Background
Meconium aspiration syndrome (MAS) is a leading cause of morbidity and mortality in
term infants. Meconium-stained amniotic fluid (MSAF) occurs in approximately 1 of
every 7 pregnancies, but only 5% of neonates exposed to MSAF develop MAS. Why some
infants exposed to meconium develop MAS while others do not is a fundamental question.
Patients with MSAF have a higher frequency of intraamniotic inflammation/infection
than those with clear fluid. We propose that fetal systemic inflammation is a risk
factor for the development of MAS in patients with MSAF.
Objective
We sought to investigate whether intraamniotic inflammation and funisitis, the histopathologic
landmark of a fetal inflammatory response, predispose to MAS.
Study Design
A prospective cohort study was conducted from 1995 through 2009. Amniotic fluid (AF)
samples (n = 1281) were collected at the time of cesarean delivery from women who
delivered singleton newborns at term (gestational age ≥38 weeks). Intraamniotic inflammation
was diagnosed if the AF concentration of matrix metalloproteinase-8 was >23 ng/mL.
Funisitis was diagnosed by histologic examination if inflammation was present in the
umbilical cord.
Results
The prevalence of MSAF was 9.2% (118/1281), and 10.2% (12/118) of neonates exposed
to MSAF developed MAS. There were no significant differences in the median gestational
age or umbilical cord arterial pH at birth between neonates who developed MAS and
those who did not (each P > .1). Mothers whose newborns developed MAS had a higher median of AF matrix metalloproteinase-8
(456.8 vs 157.2 ng/mL, P < .05). Newborns exposed to intraamniotic inflammation had a higher rate of MAS than
those who were not exposed to intraamniotic inflammation [13.0% (10/77) vs 0% (0/32),
P = .03], as did those exposed to funisitis [31.3% (5/16) vs 7.3% (6/82); relative
risk, 4.3; 95% confidence interval, 1.5–12.3]. Among the 89 newborns for whom both
AF and placental histology were available, MAS was more common in patients with both
intraamniotic inflammation and funisitis than in those without intraamniotic inflammation
and funisitis [28.6% (4/14) vs 0% (0/28), P = .009], while the rate of MAS did not show a significant difference between patients
with intraamniotic inflammation alone (without funisitis) and those without intraamniotic
inflammation and funisitis [10.9% (5/46) vs 0% (0/28)].
Conclusion
The combination of intraamniotic inflammation with fetal systemic inflammation is
an important antecedent of MAS. This concept has implications for the understanding
of the mechanisms of disease responsible for MAS and for the development of prognostic
models and therapeutic interventions for this disorder.
Key words
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References
- The epidemiology of meconium aspiration syndrome: incidence, risk factors, therapies, and outcome.Pediatrics. 2006; 117: 1712-1721
- Delivery room management of the meconium-stained newborn.J Perinatol. 2008; 28: S19-26
- Meconium aspiration syndrome: current concepts and management.Compr Ther. 1999; 25: 82-89
- Inflammatory response and apoptosis in newborn lungs after meconium aspiration.Biotechnol Prog. 2005; 21: 192-197
- Delivery room management of meconium-stained infant.Clin Perinatol. 2012; 39: 817-831
- Meconium aspiration syndrome–more than intrapartum meconium.N Engl J Med. 2005; 353: 946-948
- Meconium passage in utero: mechanisms, consequences, and management.Obstet Gynecol Surv. 2005; 60 (quiz 73-4): 45-56
- Early human development at the perinatal interface: meconium-stained amniotic fluid (MSAF) and meconium aspiration syndrome (MAS).Early Hum Dev. 2009; 85: 605
- The effect of meconium on perinatal outcome: a prospective analysis.J Matern Fetal Neonatal Med. 2002; 11: 54-59
- Prolonged in utero meconium exposure impairs spatial learning in the adult rat.Am J Obstet Gynecol. 2004; 190: 1551-1556
- A case-control study of hypoxic-ischemic encephalopathy in newborn infants at >36 weeks gestation.Am J Obstet Gynecol. 2013; 209: 29.e1-29.e19
- Risk factors for serious morbidity in term nonanomalous neonates.Am J Obstet Gynecol. 2015; 212: 799.e1-799.e7
