advanced gestation and in fetuses with meconium passage at any gestational age, possibly indicating that an element of chronic hypoxia contributes to the passage of meconium in utero (27,28). In support of a chronic stress mechanism, Manning and coworkers (29) reported that amniotic fluid meconium occurs more than twice as often if the last biophysical profile (BPP) score was 6 as compared with a BPP score of 8. Among animal studies, meconium passage commonly occurs with the occurrence of severe wastage syndrome in fetal lambs surviving an experimental model of single umbilical artery ligation (30). This finding parallels the increased incidence of

meconium passage observed in severely dysmature human fetuses subjected to chronic stress. The mechanism of stress or hypoxia-mediated meconium passage may include only defecation processes, rather than intestinal motility, because earlier studies in guinea pigs and monkeys failed to demonstrate an increase in fetal intestinal peristalsis when animals were subjected to hypoxia (31,32). Although parasympathetic-mediated gastrointestinal stimulation has been postulated to result from umbilical cord compression (31,32), Krebs et al. (33) found no correlation between the frequency of variable heart rate decelerations and the presence of meconium. Thus, the relationship between hypoxia and passage of meconium into amniotic fluid remains controversial. Ciftci et al. (34) demonstrated spontaneous in utero defecation in fetal rabbits in the absence of hypoxia. These authors suggested that rather than a fetal stress-mediated meconium passage, meconium-stained amniotic fluid indicates impaired clearance of meconium resulting from normal in utero defecation and decreased swallowing. In support of this hypothesis, studies in the ovine fetus demonstrate that acute hypoxia markedly reduces fetal swallowing activity (35). Similarly, Lopez and Martinez (36) sonographically observed spontaneous in utero fetal defecation from the 15th to the 41st week of gestation. Alternatively, whereas stimulatory mechanisms for colon contractility are likely present in the adult, inhibitory mechanisms may be predominant during fetal life. In the adult rat, the neuropeptides corticotrophin-releasing factor (CRF) and the CRF analog urocortin have been recently observed to induce defecation when animals were subjected to restraint stress (3740). These neuropeptides induce a pattern of cecocolonic myoelectric activity characterized by clustered spike bursts of long duration (41). However, the expression of CRF R1 or R2-type receptors determines whether CRF and urocortin stimulates or suppresses gastrointestinal motility. Accordingly, the CRF-receptor 1 antagonist, administered centrally or peripherally, was effective in inhibiting stress-induced defecation (42,43). Thus, the CRF/urocortin CRF-R1 system mediates defecation in adult animals under stressful conditions. Conversely, urocortin inhibits adult upper gastrointestinal (ie, gastric) motility through action at the CRF-R2 receptor (44). Placental or hypothalamic CRF and urocortin are released into the fetal circulation under stressful conditions. In the rat, stress-induced release of norepinephrine and epinephrine mobilizes placental CRF and/or urocortin (45,46). However, because recent

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studies in our laboratory indicate that urocortin inhibits cholinergic-mediated fetal sigmoid colon contractility in an organ bath system (47), we hypothesize that the preterm fetal colon may predominantly express CRF-R2 receptors. However, stress is a known inducer of CRF-R1 expression in neural cells (48) and thus fetal stress-mediated CRF-R1 receptor expression in fetal colonic tissue may ultimately potentiate in utero meconium passage. In numerous species, including humans, fetal plasma cortisol markedly increases at birth (4953) and in response to in utero stress. We hypothesize that glucocorticoid-mediated changes in CRF receptor subtype expression may potentiate colonic motility responses to CRF and/or urocortin. Notably, we recently observed that intragastric injection of betamethasone, in nearterm fetal rabbits, consistently elicits meconium passage in utero; a similar finding was not observed in saline-injected rabbits (54). Further studies are required to confirm these postulated mechanisms of fetal colonic motility and meconium passage in utero. Fetal Maturation Meconium passage is a developmentally programmed postnatal event, because 98% of healthy newborns pass meconium in the first 24 to 48 hours after birth (55). Greater than 98% of cases of meconium-stained amniotic fluid are noted in fetuses at or following 37 weeks gestation (56). Meconiumstained amniotic fluid commonly occurs in postterm pregnancies and is relatively rare in preterm deliveries (57,58). Because approximately 25% of meconium-stained amniotic fluid cases are not associated with demonstrable hypoxia (57,59), meconium passage thus may represent a normal event associated with fetal maturation. Animal studies have demonstrated the maturation of intestinal motility and colonic-emptying function with advancing gestation. Studies in guinea pig taenia coli indicate that the motility inhibitory (adrenergic) system arises before and matures more quickly than the cholinergic system. Excitatory cholinergic transmission was not seen until birth, indicating that the colonic innervation does not achieve maturity until birth (60). These mechanisms likely mediate an increase in gastrointestinal motility at term. In earlier studies, Becker and associates (31) injected radioopaque thorium salts into the amniotic sac of guinea pigs and followed the course of thorium through the intestine by radiographs. There was a more rapid transit from amniotic fluid to the stomach

