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B
Prematurity at Birth: Determinants, Consequences, and Geographic Variation

Greg R. Alexander1

Throughout the latter half of the 20th century, infant mortality rates have continued to decline in the United States (16). The ongoing reduction in the risk of an infant death has largely been driven by improvements in birth weight- and gestational age-specific infant mortality rates stemming from advancements in intensive medical care services and technology (6–8). However, as the decline in infant mortality rates has tapered off in recent years and has reversed in some states, growing concerns about the direction of future trends in U.S. infant mortality rates have emerged (9). These concerns are heightened by the simultaneous increases in low birth weight and preterm birth rates that have been observed for over 2 decades in the United States and elsewhere (3, 8, 1014). As it is unclear if yet another technological breakthrough in high-risk medical services will emerge to drive further reductions in infant death rates, the need to prevent premature births has been increasingly voiced and has become paramount (4, 15).

The importance of reducing the risk of low birth weight and preterm birth has long been recognized if for no other reason than that the health care costs associated with an extremely small or early birth are many times higher than those of infants of normal weight (16, 17). Lowering the risk of infant mortality through reductions in high-risk preterm births would likely be much more cost-effective than the current reliance on improving their

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Greg R. Alexander, M.P.H., Sc.D., Colleges of Medicine and Public Health, University of South Florida, Tampa.



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Preterm Birth: Causes, Consequences, and Prevention B Prematurity at Birth: Determinants, Consequences, and Geographic Variation Greg R. Alexander1 Throughout the latter half of the 20th century, infant mortality rates have continued to decline in the United States (1–6). The ongoing reduction in the risk of an infant death has largely been driven by improvements in birth weight- and gestational age-specific infant mortality rates stemming from advancements in intensive medical care services and technology (6–8). However, as the decline in infant mortality rates has tapered off in recent years and has reversed in some states, growing concerns about the direction of future trends in U.S. infant mortality rates have emerged (9). These concerns are heightened by the simultaneous increases in low birth weight and preterm birth rates that have been observed for over 2 decades in the United States and elsewhere (3, 8, 10–14). As it is unclear if yet another technological breakthrough in high-risk medical services will emerge to drive further reductions in infant death rates, the need to prevent premature births has been increasingly voiced and has become paramount (4, 15). The importance of reducing the risk of low birth weight and preterm birth has long been recognized if for no other reason than that the health care costs associated with an extremely small or early birth are many times higher than those of infants of normal weight (16, 17). Lowering the risk of infant mortality through reductions in high-risk preterm births would likely be much more cost-effective than the current reliance on improving their 1 Greg R. Alexander, M.P.H., Sc.D., Colleges of Medicine and Public Health, University of South Florida, Tampa.

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Preterm Birth: Causes, Consequences, and Prevention survival with high-risk intensive care services after they are born (17–19). Beyond the elevated health care costs of newborn premature infants, however, those born preterm have an appreciable risk of long-term neurological impairment and developmental delay (20–22). The ongoing medical and support service needs of these infants and their families add to the overall health care system cost burden over time and emphasize the continuing health and developmental problems that some preterm infants face. Finally, the high preterm birth rates in the United States have been identified as a major contributor to this nation’s relatively poor ranking in infant mortality among other developed countries (23). Although low birth weight has often received greater attention than preterm birth as the leading factor underlying poor pregnancy outcomes in the United States, it has been recognized that to successfully address these problems, the “key goal is prevention of preterm birth” (23). Policy makers and the public need to be kept informed of the rapid developments in research and their implications for clinical practice and public programs and policies. Because of the continuing problem that premature birth poses in the United States and other countries, as well as the rapid and ongoing developments in research in this area, there has been a recognized need for periodic forums, reports, and public investigative committees that would increase knowledge and awareness of evolving strategies for the prevention of preterm birth. In 1985, the Institute of Medicine released the report of its Committee to Study the Prevention of Low Birth Weight (24). That report addressed the epidemiology of low birth weight and assessed preventive approaches for cost and effectiveness. That same year, Émile Papiernik, an international French innovator and leader in prematurity research, organized a conference in Evian, France, entitled Prevention of Preterm Birth: New Goals and New Practices in Prenatal Care. That conference focused on reducing the risk of preterm labor and delivery and offered participants an opportunity to disclose their latest research findings (25). A follow-up to the 1985 Evian conference was held in the United States in 1988. That conference, Advances in the Prevention of Low Birth Weight, was hosted by H. Berendes, S. Kessel, and S. Yaffe and focused on the results of clinical trials and community-based interventions aimed at reducing low birth weight (25). Yet another follow-up to those conferences, The International Conference on Preterm Birth: Etiology, Mechanisms and Prevention, was held in 1997 (26). That conference was also developed to provide an overview of studies in preterm birth research, a review of risk factors and potential etiologic pathways, and an assessment of the then current intervention and prevention strategies. Other reports, conferences, and national efforts, including the current Prematurity Campaign of the National March of Dimes, have been developed over the last 2 decades to address the widely perceived problem of

