GNPRH Research Agenda
In consultation with the TAC, a research agenda has been defined. Two specific areas are the focus of the investigators, 1) Perinatal and Neonatal Research and 2) Reproductive Tract Infections. The investigators and the TAC have agreed that important work in these two areas is urgently needed and the GNPRH has the capability and expertise to develop and implement important research initiatives that will have an impact on the health of the populations we serve. No other network like this one is currently established in the world.
A major objective of the GNPRH is that of research capacity development and transference of skills through collaboration with centers and investigators from centers not part of the network and by supporting collaboration between centers part of the network.
Research Initiatives and Projects
- The International Infections in Pregnancy Study (IIP):
Defining the Relationship between Preterm Birth and Maternal Carriage of Group B Streptococcus(GBS) and Bacterial Vaginosis (BV)
- Preventing Perinatal Morbidity and Mortality by Cleansing The Birth Canal with Chlorhexidine during Labor and the Neonate after Birth: A Randomized Controlled Trial
- Initiative for reduction in Maternal Mortality associated with Post-Partum Hemorrhage
- Evaluation of the use of cervical cerclage: a commonly used intervention to prevent premature birth
- The use of Proteomics for diagnosis of Intrauterine Infection
- Description of the prevalence of smoking and exposure to second hand smoking in pregnancy
- Use of pesticides and their effect on the reproductive health of women and infants
- Identification of the best methods to predict successful induction of labor
- Evaluation with detailed sonographic (2-D and Doppler) examination of fetuses Diagnosed with Fetal Growth Retardation(FGR) to determine the optimal timing for delivery
1) Defining the Relationship between Preterm Birth and Maternal Carriage of Group B Streptococcus(GBS) and Bacterial Vaginosis (BV): A Multicenter pilot follow-up Study (The International Infections in Pregnancy (IIP) Study).
Infections in pregnancy such as Bacterial Vaginosis (BV) and Group B Streptococcus (GBS) have been associated with premature birth, low birth weight and increased risks for neonatal and maternal morbidity and mortality. This project had the objectives of determining the prevalence of these two infections in pregnant women, determine the best diagnostic methods that can be use in the field or at a point of service/care and test the value of rapid diagnostic tests for these common conditions.
Results Achieved: More than 1,400 women were enrolled in the study at 8 centers in 7 countries with funding and technical support from CDC, Population Council (Thailand) and the Department of Obstetrics and Gynecology, at the University of Alabama at Birmingham. This project accomplished development of a unique database with information that had not been generated by any other group before and allowed evaluation of epidemiological and microbiological differences between populations in different regions of the world.
Two rapid diagnostic tests (The FemExam card, Quidel Diagnostics, USA) for determination of BV and the OIA (ThermoBiostar, USA) for GBS were tested and determined to be less effective than simpler and less expensive tests currently in use in clinical practice. A new and more accurate diagnostic test was developed after our study by Quidel and is currently being used for diagnosis of BV.
This study was the first multi-site study developed and conducted by investigators part of the GNPRH. It allowed development of technical capacity at each one of the participating centers and established other collaborations with experts from the CDC who were involved with the project. The GNPRH acquired experience as did the investigators and research teams at the different centers, in evaluation of rapid diagnostic tests for infections. The project allowed for junior faculty at the centers to be involved as authors of scientific manuscripts, which have been published or are currently in the process of publication in recognized peer-reviewed journals with international circulation. This work has been continued with emphasis in development of rapid diagnostic methods for infections (see initiatives 2, 4 and 5) (See Publications and presentations Thinkhamrop at al, Whitney et al, Tolosa et al).
2) Preventing Perinatal Morbidity and Mortality by Cleansing The Birth Canal with Chlorhexidine during Labor and the Neonate after Birth: A Randomized Controlled Trial
This is the currently on-going project of the GNPRH that has the most promising potential for impact in reduction of adverse perinatal and neonatal outcomes, in a global scale. It tests the use of a simple, safe and cost-effective intervention, which can be used in different regions of the world. We are conducting a pilot study of 500 mother-baby pairs on the Maternity Ward of Harare Central Hospital (HCH) in Zimbabwe, using 1% CHD solution to cleanse the birth canal during labor and the neonate after birth.