and increased subsequent excretion of dye into the amniotic cavity in the last week of gestation. Similarly, Speert in 1943 (32) demonstrated an increase in gastrointestinal motility and rate of propagation of gastrointestinal contents with increasing gestation in Rhesus monkeys. In 1994, Kizilcan et al. (61) demonstrated that unstressed fetal goats defecate in utero at 110 to 114 days of gestation (term 147155 days). Fetal goats passed contrast into the amniotic cavity in 16 to 24 hours after nasogastric contrast injection without any signs of hypoxia. Similarly, unstressed fetal rabbits (34) and guinea pigs (31) defecate in utero, although this is uncommon in monkeys (32). In human fetuses, amniographic studies demonstrated more rapid gastrointestinal transit with increasing gestational age (62). Hormonal and neural maturation in the human fetal colon does not occur until 38 weeks of gestation (1). Studies in our laboratory have indicated that the colonic smooth muscle contractile response to bethanechol, a cholinergic agonist, is greatly augmented by fetal administration of glucocorticoid and thyroxine (63), suggesting the endocrine-mediated maturation of cholinergic colonic contractile machinery. In this connection, it is interesting to note that the intraamniotic injection of glucocorticoid and thyroxin in the fetal rhesus monkey induces meconium passage in utero (64). It should be noted here that in most species, including humans, a surge in plasma glucocorticoid and thyroid hormones occurs at birth (4953,65,66). A significant time delay in meconium passage and subsequent constipation has been reported in infants born with hypothyroidism (67). EFFECTS OF AMNIOTIC FLUID MECONIUM Amniotic fluid meconium may act both directly and indirectly on the exposed tissue, with effects dependent on the concentration of meconium, duration of exposure, and the presence of associated stress factors (eg, hypoxia and infection). Meconium can stain fetal tissues after sufficient exposure, with staining of vernix requiring 12 to 14 hours, newborn fingers 4 to 6 hours, and pigment accumulation in macrophages occurring in only 3 hours (68). The time course of staining of fetal tissues is dependent on the meconium concentration in amniotic fluid. Thus, 5% meconium may stain the umbilical cord in 1 hour, and placental and umbilical cord tissues in less than 3 hours (6971). In addition, exposure to meconium for more than 16 hours may induce um-

