Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates.
OBJECTIVE
Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model.


METHODS
A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace.


RESULTS
Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth.


CONCLUSIONS
Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA. Electronic address: adamsk@u.washington.edu.
Kristina M
KM
Adams Waldorf
Department of Obstetrics and Gynecology, Chelsea and Westminster Hospital, Imperial College London, London, United Kingdom.
Natasha
N
Singh
Department of Cancer and Surgery, Imperial College London, London, United Kingdom.
Aarthi R
AR
Mohan
Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN.
Roger C
RC
Young
Department of Pediatric Infectious Diseases and Microbiology, Seattle Children's Research Institute, Seattle, WA.
Lisa
L
Ngo
Department of Cancer and Surgery, Imperial College London, London, United Kingdom.
Ananya
A
Das
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
Jesse
J
Tsai
Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, WA.
Aasthaa
A
Bansal
School of Medicine, University of Washington, Seattle, WA.
Louis
L
Paolella
Department of Cancer and Surgery, Imperial College London, London, United Kingdom.
Bronwen R
BR
Herbert
Department of Cancer and Surgery, Imperial College London, London, United Kingdom.
Suren R
SR
Sooranna
Washington National Primate Research Center, University of Washington, Seattle, WA.
G Michael
GM
Gough
Washington National Primate Research Center, University of Washington, Seattle, WA.
Cliff
C
Astley
Washington National Primate Research Center, University of Washington, Seattle, WA.
Keith
K
Vogel
Washington National Primate Research Center, University of Washington, Seattle, WA.
Audrey E
AE
Baldessari
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
Theodor K
TK
Bammler
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA.
James
J
MacDonald
Department of Obstetrics and Gynecology, University of Washington, Seattle, WA; Global Alliance to Prevent Prematurity and Stillbirth, Seattle Children's Research Institute, Seattle, WA.
Michael G
MG
Gravett
Department of Pediatrics and Global Health, University of Washington, Seattle, WA; Department of Pediatric Infectious Diseases and Microbiology, Seattle Children's Research Institute, Seattle, WA.
Lakshmi
L
Rajagopal
Department of Obstetrics and Gynecology, Imperial College London, London, United Kingdom.
Mark R
MR
Johnson
D000650:Amnion / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008254:Macaca nemestrina; D023421:Models, Animal; D009215:Myometrium / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000503:physiopathology*; D006831:Polyhydramnios / Q000378:metabolism; D011247:Pregnancy; D011272:Pregnancy, Multiple / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013314:Stress, Mechanical; D014599:Uterus / Q000503:physiopathology*
D016207:Cytokines; D012333:RNA, Messenger; D015237:Dinoprost; D015232:Dinoprostone
Macaca nemestrina; amniocyte; amnion; chemokine (C-C motif) ligand 2; choriodecidua; cytokines; interleukin-1; interleukin-8; monocyte chemotactic protein 1; myometrium; pregnancy; preterm labor; prostaglandin E2; prostaglandin F2α; tumor necrosis factor; uterine stress; uterine stretch