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Preterm Birth as a Calendar Event or Immunologic Anomaly

Preterm Birth as a Calendar Event or Immunologic Anomaly Preterm birth is a ubiquitous yet mysterious phenomenon. Preterm birth, defined as birth prior to 37 weeks’ gestation, is now the primary worldwide cause of morbidity and mortality in the newborn period and the top cause of child mortality among those younger than 5 years, accounting for 1 million deaths every year.1 Nevertheless, it remains poorly understood. Spontaneous preterm birth is a syndrome characterized by labor that starts too soon. It is distinguished from medically indicated preterm birth, in which labor induction or operative delivery are performed to protect the health of the fetus or mother. Preterm labor is not the same as labor at term—except that, in the end, it also results in the altered physical behavior of the uterus (regular contractions) and changes in the cervix (effacement and dilatation) that lead to rupture of amniotic membranes and expulsion of a fetus.2 Unlike term labor, preterm labor is associated with pathologic activation of these labor processes by 1 or multiple mechanisms of disease, such as infection or inflammation.1 No matter what the factors associated with preterm birth might be, the specific nature of their perturbation(s) or their cause(s), or in what field they are identified (eg, psychology, sociology, or economics), they all must ultimately translate into measureable biological phenomena that have the ability to initiate or accelerate the physiology that characterizes parturition, which is largely immunologic in nature. Human pregnancy differs from most other mammalian pregnancies in that elevated progesterone levels persist until after delivery. Because progesterone has a profound effect on the immunologic disposition of pregnancy and functions to prevent the onset of parturition,3 a functional withdrawal of progesterone appears to be an important signal in the tributary of other signaling events that ensures the execution of normal parturition. The stretching of the myometrial cells may also invoke inflammatory changes, among other perturbations, which directs the flow of biochemistry toward labor and delivery. All of these things occur in the human whose head size at birth is near the limits of what is physically possible for navigation of the birth canal. This fact has required the delivery of a relatively immature fetus through a pelvis that is just large enough to support such a vaginal delivery, an evolutionary compromise to maintain the advantages of both bipedal ambulation and high intelligence.4 Evolutionary pressures to maintain these adaptations led to adjustments in the programmed immunological signals that control the timing of normal parturition. The biologic downside of these signals, which likely relate to alterations in gene expression, is the assumed risk of lethal immaturity at one end of the spectrum. This risk of prematurity is of little consequence to the human species on an evolutionary scale, as most babies will grow to adulthood and reproduce. However, this evolutionary disposition sets the stage for a more easily perturbed physiology of parturition, which has left us with the syndrome of preterm labor. The known causes of preterm birth have been discussed in detail by Romero et al,2 but this discussion does not capture what is common to normal parturition or explain early birth. In fact, a basic understanding of the mechanism(s) that control the timing and initiation of normal parturition remains elusive.5 What is most fundamental to pregnancy and, by extension, parturition is immunology, in which the maternal immune system modulates inflammatory signaling pathways to avoid rejection of the semiallograft fetus.6 These pathways are closely tied to progesterone and reflect decreased production of inflammatory cytokines (eg, tumor necrosis factor–α), increased production of anti-inflammatory cytokines (eg, interleukin-10), and inhibition of natural killer cell activity, among other biological processes and cascades that allow for maternal-fetal tolerance.3 Understanding how the mother and fetus transition from a state of mutual tolerance during pregnancy to one of defense (proinflammation) at the initiation of parturition is the key. The organ at the center of this biologic dialectic is the placenta. In particular, perturbation of placentation, the vascular development that supports pregnancy, may lead to tell-tale histopathologies associated with preeclampsia, intrauterine growth restriction, preterm labor, premature rupture of membranes, and placental abruption, which reflect differences in the nature, timing, and magnitude of signaling processes. Microbiota probably also play an important, if not essential, role in preparation of the immune system for parturition.7 In the end, all factors associated with preterm birth, such as perturbations in microbial communities or other environmental factors (eg, air pollution), must be translatable into biological terms and, ultimately, immunologic (proinflammatory) terms that reflect activation of the machinery of parturition. Understanding the ways by which cellular tolerance is initiated and maintained, and