- Changing obstetric practices associated with decreasing incidence of meconium aspiration syndrome.Obstet Gynecol. 2002; 99: 731-739
- Meconium-stained fluid: approach to the mother and the baby.Pediatr Clin North Am. 2004; 51 (ix): 655-667
- Fatal meconium aspiration syndrome occurring despite airway management considered appropriate.Am J Obstet Gynecol. 1985; 151: 731-736
- Meconium staining and the meconium aspiration syndrome: unresolved issues.Pediatr Clin North Am. 1993; 40: 955-981
- Prediction of the severity of meconium aspiration syndrome.Am J Obstet Gynecol. 1993; 169: 61-70
- Meconium-stained amniotic fluid and the meconium aspiration syndrome: an update.Pediatr Clin North Am. 1998; 45: 511-529
- Meconium-stained amniotic fluid (MSF).Am J Obstet Gynecol. 2004; 191 (author reply 6–7): 2175-2176
- Meconium-stained amniotic fluid and meconium aspiration syndrome: a prospective study.Ann Trop Paediatr. 2008; 28: 199-203
- Meconium aspiration syndrome–prevention and treatment.Early Hum Dev. 1995; 41: 183-192
- Meconium-stained amniotic fluid: discharge vigorous newborns.Arch Dis Child Fetal Neonatal Ed. 2010; 95: F69-71
- Consequences of meconium-stained amniotic fluid: what does the evidence tell us?.Early Hum Dev. 2014; 90: 333-339
- Why does meconium cause meconium aspiration syndrome? Current concepts of MAS pathophysiology.Early Hum Dev. 2009; 85: 617-620
- Meconium aspiration syndrome (MAS)–where do we go? Research perspectives.Early Hum Dev. 2009; 85: 627-629
- Oropharyngeal and nasopharyngeal suctioning of meconium-stained neonates before delivery of their shoulders: multicenter, randomized controlled trial.Lancet. 2004; 364: 597-602
- Intrapartum prevention of meconium aspiration syndrome.Lancet. 2004; 364: 560-561
- Delivery room management of the apparently vigorous meconium-stained neonate: results of the multicenter, international collaborative trial.Pediatrics. 2000; 105: 1-7
- Endotracheal suction for nonvigorous neonates born through meconium-stained amniotic fluid: a randomized controlled trial.J Pediatr. 2015; 166: 1208-1213.e1
- Meconium-stained newborns: ethics for evidence in resuscitation.J Pediatr. 2015; 166: 1109-1112
- Amnioinfusion for the prevention of the meconium aspiration syndrome.N Engl J Med. 2005; 353: 909-917
- Amnioinfusion for meconium-stained liquor in labor.Cochrane Database Syst Rev. 2014; 1: CD000014
- What (not) to do before delivery? Prevention of fetal meconium release and its consequences.Early Hum Dev. 2009; 85: 611-615
- Management of meconium at birth. SOGC Clinical practice guideline no. 224, April 2009.Int J Gynaecol Obstet. 2009; 107: 80-81
- Lung lavage for meconium aspiration syndrome in newborn infants.Cochrane Database Syst Rev. 2013; 4: CD003486
- Management strategy in case of meconium-stained amniotic fluid.Early Hum Dev. 2014; 90: 341-342
- The incidence of fetal asphyxia in six hundred high-risk monitored pregnancies.Am J Obstet Gynecol. 1975; 121: 456-459
- Risk factors for meconium-aspiration syndrome.Aust N Z J Obstet Gynaecol. 1996; 36: 401-406
- Meconium-stained amniotic fluid in very low risk pregnancies at term gestation.Eur J Obstet Gynecol Reprod Biol. 1998; 80: 169-173
- Meconium-stained amniotic fluid across gestation and neonatal acid-base status.Obstet Gynecol. 2006; 108: 345-349
- Abnormal fetal heart rate tracing patterns in patients with thick meconium staining of the amniotic fluid: association with perinatal outcomes.Am J Obstet Gynecol. 2009; 200: 283.e1-283.e7
- Abnormal fetal heart rate tracings in patients with thick meconium staining of the amniotic fluid: Xu et al.Am J Obstet Gynecol. 2009; 200: 342-343.e1-4
- The frequency of meconium-stained amniotic fluid increases as a function of the duration of labor.J Matern Fetal Neonatal Med. 2011; 24: 880-885
- Interpreting category II fetal heart rate tracings: does meconium matter?.Am J Obstet Gynecol. 2014; 211: 644.e1-644.e8
- The etiology of meconium-stained amniotic fluid: pathologic hypoxia or physiologic fetal ripening?.Early Hum Dev. 2014; 90: 325-328
- Meconium-stained amniotic fluid–risk factors and immediate perinatal outcomes among SGA infants.J Matern Fetal Neonatal Med. 2015; 28: 1064-1067
