key: cord-0737984-0tk7gv3t
authors: Sadovsky, Yoel; Mesiano, Sam; Burton, Graham J.; Lampl, Michelle; Murray, Jeffrey C.; Freathy, Rachel M.; Mahadevan-Jansen, Anita; Moffett, Ashley; Price, Nathan D.; Wise, Paul H.; Wildman, Derek E.; Snyderman, Ralph; Paneth, Nigel; Capra, John Anthony; Nobrega, Marcelo A.; Barak, Yaacov; Muglia, Louis J.
title: Advancing Human Health in the Decade Ahead: Pregnancy as a Key Window for Discovery A Burroughs Wellcome Fund Pregnancy Think-Tank
date: 2020-06-19
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.06.031
sha: 8040724e169d9d87888a85401381bee008e691ca
doc_id: 737984
cord_uid: 0tk7gv3t

Abstract Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that impact maternal-infant lifelong health and that should serve as targets for leveraging the many recent advances. This report reflects avenues for future impact that hold great potential in three major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology and diseases addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into health care systems and drive discovery to address pregnancy related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate in order to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, including computer science, engineering, mathematics, and pharmacology should be engaged at the study design phase to optimize the information gathered as well as to identify and further evaluate potentially actionable therapeutic targets. Information sources should include non-invasive, personalized sensors and monitors, alongside instructive “liquid biopsies” for non-invasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, as well as social and health disparities. Modern technologies, both for data-gathering and for data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide.

Their potential impact is particularly germane to the biology of pregnancy and perinatal 92 medicine, where limited improvement in health outcomes for women and children has remained 93 a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to 94 discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that 95 impact maternal-infant lifelong health and that should serve as targets for leveraging the many 96 recent advances. This report reflects avenues for future impact that hold great potential in three 97 major areas: developmental genomics, including the application of methodologies designed to 98 bridge genotypes, physiology and diseases addressing vexing questions in early human 99 development; gestational physiology, from immune tolerance to growth and the timing of 100 parturition; and personalized and population medicine, focusing on amalgamating health record 101 data and deep phenotypes to create broad knowledge that can be integrated into health care 102 systems and drive discovery to address pregnancy related disease and promote general health.

We propose a series of questions reflecting development, systems biology, diseases, clinical 104 approaches and tools, and population health and a call for scientific action. Clearly, 105 transdisciplinary science must advance and accelerate in order to address adverse pregnancy 106 outcomes. Disciplines not traditionally involved in the reproductive sciences, including computer 107 science, engineering, mathematics, and pharmacology should be engaged at the study design 108 phase to optimize the information gathered as well as to identify and further evaluate potentially 109 actionable therapeutic targets. Information sources should include non-invasive, personalized 110 sensors and monitors, alongside instructive "liquid biopsies" for non-invasive pregnancy 111 assessment. Future research should also address the diversity of human cohorts in terms of 112 4 geography, racial and ethnic distributions, as well as social and health disparities. Modern 113 technologies, both for data-gathering and for data-analyzing, make this possible at a scale that 114 was previously unachievable. Finally, the psychosocial and economic environment in which 115 pregnancy takes place must be considered to promote the health and wellness of communities Artificial Intelligence: the computation ability to process data, to learn from data analysis, and to 138 apply and adapt to that learned to attain goals.

Epigenetic: external modifications to DNA or RNA that lead to changes in gene expression 141 without change to the nucleic acid sequence itself. Our event aimed to assess how convening experts from divergent biomedical disciplines, with 222 many scientists from outside the field of pregnancy research, might foster productive and 223 convergent thinking and generate novel ideas to stimulate innovative research projects.

Together, the 30 participants from the United States, Canada, and United Kingdom 225 encompassed biological disciplines as listed in Table 1 . Our event was also designed to 226 reshape the BWF strategy to accelerate discovery, encouraging proposals that incorporate new 227 tools, analytic approaches, and scientific disciplines. This summary encapsulates the ideas and 228 discussions organized by broad categories that span the contributions by experts in the fields 229 represented in Table 1 , and illuminate advances in ideas, technology and talent that to have the 230 greatest potential: developmental genomics, physiology, and personalized and population 231 medicine. We generated suggested questions, and a call for scientific action, delineating next-232 generation challenges and opportunities in the science underlying pregnancy and human early 233 development.

