Mechanism(s) of in utero meconium passage
J Lakshmanan and MG Ross
Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Torrance, CA, USA
To use sheep and rat models and demonstrate that stressors activate fetal
glucocorticoid (GC) system, corticotrophin-releasing factor (CRF) system
and cholinergic neurotransmitter system (ChNS) leading to propulsive
colonic motility and in utero meconium passage. Immunohistochemical
studies (IHS) were performed to localize GC-Receptors, CRF-receptors and
key molecules of ChNS in sheep fetal distal colon. CRF expression in
placenta and enteric endocrine cells in fetal rat system were examined and
the effects of acute hypoxia on in utero meconium passage was tested. IHS
confirmed localization and gestation dependent changes in GC-Rs, CRF-Rs
and cholinergic markers in sheep fetal colon. Rat placenta and enteric
endocrine cells express CRF and gastrointestinal tract express CRF-Rs.
Hypoxia is a potent inducer of meconium passage in term fetal rats. Stress is
a risk factor for in utero meconium passage and laboratory animal models
can be used to develop pharmacotherapy to prevent stress-induced in utero
Journal of Perinatology (2008) 28, S8–S13; doi:10.1038/jp.2008.144
Newborn meconium passage, a developmentally programmed
event, normally occurs within the first 24–48h after birth,
although little is known of the regulatory process. Clinically, a
delay in newborn meconium passage has been observed in infants
born with Hirschprung disease, a defect involving the absence of
intrinsic ganglia in colon.1In contrast, we have no similar
anatomical or neurochemical explanations for the meconium
staining observed in 7–22% of all term deliveries.2Greater than
90% of cases of clinically observed meconium-stained amniotic
fluid are noted in fetuses at or following 37 weeks gestation, being
uncommon in preterm deliveries.3Passage of meconium occurs
most often in deliveries beyond 40 weeks of gestation.4An increased
incidence of meconium passage in amniotic fluid is noted in the
presence of fetomaternal stress factors such as hypoxia and
infection, independent of fetal maturation.5,6On the basis of the
clinical observations, fetal stress and gastrointestinal maturation
have been attributed as risk factors responsible for meconium
passage as well as the potential meconium aspiration in utero.
Despite these risk factors, presently very little is known of the
cascade of events that leads to meconium passage in the
newborn immediately after birth or to the mechanisms
contributing ‘premature’ meconium passage in utero. There
are no small or large animal models that could be extrapolated
to humans. We review here recent studies gathered in our
laboratory in rat and sheep models directed toward understanding
the cellular and molecular basis of stress-induced in utero
Stress and gut motility: lessons learned from
Although impact of emotional stress on gastric and colonic motor
activity has long been known in humans only during the past two
decades, much attention has been paid to understand the neural
circuitry and hormonal effectors that mediate effects of stress on
gut functions in animal models (see review7,8). The rat is a widely
used animal model for stress-related alteration on gut motor
functions, although limited investigation has also been performed
in mouse models.9Inhibition of gastric emptying, gastric secretion,
gastric contraction and stimulation of colonic motility and
defecation have now been well established in adult rats as the
hallmarks of neurovisceral motor responses to stressors of
psychological, physical, chemical and immunological origin.10–13
Members of stress hormone family, more specifically
corticotrophin-releasing factor (CRF) and urocortin, have been
shown to mimic multifaceted acute responses to stress.8Both
hormones mediate their actions through CRF-receptor subtype 1
(CRF-R1) and CRF-receptor subtype 2 (CRF-R2). Both receptors
are encoded by distinct genes and both are G protein-coupled
receptors linked to multiple intracellular signaling pathways.14
Of the two CRF receptor subtypes, CRF-R1 stimulates colonic
motility and defecation, whereas CRF-R2 inhibits gastric emptying
and gastric contraction at times of stress.15Anatomical,
physiological, pharmacological and biochemical studies have
provided unambiguous evidence that the CRF system
Correspondence: Dr MG Ross, Department of Obstetrics and Gynecology, Harbor-UCLA
Medical Center, 1000 W. Carson Street, Box 3, Torrance, CA 90502, USA.
