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Summary

ABSTRACT

In 2004, 12.5 percent of births in the United States were preterm; that is, born at less than 37 completed weeks of gestation. This rate has increased steadily in the past decade. There are significant, persistent, and very troubling racial, ethnic, and socioeconomic disparities in the rates of preterm birth. The highest rates are for non-Hispanic African Americans, and the lowest are for Asians or Pacific Islanders. In 2003, the rate for African-American women was 17.8 percent, whereas the rates were 10.5 percent for Asian and Pacific Islander women and 11.5 percent for white women. The most notable increases from 2001 to 2003 were for white non-Hispanic, American Indian, and Hispanic groups.

Infants born preterm are at greater risk than infants born at term for mortality and a variety of health and developmental problems. Complications include acute respiratory, gastrointestinal, immunologic, central nervous system, hearing, and vision problems, as well as longer-term motor, cognitive, visual, hearing, behavioral, social-emotional, health, and growth problems. The birth of a preterm infant can also bring considerable emotional and economic costs to families and have implications for public-sector services, such as health insurance, educational, and other social support systems. The annual societal economic burden associated with preterm birth in the United States was at least $26.2 billion in 2005. The greatest risk of mortality and morbidity is for those infants born at



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Preterm Birth: Causes, Consequences, and Prevention Summary ABSTRACT In 2004, 12.5 percent of births in the United States were preterm; that is, born at less than 37 completed weeks of gestation. This rate has increased steadily in the past decade. There are significant, persistent, and very troubling racial, ethnic, and socioeconomic disparities in the rates of preterm birth. The highest rates are for non-Hispanic African Americans, and the lowest are for Asians or Pacific Islanders. In 2003, the rate for African-American women was 17.8 percent, whereas the rates were 10.5 percent for Asian and Pacific Islander women and 11.5 percent for white women. The most notable increases from 2001 to 2003 were for white non-Hispanic, American Indian, and Hispanic groups. Infants born preterm are at greater risk than infants born at term for mortality and a variety of health and developmental problems. Complications include acute respiratory, gastrointestinal, immunologic, central nervous system, hearing, and vision problems, as well as longer-term motor, cognitive, visual, hearing, behavioral, social-emotional, health, and growth problems. The birth of a preterm infant can also bring considerable emotional and economic costs to families and have implications for public-sector services, such as health insurance, educational, and other social support systems. The annual societal economic burden associated with preterm birth in the United States was at least $26.2 billion in 2005. The greatest risk of mortality and morbidity is for those infants born at

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Preterm Birth: Causes, Consequences, and Prevention the earliest gestational ages. However, those infants born nearer to term represent the greatest number of infants born preterm and also experience more complications than infants born at term. Preterm birth is a complex cluster of problems with a set of overlapping factors of influence. Its causes may include individual-level behavioral and psychosocial factors, neighborhood characteristics, environmental exposures, medical conditions, infertility treatments, biological factors, and genetics. Many of these factors occur in combination, particularly in those who are socioeconomically disadvantaged or who are members of racial and ethnic minority groups. The current methods for the diagnosis and treatment of preterm labor are currently based on an inadequate literature, and little is know about how preterm birth can be prevented. Treatment has been focused on inhibiting contractions. This has not reduced the incidence of preterm birth but has delayed delivery long enough to allow the administration of antenatal steroids and transfer of the mother and fetus to a hospital where they may receive appropriate care. These interventions have reduced the rates of perinatal mortality and morbidity. Although improvements in perinatal and neonatal care have significantly improved the rates of survival for infants born preterm, these infants remain at risk for a host of acute and chronic health problems. Therapies and interventions for the prediction and the prevention of preterm birth are thus needed. Upon review of the literature assessing the causes and consequences of preterm birth, the diagnosis and treatment of women at risk for preterm labor, and treatments for infants born preterm, the committee proposes a research agenda for investigating the problem of preterm birth that is intended to help focus and direct research efforts. Priority areas are: (1) the establishment of multidisciplinary research centers; (2) improved research in three areas including better definition of the problem of preterm birth with improved data, clinical and health services research investigations, and etiologic and epidemiologic investigations; and (3) the study and informing of public policy. The committee hopes that its efforts will help provide a framework for working toward improved outcomes for children born preterm and their families. The prevalence of preterm birth in the United States constitutes a public health problem, but unlike many health problems, the rate of preterm birth has increased in the last decade. In 2004, 12.5 percent of births were

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Preterm Birth: Causes, Consequences, and Prevention preterm, or in which the infants were born at less than 37 weeks of gestation (CDC, 2005a). Since 1981, the rate has increased more than 30 percent (from 9.4 percent) (CDC, 2005a). The birth of a preterm infant results in significant health consequences to the infant and emotional and economic costs for families and communities. Although advances in perinatal and neonatal care have improved the survival for preterm infants, those infants who do survive have a greater risk of developmental disabilities, health, and growth problems than infants born at full term. Whereas the group of infants with the greatest risk of morbidity and mortality comprises those born at less than 32 weeks of gestation, infants born between 32 and 36 weeks represent the greatest number of infants born preterm. The latter group of infants also experiences a greater risk for health and developmental problems compared with the risk for infants born at term. To date, no single test or sequence of assessment measures that may accurately predict preterm birth are available, and efforts at the prevention of preterm birth have primarily focused on the treatment of women with symptomatic preterm labor. STUDY CHARGE The persistent and troubling problem of preterm birth prompted the Institute of Medicine (IOM) to convene a committee, the Committee on Understanding Premature Birth and Assuring Healthy Outcomes, to assess the current state of the science on the causes and broad consequences of preterm birth. Specifically, the charge to the committee was as follows: An IOM committee will define and address the health related and economic consequences of premature birth. The broad goals are to (1) describe the current state of the science and clinical research with respect to the causes of premature birth; (2) address the broad costs—economic, medical, social, psychological, and educational—for children and their families; and (3) establish a framework for action in addressing the range of priority issues, including a research and policy agenda for the future. In support of these broad goals, the study will: Review and assess the various factors contributing to the growing incidence of premature birth, which may include the trend to delay childbearing and racial and ethnic disparities; Assess the economic costs and other societal burdens associated with premature births; Address research gaps/needs and priorities for defining the mechanisms by which biological and environmental factors influence premature birth; and Explore possible changes in public health policy and other policies that may benefit from more research.

