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The Role of Environmental Hazards in Premature Birth: Workshop Summary Summary* The Roundtable on Environmental Health Sciences, Research, and Medicine is comprised of key stakeholders in environmental health who meet on a regular basis to discuss areas of mutual concern in a neutral environment. The purpose is to promote discussion, but not to come to consensus. Sometimes, the Roundtable convenes workshops to explore issues in greater depth and facilitate discussion. This is a summary of a workshop convened by the Roundtable on October 2–3, 2001, to look at the issues surrounding the role of the environment in premature birth. The summary has been prepared by the workshop rapporteur as a factual summary of what occurred at the workshop and should not be construed as consensus by the Roundtable or the Institute of Medicine. PRETERM BIRTH Each year in the United States, more than 440,000 babies are born too soon. These preterm births, defined as those occurring before the thirty-seventh week of pregnancy, represent nearly 12 percent of all births. Premature infants can be dangerously small—weighing less than 2,500 grams—and are at greater risk of death and lifelong disability than those born at full term. About 75 percent of infant deaths in the first month of life occur in premature infants, who are much more likely than full-term infants to have breathing problems or to suffer life- * This summary was prepared from the transcript of the meeting by Christine Coussens and Kathi Hanna as the rapporteurs.
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The Role of Environmental Hazards in Premature Birth: Workshop Summary long medical complications such as cerebral palsy, visual and hearing disabilities, and mental retardation. Premature babies often spend months fighting for survival and struggling to overcome illness. The impact on the families is often long-lasting and results in emotional and financial hardships. The enormous medical costs associated with preterm birth, during infancy and often continuing throughout the child’s life, represent about 35 percent of all medical expenditures for newborns and about 10 percent of all medical expenditures for children. Some estimates indicate that in the first year of life alone, a preterm birth costs about $15,000 more than a full-term birth. Although vast improvements have been made in preventing deaths of premature infants, little success has been attained in understanding and preventing preterm birth, and the knowledge that has been gained about preterm labor has not translated into improved perinatal outcomes. Despite all efforts to reduce the condition, the rate of preterm birth has increased during the past 20 years. Since the early 1980s, the rate of preterm birth in the United States has increased by 17 percent, and the incidence of low birth weight (less than 2,500 grams) has risen 10 percent. For reasons that are not fully understood, these problems take a disproportionate toll on African Americans and recent immigrants from Latin America. Such demographic differences have led many to characterize preterm birth as a disease of poverty. Attempts have been made to reduce the prevalence of the conditions leading to preterm birth, especially preeclampsia and fetal growth restriction. Interventions such as improved nutrition, maternal bed rest, low-dose aspirin, and calcium supplementation have been tried, but they have generally failed. Evidence suggests that although the prevalence of preeclampsia and fetal growth restriction appears to have remained unchanged, early delivery for fetal distress associated with these conditions has reduced stillbirths. Clearly, preterm birth is not an acute event. Its roots may well begin before pregnancy, perhaps even in a woman’s early life. The discussion of preterm birth is confused by a lack of firm agreement about, and understanding of, what constitutes “preterm.” The length of the natural term of pregnancy exhibits tremendous variability, and the gestational period for an infant with low birth weight can be within a normal range. Further, the assignment of due dates for delivery is an inaccurate clinical practice. In fact, only 4 percent of all women deliver on their due date. Normal pregnancy is a carefully programmed sequence of events from the perspective of uterine activity, in which one genetic function leads to another. In general, pregnancy can be divided into four stages. Most of the pregnancy is a stage of uterine quiescence, maintained by active mechanisms. This stage is followed by a stage of preparation or activation, when the contraction-activating proteins are turned on by a variety of mechanisms that prepare the uterus to become a contractile organ. The next stage, onset of labor, requires an integra-
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The Role of Environmental Hazards in Premature Birth: Workshop Summary tion of endocrine and mechanical signals to initiate and maintain uterine contractility. Parturition at the appropriate time is the final stage of a successful pregnancy. In a normal pregnancy, fetal maturation is closely synchronized with uterine quiescence to prevent birth before the fetus is viable. Many factors have been identified that contribute to uterine quiescence and contractility, and many markers have been identified that provide clues as to how disruptions in the many pathways that lead to labor and delivery can cause them to go awry. Several approaches have been taken in animal and human studies to assess the roles of endocrine hormones, steroids, immune responses, and nitric oxide in labor and parturition. The mechanisms affecting uterine contractility and cervical ripening have also been examined. Basic discoveries from these investigations provide some clues as to how environmental perturbations may affect the timing of parturition and the duration