Global Network for Perinatal and Reproductive Health

Global Network for Perinatal and Reproductive Health

Mail code: L-458
3181 SW Sam Jackson Park Road,
Portland, OR 97239

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 will continue to be that of research capacity development and transference of skills, at each one of the centers part of the network. This last goal will be secured by expansion of 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

  1. 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)
  2. Preventing Perinatal Morbidity and Mortality by Cleansing The Birth Canal with Chlorhexidine during Labor and the Neonate after Birth: A Randomized Controlled Trial
  3. Initiative for reduction in Maternal Mortality associated with Post-Partum Hemorrhage
  4. Evaluation of the use of cervical cerclage: a commonly used intervention to prevent premature birth.
  5. The use of Proteomics for diagnosis of Intrauterine Infection
  6. Evaluation with detailed sonographic (2-D and Doppler) examination of fetuses Diagnosed with Fetal Growth Retardation(FGR) to determine the optimal timing for delivery
  7. Identification of the best methods of predicting successful induction of labor
  8. Use of pesticides and their effect on the reproductive health of women and infants
  9. Description of the prevalence of smoking and exposure to second hand smoking in pregnancy

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. (Publications and presentations Thinkhamrop J.).

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.

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. Since Taha et al.(BMJ, 1997) demonstrated a reduction in the overall rate of maternal sepsis following cleansing of birth canal with Chlorhexidine (CHD) in Malawi, several clinical trials are in process focusing mainly in reduction of vertical transmission of HIV. Chlorhexidine has shown both in vivo and in vitro activity against a wide range of pathogens. No studies in Africa have so far focused on the use of CHD to reduce peripartal infection with documentation of microbiologic endpoints. 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.

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. A safety and acceptability study of vaginal washings in 50 additional women is underway.

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. An agenda to test these interventions with larger and more definitive studies will be developed by a consortium of agencies and donors.

3) Initiative for reduction in Maternal Mortality associated with Post-Partum Hemorrhage (PPH)

Postpartum hemorrhage (PPH) is the leading cause of maternal mortality, with an estimated 14 million cases occurring each year. PPH is responsible for approximately 150,000 maternal deaths annually worldwide. While PPH causes an average of 25% of worldwide maternal deaths, nearly half of all postpartum deaths in developing countries are due to this condition. 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 with completion of the first global survey on the use of the Active Management of the Third Stage of Labor (AMTSL) Festin et al, 19, 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 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).

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 and Dr. Mario Festin, MD as the Co-P.I., Dr. Tolosa is 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 (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. The largest database on this subject in existence in the world today has been created and it includes populations from eight different sites from different regions of the world (India, Thailand, Chile, Finland and the U.S.). Preliminary data analysis was presented at the 2005 meeting of the Society for Ultrasound in Obstetrics and Gynecology in Vancouver, Canada, and will be presented at the 2006 meeting of the Society for Maternal Fetal Medicine in Miami, USA and at the FIGO meeting in 2006 in Malaysia. These scientific meetings are the most important in the field in the world. (See under publications, Periera et al, 2005, 2006).

Our data will provide the evidence to demonstrate that this intervention, although promising as an aide to improve perinatal outcomes in complicated pregnancies, 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.

5) The use of Proteomics for diagnosis of Intrauterine Infection

The GNPRH has made a concerted effort 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 or cervico-vaginal secretions could provide an answer to the vexing issue of how to offer accurate, cost-effective 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, MD, under the direction of Dr. Michael Gravett, M.D., director of the Division of Maternal Fetal Medicine at OHSU. The following centers will take part:

  1. Khon Kaen University, Khon Kaen, Thailand,
    P.I. Jadsada Thinkhamrop, M.D., M.Sc.
  2. Chulalongkorn University, Bangkok, Thailand,
    P.I. Surasith Chaithongwongwatthana, M.D.
  3. University of Miami, Miami, Florida,
    P.I. Amanda Cotter, M.D.
  4. Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A.,
    P.I. Jason Baxter, M.D.
  5. 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 value of proteomics in urine, blood, 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 NICHD in the U.S. is being developed to expand the project to more sites part of the GNPRH.

6) 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 Judy Logan, M.D., 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.  

Updated on March 07, 2006

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