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Preterm Birth: Causes, Consequences, and Prevention increasing rates of low birth weight and preterm births in the United States (19). For the most part, the continued and still current consensus of all of these forums and their related reports is that the proposed interventions do not work (27–30). Although major advances have occurred in the area of preterm birth research and related perinatal and maternal-infant medical care, preterm birth rates have continued to climb. despite these developments and intervention efforts (10, 28). New social trends, including changes in the rate of multiple births, the use of assisted reproductive technology (ART), the increasing average maternal age, the proportion of married mothers, the early use of prenatal care, etc., have accompanied this increase in preterm birth rates (10). This complex array of social and medical care developments and the intractability of the present preterm birth trends necessitate the ongoing and heightened attention of health researchers, health care providers, public health practitioners, and policy makers. The impact on families is plainly too great (ranging from the risk of an infant death to long-term developmental delays and impairment), and the costs (both financial and emotional) are too high to ignore or simply accept. DEFINITION AND MEASUREMENT OF PREMATURITY Defining and Conceptualizing Preterm Birth The definition of prematurity has evolved in the literature of the last century. Initially used to designate an infant born too early or too small, it was often defined by the use of either birth weight or gestational age (31). As birth weight is more reliably measured than gestational age, low birth weight (a birth weight of <2,500 grams) was the more obvious choice to delineate a premature birth. Nevertheless, being born too small is conceptually and, in some cases, etiologically distinct from being born too early. Low birth weight may result from an early birth but also from fetal growth restriction, i.e., being small for a given gestational age. As the etiologies of these distinct types of low birth weight deliveries are different, it became more widely accepted to separate prematurity into two categories, i.e., either low birth weight or preterm. By current convention, “preterm” now refers to an early delivery and is defined by gestational age. “Low birth weight” refers to the weight of the infant at delivery. Relatedly, fetal growth refers to the birth weight of the infant for a specific gestational age. Small-for-gestational age (SGA), usually defined as less than the 10th percentile of birth weight for gestational age, is a commonly used indicator of fetal growth restriction. As illustrated in Figure B-1, these indicators may overlap; i.e., a low birth weight infant may often be preterm and SGA. They are not interchangeable, however, as each has distinct etiologies and risk factors (32, 33). Among low birth weight infants, approximately two-thirds