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Preterm Birth: Causes, Consequences, and Prevention In order to assess research gaps and needs, the committee will plan an additional meeting that will address barriers to clinical research in the area of preterm birth. A workshop hosted by the committee will seek to Identify major obstacles to conducting clinical research, which may include the declining number of residents interested in entering the field of ob-stetrics and gynecology and the resulting effect on the pipeline of clinical researchers; the impact of rising medical malpractice premiums on the ability of academic programs to provide protected time for physicians to pursue research; and ethical and legal issues in conducting research on pregnant women (for example, the consideration of safety issues and informed consent); and Provide strategies for removing barriers—including those targeting resident career choices, departments of obstetrics and gynecology, agencies and organizations that fund research, and professional organizations. Through this process the committee learned four key lessons. The first is that preterm birth is a complex expression of many conditions. Second, little is known about how preterm birth can be prevented. Great strides have been made in treating infants born preterm and improving survival. However, any significant gains to be made in the study of preterm birth will be in the area of preventing its occurrence. Third, racial-ethnic and socioeconomic disparities are striking and largely unexplained. Fourth, infants who are born near term or late preterm (at 32 to 36 weeks of gestation) are at increased risk for adverse health and developmental outcomes that should not be ignored. This summary presents an overview of the committee’s recommendations. Below, these recommendations are preceded by text summarizing the evidence base from which they are drawn. For full findings and justification of each recommendation, the reader is referred to the full committee report. APPROACH TO THE PROBLEM Three themes repeatedly emerged at the start of the committee’s deliberations that helped to organize the committee’s thinking and approach to this problem. The first was a need for clarity of terminology. In the literature, terms characterizing the duration of gestation, fetal growth, and maturation have been applied inconsistently and have been used interchangeably. This has made it difficult to interpret the data on the causes and consequences of preterm birth and to evaluate treatments. The committee uses the term preterm birth, which is based on the period of gestation, to assess this population. The evidence contained in this report draws first on the literature that uses gestational age, preterm birth, and small for gestational age as outcomes. In the absence of this information, low birth weight and other related outcomes are cited, as needed. The committee recognizes

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Preterm Birth: Causes, Consequences, and Prevention that the weight of the evidence in this field has used low birth weight to assess this population. The second theme that guided the committee’s approach to its task was the troubling evidence of long-standing disparities in the rates of preterm birth among different groups in the U.S. population. Certain subpopulations categorized by their racial, ethnic, or socioeconomic status have a greater risk and a higher proportion of preterm births. The most striking rates are for African-American women. In 2003, the proportions of preterm births for specific racial and ethnic groups were 10.5 percent for Asian Pacific Islander women, 11.5 percent for non-Hispanic white women, 11.9 percent for Hispanic women, 13.5 percent for American Indian/Alaska Native women, and 17.8 percent for non-Hispanic African American women (CDC, 2005i). Although the rate for African American women has decreased in the last decade, overall these women continue to experience a much higher proportion of preterm births. The most notable increase in the percentages of preterm birth from 2001 to 2003 was for white non-Hispanic, American Indian, and Hispanic groups. Although the rates for Hispanic and Asian Pacific Islander women are the lowest among the ethnic and racial minority groups in the United States, these are not homogeneous populations, and considerable variation in the rates of preterm birth exist among subpopulations. The third theme that guided the committee’s framing of this problem and formulation of recommendations is the complexity of the problem that it was charged with assessing. Preterm birth is not one disease for which there is likely to be one solution or cure. Rather, the committee considers preterm birth a cluster of problems with a set of overlapping factors of influence that are interrelated. This complexity makes the detection of solutions to the problem difficult. There will be no silver bullet. The complex nature of this problem led the committee to consider its causes in an integrated manner. These causes are multiple and may vary for different populations. Individual-level behavioral and psychosocial factors, neighborhood social characteristics, environmental exposures, medical conditions, infertility treatments, biological factors, and genetics may play roles to various degrees. Many of these factors are present together, particularly among women of low socioeconomic or minority status. After reviewing the evidence, the committee proposes a research agenda for investigating the problem of preterm birth. The agenda is presented to help focus and direct research efforts. The recommendations are grouped and prioritized and therefore presented in a different sequence than they appear in the full report; however, their numeric designation remains the same. Priority areas are grouped as follows:

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Preterm Birth: Causes, Consequences, and Prevention Establish Multidisciplinary Research Centers Priority Areas for Research Better define the problem of preterm birth with improved data Recommendations included in this category pertain to the need for improved collection of surveillance and descriptive data in order to better define the nature and scope of the problem of preterm birth. Improve national data Study the economic outcomes for infants born preterm Conduct clinical and health services research investigations Recommendations in this category pertain to the need to examine and improve the clinical treatment of women who deliver preterm and infants born preterm and the health care systems that care for them. Improve the methods of identifying and treating women at risk for preterm labor Study the acute and the long-term outcomes for infants born preterm Study infertility treatments and institute guidelines to reduce the number of multiple gestations Improve the quality of care for women at risk for preterm labor and infants born preterm Investigate the impact of the health care delivery system on preterm birth Conduct etiologic and epidemiologic investigations Recommendations in this category pertain to the need to examine the potential causes of preterm birth and its distribution in the population. Investigate the etiologies of preterm birth Study the multiple psychosocial, behavioral, and environmental risk factors associated with preterm birth simultaneously Investigate racial-ethnic and socioeconomic disparities in the rates of preterm birth Study and Inform Public Policy Recommendations in this final group pertain to the need to understand the impact of preterm birth on various public programs and how policies can be used to reduce rates of preterm birth.

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Preterm Birth: Causes, Consequences, and Prevention Categories under group II are not prioritized because the committee believes that they are actions that should occur simultaneously. However, recommendations within the categories are prioritized. The policy recommendations are listed last, as information resulting from previous recommendations will be needed in order to analyze and improve policies pertaining to preterm birth. AN AGENDA TO INVESTIGATE PRETERM BIRTH I. Establish Multidisciplinary Research Centers The complexity of interrelated biological, psychological, social, and environmental factors that are involved in preterm birth necessitates a multidisciplinary approach to research directed at understanding its etiologies, pathophysiology, diagnosis, and treatment. In addition to the scientific and clinical challenges, other important barriers must be addressed. Although some of these barriers are common to physician scientists in all clinical disciplines, others are unique to physician scientists trained in obstetrics and gynecology. Of primary importance are the recruitment and participation of scientists in the types of investigations that must be pursued to address preterm birth. In general, there has been a chronic lack of the resources needed to train clinical investigators and support clinical research (IOM, 1994; Nathan and Wilson, 2003; NIH, 1997; NRC, 2000, 2004). A major roadblock to advancing research on preterm birth and its consequences is thus the lack of experienced clinician scientists to conduct research and serve as mentors in obstetrics and gynecology. Other barriers include problems related to the career choices and training of new physicians (Gariti et al., 2005); the difficulties with conducting clinical investigations, particularly drug studies, during pregnancy; the relatively low levels of research funding, given the size of the problem; ethical and liability issues (A. Strunk, personal communication, January 10 and January 12, 2006); and the need for coordinated scientific leadership in the field (see Chapter 13). Recommendation V-1: The National Institutes of Health and private foundations should establish integrated multidisciplinary research centers. The objective of these centers will be to focus on understanding the causes of preterm birth and the health outcomes for women and their infants who were born preterm. Consistent with the Roadmap initiative of the National Institutes of Health, these activities should include the following:

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Preterm Birth: Causes, Consequences, and Prevention Basic, translational, and clinical research involving the clinical, basic, and behavioral and social science disciplines is needed. This research should include but not be limited to investigations covered by recommendations pertaining to the etiologies of preterm birth; the psychosocial, behavioral, sociodemographic, and environmental toxicant exposure-related risk factors associated with preterm birth; the disparities in the rates of preterm birth by race and ethnicity; the identification and treatment of women at risk of preterm labor; quality of health care provided to infants born preterm; and health services research. Sustained intellectual leadership of these research activities is essential to make progress in understanding and improving the outcomes for women and their infants who have been born preterm. Mentored research training programs should be integral parts of these centers. Fostering the development of basic and clinical researchers, including facilitating opportunities for funding and promotion, is critical. Funding agencies should provide ample and sustained funds to allow these centers to investigate the complex syndrome of preterm birth, analogous to programs developed to study cancer and cardiovascular disease. II. Priority Areas for Research Better Define the Problem of Preterm Birth with Improved Data 1. Improve National Data The concept of prematurity involves biological immaturity for extrauterine life. Maturation is the process of achieving full development or growth. Infants born preterm have immature organ systems that often need additional support to survive. The degree of maturity, therefore, is the major determinant of mortality and morbidity (the short- and long-term complications) of preterm birth. Accurate definitions of preterm birth are essential for comparing and interpreting the various studies that evaluate the etiologies and mechanisms of preterm birth; the efficacies of treatments for the prevention of preterm birth; the health and neurodevelopmental outcomes of infants born preterm; and efficacies of the strategies used to treat infants born preterm. Early efforts at defining prematurity relied on birth weight. The primary problem with the use of birth weight as a proxy for prematurity is that it identifies infants who are heterogeneous for fetal development and may miss some preterm infants. At any given gestational age, there is a distribution of birth weights such that some infants appear to be within the norm for their gestational age, some appear to be relatively light, and others appear to be quite heavy (Battaglia and Lubchenco, 1967). These categorizations of growth