- Association between value of the individual components of the 5 minute Apgar score and neonatal outcome.Am J Obstet Gynecol. 2015; 212: S10
- Neonatal acidemia in neonates with 5-minute Apgar scores greater than 7–what are the outcomes?.Am J Obstet Gynecol. 2015; 212: S256-S257
- Fetal breathing.Br Med Bull. 1975; 31: 3-7
- Breathing patterns before death in fetal lambs.Am J Obstet Gynecol. 1976; 125: 73-78
- Breathing movements before death in the primate fetus (Macaca mulatta).Am J Obstet Gynecol. 1979; 135: 71-76
- In utero meconium aspiration: an unpreventable cause of neonatal death.Br J Obstet Gynaecol. 1987; 94: 813-814
- Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases.Pathol Res Pract. 1996; 192: 1121-1128
- Chronic intrauterine meconium aspiration causes fetal lung infarcts, lung rupture, and meconium embolism.Pediatr Dev Pathol. 1999; 2: 544-551
- Apgar score, meconium and acidemia at birth in relation to neonatal neurological morbidity in term infants.Br J Obstet Gynaecol. 1986; 93: 217-222
- Meconium in the amniotic fluid and fetal acid-base status.Obstet Gynecol. 1989; 73: 175-178
- “Meconiumcrit” and birth asphyxia.Am J Obstet Gynecol. 1991; 165: 1010-1013
- Acid-base significance of meconium discovered prior to labor.Am J Perinatol. 1993; 10: 143-145
- Failure of acute perinatal asphyxia or meconium aspiration to produce persistent pulmonary hypertension in a neonatal baboon model.Am J Obstet Gynecol. 1994; 171: 43-49
- Association between umbilical blood gas parameters and neonatal morbidity and death in neonates with pathologic fetal acidemia.Am J Obstet Gynecol. 1999; 181: 867-871
- Meconium aspiration syndrome in term neonates with normal acid-base status at delivery: is it different?.Am J Obstet Gynecol. 2001; 184: 1422-1426
- Severe meconium aspiration syndrome is not caused by aspiration of meconium.Am J Obstet Gynecol. 2001; 185: 931-938
- Meconium and fetal hypoxia: some experimental observations and clinical relevance.BJOG. 2002; 109: 1171-1174
- Meconium and fetal hypoxia: some experimental observations and clinical relevance.BJOG. 2003; 110: 713
- Effect of interleukin 8 in meconium on in-vitro neutrophil chemotaxis.Lancet. 1998; 352: 102-105
- Cytokine expression in meconium-induced lungs.Indian J Pediatr. 2004; 71: 195-201
- Serum cytokine and chemokine profiles in neonates with meconium aspiration syndrome.Pediatrics. 2008; 121: e748-e753
- Studies of meconium-induced lung injury: inflammatory cytokine expression and apoptosis.J Perinatol. 2008; 28: S102-S107
- Role of meconium and hypoxia in meconium aspiration-induced lung injury in neonatal rabbits.Mediators Inflamm. 2010; 2010: 204831
- Meconium aspiration syndrome: possible pathophysiological mechanisms and future potential therapies.Neonatology. 2015; 107: 225-230
- Meconium-stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity.Am J Obstet Gynecol. 1991; 164: 859-862
- Maternal and perinatal outcome of patients with preterm labor and meconium-stained amniotic fluid.Obstet Gynecol. 1995; 86: 830-833
- Bacteria and endotoxin in meconium-stained amniotic fluid at term: could intra-amniotic infection cause meconium passage?.J Matern Fetal Neonatal Med. 2014; 27: 775-788
- Do blood and meconium affect the detection of endotoxin in amniotic fluid with the limulus amebocyte gel clot assay?.Am J Perinatol. 1987; 4: 356-359
- Differential expression of interleukin-1 beta and interleukin-6 in human fetal serum and meconium-stained amniotic fluid.J Reprod Immunol. 1998; 37: 155-161
- Meconium-stained amniotic fluid exhibits chemotactic activity for polymorphonuclear leukocytes in vitro.J Reprod Immunol. 2000; 46: 21-30
- Secreted phospholipase A2 is increased in meconium-stained amniotic fluid of term gestations: potential implications for the genesis of meconium aspiration syndrome.J Matern Fetal Neonatal Med. 2014; 27: 975-983
- The relationship between amniotic fluid matrix metalloproteinase-8 and funisitis.Am J Obstet Gynecol. 2001; 185: 1156-1161
- The importance of intra-amniotic inflammation in the subsequent development of atypical chronic lung disease.J Matern Fetal Neonatal Med. 2009; 22: 917-923