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Preterm Birth: Causes, Consequences, and Prevention FIGURE B-1 Comparison of preterm (<37 weeks of gestation), low birth weight (<2,500 grams), and SGA (less than the 10th percentile of birth weight). Source: 1985–1988 and 1995–2000 Birth Cohort Linked Birth/Infant death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS. are born preterm, whereas less than 20 percent of SGA age infants are born preterm. Typically, preterm birth is defined as a delivery or birth at a gestational age less than 37 weeks. Other commonly used subcategories of preterm birth have been established and delineate moderately preterm (birth at 33 to 36 weeks of gestation), very preterm (birth at <33 weeks of gestation), and extremely preterm (birth at ≤28 weeks of gestation). Table B-1 provides recent data on all live births to U.S. resident mothers for various gestational age and preterm categories. Preterm birth is an outcome defined by a single end point, i.e., being born before an established gestational age (37 weeks). Fundamentally, infants born preterm are assumed to have a certain added risk of death, disease, and disability compared with the risk for normal-term infants. However, although preterm births may be grouped together on the basis of having a higher risk of adverse outcomes, several distinct clinical categories of preterm delivery have been identified (34, 35). Preterm births have been classified into three separate subgroups according to clinical presentation: Births occurring after spontaneous premature labor, related to premature contractions (50% of cases)

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Preterm Birth: Causes, Consequences, and Prevention TABLE B-1 Gestational Ages of Live Births in the United States, 1995 to 2000 Gestational Age Category (Weeks of Gestation) Percentage of Births % Extremely Preterm (≤28) 0.8 % Very Preterm (≤32) 2.2 % Moderate Preterm (33-36) 8.9 % Preterm (<37) 11.2 % Preterm (37-41) 81.9 % Postterm (42+) 7.0 SOURCE: 1995–2000 Birth Cohort Linked Birth/Infant death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980– 2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS. Spontaneous rupture of the membranes (roughly 30 percent of cases) Indicated delivery of a premature infant for the benefit of either the infant or the mother (about 20 percent of cases) (36, 37) Although preterm birth may be defined as a delivery before what is considered the normal length of gestation, preterm birth is recognized as stemming from several pathways (e.g., infections and fetal growth restriction) that may operate separately or that may interact with one another. In essence, preterm birth is not a single entity but is the result of one or more causal processes, each of which may result in a similar event: being born too soon. Although the subclassification of preterm birth by clinical presentation is a step toward separating preterm deliveries into more homogeneous subgroups, there continues to be ongoing discussion regarding whether the widely used three-category classification truly defines separate preterm entities. The accurate classification of preterm birth subgroups is an important step toward establishing risk factors and ensuring that interventions are targeted at those who are truly at risk. To the extent that the components of an intervention are focused on a specific etiologic pathway for preterm birth but targeted broadly to all individuals at risk for preterm birth in general, the intervention may well appear to lack efficacy. Moreover, risk factors and predeterminants may differ by preterm subgroup, further hindering research in establishing separate and distinct categories of preterm birth. Some researchers suggest combining spontaneous premature labor (contractions) and spontaneous rupture of the membranes, and it has been noted that the risk factors for these categories are somewhat similar

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Preterm Birth: Causes, Consequences, and Prevention (34). Because of these findings, which suggest that spontaneous rupture of membranes and spontaneous labor are the result of similar processes, there is an argument for combining these back together into one group. However, some researchers further suggest that there is more etiologic overlap between spontaneous and indicated preterm birth than was first suspected (34). For example, maternal hypertension and fetal intrauterine growth restriction are indications for preterm delivery and are also suspected to be risk factors for spontaneous preterm birth (34). Notwithstanding the ongoing debates and developments about pathways, the value of identifying the distinct etiologic pathways that lead to preterm birth is evident. Limitations to the conceptualization of preterm birth and its various subtypes decidedly hinder the advancement of our understanding of the causes and prevention of preterm birth. The research results of the investigation of poorly defined preterm etiologic categories may prove misleading despite impressive statistical findings. The ongoing refinement of a better conceptualization of preterm birth and the articulation of its numerous etiologic pathways are essential for improving research on the prevention of preterm birth. Measurement of Gestational Age Over and above the classification of preterm etiologic subcategories, the basic determination of whether a delivery was “too soon” depends on the measurement of gestational age. An accurate estimate of gestational age is essential, not just for research on preterm birth but also for the management of the pregnancy and newborn infants (38, 39). Gestational age is a proxy for the extent of fetal development and the fetus’s readiness for birth. As an indicator of the maturity of a newborn, gestational age is closely associated with the newborn’s chances for survival and the likelihood that the infant will develop complications as a neonate. Moreover, knowledge of gestational age is necessary for interpreting the results of a preterm infant’s neurodevelopmental examination and for assessing the infant’s developmental progress. Gestational age is used for a variety of statistical indicators that gauge the health status of populations and assess the need for interventions (39). Hence, the percentages of infants born preterm and very preterm may reflect the prevalence of a variety of population-specific perturbations, including infection, psychosocial and physical stresses, poor nutrition, and substance abuse. The percentages of infants born SGA, based on percentiles of birth weight for gestational age, are used to provide some indication of nutritional deficits during pregnancy. Lastly, gestational age is used in conjunction with the month that prenatal care began and the number of prenatal care visits to calculate indices of adequacy of prenatal care utiliza-