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Preterm Birth: Causes, Consequences, and Prevention for gestational age have implications for mortality and morbidity. Thus, many preterm infants who are large for gestational age have normal birth weights but have rates of mortality and morbidity different from those of full-term infants with normal birth weights. Few studies report outcomes by gestational age category. The inaccuracy of data on gestational age is a major problem for research on preterm birth. Several methods are used to determine gestational age. Early prenatal ultrasounds (before 20 weeks of gestation) are more accurate than any other prenatal or postnatal estimate of pregnancy duration (Alexander et al., 1992; Chervenak et al., 1998; Nyberg et al., 2004). Despite its accuracy in estimating gestational age, the routine use of prenatal ultrasounds to estimate the duration of pregnancy is limited by several factors. Access to prenatal care is an issue for many of the women who are at the highest risk of preterm delivery (i.e., young, poor, and immigrant women); and there are racial disparities in prenatal care. In addition, the United States has no national standard for the routine use of prenatal ultrasound. Although more pregnant women in the United States are receiving ultrasounds than in the past (68 percent in 2002 versus 48 percent in 1989), many may be performed too late in pregnancy or the quality of the ultrasound may not be sufficient for the accurate and reliable estimation of the duration of pregnancy (Martin et al., 2003). Although early prenatal ultrasound is a good recommendation for obstetric practice, for research an earlier ultrasound (well within the first trimester) would be better, as it would allow investigation of potential factors that affect the growth trajectory earlier in pregnancy. Although much attention has been paid to obtaining accurate obstetric estimates of gestational age, there is a similar need for more methods of assessing fetal and infant maturity. Maturity assessment is even more important when gestational age is unknown or uncertain. In lieu of functional measures of fetal or infant maturity, accurate measures of gestational age are essential for clinical care as well as research on the causes, mechanisms, and outcomes of preterm birth. The National Center for Health Statistics develops standards for uniform reporting of live births and fetal, neonatal, and infant deaths to national public health databases. Although birth certificates are intended to establish the date of birth, citizenship, and nationality, they contain valuable public health information and are the only national source of birth weight and gestational age data. Large state and national population databases with birth and death certificate data have been used to plot gestational age distributions, birth weight for gestational age, and gestational age- and birth weight-specific rates of neonatal mortality. Gestational age is used to calculate a variety of statistical indicators used to monitor the health

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Preterm Birth: Causes, Consequences, and Prevention of mothers and their children in a population. These indicators can be used to target public health interventions and monitor their effects. Recommendation I-1: Promote the collection of improved perinatal data. The National Center for Health Statistics of the Centers for Disease Control and Prevention should promote and use a national mechanism to collect, record, and report perinatal data. The following key elements should be included: The quality of gestational age measurements in vital records should be evaluated. Vital records should indicate the accuracy of the gestational age determined by ultrasound early in pregnancy (less than 20 weeks of gestation). Birth weight for gestational age should be considered one measure of the adequacy of fetal growth. Perinatal mortality and morbidity should be reported by gestational age, birth weight, and birth weight for gestational age. A categorization or coding scheme that reflects the heterogeneous etiologies of preterm birth should be developed and implemented. Vital records should also state whether fertility treatments (including in vitro fertilization and ovulation promotion) were used. The committee recognizes that the nature of these data is private and sensitive. Recommendation I-2: Encourage the use of ultrasound early in pregnancy to establish gestational age. Because it is recognized that more precise measures of gestational age are needed to move the field forward, professional societies should encourage the use of ultrasound early in pregnancy (less than 20 weeks of gestation) to establish gestational age and should establish standards of practice and recommendations for the training of personnel to improve the reliability and the quality of ultrasound data. Recommendation I-3: Develop indicators of maturational age. Funding agencies should support and investigators should develop reliable and precise perinatal (prenatal and postnatal) standards as indicators of maturational age. 2. Study the Economic Outcomes for Infants Born Preterm To date, research on the medical cost of prematurity has focused nearly exclusively on inpatient care and has primarily focused on the cost for the initial hospitalization of the infant (see the review by John Zupancic in

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Preterm Birth: Causes, Consequences, and Prevention Appendix D). Several of these studies have provided estimates of the hospitalization cost exclusively by low birth weight (Rogowski, 1999), others have provided estimates exclusively by gestational age (Phibbs and Schmitt, 2006), whereas still others have provided estimates by both gestational age and low birth weight (Gilbert et al., 2003; Schmitt et al., 2006). This literature has drawn specific attention to the high costs associated with neonatal intensive care for preterm infants. Little is known, however, about the medical care costs of preterm birth beyond early hospitalization or about the costs associated with early intervention services, special education, or indirect costs, such as lost productivity. Lifetime estimates of cost, however, have been made for certain critical conditions and developmental disabilities associated with preterm birth and low birth weight, such as specific birth defects (Waitzman et al., 1996), cerebral palsy (CDC, 2004c; Honeycutt et al., 2003; Waitzman et al., 1996), mental retardation, and hearing loss and vision impairment (CDC, 2004c; Honeycutt et al., 2003). On the basis of new estimates provided by the committee, the annual societal economic burden associated with preterm birth in the United States was at least $26.2 billion in 2005, or $51,600 per infant born preterm. Nearly two-thirds of the societal cost was accounted for by medical care. The share that medical care services contributed to the total cost was $16.9 billion ($33,200 per preterm infant), with more than 85 percent of those medical care services delivered in infancy. Maternal delivery costs contributed another $1.9 billion ($3,800 per preterm infant). Early intervention services cost an estimated $611 million ($1,200 per infant), whereas special education services associated with a higher prevalence of four disabling conditions, including cerebral palsy, mental retardation, vision impairment, and hearing loss among premature infants added $1.1 billion ($2,200 per preterm infant). Lost household and labor market productivity associated with those disabling conditions contributed $5.7 billion ($11,200 per preterm infant). Recommendation IV-2: Investigate the economic consequences of preterm birth. Researchers should investigate the gaps in understanding of the economic consequences of preterm birth to establish the foundation for accurate economic evaluation of the relative value of policies directed at prevention and guidelines for treatment. This research should: Assess the long-term educational, social, productivity, and medical costs associated with preterm birth, as well as the distributions of such costs;