Rationale of the study and statement of the problem: Worldwide, approximately two-thirds of infant deaths and over one third of under-five mortality occur in the first month of life. Infections are the single most important cause of neonatal deaths and are responsible for 32% of all neonatal mortality. In Zimbabwe the neonatal mortality rate is estimated at about 30 per 1000 live births, with an estimated 10 000 deaths per year. In Harare the leading agents of neonatal sepsis appear to be S. Aureus (31%), GBS (12%), Klebsiella species (8%), E. Coli (5 %). With respect to maternal health, 35% of all maternal deaths in Zimbabwe are due to puerperal and post abortal sepsis. Endometritis, the most common puerperal infection results largely from contamination of the uterine cavity with vaginal organisms during labor and birth. Endometritis is usually polymicrobial, often due to the same microorganisms involved in neonatal sepsis.
Interest in the use of vaginal washing during childbirth to reduce infection has grown over the past 20 years. Taha et al.(BMJ, 1997) demonstrated a reduction in the overall rate of neonatal mortality and mortality due to infectious causes and maternal sepsis following cleansing of birth canal with Chlorhexidine (CHD) in Malawi. The results have not been accepted by the scientific community due in part to the study design used by Taha et al. Chlorhexidine has shown both in vivo and in vitro activity against a wide range of pathogens. No RCTS in sub-Saharan Africa have so far focused on the use of CHD to reduce neonatal mortality due to infection and reduce neonatal deaths with documentation of microbiologic endpoints.
Timeline: Pilot study and baseline data collection January 2005 to October 2005. Completion of pilot data analysis in 500 mother-baby pairs by March 2006.
Intended use of pilot study results: The project proposal tests a very simple, cost-effective method for reducing neonatal and maternal morbidity and mortality in Zimbabwe. If results of this pilot study demonstrate that cleansing the birth canal during labor and the neonate after birth with 1% CHD is safe and that a larger clinical trial is feasible, then a larger randomized clinical trial at HCH is planned to determine the efficacy of CHD washing to reduce the incidence of neonatal septic morbidity and mortality and maternal septic morbidity.
Results achieved to date: 500 mother-infant pairs have been recruited at Harare Central Hospital in Zimbabwe and a meeting of investigators was completed in September 2005, for analysis of data in Zimbabwe and dissemination of the results with preparation of scientific manuscripts.
As a result of this work, which has required 5 years of preparation, other centers of the GNPRH have developed similar research concepts in India and Bangladesh. USAID is considering funding of a project in Bangladesh. The GNPRH is one of only four recognized groups in the world currently developing this research, which has enormous potential for having favorable impact on the Global Public Health. The GNPRH was invited to present results of this work at a conference on the subject in October 2005 in Washington, convened by NICHD, USAID and private foundations.
3) Initiative for reduction in Maternal Mortality associated with Post-Partum Hemorrhage (PPH)
Postpartum hemorrhage (PPH) is the leading cause of maternal mortality, approximately half of the 600,000 maternal deaths annually are worldwide associated with PPH. A largely preventable and manageable condition in the developed world, in developing countries it is often fatal. Routine prevention of PPH is the approach most likely to achieve measurable impact in reducing maternal deaths in developing countries.
The GNPRH initiated this effort in 1999 with completion of the first global survey on the use of the Active Management of the Third Stage of Labor (AMTSL) (Festin et al), intervention that has been shown through well conducted randomized controlled trials to reduce post-partum hemorrhage (PPH). This practice is underutilized in a global scale and it is not clear if of three components that make the AMTSL (early cord clamping and cutting, administration of an oxytocic agent soon after delivery of the neonate and traction of the placenta), administration of the oxytocic agent alone could be the main component that results in benefit and reduction in PPH.
Results Achieved: Publication in 2003 of (to date) the largest descriptive project on evaluation of the use of AMTSL. This work by the GNPRH has been used to promote the use of AMTSL by FIGO and to highlight the need for additional work in this field, as reduction in maternal mortality on a global scale, remains as an elusive goal. (see Publications and Presentations Festin et al). A second survey at two centers in Nepal is ongoing.
Findings: The survey revealed significant intra and inter country variation in the practice of the AMTSL and confirmed the existence of a large gap between knowledge and practice. Areas identified for improvement are the urgent implementation of this evidence based clinical management practice, AMTSL, increased accessibility to systematic reviews in developing nations, and the conduction of clinical trials that assess the impact of this intervention in other settings, including primary health centers.