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Preterm Birth: Causes, Consequences, and Prevention tion. These gestational age–based health status and health care utilization indices are useful on a population level to ensure that service needs are met, target services to at-risk populations, and evaluate the efficacies of those interventions. Gestational age has typically been defined as the length of time from the date of the last normal menses to the date of birth (40, 41). This definition may overestimate the actual duration of pregnancy by approximately 2 weeks, which is the average interval from the beginning of the last menstrual cycle to the point of conception. The definition of gestational age, based on the last menstrual period (LMP), has several limitations (42–46). There is wide individual variability (i.e., ~7 to 25 days) in the interval between the onset of the LMP and the date of conception. Errors in correctly recalling the date of LMP may occur because of irregular menses and bleeding early in pregnancy. Approximately 20 percent of live birth certificates in the United States have been reported to have a missing or incomplete date of LMP, and greater proportions of missing or implausible dates of LMP have been reported for women of lower socioeconomic status, who by virtue of their higher rates of preterm delivery and the delivery of infants who are SGA often have the greatest medical need for an accurate estimate of gestational age. The interval between the date of LMP and the date of birth has served as the “gold standard” for determining the gestational age of the infant and, as such, has been used in studies for validation of alternative gestational age estimation methods (47). Studies of the validity and reliability of alternative gestational age measures are needed to assess the degree to which the alternative measures consistently predict, agree with, or are correlated with the selected gold standard measure across the full range of gestational age values. These studies may further look for evidence of any systematic biases that might stem from examination procedures or study population characteristics. Because of the widely recognized limitations to the estimation of gestational age by LMP, a number of alternative prenatal and postnatal approaches to the determination of gestational age have been developed (47–49). Table B-2 provides a list of prenatal measures for estimating gestational age and further indicates the specific focus of the measures (39). Obstetric measures of fetal heart tones, quickening, and uterine fundal growth have often been used to confirm gestational age on the basis of LMP but are limited because of wide individual variability, confounding variables (e.g., polyhydramnios), and the requirement of an early initiation of prenatal care (39). Many view early prenatal ultrasound (e.g., in the first trimester or early in the second trimester) as the new gold standard for validation of new gestational age measures, even though ultrasound methods were originally validated with LMP as the gold standard. Ultrasound estimates of gestational age are based on different measures of fetal size