then disrupted, is fundamental to understanding not only normal parturition and preterm birth, but probably also cancer, autoimmunity, and a variety of other oxidative conditions, such as cardiovascular disease, or even aging itself.8 For something as important to the species as gestation and, by biologic imperative, reproduction, we would expect many checks and balances to perfect and maintain tolerance during gestation. Thus, it is not surprising that there are many causes of preterm birth, which probably reflect perturbations of the many checkpoints in the biology that maintain a pregnancy until just the right moment for our species. This biology is only recently being addressed through the study of regulatory T cells and the systematic exploration of cellular invasion, cytoprotection, angiogenesis, and immunomodulation during pregnancy and other conditions.9 Pregnancy relies on the delicate balance of tolerance and defense among individual maternal cells, myometrial and cervical in origin, and immune cells circulating in tissues of the mother and fetus. The signaling behaviors of these cells may reflect the various outcomes of pregnancy—early parturition (pathologic) or term parturition (physiologic). Certain ancient enzymatic systems and genes that control this balance may sit at the foundation of immunoregulatory responses (eg, heme oxygenase).8 There is not likely to be one causal pathway, a “holy grail of parturition biochemistry.” But we will certainly have better ways of predicting the onset of preterm birth with an understanding of the proinflammatory signals contributing to preterm parturition and the immunologic predisposition to it, in some cases. We may discover direct ways to control the biologic cascades that coordinate parturition. We may also discover community-based interventions that indirectly affect this biology, such as implementation of policies related to socioeconomic disparities, racial disparities, food composition, food security, or environmental pollution. However, a better understanding of preterm birth will require careful judgments about when to intervene and when to leave nature alone. Certainly, there will be a place for intervention, perhaps many places, and preterm birth will be reduced incrementally. But we will need to understand the consequences of those decisions, as we create newborn and adult phenotypes not previously seen. Most importantly, our viewpoint is that, to solve the most complex human problems, such as preterm labor and birth, it will be necessary to link and integrate many different kinds of data from various levels of inquiry—from population scale (epidemiologic) to individual scale (genetic and cellular)—to look for predictive, diagnostic, and causal pathways that might be safely targeted for prevention or amelioration. In the case of preterm birth, we believe that these pathways are likely defined immunologically and should be targeted accordingly. Back to top Article Information Corresponding Author: David K. Stevenson, MD, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, 1265 Welch Rd, Stanford, CA 94305-5415 (dstevenson@stanford.edu). Published Online: April 18, 2016. doi:10.1001/jamapediatrics.2016.0213. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grant R01 HD075761 from the National Institutes of Health, the March of Dimes Prematurity Research Center at Stanford University, the Stanford Child Health Research Institute at Stanford University School of Medicine, grant OPP1112382 from the Bill and Melinda Gates Foundation, and grant UL1 TR001085 from the Clinical and Translational Science Award program, funded by the National Center for Advancing Translational Sciences. We also acknowledge unrestricted research gift funds from the Hess Research Fund and the Lui Research Fund. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication. References 1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.PubMedGoogle ScholarCrossref 2. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-765.PubMedGoogle ScholarCrossref 3. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol. 2005;97(5):389-396.PubMedGoogle ScholarCrossref 4. Wittman AB, Wall LL. The evolutionary origins of obstructed labor: bipedalism, encephalization, and the human obstetric dilemma. Obstet Gynecol Surv. 2007;62(11):739-748.PubMedGoogle ScholarCrossref 5. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med. 2010;362(6):529-535.PubMedGoogle ScholarCrossref 6. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7(3):241-246.PubMedGoogle ScholarCrossref 7. DiGiulio DB, Callahan BJ, McMurdie PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A. 2015;112(35):11060-11065.PubMedGoogle ScholarCrossref 8. Zhao H, Ozen M, Wong RJ, Stevenson DK. Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis [published online January 14, 2015]. Front Pharmacol. doi:10.3389/fphar.2014.00295.PubMedGoogle Scholar 9. Gaudillière B, Ganio EA, Tingle M, et al. Implementing mass cytometry at the bedside to study the immunological basis of human diseases: distinctive immune features in patients with a history of term or preterm birth. Cytometry A. 2015;87(9):817-829.PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Pediatrics American Medical Association