- Clinical significance of oligohydramnios in patients with preterm labor and intact membranes.J Perinat Med. 2011; 39: 131-136
- The frequency and clinical significance of intra-amniotic inflammation in women with preterm uterine contractility but without cervical change: do the diagnostic criteria for preterm labor need to be changed?.J Matern Fetal Neonatal Med. 2012; 25: 1212-1221
- An elevated maternal serum C-reactive protein in the context of intra-amniotic inflammation is an indicator that the development of amnionitis, an intense fetal and AF inflammatory response are likely in patients with preterm labor: clinical implications.J Matern Fetal Neonatal Med. 2013; 26: 847-853
- The frequency and clinical significance of intra-amniotic inflammation defined as an elevated amniotic fluid matrix metalloproteinase-8 in patients with preterm labor and low amniotic fluid white blood cell counts.Obstet Gynecol Sci. 2013; 56: 167-175
- Fetal, amniotic and maternal inflammatory responses in early stage of ascending intrauterine infection, inflammation restricted to chorio-decidua, in preterm gestation.J Matern Fetal Neonatal Med. 2014; 27: 98-105
- The relationship among inflammatory lesions of the umbilical cord (funisitis), umbilical cord plasma interleukin 6 concentration, amniotic fluid infection, and neonatal sepsis.Am J Obstet Gynecol. 2000; 183: 1124-1129
- Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.J Matern Fetal Neonatal Med. 2002; 11: 18-25
- Placental diagnostic criteria and clinical correlation–a workshop report.Placenta. 2005; 26: S114-S117
- Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation.J Matern Fetal Neonatal Med. 2006; 19: 693-697
- The antenatal identification of funisitis with a rapid MMP-8 bedside test.J Perinat Med. 2008; 36: 497-502
- Amniotic fluid volume in intra-amniotic inflammation with and without culture-proven amniotic fluid infection in preterm premature rupture of membranes.J Perinat Med. 2010; 38: 39-44
- The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor.J Matern Fetal Neonatal Med. 2011; 24: 37-42
- Acute funisitis is associated with distinct changes in fetal hematologic profile.J Matern Fetal Neonatal Med. 2015; 28: 588-593
- Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance.Am J Obstet Gynecol. 2015; 213: S29-S52
- Meconium aspiration syndrome: intrapartum and neonatal attributes.Am J Obstet Gynecol. 1989; 161: 1106-1110
- Intratracheal suctioning, systemic infection, and the meconium aspiration syndrome.Pediatrics. 1992; 89: 203-206
- Meconium aspiration syndrome.Neonatal Netw. 2008; 27: 81-87
- Prediction of birth asphyxia in term neonates.Am J Obstet Gynecol. 2014; 210: S288
- Meconium stimulates neutrophil oxidative burst.Am J Perinatol. 2002; 19: 279-284
- Meconium is a source of pro-inflammatory substances and can induce cytokine production in cultured A549 epithelial cells.Pediatr Res. 2003; 54: 491-495
- Meconium induces only localized inflammatory lung injury in piglets.Pediatr Res. 2003; 54: 192-197
- Effects of meconium aspiration in isolated perfused rat lungs.Pediatr Pulmonol. 2005; 39: 368-373
- Lung inflammation and pulmonary function in infants with meconium aspiration syndrome.Pediatr Pulmonol. 2007; 42: 898-905
- Role of complement and CD14 in meconium-induced cytokine formation.Pediatrics. 2008; 121: e496-505
- Phospholipase A2 in meconium-induced lung injury.J Perinatol. 2008; 28: S120-S122
- Introduction: Proceedings of the First International Conference for Meconium Aspiration Syndrome and Meconium-induced Lung Injury.J Perinatol. 2008; 28: S1-S2
- Perinatal listeriosis–a review of twelve patients.Am J Obstet Gynecol. 1979; 133: 405-410
- Isolation of Mycoplasma hominis and Ureaplasma urealyticum from amniotic fluid at 16-20 weeks of gestation: potential effect on outcome of pregnancy.Sex Transm Dis. 1983; 10: 294-302
- Listeria monocytogenes. The role of transabdominal amniocentesis in febrile patients with preterm labor.Arch Gynecol Obstet. 1992; 252: 109-112
- Meconium-stained amniotic fluid in preterm delivery is an independent risk factor for perinatal complications.Eur J Obstet Gynecol Reprod Biol. 1998; 81: 9-13
- Sterile intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix: prevalence and clinical significance.J Matern Fetal Neonatal Med. 2014 Sep 24; ([Epub ahead of print]): 1-17
- A receptor for danger signals, advanced glycation end products (RAGE) in fetal systemic inflammation and clinical chorioamnionitis.Am J Obstet Gynecol. 2015; 212: S298
- Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.Am J Physiol Lung Cell Mol Physiol. 2004; 287: L1178-85
- Evidence of the involvement of caspase-1 under physiologic and pathologic cellular stress during human pregnancy: a link between the inflammasome and parturition.J Matern Fetal Neonatal Med. 2008; 21: 605-616
- Soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) in amniotic fluid: modulation by infection and inflammation.J Perinat Med. 2008; 36: 388-398
- Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1.J Matern Fetal Neonatal Med. 2011; 24: 1444-1455
- Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE.J Matern Fetal Neonatal Med. 2012; 25: 558-567
- A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes.Am J Reprod Immunol. 2014; 71: 330-358
- Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes.Am J Reprod Immunol. 2014; 72: 458-474
- Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes.J Matern Fetal Neonatal Med. 2015; 28: 1394-1409
- Clinical chorioamnionitis at term I: microbiology of the amniotic cavity using cultivation and molecular techniques.J Perinat Med. 2015; 43: 19-36
- The role of pulmonary inflammation in the development of pulmonary hypertension in newborn with meconium aspiration syndrome (MAS).Pediatr Pulmonol Suppl. 1999; 18: 205-208
- IL-1 mediates pulmonary and systemic inflammatory responses to chorioamnionitis induced by lipopolysaccharide.Am J Respir Crit Care Med. 2009; 179: 955-961
- Pulmonary and systemic inflammatory responses to intra-amniotic IL-1alpha in fetal sheep.Am J Physiol Lung Cell Mol Physiol. 2011; 301: L285-L295
- Meconium aspiration delays normal decline of pulmonary vascular resistance shortly after birth through lung parenchymal injury.Neonatology. 2011; 99: 272-279
- Effects of chorioamnionitis on the fetal lung.Clin Perinatol. 2012; 39: 441-457
- Thrown off balance: the effect of antenatal inflammation on the developing lung and immune system.Am J Obstet Gynecol. 2013; 208: 429-437
- Association of non-reassuring fetal heart rate and fetal acidosis with placental histopathology.Placenta. 2011; 32: 450-453
- Intrauterine bacterial infection of the newborn infant: frozen sections of the cord as an aid to early detection.J Pediatr. 1959; 54: 11-18
- Placental biopsy by frozen section: does it have a role in evaluation of fetal well-being?.Aust N Z J Obstet Gynaecol. 2003; 43: 433-437
- Frozen section of placental membranes and umbilical cord: an aid to early postpartum diagnosis of intra-amniotic infection.Am J Clin Pathol. 2014; 142: 202-208
- Risk of meconium-stained amniotic fluid in different ethnic groups.J Perinatol. 2000; 20: 257-261
- Trends in obstetric practices and meconium aspiration syndrome: a population-based study.BJOG. 2011; 118: 1601-1607
- Meconium aspiration syndrome: have we made a difference?.Pediatrics. 1990; 85: 715-721
- Handling the meconium-stained infant.Semin Neonatol. 2001; 6: 225-231
Article info
Publication history
Published online: October 18, 2015
Accepted:
October 7,
2015
Received in revised form:
September 26,
2015
Received:
August 5,
2015
Footnotes
Supported by Grant No. 03-2011-0200 from Seoul National University Hospital, Republic of Korea, and a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant No. HI12C0768). This work was also supported, in part, by the Perinatology Research Branch, Division of Intramural Research, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/US Department of Health and Human Services.
The authors report no conflicts of interest.
Cite this article as: Lee J, Romero R, Lee KA, et al. Meconium aspiration syndrome: a role for fetal systemic inflammation. Am J Obstet Gynecol 2016;214:366.e1-9.
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