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Objective 4: Global Pregnancy Collaboration update (Nov 2017 - Jan 2018)

During the Global Pregnancy Collaboration (CoLab) 2017 annual meeting, we reviewed our 2016 activities, planned how to continue our ongoing activities and—most importantly—established new directions for the upcoming year. Our workshop this year, entitled “Periconceptional and Pregnancy Nutrition: Role in Adverse Pregnancy Outcomes,” stimulated projects for the upcoming year. In addition, an existing project to examine early pregnancy changes in the relation to preeclampsia, preterm birth and fetal growth restriction was reinvigorated. Immediately following the meeting Drs. Jim Roberts, Chris Redman and Annetine Staff visited Indonesia where they presented to the Indonesian ISSHP. They took advantage of the opportunity to work with Indonesian investigators to develop a consortium that will become part of the CoLab.

New Activities

Plan to seek funding to test a periconceptional nutrition and health behavior web application (app) in LMIC
Régine Steegers-Theunissen, a CoLab investigator, has developed an app for modifying periconceptional behavior, including nutrition, that has been shown to effectively modify behavior in studies in Netherlands and England. We plan to test this app in a low resource setting to examine whether the app can modify activity with the eventual goal to determine that this behavioral modification improves pregnancy outcome. We are currently working with Iberoamerican Adverse Pregnancy Network as a potential site for the studies.

Preparation of a nutritional position paper
Several of the presentations in the annual meeting workshop set the stage for a manuscript to be authored by several of the presenters to address the current state of information on nutrition, lifelong, periconceptional and during pregnancy effects on pregnancy outcome. The manuscript will address what is known, what is not known and suggest appropriate targets for future research.

IRMA (Indonesia Reducing Maternal Mortality) consortium
During a visit as invited guest speakers at the 3rd Biennial Congress of ISSHP in Bandung, Indonesia, in October 2017, Drs. Roberts, Redman and Staff met with many Indonesian clinicians/investigators. By request, CoLab wrote a letter to the Indonesian Ministry of Women Empowerment and Child Protection regarding issues they raised during our discussions and confirming our commitment to work with them. We are working to assist with forming a consortium and searching for possible funding sources to provide training for “future leaders”. Toward that end, we welcomed IRMA, a group of 13 centers, to membership. Drs. Muhammad Ilham Aldika Akbar (Universitas Airlangga/UNAIR) and Adrianes Bachnas (Universitas Negeri Sebelas Maret/UNS) will represent their group and participate in monthly Steering Committee conferences and other activities. Dr. Gus Decker, who is based in Australia and a visiting faculty at one of the Indonesian medical schools of IRMA, has agreed to be a member the Steering Committee and serve as a local contact.
 
R21 in Bolivia funded
Dr. Lorna Moore, a professor at the University of Colorado Denver Anschutz Medical Campus, was awarded funding for her NIH R21 in Bolivia. Her research team has been working in Bolivia since 1999. The project centers on updating their diagnosis and treatment of preeclampsia and its implications for later-in-life cardiovascular disease. They will also create a pilot perinatal registry and conduct a pilot study. CoLab has agreed to support the application and to assist in creating workshop(s) to address the following: (1) changes in diagnostic criteria for preeclampsia and other hypertensive disorders of pregnancy; (2) their sequelae for maternal and infant health; and (3) the importance of extending such knowledge to LMIC. It is of particular interest in countries like Bolivia where hypertensive disorders of pregnancy are one of the major contributors to Bolivia’s infant and maternal mortality, which is the highest in South America. We will also provide the COLLECT database (translated into Spanish) and the planned Birth Registry modification, CONNECT, which is a subset of the COLLECT minimal database. CONNECT will enable acquisition of obstetrical information at time of delivery in standardized way with the advantages of ease of integration with other institutions worldwide.

We have taken advantage of this opportunity to introduce Dr. Moore to the CoLab supported Iberoamerican Adverse Pregnancy Network of 11 centers from Latin America who will now be participating in the meeting.

Ongoing Projects

Iberoamerican Adverse Pregnancy Network
We have assisted a group of investigators in Latin America to set up a recently funded research consortium to be part of CoLab.  We are helping to identify funding sources and then assisting in grant writing. Once projects are funded, we will continue to serve as consultants on the project. We also have a future vision when funding can be obtained to provide a training program for research leaders. The group recently received extramural funding to support their activities.
 
PREPARE (Prematurity reduction by pre-eclampsia care)
PREPARE includes a stepped wedge randomized controlled trial (RCT) to attempt to use objective criteria to avoid inappropriate premature deliveries for preeclampsia. In addition, the trial includes a knowledge transfer component to both facilitate this objective and to stimulate the use of WHO guidelines for the management of hypertension in pregnancy.
 
The study will recruit a group of high-risk, lower socioeconomic women for the RCT, which is moving forward. Baseline data has been collected from the seven centers and two centers have been randomized to begin the implementation. The CoLab consultation group will travel to Brazil in April 2018 to visit several centers, to present a workshop on preeclampsia and to evaluate progress directly. We have assembled a Data Monitoring Committee (DMC) that will meet in early February 2018.
 
Additionally, the cohort component of PREPARE will assemble a biorepository of plasma, serum, DNA, urine and placentas. The collection of plasma, serum and urine is being carried out in 7,000 women at four times during pregnancy. This is already resulted in an additional industry grant from Roche Diagnostics titled “Angiogenic factors Will Add in Risk Evaluation (AWARE).”
 