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bilical cord ulceration and vascular necrosis, potentially compromising fetal oxygenation (5). These effects may be the result of bile acids present in meconium, although the complex composition of meconium makes identification of a precise agent difficult. Meconium may have a vasoconstrictive effect on the umbilical vein that has been postulated to induce vasospasm and impaired fetalplacental blood flow (5,72), although this effect has not been demonstrated in vivo. In vitro placental studies with oxytocin perfusion demonstrate increased vasoconstrictive effects in meconium-impregnated placenta (73). Several authors have reported increased rates of chorioamnionitis with meconium-stained amniotic fluid (7476), although it is unclear whether this is a cause or effect phenomenon. Exposure to meconium can alter the bactericidal properties of amniotic fluid and increase the growth of Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes significantly earlier than in exposed controls (77,78). Inhibition of amniotic fluid antibacterial activity (79) may occur through inhibition of neutrophil phagocytic activity (80) and alterations in zinc concentration (81). Fetal microbial invasion has been proposed to cause inflammatory brain damage through the effects of elevated cytokines (eg, TNF alpha, IL-1 beta, IL-6), and it could be postulated that the meconium contributes to this effect by its inhibition of antibacterial effects of amniotic fluid (81,82). MECONIUM ASPIRATION SYNDROME At the pulmonary level, MAS is believed to be caused by a combination of mechanical blockage of small airways and production of chemical pneumonitis by the meconium particles inhaled by the infant (8385). The resulting vasospasm, hypertrophy of the pulmonary musculature, and pulmonary hypertension lead to right-to-left shunting through the foramen ovale or ductus arteriosus. Meconium directly inhibits pulmonary function by displacing surfactant with its free fatty acid content (86) and by direct inhibition of surfactant function (8790). Meconium can cause a dose-dependent oxidative burst in neutrophils with increased levels of leukotrienes, endothelin-1, and big ET and ET-1 (vasoactive peptides). Big ET and ET-1 are vasoconstrictors that stimulate NO production and expression of iNOS in the alveolar macrophages by activation of nuclear factor kappa B, COX2, and NOS2 gene expression. This in turn increases stimulation of macrophages leading to local tissue damage in the target organs exposed to meconium (9197). Further, interleukin 8 and phos-

pholipase A2 present in the meconium can lead to damage of lung tissue by activation of neutrophilic chemotaxis and neutralization of surfactant, respectively. In the murine model, meconium aspiration produces airway hyperresponsiveness and eosinophil inflammation along with elevated IL-5, IL-13, BALF, lymphocytic inflammation, and goblet cell metaplasia leading to airway dysfunction (98). MAS appears dependent on both meconium and fetal hypoxia. In humans, fetal inhalation of the amniotic fluid was demonstrated by injections of chromiumlabeled red blood cells into the amniotic fluid (99). The fetal gasping movements noted with hypoxia increase meconium aspiration into the lungs and hence the possibility of MAS (100). Ramin et al. reported that 68% of MAS neonates showed fetal heart rate abnormalities (101). Other studies have demonstrated fetal tachycardia (102,103), increased incidence of late decelerations (104,105), and the presence of acidosis in approximately 50% of MAS newborns (101,106,107). Similarly, animal studies have demonstrated that fetal meconium aspiration is promoted by fetal hypoxia (term fetal sheep) (108), fetal hypoxia or acidosis (monkeys) (12,109), and by acidosis with or without hypoxia (baboons) (110). However, Cornish et al. (111) demonstrated that meconium aspiration alone does not lead to pulmonary hypertension in term baboons. In this study, the presence of meconium in the lungs significantly impaired fetal oxygenation and increased the need for ventilatory support. Concurrent asphyxia further potentiated this effect, although acute meconium aspiration did not result in systemic or pulmonary hypertension, or abnormal pulmonary arteriolar muscularization. Evidence from animal models in which pulmonary instillation of meconium was done before the first breath demonstrate lung injury reversible with surfactant administration with symptoms similar to that of mild and moderate human MAS (88). Despite the commonly assumed association of fetal stress, meconium passage, and MAS, Ghidini and Spong (6) questioned the role of acute and chronic hypoxia, and infection in the development of MAS. These authors suggested that mild and moderate MAS results from in utero inhalation of meconium (consistent with animal studies discussed here), whereas severe MAS is a multifactorial disease requiring the presence of hypoxia along with other factors, as yet poorly understood. This hypothesis is supported by the lack of studies that directly correlate the severity of MAS with the amount of meconium aspirated, the duration of exposure to meconium, or the thickness of meconium. Similarly, studies have been unable to correlate the presence of meconium in