Preterm Birth as a Calendar Event or Immunologic Anomaly

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American Medical Association
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Copyright © 2016 American Medical Association. All Rights Reserved.
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2168-6203
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2168-6211
DOI
10.1001/jamapediatrics.2016.0213
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Abstract

Preterm birth is a ubiquitous yet mysterious phenomenon. Preterm birth, defined as birth prior to 37 weeks’ gestation, is now the primary worldwide cause of morbidity and mortality in the newborn period and the top cause of child mortality among those younger than 5 years, accounting for 1 million deaths every year.1 Nevertheless, it remains poorly understood. Spontaneous preterm birth is a syndrome characterized by labor that starts too soon. It is distinguished from medically indicated preterm birth, in which labor induction or operative delivery are performed to protect the health of the fetus or mother. Preterm labor is not the same as labor at term—except that, in the end, it also results in the altered physical behavior of the uterus (regular contractions) and changes in the cervix (effacement and dilatation) that lead to rupture of amniotic membranes and expulsion of a fetus.2 Unlike term labor, preterm labor is associated with pathologic activation of these labor processes by 1 or multiple mechanisms of disease, such as infection or inflammation.1 No matter what the factors associated with preterm birth might be, the specific nature of their perturbation(s) or their cause(s), or in what field they are identified (eg, psychology, sociology, or economics), they all must ultimately translate into measureable biological phenomena that have the ability to initiate or accelerate the physiology that characterizes parturition, which is largely immunologic in nature. Human pregnancy differs from most other mammalian pregnancies in that elevated progesterone levels persist until after delivery. Because progesterone has a profound effect on the immunologic disposition of pregnancy and functions to prevent the onset of parturition,3 a functional withdrawal of progesterone appears to be an important signal in the tributary of other signaling events that ensures the execution of normal parturition. The stretching of the myometrial cells may also invoke inflammatory changes, among other perturbations, which directs the flow of biochemistry toward labor and delivery. All of these things occur in the human whose head size at birth is near the limits of what is physically possible for navigation of the birth canal. This fact has required the delivery of a relatively immature fetus through a pelvis that is just large enough to support such a vaginal delivery, an evolutionary compromise to maintain the advantages of both bipedal ambulation and high intelligence.4 Evolutionary pressures to maintain these adaptations led to adjustments in the programmed immunological signals that control the timing of normal parturition. The biologic downside of these signals, which likely relate to alterations in gene expression, is the assumed risk of lethal immaturity at one end of the spectrum. This risk of prematurity is of little consequence to the human species on an evolutionary scale, as most babies will grow to adulthood and reproduce. However, this evolutionary disposition sets the stage for a more easily perturbed physiology of parturition, which has left us with the syndrome of preterm labor. The known causes of preterm birth have been discussed in detail by Romero et al,2 but this discussion does not capture what is common to normal parturition or explain early birth. In fact, a basic understanding of the mechanism(s) that control the timing and initiation of normal parturition remains elusive.5 What is most fundamental to pregnancy and, by extension, parturition is immunology, in which the maternal immune system modulates inflammatory signaling pathways to avoid rejection of the semiallograft fetus.6 These pathways are closely tied to progesterone and reflect decreased production of inflammatory cytokines (eg, tumor necrosis factor–α), increased production of anti-inflammatory cytokines (eg, interleukin-10), and inhibition of natural killer cell activity, among other biological processes and cascades that allow for maternal-fetal tolerance.3 Understanding how the mother and fetus transition from a state of mutual tolerance during pregnancy to one of defense (proinflammation) at the initiation of parturition is the key. The organ at the center of this biologic dialectic is the placenta. In particular, perturbation of placentation, the vascular development that supports pregnancy, may lead to tell-tale histopathologies associated with preeclampsia, intrauterine growth restriction, preterm labor, premature rupture of membranes, and placental abruption, which reflect differences in the nature, timing, and magnitude of signaling processes. Microbiota probably also play an important, if not essential, role in preparation of the immune system for parturition.7 In the end, all factors associated with preterm birth, such as perturbations in microbial communities or other environmental factors (eg, air pollution), must be translatable into biological terms and, ultimately, immunologic (proinflammatory) terms that reflect activation of the machinery of parturition. Understanding the ways by which cellular tolerance is initiated