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Preterm Birth: Causes, Consequences, and Prevention TABLE B-2 Prenatal Methods for Determining Gestational Age Method Focus of Measure Last menstrual perioda pregnancy duration Fetal heart tonesb physical and neurological maturity Quickeningb physical and neurological maturity Uterus at umbilicusb fetal size Uterine fundal heightb fetal size Presence of embryo sacc fetal size Crown-rump lengthd fetal size Head circumferenced fetal size Biparietal diameterd fetal size Femur lengthd fetal size Sacral length fetal size Foot length fetal size Jaw size fetal size Chest diameter fetal size Abdominal Circumferencee fetal size aTraditional measure of gestational age duration commonly used in population-based, public health studies that use vital records. bTypically monitored by obstetricians during prenatal care visits. cMore recently developed ultrasound measure for clinical use. dCommonly used ultrasound measures for estimation of gestational age. eMore typically used to assess adequacy of growth for gestational age. (e.g., crown-rump length; biparietal diameter; femur length; sacral length; foot length; jaw size; and abdominal, chest, and head circumference) and are the most accurate early in gestation. As the pregnancy progresses beyond the second trimester, there is more individual variation in normal fetal growth increases, and variations in fetal growth are decidedly influenced by individual and environmental factors, including uteroplacental insufficiency, maternal exposure to drugs or toxins, and congenital infections. Although many pregnant women in the United States may receive an ultrasound, far fewer receive an ultrasound early enough to obtain the most reliable estimate of gestational age. Minority and impoverished women, who often face barriers to access to prenatal care services, may be less likely to obtain an early ultrasound. As such, ultrasound-based gestational age estimates may be less accurate for these groups. Furthermore, ultrasound is not universally available, particularly in less developed countries. Finally, the quality of the ultrasound equipment and the level of training of the ultrasound technicians may vary across sites of care, and the reference populations used to validate the various ultrasound measures may differ. Because accurate prenatal estimates of gestational age are not universally available, postnatal assessments of gestational age have also been developed (39). Examining the physical and neurological characteristics of the

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Preterm Birth: Causes, Consequences, and Prevention TABLE B-3 Postnatal Methods for Determining Gestational Age Method Focus of Measure Birth weighta infant size Head circumference infant size Foot length infant size Crown-heel length infant size Dubowitzb physical and neurological maturity Ballardc physical and neurological maturity Revised Ballardd physical and neurological maturity Lens vesselsd physical maturity Cranial ultrasound physical and neurological maturity Nerve conduction velocities physical and neurological maturity aStill used as a gross indicator of gestational age, although limitations are widely known. Birth weight is more typically used to assess the adequacy of growth for gestational age and as a research method to impute missing gestational age values and to identify grossly inaccurate gestational age values bBecause of a preference for the Ballard measure, this measure may have limited use in the United States. cProbably the most commonly used means of estimating the gestational ages of newborns in the United States. dApplicable only to a limited range of gestational ages. newborn, Dubowitz and coworkers devised a scoring system to estimate gestational age (47). It was later revised and shortened by Ballard and colleagues (48, 49), and other postnatal methods of determining gestational age have also been developed. Concerns have been raised regarding the accuracy of these approaches, particularly for preterm and very preterm infants (43). Among these concerns is their ability to be universally applied to various subpopulations, including different racial groups (50). Table B-3 details the postnatal approaches to the determination of gestational age (39). The specific trait being measured by each gestational age estimation method, e.g., pregnancy duration, fetal size, or physical and neurological maturity, is also provided. There are distinct conceptual differences among the alternative strategies for estimating gestational age, and these differences have implications for research on preterm birth and international comparisons of the percentages of infants born preterm. Gestational age based on LMP is a direct measure of the duration of the pregnancy and is thus a unit-of-time measure. Many of the prenatal measures of gestational age (uterine fundal height and ultrasound) and the newborn measures of gestational age (birth weight, length, head circumference, and foot length) are direct measures of fetal or infant size, and these use the extent of fetal growth as an indirect measure of the duration of gestation. The remaining postnatal measures (e.g., the