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Preterm Birth: Causes, Consequences, and Prevention Evaluations of the Medicaid expansions have not found reduced rates of preterm birth or improvements in maternal outcomes in association with these increases in the levels of insurance coverage for pregnant women (Piper et al., 1990). One reason that the expansions may not have been effective in reducing the rates of preterm birth may be that current prenatal care is focused on risks other than preterm birth (see Chapter 9). Nonetheless, prenatal care provides the framework though which interventions can be implemented and thus plays an important role in the potential to reduce preterm birth rates in the future. The organization of the health care delivery system has long been viewed as a key determinant of birth outcomes. In the 1970s, the March of Dimes developed practice guidelines advocating for the regionalization of perinatal care in the United States (Committee on Perinatal Health, 1976), based on research linking the regionalization of neonatal care with improved neonatal survival and overall outcomes. As initially envisioned, regionalized perinatal care involved the designation of three levels of care on the basis of the clinical conditions of the patients—both the mother and the infant. Level I centers were able to provide basic or routine obstetrical and newborn care, whereas Level II centers had the capability to care for patients of moderate risk, with Level III centers being reserved for those with the ability to tend to the most specialized high-risk cases. In addition to the designation of levels, regionalized perinatal care was to include the coordination of care among the region’s hospitals. Research demonstrated an increase in regionalization with a concomitant marked improvement in the rates of survival of the neonates (McCormick et al., 1985). By the latter half of the decade, however, the emphasis on the regionalization of perinatal care was being replaced by an interhospital competition driven by the reimbursement policies of an increasingly managed care environment. To compete for managed care contracts and to maintain and attract obstetric patients, smaller community hospitals were hiring neonatalogists and building new NICUs, even in the absence of increased obstetric volume or the ability to provide comprehensive neonatal services. Follow-up studies revealed a reversal in regionalization, increased competition between hospitals, and blurred distinctions between levels of care (Cooke et al., 1988). Between 1990 and 1994 an increase in the number of self-designated Level II facilities occurred compared with the number between 1982 and 1986, with a concomitant decrease in the number of Level I institutions (Yeast et al., 1998). However, the relative risk of neonatal mortality for infants born with very low birth weights was twofold higher in Level II centers than in Level III centers. More recently, the private sector has begun a trend toward moving patients to high-quality hospitals through evidence-based selective referral.

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Preterm Birth: Causes, Consequences, and Prevention Evidence-based hospital referral in its broadest sense means making sure that patients with high-risk conditions are treated in hospitals with the best outcomes. Evidence-based hospital referral standards for infants with very low birth weights required that infants with expected birth weights of less than 1,500 grams, a gestational age of less than 32 weeks, or correctable major birth defects should be delivered at a regional NICU with an average daily census of 15 patients or more. Evidence suggests that although patient volume and NICU level of care are statistically significant determinants of outcomes, they explain little of the variation in the rates of mortality among very-low-birth-weight infants among hospitals (Rogowski et al., 2004a). In general, large variations in outcomes exist among NICUs that cannot be explained by patient mix or other readily observable hospital characteristics, such as volume and level of care. More research will be needed on the determinants of high-quality care so that patients may be sent to the best hospitals. Recommendation V-3: Conduct research to understand the impact of the health care delivery system on preterm birth. The National Institutes of Health, the Agency for Healthcare Quality and Research, and private foundations should conduct and support research to understand the consequences of the organization and financing of the health care delivery system on access, quality, cost, and the outcomes of care as they relate to preterm birth throughout the full reproductive and childhood spectrum. Conduct Etiologic and Epidemiologic Investigations 1. Investigate the Etiologies of Preterm Birth It is clear that the causes of preterm labor are multifactorial and vary according to gestational age. Biological pathways include systemic and intrauterine infections (which are responsible for the majority of extremely preterm births), maternal stress, uteroplacental thrombosis and intrauterine vascular lesions associated with fetal stress or decidual hemorrhage, uterine overdistension, and cervical insufficiency. Each of these pathways may be influenced by gene-environment interactions. In the past, obstetricians and epidemiologists have tended to combine, for statistical purposes, all preterm births occurring between 20 and 37 weeks of gestation. This has obscured the opportunity to study preterm birth as a final common end point and has led to uniform, largely empirical, and unsuccessful treatment strategies. Each pathway to preterm labor can be characterized by its own unique upstream initiators of preterm parturition. Nonetheless, all share common downstream effectors of preterm contractions.