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the trachea with clinical MAS symptoms. In addition, chest radiographs have not been able to predict the severity of MAS, implying that additional factors are responsible for pulmonary symptoms. Thus, the diagnosis of MAS should be made only after ruling out all other causes for neonatal respiratory compromise. Ghidini and Spong further postulated that severe MAS results from either chronic asphyxia or intrauterine infection: Chronic hypoxia induces a fetal wasting syndrome, associated with placental ischemic changes, pulmonary vascular hypertrophy, and possibly stimulation of hypoxia-sensitive genes. Alternatively, intrauterine infection may induce fetal inflammation syndrome, which consists of activation of neutrophils, macrophages, cytokines, and the complement system resulting in tissue destruction. Thus, in utero events other than meconium passage likely contribute to the complex findings of MAS. Animal models such as the null mutant mice of activating transcription factor 2 (ATF-2) may ultimately aid in our understanding of MAS pathogenesis. Null ATF-2 mice develop MAS at delivery and die with similar features as those exhibited by humans with MAS (112). Activating transcription factor 2 is known to induce a number of genes, including the hypoxia-inducible genes and platelet-derived growth factor receptors (112). Because the latter is known to mediate trophoblast mitogenesis, the placenta of these mutant mice contained a reduced number of cytotrophoblast. Whether hypoxia alone, or secondary effects from upregulation of genes and proteins associated with ATF-2 mutations (eg, glucose transporter-3, epidermal growth factor-like growth factor, GADD45, and insulin growth factorII), contribute to meconium passage and the pulmonary findings of MAS remain to be determined. CLINICAL OUTCOME IN THE PRESENCE OF MECONIUM Second-Trimester Passage of Meconium The incidence of meconium-stained amniotic fluid obtained from second-trimester amniocentesis approximates 1 in 4055, although various nonstandardized methods have been used to identify meconium (113115). Some studies used visual inspection or spectrophotometry (81,116119), although it is not possible to distinguish between blood and meconium content by either means. Zorn et al. (119) recommended electrophoresis and gel chromatography to differentiate meconium from blood pigment in the amniotic fluid. These authors reported hemoglo-

bin to be the major coloring agent in 33 of 34 specimens of stained amniotic fluid, with only 3 of the 34 specimens reported to have a pigment consistent with meconium. Although fetal loss rates varying from 5% to 30% have been associated with the presence of second-trimester meconium-stained amniotic fluid, this staining likely represents hemoglobin because there was a further increase in fetal loss rates in patients with a history of first-trimester bleeding (116,119). No difference in the outcome was noted between patients with thick or thin meconium-stained amniotic fluid derived from midtrimester genetic amniocentesis (115). These authors similarly reported increased perinatal complications in the presence of stained amniotic fluid, regardless of meconium or hemoglobin, with a 9% loss rate in patients with discolored amniotic fluid as compared with 1.6% among all amniocentesis patients. Based on these studies, it remains uncertain whether meconium contributes significantly to stained amniotic fluid or, more importantly, to fetal loss after secondtrimester amniocentesis. Third-Trimester Passage of Meconium Using an amnioscope, Lee (120) noted the presence of meconium in amniotic fluid in 67 of 681 high-risk patients (10%), with a perinatal mortality rate of 4 of 1000 in these patients. Similarly, Mandelbaum (121) detected meconium-stained amniotic fluid in 11.3% of patients having serial amniocentesis beginning at 30 to 32 weeks gestation. Of these patients, 26% experienced fetal demise and 41% had neonatal complications. Based on these observations, the author recommended active intervention in patients with meconium-stained amniotic fluid in the third trimester. Similarly, Kasper et al. (122) noted comparatively worse outcomes in fetuses exposed to meconium chronically as opposed to acutely. Conversely, Saldana et al. (123) performed weekly amnioscopy, detecting meconium-stained amniotic fluid in only 2.2% of the 508 patients. No adverse effects were found when these patients were managed either conservatively or actively (ie, induction of labor). These authors concluded that meconium-stained amniotic fluid by itself is not an indication for intervention, although patients with this finding should be subjected to further fetal evaluation/surveillance. Intrapartum Meconium The incidence of the passage of meconium at the time of delivery ranges from 7% to 22% for term