We have had the good fortune to add placental evaluation to the PREPARE study. An investigator at the University of Pittsburgh will work with colleagues in Brazil to establish a standardized assessment of placentas collected in the PREPARE study. He is underwriting the collection of placentas. This has also allowed us to provide samples to a MD–PhD student at the University of Pittsburgh for his thesis, in which he aims to compare placental findings from both standard exams as well as those guided by specific hypotheses in women the low resource setting, Brazil, and high resource setting, Pittsburgh, PA.
 
All Children Thriving (ACT): South Africa
The project with Program for Appropriate Technology in Health (PATH) and LifeAssay, a company of South Africa, brings samples from the CAP study to test an inexpensive protein creatinine strip. Previous laboratory studies by CoLab had demonstrated good correlation of findings with this strip with either biochemical determinations of this ratio or the results with a far more expensive strip. The study aims to test accuracy in the field and to determine whether as a diagnostic it offers advantages over a standard protein only strip. This study enables us to set up a biorepository at Stellenbosch University in Cape Town for long-term storage of samples from Africa.
 
The CAP study team and CoLab collaborated with GSK Maternal and Neonatal Health Unit, Global Health R&D Unit and R&D Alternative Discovery & Development, who measured a comprehensive panel of putative preeclampsia biomarkers on a subset of CAP study population. Laboratory analyses in the United Kingdom are complete. The GSK group has donated residual samples to be used by CoLab. Originally samples were to be stored in the United States, but we now plan to use the Stellenbosch biobank in South Africa.
 
Empowering Progress in Obstetric and Women’s hEalth Research (EMPOWER)
The EMPOWER program was established to create partnerships between mentors and single sites in LMIC to improve clinical and health services research of the hypertensive disorders of pregnancy. This is accomplished by providing funding ($60,000 USD over two years) and a mentor who will visit the site and maintain contact electronically. Not only did CoLab supply $10,000 towards this study, but most of the mentors for applicants came from CoLab. Dr. Sarah Manyame, a CoLab LMIC representative working in Zimbabwe, was awarded an EMPOWER grant for her project, “Urine biomarkers for preeclampsia in women.” Her work is being performed as a nested cohort study within the CAP trial.
 
Dr. Roberts visited Dr. Manyame in South Africa in March 2017 and the two continue to meet weekly via Skype. Work was delayed somewhat by an unexpected but greatly appreciated pregnancy that has culminated in the birth of a healthy son, Matthew. The organizers of EMPOWER encouraged a maternity leave which ended in early January 2018.  Weekly calls with Sarah have resumed and urine samples are being organized for protein/creatinine, calcium/creatinine measurement copeptin, PlGF, and Congo Red measurements. 
 
COLLECT and CONNECT
The COLLECT database has been completed and is now ready for use. The availability of the database has been publicized in Placenta, British Journal of Obstetrics and Gynecology, the FIGO Journal and on our website (https://pregnancycolab.tghn.org/), which is part of the Global Health Network. The editorials are all either published or in press. To be submitted are editorials for Obstetrics and Gynecology, Hypertension, and Hypertension in Pregnancy. An abstract has been submitted to the Society for Reproductive Investigation meeting and was highlighted in a recent review prepared for an American Physiological Society Journal prepared by Dr. Roberts.
 
We have “rebranded” the database as a generic pregnancy database rather than a preeclampsia database, emphasizing that the modular design currently includes modules for preeclampsia and environmental pollution. We have also emphasized that additional modules for other pregnancy outcomes can be developed.
 
Currently, the database is being used by the PREPARE study, the PRECISE African network, a RCT in England entitled PARROT, and a program beginning in Bolivia. We are working with investigators in England to prepare an application for the Medical Research Council (MRC) based upon discussions with the global health group at MRC. The application will attempt to obtain funding to make COLLECT the database used by MRC funded global health programs.
 
We continue to explore the development of an obstetrical registry, CONNECT, that can be used in LMIC. The goal is to prepare a very simple registry that can be used in any international setting. It will be web-based if possible and, if not possible, it will be electronic and reside on local computers. The goal is to use this to replace paper-based delivery room logs. The purpose is to provide harmonizable data from low resource settings to obtain reliable statistics to guide the need for future studies and to provide entry level data for subsequent use in COLLECT. Based on recommendations from experts, we anticipate that our simplest version would include 12-15 (maximum) data fields. This can be expanded and with additional modules would be compatible with the COLLECT database.
 
Through conversations with the WHO we were placed in contact with the developers of a database, DHIS-2, which is being used extensively (60 countries) in centers around the world. This is headed by Frederik Froen with whom we have had in-depth conversations to determine how our two programs might be complementary. DHIS-2 is not designed for sharing between centers.

Summary

CoLab continues to provide samples and data to investigators worldwide (currently 15 projects ongoing).  We identify targets for research through our workshops and publicize these through position papers and published Proceeding of our meetings. We have worked with Investigators in low resource settings to help them to obtain extramural funding. Additionally, we have established consortia in Latin America and Indonesia continue to assist these colleagues with their research efforts. The consortia will prove invaluable as we utilize their infrastructure for studies. We have finished a harmonized database for studies of pregnancy that is available for investigators worldwide and that will greatly facilitate future efforts at sharing data. Finally, we have begun to the birth registry, CONNECT, for use at the end of pregnancy that will also provide accurate harmonized information from low resource settings.

Recent Publications:

Proceedings of the 2016 CoLab Global Pregnancy Collaboration Symposium: Prepregnancy and Early Pregnancy Antecedents of Adverse Pregnancy Outcomes, have been published in Placenta.

Additional CoLab publications include: