Fetal exposures are known to influence lung function in childhood and later life. Although about 7% of all births are categorized as late-preterm (births at 32o-366 wks gestation) and these infants are at increased risk for lung related problems in childhood, this population has been minimally studied for lung outcomes. Fetal exposure to chorioamnionitis (inflammation/infection) can adversely affect lung development and modulate fetal immune function. The most frequent organism associated with fetal inflammation/chronic chorioamnionitis in the human is Ureaplasma spp. We hypothesize that fetal exposure to Ureaplasma spp modulates immune responses and increases the risk of lung disease in early childhood in late-preterm infants. We will test this hypothesis with a clinical study and a parallel experimental study with U. parvum chorioamnionitis in fetal sheep. The clinical study will select cohorts of late preterm infants based on cultures for Ureaplasma spp, and histopathology for chorioamnionitis. Fetal inflammatory responses will be evaluated by cytokine/chemokine profiles in cord blood, molecular phenotypes and immune modulation by cord blood monocytes, and dendritic cells will characterize fetal immune status. The ureaplasma exposed and unexposed late-preterm infants will have lung health assessments at 9 mos and 2 yrs, and pulmonary function tests at 9 mos to evaluate lung outcomes. In parallel experiments we will characterize the inflammatory and immune modulatory responses of fetal sheep to the chorioamnionitis caused by intra-amniotic injection of U. parvum. We will explore the in vivo inflammatory/immune responses to multi-banded antigen (MBA) variability because MBA has been identified in vitro as the virulence factor for U. parvum. We will characterize how gestational age and interval from exposure to delivery modulate the fetal immune and inflammatory responses to U. parvum. We will allow U. parvum exposed fetuses to deliver and measure immune status lung function and structure at 2 wks and 2 mos of age. The experiments are innovative be cause we will focus on late-preterm infants, a large understudied population, to define immune status at birth. We will correlate of fetal ureaplasma exposure and chorioamnionitis with pulmonary outcomes and with immunologic measurements. We will use a clinically relevant model of chorioamnionitis in sheep to evaluate aspects of immune modulation that are not possible in humans. The results will link for the first time a specific and common fetal inflammatory exposure with lung outcomes. The research will be performed by a team of experienced investigators with expertise for each component of the project: the biology of Ureaplasma spp, immune and inflammatory responses in the newborn human and fetal sheep, animal models of chorioamnionitis, and pulmonary assessments of children.

Public Health Relevance

Fetal exposures to chorioamnionitis increase the risks for bronchopulmonary dysplasia and lung abnormalities in childhood in very preterm infants. Late-preterm infants have increased lung disease in childhood, but are a large and minimally studied population. We will evaluate the most common fetal inflammatory exposure - Ureaplasma spp associated chorioamnionitis - in the human and in a relevant sheep model by inflammatory, immune, and lung outcome assessments. The results will provide the information to identify infants at risk and to develop preventative and treatment strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Blaisdell, Carol J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Babushok, Daria V; Stanley, Natasha; Xie, Hongbo M et al. (2017) Clonal Replacement Underlies Spontaneous Remission in Paroxysmal Nocturnal Haemoglobinuria. Br J Haematol 176:487-490
Betensky, Marisol; Babushok, Daria; Roth, Jacquelyn J et al. (2016) Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia. Cancer Genet 209:1-10
Sweeney, Emma L; Kallapur, Suhas G; Gisslen, Tate et al. (2016) Placental Infection With Ureaplasma species Is Associated With Histologic Chorioamnionitis and Adverse Outcomes in Moderately Preterm and Late-Preterm Infants. J Infect Dis 213:1340-7
Prince, Amanda L; Ma, Jun; Kannan, Paranthaman S et al. (2016) The placental membrane microbiome is altered among subjects with spontaneous preterm birth with and without chorioamnionitis. Am J Obstet Gynecol 214:627.e1-627.e16
Liu, Wei Ping; Wang, Xiao Pei; Zheng, Wen et al. (2016) Hepatitis B virus reactivation after withdrawal of prophylactic antiviral therapy in patients with diffuse large B cell lymphoma. Leuk Lymphoma 57:1355-62
McDowell, Karen M; Jobe, Alan H; Fenchel, Matthew et al. (2016) Pulmonary Morbidity in Infancy after Exposure to Chorioamnionitis in Late Preterm Infants. Ann Am Thorac Soc 13:867-76
Babushok, Daria V; Grignon, Anne-Laure; Li, Yimei et al. (2016) Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres. Am J Hematol 91:243-7
Babushok, Daria V; Bessler, Monica; Olson, Timothy S (2016) Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults. Leuk Lymphoma 57:520-36
Rueda, Cesar M; Wells, Casey B; Gisslen, Tate et al. (2015) Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates. Hum Immunol 76:65-73
Babushok, Daria V; Perdigones, Nieves; Perin, Juan C et al. (2015) Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet 208:115-28

Showing the most recent 10 out of 25 publications