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fetuses and increases up to 40% in postterm fetuses (124,125). Initial studies observed that meconium passage in conjunction with an abnormal fetal heart tracing increased perinatal morbidity and mortality rates (33,126128) with an increased incidence of low 1-minute and 5-minute Apgar scores (33,129 133), although additional studies have not demonstrated these findings (28,107,134,135). Similarly, the association between fetal acidosis and meconium passage during labor is controversial, being observed by some authors (124,129,132,133) and not others (27,28,33,135,136). Meconium appears to not be an independent predictor of acidosis (131,137). Thus, in the absence of fetal heart rate abnormalities, the presence of meconium does not indicate fetal compromise and no intervention is necessary other than close monitoring (128,137,138). Similarly, among postterm patients with normal antepartum testing, women with heavy meconium in early labor have no greater risk for fetal distress or perinatal morbidity than women with clear amniotic fluid. These findings suggest that postterm patients with heavy meconium in early labor and normal antepartum testing can be managed in labor in the same manner as low-risk patients without meconium (138). AMNIOINFUSION FOR AMNIOTIC FLUID MECONIUM The association between oligohydramnios and fetal heart tracing abnormalities, particularly variable decelerations, is well known. Amnioinfusion to correct oligohydramnios acts by decreasing umbilical cord compression, which potentially improves fetal oxygenation. Although the majority of meconium aspiration likely occurs before labor (discussed previously in this article), it has been hypothesized that amnioinfusion for meconium-stained amniotic fluid is a result of a reduction in fetal hypoxia-induced gasping and subsequent meconium aspiration. Because thick meconium generally occurs in the presence of oligohydramnios, a more likely explanation for the beneficial effects of amnioinfusion for meconium is the prevention of variable fetal heart rate decelerations by amelioration of oligohydramnios. Because hypoxia may aggravate the effects of previously aspirated meconium, prevention of fetal hypoxia by amnioinfusion may reduce the incidence of MAS. The prophylactic use of amnioinfusion for meconium in the absence of fetal heart rate decelerations has been a controversial topic, in part as a result of the limited studies specifically addressing the ques-

tion. As discussed subsequently, the vast majority of studies have compared outcomes among patients receiving prophylactic amnioinfusion for meconium (and often oligohydramnios) with patients who were not provided amnioinfusion, regardless of subsequent fetal heart rate patterns or the development of oligohydramnios-associated fetal heart rate decelerations. For example, although Wenstrom and Parsons (139) used a randomized design to examine the effects of prophylactic amnioinfusion in laboring patients with thick meconium-stained amniotic fluid and no fetal heart rate abnormalities, the control group was not provided amnioinfusion despite the appearance of variable heart rate decelerations. In this study, mothers who received amnioinfusion had significantly fewer operative deliveries and had infants with higher 1-minute Apgar scores and less meconium below the vocal cords than patients who were not provided amnioinfusion. Three cases of MAS were noted in the control group compared with none in the amnioinfused group (not statistically significant). In a randomized study of laboring patients with moderate to thick meconium-stained amniotic fluid, Sadovsky et al. (140) reported that amnioinfusion reduced the concentration of meconium from 79% to 5% and decreased the rate of variable fetal heart rate decelerations and rate of neonatal acidemia, although there was no change in Apgar scores. There was no evidence of meconium below the vocal cords in the amnioinfusion group, as compared with 29% incidence in the control group. Similar observations were noted by others (141144). Although these studies may initially suggest that amnioinfusion is beneficial for patients with meconium, one needs to determine if there is a benefit to the use of amnioinfusion prophylactically for meconium alone or therapeutically if fetal heart rate decelerations occur. In a randomized, prospective study of patients with moderate to thick meconium, Spong et al. (145) compared prophylactic amnioinfusion with standard obstetric care, which included therapeutic amnioinfusion only if fetal heart rate decelerations occurred. There were no significant differences in the incidence of operative delivery, fetal distress, or meconium below the cords or in newborn Apgar scores and umbilical artery gas values between the prophylactic amnioinfusion and control patients. There were 4 cases of meconium aspiration, 3 in the amnioinfusion group and 1 in the standard care group. Furthermore, the rate of endometritis chorioamnionitis was significantly higher in the amnioinfusion (16%) than in the control group (8%). These results suggest that the benefit of amnioinfu-

