The objectives of this research proposal are to assess the therapeutic effect of antenatal maternal antibiotic therapy in preventing or mollifying cerebral white matter damage in the neonate (as a consequence of prolonged U.parvum intra-amniotic infection, IAI) and to correlate neurobehavioral outcomes with neuropathologic findings of neonatal brain injury. Our central hypothesis is that prenatal treatment of prolonged U.parvum IAI with a specific macrolide antibiotic, azithromycin (AZI) will mitigate fetal origins of cerebra white matter injury and decrease the severity of perinatal neurological impairment. The experimental approach will utilize our non-human primate model of IAI, with mid-gestation inoculation of U.parvum (105 CFU/ml, serovar 1) at 105 days gestation. We predict our new approach will mimic the indolent nature of Ureaplasma spp. infections during human pregnancies by prolonging fetal exposure to these microorganisms and the resultant inflammatory milieu, with the potential for intensified periventricular white matter injury. Fetal cardiovascular hemodynamic and regional circulatory changes in response to prolonged U.parvum IAI, and maternal antenatal therapy, will be monitored by Doppler ultrasonography and linked with magnetic resonance imaging (MRI) of the fetal brain during critical periods of development. Serial MRI scans of fetal (in utero) and infant brains will provide insight into the nature and timing of potential white matter injury occurring during U.parvum IAI and in the neonatal period. Postnatal follow-up studies are designed to correlate adverse neurodevelopmental outcomes such as dysfunctional neuromuscular dexterity, neurobehavioral and cognitive abnormalities with neuropathologic findings of chronic perinatal white matter inflammation (i.e., microgliosis, astrogliosis &arrested oligodendrocyte maturation). A number of mechanistic endpoints will be ascertained that will aid in our understanding of the causal links among Ureaplasma infections, fetal inflammatory responses, and hemodynamic adaptations which portend cerebral white matter damage and neurological disabilities. Biochemical markers characteristic of the fetal inflammatory response, i.e., amniotic fluid levels of PGE2, PGF2?, pro-inflammatory cytokines (IL-6, TNF-?, IL-1?), total leukocyte counts and uterine contractility will be correlated with quantitative culture &PCR for U.parvum from the amniotic fluid, fetal cord blood and neonatal samples, in order to establish prognostic indicators of antibiotic therapy which may help improve clinical management decisions. A major strength of our application lies in our ability to incorporate an """"""""in utero"""""""" treatment strategy to prevent adverse neurologic sequelae with postnatal functional assessments of neurobehavioral and cognitive development in a unique and relevant animal model. Given the confluence of resources and expertise of our multidisciplinary investigative team, our scientific approach has a high probability of translating to clinical applications which will reduce adverse neurologic sequelae in prematurely born human infants.]

Public Health Relevance

Intra-amniotic infection by genital Mycoplasmas (i.e., Ureaplasma spp.) is a predominant cause of early preterm birth;arguably the most important unresolved public health issue in obstetric medicine. Preterm infants often have life-long health complications including neurodevelopmental disabilities such as cerebral palsy. This proposal will expand our understanding of the causal relationships among intra-amniotic Ureaplasma infections, fetal brain injury and adverse neurological development in the preterm neonate.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
Program Officer
Parisi, Melissa
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Oregon Health and Science University
Obstetrics & Gynecology
Other Domestic Higher Education
United States
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Ellery, Stacey J; Kelleher, Meredith; Grigsby, Peta et al. (2018) Antenatal prevention of cerebral palsy and childhood disability: is the impossible possible? J Physiol 596:5593-5609
Kelleher, Meredith A; Liu, Zheng; Wang, Xiaojie et al. (2017) Beyond the uterine environment: a nonhuman primate model to investigate maternal-fetal and neonatal outcomes following chronic intrauterine infection. Pediatr Res 82:244-252
Grigsby, Peta L (2016) Animal Models to Study Placental Development and Function throughout Normal and Dysfunctional Human Pregnancy. Semin Reprod Med 34:11-6
Frias, Antonio E; Schabel, Matthias C; Roberts, Victoria H J et al. (2015) Using dynamic contrast-enhanced MRI to quantitatively characterize maternal vascular organization in the primate placenta. Magn Reson Med 73:1570-8
Acosta, Edward P; Grigsby, Peta L; Larson, Kajal B et al. (2014) Transplacental transfer of Azithromycin and its use for eradicating intra-amniotic ureaplasma infection in a primate model. J Infect Dis 209:898-904
Grigsby, Peta L; Novy, Miles J; Sadowsky, Drew W et al. (2012) Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Am J Obstet Gynecol 207:475.e1-475.e14
Roberts, V H J; Räsänen, J P; Novy, M J et al. (2012) Restriction of placental vasculature in a non-human primate: a unique model to study placental plasticity. Placenta 33:73-6