The field of developmental genomics applies state-of-the-art methodologies that strive to assist 238 in bridging genotypes, physiology and disease as specifically applied to developmental process 239 from embryogenesis though parturition biology. From identification of genetic variants through 240 sequencing or genome-wide association studies (GWAS), to defining nucleotide changes and 241 investigating their downstream proteomic, metabolomic, and physiological consequences that 242 may play an etiological role in phenotypic consequences during pregnancy, numerous 243 interrelated steps are logically aligned in order to chart the molecular maps underlying diseases 244 3 (Fig. 1) . Pregnancy phenotypes are shaped by the maternal, fetal and placental genomes and 245 epigenomes, and therefore the genomic studies of these phenotypes would benefit from an 246 10 integrative approach in mother/infant pairs. Further, these maps are not two-dimensional, but 247 include regulatory elements that form three-dimensional DNA loop configurations to influence 248 more than one proximal or distal gene 4 . Notably, gene-regulatory elements comprise modular 249 arrays of binding sites for transcription factors whose expression is context and time-specific, 

Incorporating evolution in pregnancy: By viewing the genesis of pregnancy through an 267 evolutionary biology lens, significant insights have been gained, for example into the signals 268 required to maintain the long gestations that many mammals display. One recent elegant study 269 by Griffith 9 and colleagues found by studying marsupial pregnancy that the implantation 270 reaction of eutherians (formerly "placentals") derives from the attachment reaction in ancestral 271 therian mammals (encompasses both eutherians and marsupials). In marsupials such as the 272 11 opossum, this event leads to prompt parturition. The ability to shift from the inflammatory 273 attachment reaction to a prolonged noninflammatory period in gestation is a central innovation 274 in eutherian mammals that allowed an extended period of intimate placentation.

Whereas inferences based in evolutionary biology are powerful in mapping regulatory elements 277 and traits at the organism-level, the rapid evolutionary changes in relevant organs, such as the 278 placenta 10 , may benefit from system-specific and well thought-out machine learning 279 approaches to link genomes to phenomes. Although the genomic roots of maternal-fetal 280 tolerance and exchange are ancient, dating back to reptiles, fish, and velvet worms, at term only 281 a small fraction of genes represent the core placental transcriptome that is conserved across 282 mammalian or marsupial species 11 . Moreover, eutherian and marsupial mammals have evolved 283 imprinting (a way of generating monoallelic expression) as an additional mechanism to tune 284 gene expression in a manner informed by parent of origin. It is possible that pharmacologically 285 induced diseases in model organisms, such as the stimulation of preterm birth in mice, might 286 not be as revealing as naturally arising variations in the timing of birth. In this instance, a mouse 287 strain that evolved to spontaneously deliver its pups three days early might be more informative.

This approach has been utilized in genetically inbred mouse strains to determine genetic 289 contributors to gestational duration and also the coordination of gestational duration with rates 290 of organ maturation. 12, 13 Importantly, the divergent strategies between species to optimize 291 reproductive outcomes may in themselves prove informative for greater mechanistic insights 292 into healthy and complicated pregnancies. 

Natural selection may favor rapid intrauterine growth of the human brain during fetal 352 development, driving birth to occur relatively early, either before the fetal head becomes larger 353 than the pelvic outlet, or due to maternal metabolic constraints. 24, 25 Yet, such acceleration in 354 birth timing leads to an altricial neonate in terms of neurodevelopment and the lack of early 355 independence. The traits may have influenced endocrine signals between the fetoplacental unit 356 and the mother, thus linking fetal maturation (especially brain development) and to one of the 

Pregnancy can be viewed as a physical, cardiovascular, immunologic, metabolic, physiologic 367 and psychosocial stress test for the mother whose homeostatic systems are challenged by 368 placental hormones to mostly favor uterine quiescence while providing the fetus with resources 369 needed to complete its growth and developmental program. In the future, gestational age as a proven health care and research, and can be costly. In contrast, population medicine seeks to 388 structure, deliver and make cost-effective high value health care that improves the overall health 389 of a given population. A key goal for medicine is to integrate the two approaches to achieve the 390 best outcome for the largest number of patients. That integration is now a realistic goal and 391 should be a high priority framework for health care systems, patients, investigators, and funders.

Capturing clinical evaluations along with deep phenotypes through electronic health record data 393 and integrating findings with genomics, social determinants, environmental insults and health 394 behaviors to develop personal health plans is a realistic goal 29, 30 . How do we exploit these 395 advances to optimize pregnancy and lifelong health?

One addition to healthcare delivery today is that while we continue to emphasize the 398 identification of specific diseases, there is a parallel proactive, holistic and personalized 399 approach to health, with participatory involvement from the individual that focuses more on 

• How can data arising data from many levels -social, psychological, physiologic, 536 metabolic, genomic -best be integrated into a real agenda for improved pregnancy 537 health?

