Preterm birth and stillbirth are among the greatest health burdens associated with pregnancy and childbirth. Fifteen million babies are born preterm each year, causing about 1 million deaths annually and lifelong problems for many survivors; 3 million stillbirths also occur annually. Worldwide, the number of women and children who die during pregnancy and childbirth exceeds the total number of births in the United States. New approaches could provide a greater understanding of prematurity, stillbirth, and maternal complications of pregnancy and childbirth. Integrated multidisciplinary investigations of the mother, fetus, and newborn in different contexts and populations could elucidate the biological pathways that result in adverse outcomes and how to prevent them. Descriptive research can determine the burden of disease, while more mechanistic discovery research could explore the physiology and pathophysiology of pregnancy and childbirth. Together, this research can lead to the development and delivery of new and much more effective interventions, even in low-resource settings. Recent surveys of researchers and funders reveal a striking lack of consensus regarding priority areas for research and the development of interventions. While researchers enumerate unanswered questions about pregnancy and childbirth, they lack consensus on priorities. Funders are equally uncertain about research and development projects that need to be undertaken, and many are hard-pressed to support research on the complex problems of pregnancy and childbirth given competing priorities. This lack of consensus provides an opportunity to engage with funders and researchers to recognize the importance of understanding healthy pregnancies and the consequences of adverse pregnancy outcomes. A strategic alliance of funders, researchers, nongovernmental organizations, the private sector, and others could organize a set of grand challenges centered on pregnancy and childbirth that could yield a substantial improvement in reproductive health.
Today, mothers and their children around the world pay an immense toll in terms of mortality and morbidity due to a lack of knowledge about pregnancy, childbirth, and early life. Fifteen million babies are born prematurely each year causing about 1 million of the >3 million neonatal deaths that occur annually. Prematurity is now the second leading cause of death in children <5 years of age and the leading cause of death in the first month of life. Three million stillbirths occur globally each year, and more than a quarter million women die from complications during pregnancy and childbirth. The health effects of prematurity extend far beyond birth. Prematurity increases the risk for hypertension, mental health disorders, chronic respiratory disease, and neurologic and learning disabilities.
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Despite the enormity of these problems, research on pregnancy is not well coordinated and is far too limited in scope, and funding is not scaled to the enormity of the burden in the developed and developing world. But preterm births create large health care costs–estimated in 2005 in the United States as $26 billion annually in short-term health care costs alone. Likewise there is a disparity in resources allocated to research on care of the preterm infant rather than on research that will lead to prevention strategies. A balanced research agenda that emphasizes prevention as well as care of the woman in preterm labor and the preterm infant is paramount to decrease the impact of morbidity and mortality caused by preterm birth around the globe. A variety of factors contribute to the relative neglect of research on pregnancy, childbirth, and early life. Pregnancy is extremely complicated scientifically, yet nonscientists view it as a straightforward, normal life event. Often, political pressures bring focus on other diseases. Historically, research on women’s health issues has been slighted, and in many parts of the world women still lack basic health care and fundamental human rights. Thus, pregnancy remains one of the least explored aspects of human biology, creating a tremendous opportunity. Long-term funding commitments for research could advance discovery science and the development of interventions targeted at pregnancy and early life and impact maternal and newborn health around the world.
To address these opportunities and funding challenges, The Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) gathered and synthesized information on the health of women and their children from conception to age 2 years. This paper presents the analyses of information from 3 sources: a technical team of experts convened by GAPPS to review research in this area and identify gaps that need to be filled; perspectives and insights of prominent scientists who are familiar with but not directly involved in research on pregnancy, childbirth, and early life; and representatives of organizations that fund large-scale research and intervention efforts in health-related areas.
The intent was to facilitate the development of a scientific and strategic framework showcasing the critical need for strategic research related to the health of women and their infants. By identifying common ground and possibilities for collaboration between key stakeholders, it provides a framework for engagement of a broad alliance of funders, researchers, and advocates to raise the profile of research on pregnancy, childbirth, and early life.
A scientific framework
The GAPPS technical team of 13 prominent researchers from multiple disciplines in the developed and developing world worked to help outline a research agenda related to pregnancy, childbirth, and early life (listed in acknowledgements). Their analysis began with the assumption that health problems that occur during pregnancy, childbirth, and early life are complex syndromes with multiple causes and outcomes, occurring on a continuum that begins at conception. Understanding the determinants of a healthy pregnancy and the mechanisms responsible for adverse outcomes is one of the most difficult, as well as one of the most important, questions in biomedical research today. It requires an interdisciplinary approach. Different biological pathways are involved in the adverse outcomes of pregnancy, and these can be characterized at different biological levels, from the genome to the exposome (the combined effects of environmental influences). All of these causes and mechanisms will need to be studied through integrated investigations of the mother, fetus, and newborn.