Journal of Perinatology (2008) 28, S8–S13
r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30
21 Lakshmanan J, Ahanya SN, Rehan V, Oyachi N, Ross MG. Elevated plasma
corticotrophin release factor levels and in utero meconium passage. Pediatr Res 2007;
Lakshmanan J, Salido E, Amidi F, Amidi E, Raj R, Ross MG. Rat placenta expresses
corticotrophin releasing factor protein and mRNA. Reproductive Sciences 2007;
14(1 Suppl): 175A.
Frim DM, Emanuel RL, Robinson BG, Smas CM, Adler GK, Majzoub JA.
Characterization and gestational regulation of corticotropin-releasing hormone
messenger RNA in human placenta. J Clin Invest 1988; 82: 287–292.
Lakshmanan J, Richard JD, Liu GL, Ross MG. Corticotrophin releasing factor is a fetal
gut hormone. Reprod Sci 2007; 14(1 Suppl): 251A.
Kawahito Y, Sano H, Kawata M, Yuri K, Mukai S, Yamamura Y et al. Local secretion of
corticotropin-releasing hormone by enterochromaffin cells in human colon.
Gastroenterology 1994; 106: 859–865.
Richard JD, Lakshmanan J, John TA, Ross MG. Rat fetal gastrointestinal tract is a target
organ for corticotrophin-releasing factor family neuropeptides. Am J Obstet Gyn 2006;
195(6 Suppl): S214.
Ross B, Bradley K, Nijland MJ, Polk DH, Ross MG. Increased fetal colonic muscle
contractility following glucocorticoid and thyroxine therapy: implications for
meconium passage. J Matern Fetal Med 1997; 6: 129–133.
Acosta R, Oyachi N, Lee JJ, Lakshmanan J, Atkinson JB, Ross MG.
Mechanisms of meconium passage: cholinergic stimulation of
electromechanical coordination in the fetal colon. J Soc Gynecol Investig
2005; 12: 169–173.
29 Lakshmanan J, Oyachi N, Ahanya SA, Liu G, Mazdak M, Ross MG.
Corticotropin-releasing factor inhibition of sheep fetal colonic contractility: mechanisms
to prevent meconium passage in utero. Am J Obstet Gynecol 2007; 196: 357.
Lakshmanan J, Oyachi N, Liu GL, Choi GY, Ross MG. Fetal colonic enteric nervous
system is a site of glucocorticoid-induced gastrointestinal maturation. Reprod Sci 2007;
14(1 Suppl): 287A.
Lakshmanan J, Liu GL, Oyachi N, Ross MG. Evidence for pre-receptor metabolism of
glucocorticoids in ovinee fetal distal colonic enteric nervous system. Reprod Sci 2007;
14(1 Suppl): 288A.
Lakshmanan J, Liu GL, Oyachi N, Ross MG. Localization and gestation-dependent
pattern of CRF-receptos (R1, R2) expression in ovine fetal distal colon. Reprod Sci
2007; 14(1 Suppl): 258A.
Seasholtz AF, Valverde RA, Denver RJ. Corticotropin-releasing hormone-binding
protein: biochemistry and function from fishes to mammals. J Endocrinol 2002; 175:
Lakshmanan J, Liu GL, Oyachi N, Ross MG. Cellular localization of corticotrophin
releasing factor binding protein (CRF-BP) in fetal ovine distal colon: a possible local
inhibitor of stress-induced colonic motility. Reprod Sci 2007; 14(1 Suppl): 288A.
Lakshmanan J, Lips KS, Liu GL, Ross MG. Maturational changes in ovine fetal colonic
cholinergic circuitry parallels plasma glucocorticoid surge. Reprod Sci 2007;
14(1 Suppl): 249A.
Lakshmanan J, Liu GL, Ross MG. Localization of inhibitory and stimulatory muscarinic
receptor subtypes in ovine fetal distal colon: implications for meconium passage.
Reprod Sci 2007; 14(1 Suppl): 168A.
Mechanism of in utero meconium passage
J Lakshmanan and MG Ross
Journal of Perinatology