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Preterm Birth: Causes, Consequences, and Prevention There is much interest in using relevant animal models to help understand the mechanisms of preterm birth and the sequelae of preterm birth for the neonate and to develop rational and effective treatment and prevention strategies. The most compelling data from animal models are derived from the role of infection and inflammation in preterm birth (Gravett et al., 1994; Vadillo-Ortega et al., 2002; see Elovitz and Mrinalini [2004] for a review) and the positive effects of treatment with antibiotics and immunomodulators (Gravett et al., 2003). Until recently, the roles of genetic susceptibility and gene-environment interactions in preterm birth have largely been unexplored. There is some evidence of a genetic predisposition to preterm birth and the existence of gene-environment interactions. To date, however, only limited studies on the role of gene-environment interactions in preterm birth have been published (Genc et al., 2004; Macones et al., 2004; Nukui et al., 2004; Wang et al., 2000, 2002). Nevertheless, the available literature has provided some evidence of a familial or intergenerational influence on low birth weight and preterm birth (Bakketeig et al., 1979; Carr-Hill and Hall, 1985; Khoury and Cohen, 1987; Porter et al., 1997; Varner and Esplin, 2005). With recent advances in human genetics and molecular biology, assessment of the genetic contributions to human diseases has progressed from indirect measurements based on family history to direct measures of an individual’s genotype at particular loci. Nevertheless, the family history and a woman’s past medical history remain valuable tools in assessment of the risk for preterm birth. Understanding these factors and their interactions could lead to improvements in the diagnosis, prevention, and treatment of women at risk for preterm birth. This quickly expanding field will require new paradigms for interdisciplinary collaborations, as reflected in Recommendation V-1. The potential risk of preterm birth as a result of exposures to environmental pollutants is poorly understood. Few environmental pollutants have been investigated for their potential to increase the risk for preterm birth, and even among those pollutants that have been studied, the information available for most of them is limited. This lack of knowledge presents a potentially significant shortcoming for the design of public health preventive strategies. The most robust support for the relationship between exposures and preterm birth are for lead (see Andrews et al. [1994] for a review) and environmental tobacco smoke (Ahlborg and Bodin, 1991; Ahluwalia et al., 1997; Jaakkola et al., 2001), for which the weight of evidence suggests that maternal exposure to these pollutants increases the risk for preterm birth. In addition, a number of epidemiological studies have found significant relationships between exposures to air pollution and preterm birth, particularly for sulfur dioxide and particulates, suggesting that exposure to

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Preterm Birth: Causes, Consequences, and Prevention these air pollutants may increase a woman’s risk for preterm birth (Liu et al., 2003; Mohorovic, 2004; Xu et al., 1995). Recommendation II-1: Support research on the etiologies of preterm birth. Funding agencies should be committed to sustained and vigorous support for research on the etiologies of preterm birth to fill critical knowledge gaps. Areas to be supported should include the following: The physiological and pathologic mechanisms of parturition across the entire gestational period as well as the pregestational period should be studied. The role of inflammation and its regulation during implantation and parturition should be studied. Specifically, perturbations to the immunologic and inflammatory pathways caused by bacterial and viral infections, along with the specific host responses to these pathogens, should be addressed. Preterm birth should be defined as a syndrome of multiple pathophysiological pathways, with refinement of the phenotypes of preterm birth that recognizes and accurately reflects the heterogeneity of the underlying etiology. Animal models, in vitro systems, and computer models of human implantation, placentation, parturition, and preterm birth should be studied. Simple genetic and more complex epigenetic causes of preterm birth should be studied. Gene-environment interactions and environmental factors should be considered broadly to include the physical and social environments. Biological targets and the mechanisms and biological markers of exposure to environmental pollutants should be studied. 2. Study Multiple Psychosocial, Behavioral, Sociodemographic, and Environmental Risk Factors Associated with Preterm Birth Simultaneously Behavioral determinants of preterm birth have been of interest, given the fact that they are subject to change and could reduce the frequency of preterm birth directly. A large number of observational studies on a variety of behaviors have been conducted, including tobacco, alcohol, and illicit drug use; nutrition; physical and sexual activity; employment; and douching. Although each of these behaviors poses specific challenges in discerning cause-and-effect relationships, two key, generic concerns crosscut them all.

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Preterm Birth: Causes, Consequences, and Prevention First, it is a challenge to measure many of these behaviors with accuracy because of their inherent complexity, the inability of individuals to completely recall past behaviors, or the stigma associated with the behavior. The challenge is especially heightened for women who are pregnant. Behavioral factors are highly susceptible to confounding, so that any true causal effects of the behavior of interest on preterm birth are distorted by the association of that behavior with antecedent factors like socioeconomic conditions or with other behaviors. However, when considered in conjunction with other lines of research involving mechanistic studies and randomized trials, observational studies of behavioral influences on preterm birth, when it is feasible to conduct such studies, have been highly informative. Cocaine use is associated with an increased risk for preterm birth (Holzman and Paneth, 1994), and leisure time physical activity has been associated with a reduced risk of preterm birth (Evenson et al., 2002). Dietary constituents have been examined to a limited degree, with mixed evidence on the potential benefits of increased levels of iron (Villar et al., 1998), long-chain fatty acids (Olsen et al., 2000), folate (Rolschau et al., 1999; Savitz and Pastore, 1999), and vitamin C (Siega-Riz et al., 2003) being found. Although none of these dietary constituents is well established as having effects that prevent preterm birth, all warrant further evaluation. The findings of research on psychosocial factors and preterm birth have accumulated rapidly in recent years. Psychosocial factors such as stress, life events (for example, divorce, illness, injury, or job loss), anxiety, depression, and racism are distinct factors. Consistent evidence indicates that some factors, such as major life events (Dole et al., 2003, Zambrana et al., 1999), chronic and catastrophic stress (Lederman et al., 2004; Misra et al., 2001; Stein et al., 2000), maternal anxiety (Rini et al., 1999), racism (Collins et al., 2004), and intendedness of pregnancy (Orr et al., 2000), are associated with an increase in preterm birth. A small but growing body of work suggests that women who experience domestic or personal violence during pregnancy are at risk for adverse birth outcomes (Amaro et al., 1990; Coker et al., 2004; Parker et al., 1994a; Rich-Edwards et al., 2001; Shumway et al., 1999). The extent to which this is the result of stress processes rather than other mediating processes is unclear, however. Neighborhood conditions that are hypothesized to either directly or indirectly influence health are features of the neighborhood’s social environment (e.g., neighborhood cohesion, crime, socioeconomic composition, and residential stability), service environment (e.g., access to quality health care, grocery stores, recreational facilities), and physical characteristics (e.g., exposure to toxicants, noise and air pollution, and housing quality). A number of studies have documented a significant association between neighborhood-level socioeconomic disadvantage and birth outcomes (Collins and David, 1990, 1997; Elo et al., 2001; O’Campo et al., 1997; Roberts, 1997).