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sion for meconium-stained amniotic fluid is a result of the alleviation of variable fetal heart rate decelerations rather than meconium dilution. Thus, for patients with moderate to thick meconium and no fetal heart rate abnormalities, physicians may elect either to use prophylactic amnioinfusion or therapeutic amnioinfusion (should variable fetal heart rate decelerations occur). NEONATAL INTERVENTIONS Management Although the current definition of MAS suggests a neonatal syndrome, it has its pathophysiological origin in intrauterine events. Initially, it was believed that MAS was caused by inhalation of meconium at the time of the first breath, because meconium was noted in the trachea of infants that developed severe respiratory distress and MAS (11,58,105). Consequently, much of the focus was placed on clearing meconium out of the infants pharynx and trachea to prevent MAS. Carson et al. (146) were the first to demonstrate that DeLee suctioning of the pharynx before birth with selective intubation reduced the incidence as well as the severity of the MAS. Others noted similar results by aggressive tracheal suctioning (58,147). Controversies have continued regarding oral, nasal, and tracheal suctioning. In fetal kittens, catheter suctioning removed larger quantities of meconium than bulb suctioning (148). Pfenninger et al. (149) demonstrated that oral suctioning is better than nasal suctioning, although they recommended that both should be used in clinical practice together. Several authors have demonstrated similar efficacy of bulb or DeLee suctioning (11), as well as similar outcomes with DeLee suctioning before the first breath as compared with after complete delivery. Despite the apparent progress in suctioning for meconium, several retrospective studies did not note any difference in the incidence of meconium below the vocal cords or the incidence of MAS with or without routine suctioning (150,151) or with vigorous suctioning before birth (3,152154). The lack of impact of these interventions may be a result of in utero meconium aspiration, as demonstrated in animal models of fetal hypoxia or acidosis (110). Studies of infants who underwent vigorous suctioning before the first breath and studies of autopsies of stillbirths, which found meconium in alveolar spaces, similarly suggest that the incidence of MAS is not affected by routine suctioning of the newborn (12 14). Under the present clinical conditions, we recom-

mend nasal or oral suctioning of the meconiumstained fetus on delivery of the head. Pediatric intubation and suctioning is often dependent on the newborn respiratory condition, with suctioning often not performed in the presence of spontaneous newborn breathing. These results further emphasize the importance of the intrauterine and prelabor process for meconium aspiration. However, because the combination of hypoxia and meconium passage may potentiate MAS, delivery of the newborn without severe acidosis may be the primary action that prevents MAS. SUMMARY Passage of meconium is a highly regulated postnatal event. The majority of newborns pass meconium within 48 hours after birth, and 10% to 12% of fetuses pass meconium prematurely in utero. The mechanism of regulation of meconium passage is unknown, although fetal stress and maturity may contribute to gastrointestinal motility. Prolonged exposure of meconium to the fetal and placental tissue may potentially contribute to adverse effects, although there are limited in vivo studies. Currently, there is no known way to precisely ascertain the timing of meconium passage. Importantly, the presence of meconium alone may not lead to MAS. The majority of the patients with stained amniotic fluid identified during genetic amniocentesis ultimately have clear amniotic fluid at delivery. Whether this staining represents hemoglobin from the amniotic environment or colonic meconium is unknown. However, these patients demonstrate an increased risk of adverse outcomes if accompanied by firsttrimester bleeding. At present, no intervention is recommended for these patients other than surveillance during pregnancy. Patients with meconium-stained amniotic fluid noted during the third trimester may need additional maternal and fetal surveillance, although there is no consensus regarding management or prognosis. Patients with moderate or thick meconium-stained amniotic fluid during the intrapartum period require continuous fetal monitoring throughout labor and delivery. In laboring patients with thin or thick meconium, in the absence of fetal heart rate decelerations, there appears to be no benefit of prophylactic amnioinfusion versus therapeutic amnioinfusion (performed if fetal heart rate decelerations occurred). Alternatively, there are minimal risks of amnioinfusion, such that prophylactic amnioinfusion for moderate or thick meconium, in the absence of fetal heart

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rate decelerations, may be a therapeutic option. Clearly, amnioinfusion efficacy has been demonstrated for patients with moderate or thick meconium, together with fetal heart rate variable decelerations. Further research is required to understand the role of chronic hypoxia, infection, and other fetomaternal stress factors in the development of MAS. Research into the understanding of intestinal maturation and the mechanism of meconium passage may aid in reducing the incidence of meconium passage in utero and improving perinatal outcome. With understanding of the in utero fetal and maternal stress factors responsible for meconium passage, we may be better able to prevent the severe complications of MAS. ACKNOWLEDGMENTS This work has been supported by a grant from the March of Dimes (MGR). REFERENCES
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