Action plan: Together with The University of The Philippines in Manila Mario Festin, M.D. and Jorge Tolosa, M.D., are preparing a pilot study. This study will be developed in collaboration with the Program for Assessment of Technology in Health (PATH, Washington, USA.) The study will test the use of the AMTSL at Primary Health Care Centers and intends to explore the feasibility of its use in home deliveries. The use of a device developed by PATH (Uniject™) with 10 units of oxytocin will be tested, as the administration of Oxytocin in Uniject™ could be a major factor in reducing PPH globally.
The goal of this project is to reduce the incidence of PPH and prevent maternal deaths. A secondary goal is to reduce infant deaths, as studies show that in developing countries, when a mother dies, her newborn nearly always dies as well. Other centers part of the GNPRH in Colombia, Thailand and in India are considering similar projects.
4) Evaluation of the use of cervical cerclage: a commonly used intervention to prevent premature birth.
The GNPRH has completed the largest historical cohort study (to date) to assess the use and effectiveness of a commonly practiced intervention worldwide to reduce premature birth and low birth weight. This intervention (clinically-indicated cervical cerclage,) although being commonly used, has not been properly assessed in terms of safety and effectiveness.
Results Achieved: A multi-center retrospective cohort study is on going. It includes populations from nine different sites from different regions of the world (India, Thailand, Chile, Ireland, Finland and the U.S.). Preliminary results were presented at the 2005 meeting of the Society for Ultrasound in Obstetrics and Gynecology in Vancouver, Canada, and at the 2006 meeting of the Society for Maternal Fetal Medicine in Miami, USA and will be presented at the FIGO meeting in 2006 in Malaysia. These scientific meetings are the most important in the field in the world. (See under publications, Pereira et al, 2005, 2006).
Our data will provide the evidence to demonstrate that this intervention, although promising as an aid to improve perinatal outcomes in complicated pregnancies (especially after tests are done to rule out infection of the amniotic fluid), needs thorough assessment before it continues to be used. A proposal for development of a Randomized Controlled Trial which will be conducted at multiple sites part of the GNPRH in developing and developed countries will be completed in 2006. Rapid test for diagnosis of infection of the amniotic fluid are in development. (Initiative #5, below)
5) The use of Proteomics for diagnosis of Intrauterine Infection
The GNPRH has made it a priority to participate in development of urgently needed rapid diagnostic tests for infections in pregnancy that are associated with adverse outcomes of pregnancy including stillbirth, low birth weight and premature birth, especially in women living in less developed countries or with limited access to health care services. Modern technologies such as Proteomics to test for presence of specific proteins in urine, serum or cervico-vaginal secretions could provide an answer to the vexing issue of how to offer accurate, cost-effective, rapid, diagnostic testing at the point of care in developing country settings.
Results Achieved: A proposal has been developed by the Co-P.I. for the GNPRH at OHSU, Dr. Leonardo Pereira, under the direction of Dr. Michael Gravett, director of the Division of Maternal Fetal Medicine at OHSU and Dr. Srinivasa Nagalla, in the department of Biomedical Discovery. The following centers will take part:
- Khon Kaen University, Khon Kaen, Thailand,
P.I. Jadsada Thinkhamrop, M.D., M.Sc.
- Chulalongkorn University, Bangkok, Thailand,
P.I. Surasith Chaithongwongwatthana, M.D.
- University of Miami, Miami, Florida,
P.I. Amanda Cotter, M.D.
- Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.,
P.I. Jason Baxter, M.D.
- Clínica Universitaria Bolivariana. Medellín, Colombia,
P.I. Jose Sanín-Blair, M.D.
Centers have been identified for development of a multi-center study that will test the diagnostic value for intrauterine infection of proteomics in urine, serum, cervico-vaginal secretions and if possible amniotic fluid, in women with pregnancies complicated by premature labor and at risk for premature birth and for delivering low birth weight babies. Funding and technical support for the initial project have been secured. An application to NIH in the U.S. is being developed to expand the project to more sites part of the GNPRH.
6. Description of the Prevalence of Smoking and exposure to second hand smoking in pregnancy in the world
According to the World Health Association, approximately 250 million women smoke world wide. In the Unites States, 18.5% of women used cigarettes in 2004 and 10.7% of women giving birth in 2003 reported having smoked. Among pregnant women, there is an increased prevalence of smoking amongst the youngest (<20) and oldest (>35) of this population. India, the world’s second largest tobacco consumer after China, accounted for one-fifth of the 4 million deaths resulting from tobacco-related illnesses in 2000.