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Preterm Birth: Causes, Consequences, and Prevention These studies have used birth weight rather than gestational age, which is a major limitation of this work. Differences in the rates of low birth weight according to race and ethnicity remain, with African-American mothers bearing a substantially higher risk than white mothers, even after individual and community-level factors are taken into account (Roberts, 1997). Some specific neighborhood-level characteristics that have been associated with birth weight and the risk of low birth weight include indicators of neighborhood economic deprivation and crime (Elo et al., 2001). Adverse neighborhood conditions have also been found to lessen the effects of protective factors, such as prenatal care (O’Campo et al., 1997). Recommendation II-2: Study multiple risk factors to facilitate the modeling of the complex interactions associated with preterm birth. Public and private funding agencies should promote and researchers should conduct investigations of multiple risk factors for preterm birth simultaneously rather than investigations of the individual risk factors in isolation. These studies will facilitate the modeling of these complex interactions and aid with the development and evaluation of more refined interventions tailored to specific risk profiles. Specifically, these studies should achieve the following: Develop strong theoretical models of the pathways from psychosocial factors, including stress, social support, and other resilience factors, to preterm delivery as a basis for ongoing observational research. These frameworks should include plausible biological mechanisms. Comprehensive studies should include psychosocial, behavioral, medical, and biological data. Incorporate understudied exposures, such as the characteristics of employment and work contexts, including work-related stress; the effects of domestic or personal violence during pregnancy; racism; and personal resources, such as optimism, mastery and control, and pregnancy intendedness. These studies should also investigate the potential interactions of these exposures with exposure to environmental toxicants. Emphasize culturally valid measures in studies of stress and preterm delivery to consider the unique forms of stress that individuals in different racial and ethnic groups experience. Measurement of stress should also include specific constructs such as anxiety. Expand the study of neighborhood-level effects on the risk of preterm birth by including novel data in multilevel models. Data that address this information should be made more available to researchers for such activities. Interagency agreements for the sharing of data should be reached to support the development of cartographic modeling of neighborhoods.

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Preterm Birth: Causes, Consequences, and Prevention Work toward the development of primary strategies for the prevention of preterm birth. When there is evidence of modest effects of multiple causes, interventions that address all of these factors should be considered. Have designs that are common enough to allow for pooling of data and samples, and consider studying high-risk populations to increase the power of the study. 3. Investigate Racial-Ethnic and Socioeconomic Disparities in the Rates of Preterm Birth As discussed above, preterm birth rates vary substantially by race and ethnicity. The greatest differences in the rates of preterm birth are between African-American and Asian women. Knowledge can be gained by obtaining an understanding of the differences between groups as well as differences among Asian subgroups. Preterm birth rates also vary by nativity and the duration of residence. In 2003, the preterm birth rate was 13.9 percent for foreign-born African Americans but 18.2 percent for U.S.-born African Americans (CDC, 2005i). It is not known, however, why foreign-born and U.S.-born women of the same racial descent have such disparate rates of preterm birth, given their supposedly common genetic ancestry. Even the duration of residence seems to have an effect on preterm birth rates. A study in California found that long-term Mexican immigrants who had lived in the United States for more than 5 years were more likely to deliver their infants preterm than newcomers who had lived in the United States for 5 years or less (Guendelman and English, 1995). A number of explanations have been studied, including differences in socioeconomic status (SES), maternal risk behaviors, prenatal care, maternal infection, maternal stress, and genetics. Findings related to SES suggest that the disparities in the rates of preterm birth between African American and white women persist after attempts to adjust for socioeconomic differences (Collins and David, 1997; McGrady et al., 1992; Schoendorf et al., 1992; Shiono et al., 1997). Disparities in preterm birth rates by SES have been well documented not only in the United States (Parker et al., 1994a) but also in other countries, such as Canada (Wilkins et al., 1991), Sweden (Koupilova et al., 1998), Finland (Olsen et al., 1995b), Scotland (Sanjose et al., 1991), and Spain (Rodriguez et al., 1995), where the levels of poverty are lower and where the population has universal access to high-quality prenatal and other medical care. Furthermore, socioeconomic disparities are associated with other factors, such as maternal nutrition (Hendler et al., 2005), maternal drug use (Kramer et al., 2000), maternal employment (Mozuekewich et al., 2000), prenatal care (CDC, 2005i), and maternal infection. Given the serious doubt about the effects of prenatal care on reduc-