of labor. However, much of what has been learned about labor and parturition has come from experiments with sheep and other animal models. Although these findings cannot be completely extrapolated to humans, they do provide important insights about what underlies normal and abnormal parturition in humans. Epidemiological research on the association between preterm delivery and such factors as life-style behaviors (e.g., tobacco use, cocaine use, alcohol use, physical inactivity), nutrition (e.g., lack of iron or folate), infection (e.g., bacterial vaginosis), and psychological stress (e.g., anxiety, depression) has been under way for some time. This research suggests possible etiologic pathways to preterm birth, offers insights into methodological challenges, and identifies potential confounding factors. At present, strong predictors of preterm birth are limited to multiple gestation, prior preterm birth, and African-American ethnicity; weaker but modifiable influences include infection, tobacco use, low prepregnancy weight, and lower socioeconomic status. Numerous studies in humans have suggested the strong predictive value of social and psychological stress in initiating preterm labor. Studies at the tissue, cellular, and molecular levels have provided some preliminary understanding of how social and environmental stressors can disrupt the normal pathways that lead to labor and parturition. However, some workshop participants noted that more information is needed on interspecies differences and on critical periods in, and mechanisms for, the initiation of labor. Some workshop participants stressed the importance of improved interactions across disciplines—particularly among epidemiologists, reproductive biologists, and toxicologists—to elucidate the root causes of preterm birth (see summary box for a listing of research opportunities). Epidemiologists can identify associations of exposures and risks, but they are not likely to identify causal relationships. Reproductive biologists and toxicologists can provide biologically plausible mechanisms that may explain these epidemiological associations. In addition, studies in which reproductive biologists and toxicologists collaborate
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The Role of Environmental Hazards in Premature Birth: Workshop Summary BOX S.1 Major New Research Opportunities During the workshop, participants listed a number of research opportunities for research in preterm birth. These included the following: Improved animal models for the various etiologies of premature birth. Molecular classification of preterm stages by genomics-based assays. Molecular classification of exposures by improved genomic-based assays. Further definition of biological pathways involved in term and preterm birth. Improved surveillances and registries. could lead to the identification of potential chemical hazards, and epidemiological studies could reveal the relevance of these other studies to humans. Experience suggests that multidisciplinary collaborations are greatly needed to assess comprehensively the role of social and environmental factors, genetic factors, and gene–environment interactions in influencing preterm births. The gene–environment approach is likely to improve knowledge of the pathogenesis of preterm birth and to help develop a generic analytical approach to understanding the genetic contribution in populations with marked differences in social status and experience. Conventional interventions to reduce spontaneous preterm birth include prenatal care, across-the-board nutritional supplementation, and social support or home visiting. More targeted, experimental interventions may include specific aspects of prenatal care, such as risk screening, nutrition counseling, caloric supplementation, protein supplementation, iron supplementation, labor-inhibiting agents, bed rest, hydration, home uterine activity monitoring, and drug, alcohol, and tobacco cessation programs. However, these types of interventions have rarely been shown to be beneficial in reducing the rate of preterm birth. In fact, there is little evidence that any of the numerous strategies currently used to reduce preterm birth are effective when applied to various populations. The ability to predict individuals at higher risk of preterm birth without the ability to provide an effective treatment results in an increased use of ineffective interventions and higher costs, as well as a potential increase in iatrogenic complications. However, advances in molecular biology may lead to predictive “tests” to identify those at risk for preterm birth and to provide clues to potential therapies. Workshop participants generally agreed that the desired outcomes of interventions would be reduced mortality of the mother and reduced mortality or morbidity of the infant, reduced incidence of long-term disability in children, and reduced rates of severe neonatal morbidity.
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The Role of Environmental Hazards in Premature Birth: Workshop Summary Some workshop participants questioned whether the disappointing trend toward an increase in preterm birth rate reflects a failure to prevent preterm delivery, or whether it results from relying on the increased use of early ultrasound for estimating gestational age, early delivery for extreme fetal growth retardation and severe preeclampsia, multiple gestation, inclusion of newborns near the borderline of viability on registries, or changes in sociodemographic or behavioral determinants of preterm birth. These questions can be answered, many participants concluded, by conducting carefully designed interdisciplinary studies that account for the environmental influences and biological mechanisms that cause a pregnancy to end prematurely, placing the fetus, and sometimes the mother, at increased risk.
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