Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model.

Citation metadata

Publisher: Elsevier B.V.
Document Type: Report
Length: 945 words

Document controls

Main content

Abstract :

Key words bronchopulmonary dysplasia; chorioamnionitis; fetus; inflammation; intra-amniotic infection; lung; nonhuman primate; pigtail macaque; placenta; pregnancy; preterm birth Background Intra-amniotic infection or inflammation is common in early preterm birth and associated with substantial neonatal lung morbidity owing to fetal exposure to proinflammatory cytokines and infectious organisms. Amniotic fluid interleukin 8, a proinflammatory cytokine, was previously correlated with the development of neonatal bronchopulmonary dysplasia, but whether amniotic fluid cytokines or placental pathology more accurately predicts neonatal lung pathology and morbidity is unknown. We have used a pregnant nonhuman primate model of group B Streptococcus infection to study the pathogenesis of intra-amniotic infection, bacterial invasion of the amniotic cavity and fetus, and microbial-host interactions. In this nonhuman primate model, we have studied the pathogenesis of group B Streptococcus strains with differing potential for virulence, which has resulted in a spectrum of intra-amniotic infection and fetal lung injury that affords the opportunity to study the inflammatory predictors of fetal lung pathology and injury. Objective This study aimed to determine whether fetal lung injury is best predicted by placental histopathology or the cytokine response in amniotic fluid or maternal plasma. Study Design Chronically catheterized pregnant monkeys (Macaca nemestrina, pigtail macaque) at 116 to 125 days gestation (term at 172 days) received a choriodecidual inoculation of saline (n=5), weakly hemolytic group B Streptococcus strain (n=5, low virulence), or hyperhemolytic group B Streptococcus strain (n=5, high virulence). Adverse pregnancy outcomes were defined as either preterm labor, microbial invasion of the amniotic cavity, or development of the fetal inflammatory response syndrome. Amniotic fluid and maternal and fetal plasma samples were collected after inoculation, and proinflammatory cytokines (tumor necrosis factor alpha, interleukin beta, interleukin 6, interleukin 8) were measured by a multiplex assay. Cesarean delivery was performed at the time of preterm labor or within 1 week of inoculation. Fetal necropsy was performed at the time of delivery. Placental pathology was scored in a blinded fashion by a pediatric pathologist, and fetal lung injury was determined by a semiquantitative score from histopathology evaluating inflammatory infiltrate, necrosis, tissue thickening, or collapse scored by a veterinary pathologist. Results The principal findings in our study are as follows: (1) adverse pregnancy outcomes occurred more frequently in animals receiving hyperhemolytic group B Streptococcus (80% with preterm labor, 80% with fetal inflammatory response syndrome) than in animals receiving weakly hemolytic group B Streptococcus (40% with preterm labor, 20% with fetal inflammatory response syndrome) and in controls (0% preterm labor, 0% fetal inflammatory response syndrome); (2) despite differences in the rate of adverse pregnancy outcomes and fetal inflammatory response syndrome, fetal lung injury scores were similar between animals receiving the weakly hemolytic group B Streptococcus strains and animals receiving the hyperhemolytic group B Streptococcus strains; (3) fetal lung injury score was significantly correlated with peak amniotic fluid cytokines interleukin 6 and interleukin 8 but not tumor necrosis factor alpha or interleukin 1 beta; and (4) fetal lung scores were poorly correlated with maternal and fetal plasma cytokine levels and placental pathology. Conclusion Amniotic fluid interleukin 6 and interleukin 8 levels were superior predictors of fetal lung injury than placental histopathology or maternal plasma cytokines. This evidence supports a role for amniocentesis in the prediction of neonatal lung morbidity owing to intra-amniotic infection, which cannot be provided by cytokine analysis of maternal plasma or placental histopathology. Author Affiliation: (a) Department of Obstetrics and Gynecology, University of Washington, Seattle, WA (b) Department of Laboratory Medicine and Pathology, University of Washington, Seattle Children's Hospital, Seattle, WA (c) Department of Comparative Medicine, University of Washington, Seattle, WA (d) Washington National Primate Research Center, University of Washington, Seattle, WA (e) Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA (f) Department of Pediatrics, Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA (g) Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA (h) Department of Obstetrics and Gynecology and Global Health, University of Washington, Seattle, WA (i) Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA (j) Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA (k) Sahlgrenska Academy, University of Gothenburg, Sweden * Corresponding author: Kristina M. Adams Waldorf, MD. Article History: Received 26 October 2020; Revised 20 December 2020; Accepted 30 December 2020 (footnote) The authors report no conflict of interest. (footnote) This work was supported by funding from the National Institutes of Health (NIH) (grant numbers R01AI133976, R01AI145890, R01AI143265, and R01HD098713 to L.R. and K.M.A.W and R01AI152268 to L.R.) and seed funds from the Seattle Children's Research Institute (L.R.). In addition, this work was supported by grant number P51OD010425, which is the core grant of the Washington National Primate Research Center. (footnote) The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. (footnote) The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. (footnote) A preliminary version of this article was presented at the 2015 Infectious Diseases of Obstetrics and Gynecology meeting, Portland, OR, Aug. 7, 2015. (footnote) Cite this article as: McCartney SA, Kapur R, Liggitt HD, et al. Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model. Am J Obstet Gynecol 2021;225:89.e1-16. Byline: Stephen A. McCartney, MD, PhD (a), Raj Kapur, MD, PhD (b), H. Denny Liggitt, DVM, PhD (c), Audrey Baldessari, DVM (d), Michelle Coleman, PhD (e), Austyn Orvis, BS (e), Jason Ogle (d), Ronit Katz, DPhil (a), Lakshmi Rajagopal, PhD (f,g), Kristina M. Adams Waldorf, MD [adamsk@uw.edu] (h,i,j,k,*)

Source Citation

Source Citation   

Gale Document Number: GALE|A666889386