and maintained, and then disrupted, is fundamental to understanding not only normal parturition and preterm birth, but probably also cancer, autoimmunity, and a variety of other oxidative conditions, such as cardiovascular disease, or even aging itself.8 For something as important to the species as gestation and, by biologic imperative, reproduction, we would expect many checks and balances to perfect and maintain tolerance during gestation. Thus, it is not surprising that there are many causes of preterm birth, which probably reflect perturbations of the many checkpoints in the biology that maintain a pregnancy until just the right moment for our species. This biology is only recently being addressed through the study of regulatory T cells and the systematic exploration of cellular invasion, cytoprotection, angiogenesis, and immunomodulation during pregnancy and other conditions.9 Pregnancy relies on the delicate balance of tolerance and defense among individual maternal cells, myometrial and cervical in origin, and immune cells circulating in tissues of the mother and fetus. The signaling behaviors of these cells may reflect the various outcomes of pregnancy—early parturition (pathologic) or term parturition (physiologic). Certain ancient enzymatic systems and genes that control this balance may sit at the foundation of immunoregulatory responses (eg, heme oxygenase).8 There is not likely to be one causal pathway, a “holy grail of parturition biochemistry.” But we will certainly have better ways of predicting the onset of preterm birth with an understanding of the proinflammatory signals contributing to preterm parturition and the immunologic predisposition to it, in some cases. We may discover direct ways to control the biologic cascades that coordinate parturition. We may also discover community-based interventions that indirectly affect this biology, such as implementation of policies related to socioeconomic disparities, racial disparities, food composition, food security, or environmental pollution. However, a better understanding of preterm birth will require careful judgments about when to intervene and when to leave nature alone. Certainly, there will be a place for intervention, perhaps many places, and preterm birth will be reduced incrementally. But we will need to understand the consequences of those decisions, as we create newborn and adult phenotypes not previously seen. Most importantly, our viewpoint is that, to solve the most complex human problems, such as preterm labor and birth, it will be necessary to link and integrate many different kinds of data from various levels of inquiry—from population scale (epidemiologic) to individual scale (genetic and cellular)—to look for predictive, diagnostic, and causal pathways that might be safely targeted for prevention or amelioration. In the case of preterm birth, we believe that these pathways are likely defined immunologically and should be targeted accordingly. Back to top Article Information Corresponding Author: David K. Stevenson, MD, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University, 1265 Welch Rd, Stanford, CA 94305-5415 (dstevenson@stanford.edu). Published Online: April 18, 2016. doi:10.1001/jamapediatrics.2016.0213. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by grant R01 HD075761 from the National Institutes of Health, the March of Dimes Prematurity Research Center at Stanford University, the Stanford Child Health Research Institute at Stanford University School of Medicine, grant OPP1112382 from the Bill and Melinda Gates Foundation, and grant UL1 TR001085 from the Clinical and Translational Science Award program, funded by the National Center for Advancing Translational Sciences. We also acknowledge unrestricted research gift funds from the Hess Research Fund and the Lui Research Fund. Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication. References 1. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.PubMedGoogle ScholarCrossref 2. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-765.PubMedGoogle ScholarCrossref 3. Druckmann R, Druckmann MA. Progesterone and the immunology of pregnancy. J Steroid Biochem Mol Biol. 2005;97(5):389-396.PubMedGoogle ScholarCrossref 4. Wittman AB, Wall LL. The evolutionary origins of obstructed labor: bipedalism, encephalization, and the human obstetric dilemma. Obstet Gynecol Surv. 2007;62(11):739-748.PubMedGoogle ScholarCrossref 5. Muglia LJ, Katz M. The enigma of spontaneous preterm birth. N Engl J Med. 2010;362(6):529-535.PubMedGoogle ScholarCrossref 6. Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7(3):241-246.PubMedGoogle ScholarCrossref 7. DiGiulio DB, Callahan BJ, McMurdie PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A. 2015;112(35):11060-11065.PubMedGoogle ScholarCrossref 8. Zhao H, Ozen M, Wong RJ, Stevenson DK. Heme oxygenase-1 in pregnancy and cancer: similarities in cellular invasion, cytoprotection, angiogenesis [published online January 14, 2015]. Front Pharmacol. doi:10.3389/fphar.2014.00295.PubMedGoogle Scholar 9. Gaudillière B, Ganio EA, Tingle M, et al. Implementing mass cytometry at the bedside to study the immunological basis of human diseases: distinctive immune features in patients with a history of term or preterm birth. Cytometry A. 2015;87(9):817-829.PubMedGoogle ScholarCrossref

Journal

JAMA PediatricsAmerican Medical Association

Published: Jun 1, 2016

Keywords: infant, premature,labor,time factors,epidemiologic causality,placenta,progesterone,premature birth,immunology,causality

References