Healthy pregnancies can have different characteristics in different contexts and among different population groups. Research in different settings and with different populations will produce results that are more widely applicable than research that is limited to high-resource countries.
Closing the knowledge and solution gaps
The technical team observed that current research funding is fragmented and uncoordinated, lacking central leadership. Funders do not understand where the field is going; this undercuts any systematic approach to prioritizing research investments. Research focuses excessively on short-term outcomes rather than long-term prevention of adverse health outcomes. Further, there has been a failure to fund implementation research, and existing effective interventions have not been analyzed in a way that they can be scaled up and implemented elsewhere.
Understanding pregnancy will require both descriptive research to characterize the attributes of healthy pregnancies and adverse outcomes and discovery research to probe the determinants and consequences of those outcomes ( Table 1 ) . Descriptive research is needed to define pregnancy outcomes and correlate outcomes with fetal, infant, and early life development across a range of contexts and settings. This should include data from prospective longitudinal studies of mothers to determine the burden of childhood and adult disease attributable to adverse pregnancy outcomes. It also requires standardized definitions and classification schemes, including risk factors, phenotypic definitions, disease classifications, and outcomes.
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Discovery research is needed to explore the physiology and pathophysiology of fetal, neonatal, infant, and early childhood development. State-of-the-art technologies can elucidate the many different biological pathways involved in pregnancy and early life. High-throughput systems biology can help unravel the complex biological networks at the heart of pregnancy and early life. Basic research into genetics, epigenetics, pathophysiology, and epidemiology will continue to generate new therapeutics, diagnostics, preventive measures, services, and education. Particularly promising is the potential development of validated biomarkers of healthy pregnancies and adverse outcomes in the short and long term for the mother and child.
Few interventions exist today to reduce preterm birth. Even if all the current interventions were universally applied, we estimate that the preterm birthrate would drop by <20%. And, many of those interventions would be impossible to implement fully due to cultural and resource constraints. Research leading to new, low-cost, high-impact interventions could achieve large health gains.
Descriptive and discovery science can lead to the development and delivery of effective interventions that may include nutritional modifications, changes in environmental exposures, improved care during pregnancy, or identification and control of infection. Economic modeling of the cost and burden of disease and the costs of interventions can help generate support for additional research or scaled-up interventions. Technology transfer and adaptation are needed to enable the appropriate use of technologies in low-resource settings and between countries. Predictive algorithms using easy-to-assess risk factors need to be developed for all settings that are able to robustly predict later risk to mother and child based on pregnancy outcomes and other biomarkers.
As with efforts to close the knowledge gap, closing the solutions gap requires an interdisciplinary approach. New multidisciplinary structures will be needed to link research with the development of interventions in a productive interchange.
Coordinating research and implementing interventions
Closing the knowledge and solution gaps requires a coordinated research and funding strategy. A system of integrated global multidisciplinary research centers could provide sustainable intellectual leadership, promote increased collaboration, and support longitudinal mapping studies of pregnancy–tracking what might be called the “gestome.” In particular, detailed longitudinal follow-up of children is needed to determine the burden of childhood and adult disease that is attributable to adverse pregnancy outcomes. Strengthening the research infrastructure in low- and middle-income countries (LMICs) is needed to facilitate collection of essential longitudinal data on mothers and their children. A system of global biorepositories in LMICs as well as in high-income countries could support research and development through, for example, the international development, harmonization, and validation of biomarkers. This work requires a combination of low-technology methods and high-throughput systems biology to assess biomarkers and health outcomes along with bioinformatic tools to disseminate capabilities and information widely. Biobank materials should include, with appropriate demographic data, specimens from mothers, newborns, and fathers. Tissue collection, separation, and storage techniques need to be improved. Future samples will need to be collected, processed, and stored under standardized protocols. Pairing these samples with rich phenotypic data will expand research opportunities.
The interdisciplinary research that is needed calls for professional development to build cross-disciplinary expertise and promote collaboration within and between countries and between discovery, development, and implementation research. Opportunities exist for translational research and development in high-burden settings to lead to scalable interventions. Descriptive and discovery science will facilitate development of and delivery of interventions. Similarly, implementation and delivery of effective interventions will stimulate discovery science and may lead to further refinement of prevention strategies in a positive feedback fashion ( Figure ).
