Preterm Birth
Toll-Like Receptor Antagonism as a Potential Treatment for Preterm Labor (K08)
Kristina Adams Waldorf, MD; Michael Gravett, MD (Co-investigator/Mentor)
The main objective of this research is to determine whether the innate immune response to intra-amniotic infection is a critical event in the pathogenesis of infection-induced preterm labor and fetal acute lung injury (ALI). Intra-amniotic infection causes the majority of early preterm births, which represent a significant economic and public health burden. Immune responses to bacteria are thought to drive infection-induced preterm labor and no therapy exists to prevent preterm birth.
The proposed study will determine the efficacy of a novel immunomodulator to prevent infection-induced preterm birth and fetal ALI by blocking the earliest immune response and may result in an effective treatment for preterm labor. The unifying hypothesis is that blockade of innate immune responses by intra-amniotic infusion of a toll-like receptor 4 (TLR4) antagonist will inhibit uterine activity and fetal ALI due to lipopolysaccharide (LPS) in our chronically catheterized nonhuman primate (NHP) model. LPS is a gram-negative bacterial product recognized by TLR4, an innate immune receptor. Antagonism of TLR4 in an LPS model allows investigation of the specific effect of innate immune response blockade on preterm labor and fetal ALI.
Investigating a new drug targeting infection-induced preterm birth and fetal ALI based on well-defined immunologic mechanisms may result in an effective treatment for preterm labor.
Funding Source: NIH
Contact: Kristina M Adams Waldorf, (206) 543-5555
Ends 3/14/12
New Model of Ascending Infection Related Preterm Birth
Kristina Adams Waldorf, MD; Michael Gravett, MD (Co-Principle Investigator)
Preterm birth remains a significant economic and public health burden and the incidence is rising. Infection induced inflammation plays a significant role in preterm birth and is thought to occur as a result of either direct microbial infection or microbial byproduct stimulation of inflammatory mediators, which promotes premature myometrial responses and uterine contractions. Intra-amniotic infection (IAI) is thought to be the result of ascending bacterial infection from the vagina, and immune responses to bacteria are thought to drive preterm labor and promote fetal acute brain and lung injury.
Obstetrical research has yet to identify effective preventive interventions for preterm labor. The overall objective of this proposal is to develop a model system which emulates human preterm birth to ultimately elucidate molecular mechanisms of infection-induced preterm labor and related adverse neonatal sequelae (e.g. brain injury). We propose to develop a nonhuman primate model in the rhesus monkey that closely mimics an ascending lower genital tract infection at the chorio-decidual interface in the lower uterine segment. This model could provide important mechanistic observations that cannot be determined in lower mammalian models of preterm birth, due to known differences in placentation and parturition (onset of labor).
The central hypothesis is that infection with group B streptococcus (GBS) at the chorio-decidual interface in the lower uterine segment will result in an inflammatory response that stimulates premature myometrial contractions, IAI, and premature delivery. We propose to establish a model of preterm labor that more closely replicates the natural history of human preterm labor than prior animal models, by mimicking an ascending lower genital tract infection in a rhesus monkey. The new model will introduce GBS at the chorio-decidual interface in the lower uterine segment of a pregnant dam, monitor maternal and fetal physiological responses before and during infection, and sequentially sample the maternal, fetal, and amniotic fluid compartments.
We believe these initial experiments will lay the foundation for our longer term objectives which include:
- to elucidate the pathophysiologic mechanisms of ascending infection-induced preterm labor;
- to establish the cellular and molecular links among intrauterine infection and preterm labor using genomics; and
- to develop non-invasive diagnostic strategies for detecting infection-associated preterm labor.
Funding Source: March of Dimes
Contact: Kristina M Adams Waldorf, (206) 543-5555
Ends 3/14/12
Non-Human Primate Model of Stretch-Induced Preterm Labor
Preterm birth remains a significant economic and public health burden and the incidence is rising. Our objective is to develop a non-human primate model of stretch-induced preterm labor (PTL) to elucidate the mechanisms involved and to test novel therapies. Uterine stretch is often responsible for the onset of PTL in multiple gestation, which accounts for 15% of preterm births and 50% of the increase in preterm birth rates over the last decade. Women with a multiple gestation can be identified by early ultrasound, making them an ideal group to target for prophylactic interventions. The unifying hypothesis is that a novel non-human primate model of uterine stretch will emulate human stretch-induced PTL and define the initiating and subsequent events in the pathogenesis of this type of PTL.
Previously, we have defined intracellular mechanisms responsible for stretch-induced expression of labor-associated genes in vitro and now need to establish an animal model in which to test potential therapeutic intervention. We will take advantage of a well-established, chronically-catheterized, non-human primate model to create stretch-induced PTL by inflating an intra-amniotic balloon. Our non-human primate model is superior to lower mammalian models of PTL since it shares many features with human pregnancy, including placental structure and hormonal control of parturition.
This model will allow sequential sampling of myometrium, maternal, and amniotic fluid compartments before and after uterine stretch. If interventions to prevent PTL in multiple gestations are to be achieved, then pathways activated by uterine stretch must be elucidated in a model that emulates the human condition.
Funding Source: March of Dimes Birth Defects Foundation
Contact: Kristina M Adams Waldorf, (206) 543-5555
Ends 3/14/12
Global Alliance for the Prevention of Prematurity and Stillbirth
Globally, preterm births and stillbirths represent major public health challenges. It is estimated that there are 14 million preterm births globally each year. Premature birth is the leading cause of death in the neonatal period, responsible for more than a million deaths globally each year. In addition, an estimated 3.2 million stillbirths occur each year worldwide.
The Global Alliance for the Prevention of Prematurity and Stillbirth (GAPPS) is an alliance of internationally renowned core investigators, under the direction of Craig E. Rubens, MD. PhD, intended to bridge basic science, epidemiology, and applied public health research to accelerate discovery and translational science for interventions to improve maternal and neonatal health.
Funding Source: Bill and Melinda Gates Foundation, Children's Hospital Regional Medical Center
Ends 5/2012
Risk Reduction Education in Patients with Prior Preterm Birth
This project is primarily intended to address the March of Dimes' funding priority:
- Increasing risk reduction education and/or services in women at high risk due to previous adverse pregnancy outcomes in which pre/interconception or prenatal care could help prevent adverse outcomes and funding priority
- Increasing professional education about 17α-hydroxyprogesterone caproate treatment for women who had a previous singleton preterm infant
History of a previous preterm birth is a primary factor prior to pregnancy that identifies women at substantial risk for recurrent preterm birth and is present in 10% of all women delivering preterm. These women have at least a 3X higher risk of preterm birth in a subsequent pregnancy, with rates ranging from a low of 25% to a high of 55%, depending primarily on ethnicity, number of previous preterm births, and interpregnancy interval. In this 3-year demonstration project we will provide enhanced preconception care to women who have delivered a preterm infant.
We propose to conceptually expand the preconception time to begin immediately after birth and to include the first six weeks of the postpartum period, times we have found to be teachable moments for patients having suffered the experience of a preterm birth. We will develop and provide both in-hospital and outpatient education materials to patients regarding strategies with a high likelihood of reducing their risk of recurrent preterm birth: reliable contraception for at least one year, 17-OH progesterone, and counseling about smoking cessation, dental hygiene, and stress reduction. We will coordinate and share outpatient educational activities with the patient's primary care obstetric provider. We will assess patient satisfaction with these educational interventions and follow the patients at 6-month intervals
Funding Source: March of Dimes, Washington Chapter
Contact: Thomas J Benedetti, MD, MHA, (206) 543-3729
Ends 1/31/2011