Tobacco use in pregnancy is associated with higher rates of pregnancy complications and adverse birth outcomes when compared to non-smoking women. Heavy smoking (>15 cigarettes per day) leads to increased risk of ectopic pregnancy, placenta previa, placental abruption, stillbirth, and premature rupture of membranes. The most common adverse outcomes are related to increased rates of low birth weight and preterm labor and delivery. These babies have increased risk for respiratory dysfunction with development of neonatal respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis and retinopathy of prematurity. Heavy smoking in pregnancy leads to higher likelihood of neonatal morbidity and mortality accounting for 5% of perinatal deaths.
Tobacco use and its morbidities extend beyond the prenatal period affecting both the mother and infant. Tobacco use in postpartum women is associated with lower rates of breastfeeding initiation and reduced duration. Maternal lifetime complications are numerous and include atherosclerotic disease, lung cancer, chronic obstructive pulmonary disease, lung disease, increase risk of ectopic pregnancy, premature menopause, infertility, and osteoporosis. Infant exposure to tobacco smoke increases the risk of sudden infant death syndrome (SIDS), respiratory infections, reactive airway diseases, otitis media, bronchiolitis, short stature, hyperactivity, and decreased school performance.
The prevalence of smoking in pregnancy will be studied at all centers part of the GNPRH, including rates of second-hand exposure of pregnant women. Interventions to reduce smoking in pregnancy and exposure to second hand smoking will be introduced and or tested.
7. Use of Pesticides and Their Effect on Reproductive Health
A project to study the effect of exposure to pesticides and herbicides used in the flower industry, on the reproductive health of women, men and children, is on-going in Colombia. It has been developed together with the Department of Environmental and Occupational Health at Emory University, the Colombian Association of Flower Exporters and the Colombian National Institutes of Health.
Field work was completed to determine the types of pesticides used, how they are used and which are the opportunities for human exposure. A cost-effectiveness analysis of the current biological markers used to monitor workers exposure will be done, as well as a study of the attitudes and beliefs of the workers with respect to the utilization of safety equipment and recommended safe practices to reduce exposures.
In a follow-up project biological markers for exposure will be developed and a cohort of women, men and children will be followed to determine if there are associations between exposure and adverse reproductive health outcomes, including those during pregnancy.
8) Identification of the best methods for predicting successful induction of labor
Labor induction is one of the most common and fastest growing medical procedures in the world. While the number of medically indicated inductions has remained relatively stable over time, the number of elective inductions has increased dramatically. Induction of labor, however, is not without risk. Both medically indicated and elective inductions are associated with an increased risk of maternal and neonatal morbidity. This is particularly true if the physical status of the cervix is deemed to be “unfavorable”. At present, the standard practice for pre-induction cervical assessment is a digital examination and assignment of a Bishop score. Several studies, however, have shown that the Bishop score has a poor predictive value for the result of induction. In recent years, newer, more objective methodologies including fetal fibronectin (fFN) and transvaginal ultrasound cervical length measurement (TVCL) have shown promise in predicting outcomes of labor induction. To date, however, no useful algorithm for clinical practice has been identified.
Study Objective: Our main study objective is to prospectively evaluate and compare the ability of the Bishop score, fetal fibronectin (fFN), transvaginal ultrasound cervical length measurement (TVCL), or any combination of the three to predict mode of delivery, time to delivery, and active phase labor in women undergoing induction at term. Our secondary objective is to identify and define a clinical algorithm that may be useful for counseling and better selecting patients for induction.
9) Evaluation with detailed sonographic (2-D and Doppler) examination of fetuses Diagnosed with Fetal Growth Retardation(FGR) to determine the optimal timing for delivery
A multi-center study is being develop to examine in a longitudinal manner fetuses diagnosed with FGR. We will study the hemodynamic changes that occur as pregnancy progresses and compare the use of ultrasonographic parameters alone (umbilical cord Doppler, ductus venosus waveforms, aorthic isthmus direction of flow, middle cerebral artery waveforms and velocities) among others, with electronic fetal monitoring testing, maternal report of fetal behaviour and activity and the biophysiscal profile. Cord blood samples will be collected at birth for analysis of biological markers of cardiac dysfunction and a bank of tissue created. Once this longitudinal study is completed and centers part of the GNPRH certified in the use of these techniques, a RCT will be developed to determine the best combination of diagnostic tests to optimize timing of delivery.
A novel component of this initiative is the development and use of a web based data entry system, together with the Department of Medical Informatics and Dr. Judy Logan, at OHSU. This will be the first time for the GNPRH and at OHSU that such technology will be used, which will permit precise, secure and expedited data entry from multiple centers.