How can newly arising population risks for poor pregnancy outcomes from infectious, While addressing diverse questions, Think Tank participants converged on several themes that 544 cross biomedical disciplines and research trajectories (Fig. 2) . First and foremost, the 545 transdisciplinary approaches weaved together by our diverse experts led to identification of key 546 areas that need further exploration in order to advance and accelerate the solution to the 547 identified, complex challenges. The science underlying pregnancy and its translation to 548 medicine is complicated and multi-dimensional, requiring the assembly of distinct expertise, 549 working at many scientific levels and focusing on shared goals. Such assembly may pave the 550 way to improved pregnancy health, personalized for the individual and applicable to the 551 population and drawn up on the basis of all the data that can be collected and monitored for and 552 by each patient. Disciplines not traditionally involved in the reproductive sciences, including 553 computer science, engineering, mathematics, and pharmacology should be engaged at the 554 study design phase to optimize the information gathered as well as to identify and further 555 evaluate potentially actionable therapeutic targets.

There has been an impression that pregnancy research is not in vogue, creating an opportunity 558 for new, talented scholars to join the field. Greatly needed advances in the field will depend on 559 the next generation of scholars. This should become a priority for the academic world.

Furthermore, medical schools should place grater emphasis on training students to handle new, 561 multidimensional information and discuss it with patients, accommodating to the way care is 562 poised to be delivered in the not-so-distant future.

Future research should include enough participants to span the diversity of human cohorts in 565 terms of geography, racial and ethnic distributions, as well as social and health disparities.

Broad studies must be introduced based on ethical principles and regulatory compliance. To 567 23 attain larger and more useful data sets, it may be time to include more heterogenous data and 568 thus better reflect the "real world" of clinical practice, offering more robust conclusions. Bigger, 569 more population-representative data sets will provide important insights that can be validated in 570 more controlled settings. Modern technologies, both for data-gathering and for data-analyzing, 571 make this possible at a scale that was previously unachievable.

Research in the pre-pregnancy period and across the 9 months of pregnancy may benefit from 574 the introduction of non-invasive, personalized sensors and monitors, alongside informative 575 "liquid biopsies" for non-invasive pregnancy assessment. These will advance the application of 576 mechanistic knowledge into human health and enrich disease-based and general precision 577 medicine paradigms. Access to much-needed tissues from early pregnancy can be promoted by 578 broader international collaborations. Further, the psychosocial and economic environment in 579 which pregnancy takes place cannot be ignored.

Overall, real progress in the understanding of pregnancy will take not only integrative science, 582 but also more time and, most importantly, more imagination. BWF and other funding agencies 583 should find ways to promote innovation, and not averting from "risk" in approaches. Academic 584 departments at most universities should encourage and foster innovative, multidimensional and 585 transdisciplinary science, and its application to integrative health and wellness. 

Risks Associated With Adverse Pregnancy Outcomes: JACC Review Topic of the Week

The enigma of spontaneous preterm birth

Genetic studies of 615 gestational duration and preterm birth

Beyond the ENCODE project: using genomics and epigenomics 618 strategies to study enhancer evolution

Maternal 621 obesity, diabetes during pregnancy and epigenetic mechanisms that influence the 622 developmental origins of cardiometabolic disease in the offspring

Pregnancy Immunogenetics and Genomics: Implications for 625 Pregnancy-Related Complications and Autoimmune Disease

Genetic origins of low birth weight

FTO Obesity Variant Circuitry and Adipocyte 630 Browning in Humans

Embryo 632 implantation evolved from an ancestral inflammatory attachment reaction

Genome-wide maps of distal gene regulatory enhancers 635 active in the human placenta

A review of inter-and intraspecific variation in the 637 eutherian placenta

Maternal synchronization of gestational length and 639 lung maturation

Mouse gestation length is genetically determined

Single-cell reconstruction of the early 643 maternal-fetal interface in humans

Review: Histotrophic nutrition and the 645 placental-endometrial dialogue during human early pregnancy

Trophoblast organoids as a model for maternal-fetal 647 interactions during human placentation

Why is placentation abnormal in preeclampsia?

Genetic Associations with Gestational Duration and 653 Spontaneous Preterm Birth

Long-term, hormone-responsive organoid cultures 655 of human endometrium in a chemically defined medium

Maternal allo-recognition of the fetus

Handbook of Life Course Health 660 Development

Early rapid growth, early birth: accelerated fetal 662 growth and spontaneous late preterm birth

Birth, obstetrics and human evolution

Metabolic hypothesis for 666 human altriciality

Preventing preterm birth: the past limitations and new 668 potential of animal models

Rationale for current and future progestin-based therapies 670 to prevent preterm birth

Promises, promises, and precision medicine

Personalized health care: from theory to practice

To adopt precision medicine, redesign clinical care. NEJM 676 Catalyst Innovations in Care Delivery

Deep phenotyping during pregnancy for 678 predictive and preventive medicine

Molecular signatures from omics 680 data: from chaos to consensus

Child Poverty and the Promise of Human Capacity: Childhood as a Foundation 684 for Healthy Aging

We thank Lori Hedrick for Pregnancy Think Tank meeting planning, Russ

Campbell and Seamus Duerr for assistance with the figures, and Sandra Ackerman for meeting