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Preterm Birth: Causes, Consequences, and Prevention ing the risk of preterm birth (Alexander and Kotelchuck, 2001; Lu and Halfon, 2003), it too seems an unlikely mediator of socioeconomic disparities in preterm birth. Bacterial vaginosis is more common among women of low SES (Hillier et al., 1995; Meis et al., 1995); however, clinical trials of screening and treatment have yielded conflicting results (Carey et al., 2000; McDonald et al., 2005). Finally, women of low SES women experience more stressful life events and more chronic stress (Lu et al., 2005; Peacock et al., 1995), which are linked to preterm birth. Other behavioral and social differences between African American and white women have been evaluated as potential causes of the disparity in preterm birth rates. Proportionately fewer African American women smoke cigarettes (Beck et al., 2002; Lu et al., 2005) and their rate of use of drugs and alcohol is no higher than white women’s (Serdula et al., 1991). The effectiveness of prenatal care for preventing prematurity has yet to be conclusively demonstrated (Alexander and Kotelchuck, 2001; Lu and Halfon, 2003; CDC, 2005i). African American women are more likely than white women to experience infections, including bacterial vaginosis and sexually transmitted infections (Fiscella, 1995; Meis et al., 2000). However, the cause of this increased susceptibility to infections among pregnant African American women largely remains unknown, and treatment has yielded modest or no benefits (Carey et al., 2000; King, 2002; McDonald et al., 2005). Insofar as African American women may experience more stress in their daily lives than white women, it has been suggested that maternal stress may contribute to the disparities in the rates of preterm birth between African American and white women (James, 1993; Krieger, 2002; Lu and Chen, 2004). Although a woman’s genetic makeup undoubtedly plays a role in the pathogenesis of preterm birth, the potential genetic contribution to racial disparities in preterm birth is unknown (Cox et al., 2001; Hassan et al., 2003; Hoffman et al., 2002; Varner and Esplin, 2005). Recommendation II-3: Expand research into the causes and methods for the prevention of the racial-ethnic and socioeconomic disparities in the rates of preterm birth. The National Institutes of Health and other funding agencies should expand current efforts in and expand support for research into the causes and methods for the prevention of the racial-ethnic and socioeconomic disparities in the rates of preterm birth. This research agenda should continue to prioritize efforts to understand factors contributing to the high rates of preterm birth among African American infants and should also encourage investigation into the disparities among other racial-ethnic subgroups.

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Preterm Birth: Causes, Consequences, and Prevention III. Study and Inform Public Policy Because preterm birth is concentrated in populations of low socioeconomic status, the cost of preterm birth generates a considerable burden on public programs, many of which target low-income and other vulnerable populations. As noted above, pregnant women who have received ART may not be representative of all pregnant women (among other things, evidence suggests that they are from socioeconomically advantaged backgrounds). Thus, this fact should be taken into account when generalizations are made from the findings for births that result from ART. The costs of preterm birth extend beyond the medical costs associated with the actual birth of the infant. There are significant lifetime consequences of preterm birth for many infants. Therefore, the consequences of preterm birth span a broad range of services and social supports. These may include early intervention programs; special education; income supports, including those provided by the Supplemental Security Income program and Temporary Assistance to Needy Families; Title V Maternal and Child Health Programs; foster care; and the juvenile justice system. Little is known about the magnitude of the public burden, aside from the costs associated with the medical care provided through Medicaid. It is not possible to assign dollar costs associated with preterm birth to other services and programs because of a lack of data. A second aspect of public policy is that it can be used to potentially reduce preterm birth rates and improve health outcomes for infants. Public policies have the potential to reduce the rates of preterm birth and improve outcomes for children and families through the financing of health care, the organization of care and improvements in the quality of care, and other social policies. Better measures of the quality of health care need to be developed to enable quality improvement efforts and guide public policy. However, effective public policies will require a better understanding of the determinants of preterm birth. Recommendation V-4: Study the effects of public programs and policies on preterm birth. The National Institutes of Health, the Centers for Medicare and Medicaid Services, and private foundations should conduct and/or support research on the role of social programs and policies on the occurrence of preterm birth and the health of children born preterm. Recommendation V-5: Conduct research that will inform public policy. In order to formulate effective public policies to reduce preterm birth and assure healthy outcomes for infants, public and private funding agencies and organizations, state agencies, payors,

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Preterm Birth: Causes, Consequences, and Prevention professional societies, and researchers will need to work to implement all of the previous recommendations. Research in the areas of better defining the problem of preterm birth, clinical investigations, and etiologic and epidemiologic investigations is critical to conduct before policy makers can create policies that will successfully address this problem. CONCLUDING REMARKS Although significant improvements in treating infants born preterm and improving survival have been made, little success has been attained in understanding and preventing preterm birth. The challenge remains to identify interventions that prevent preterm birth, reduce the rates of morbidity and mortality of the mother or the infant once a preterm birth occurs, and reduce the incidence of long-term disability among children who were born preterm in the most comprehensive and cost-effective manner possible. The recommendations of this report are intended to assist policy makers, academic researchers, funding agencies and organizations, third-party payers, and health care professionals with the prioritization of research activities and to inform the public about the problem of preterm birth. The ultimate goal of the committee’s efforts is to work toward improved outcomes for children and their families.

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