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Preterm Birth: Causes, Consequences, and Prevention Dubowitz score, the Ballard score, lens vessels, nerve conduction velocities, and cranial size by ultrasound) evaluate different aspects of infant maturity by using physical or neurological milestones that are typically observed by a certain gestational age. All of the alternative measures of gestational age translate their findings to the same scale as gestational age from LMP (20 to 44 weeks of gestation), even though “weeks” is strictly a measure of duration of time. Although these measures are highly correlated, they are not the same. Their absolute agreement may vary across the range of gestational ages. To the extent that different populations use different gestational age estimates, either separately or in combination, direct comparisons of preterm birth rates are compromised. Underpinning these indirect measures of the duration of gestational age are three assumptions: (a) that the extent of normal growth and maturation observed occurs in most infants at a similar point in time in each pregnancy, (b) that the normal rate of intrauterine growth and maturation is about the same, and (c) that readiness for birth is a direct function of time in utero. Although pregnancy duration, fetal size, and newborn physical and neurological maturation are clearly associated with one another and, furthermore, are associated with infant morbidity and mortality, it must be emphasized that all of these gestational age estimation measures are attempting to define operationally variations in the underlying biological conditions that correspond to an optimal point of readiness for birth. This relationship between the duration of pregnancy, the extent of fetal size, the degree of physical and neurological maturation, and the readiness for birth may well vary among populations and may be influenced by a variety of factors. As such, the validity of these gestational age measures, as indicators of readiness for birth, is based on a set of assumptions that have proven more tenuous as our medical technology has extended the limits of viability to the extremes of gestational age. There is growing evidence in the literature that these alternative measures of gestational age do not correspond with one another to the extent once believed, even within the basic prenatal and postnatal categories. Some gestational age measures may tend to underestimate the gestational age and others may tend to overestimate it, and this may vary by gestational age (42, 43). Furthermore, some measures may not provide consistently valid estimates for specific subgroups (43). Herein lie the concerns for research on preterm birth. Studies that change their means of measuring gestational age during the course of the investigation may uncover trends in the rate or incidence of preterm birth that merely reflect the change in measurement approach. Such biased results may provide inaccurate assessments of the impacts of interventions. Other studies that use different gestational age measures more frequently for some population subgroups, or geographic areas than others may artificially inflate or deflate the preterm birth rates

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Preterm Birth: Causes, Consequences, and Prevention for those comparison groups. This may lead to the inaccurate determination of cases of preterm birth and a biased establishment of risk characteristics and high-risk areas. As indicated earlier, this represents a major concern for international comparisons of preterm birth rates. Epidemiological studies of preterm birth in large populations, which often use vital records, typically rely on LMP or, more recently, LMP and the clinical estimate as reported on the birth certificate to define gestational age. It is these studies that have typically established current national trends and international comparisons in preterm birth rates. Meanwhile, clinical studies may more typically have access to early ultrasound data, although the study populations selected may be less representative of the larger population at risk of preterm birth. These measurement issues hinder comparisons among study findings, limit the interpretation and generalizability of the results, and persist as an ever lurking potential bias to research on preterm birth. TRENDS, VARIABILITY, AND RISK Trends During the last 2 decades of the 20th century, preterm birth rates in the United States exhibited a steady increase. As depicted in Figure B-2, an approximately 30 percent increase was observed for both the preterm birth and the very preterm birth rates between 1980 and 2000. Furthermore, examination of the gestational age distribution during the latter part of this period reveals a slight decrease in mean gestational age from 39.2 weeks for 1985 to 1988 to 38.8 weeks for 1995 to 2000. Additionally, there is an overall shift in the distribution, resulting in a great proportion of preterm births and a decrease in postterm births (42-plus weeks of gestation). These patterns are illustrated in Figure B-3, which displays the gestational age distributions of live births to U.S. resident mothers, using data from the NCHS linked live birth infant death cohort files. For the two time periods portrayed in Figure B-3, Table B-4 provides the proportion of births for the various preterm birth categories. Between 1985–1988 and 1995–2000, the proportion of preterm birth rose approximately 15 percent. These increasing trends in preterm delivery have not been consistent among racial groups in the United States. Figure B-4 provides trends in the percentages of preterm and very preterm births for whites and African Americans on the basis of the reported race of the mother. Although a steady increase in these rates is evident for whites, this temporal pattern is not evident for African Americans. This divergence in trends in the rates of preterm delivery has been the subject of investigation (8, 51). Differential

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Preterm Birth: Causes, Consequences, and Prevention FIGURE B-15 Percent decline in gestational age-specific infant mortality rates between 1985–1988 and 1995–2000. Source: 1985–1988 and 1995–2000 Birth Cohort Linked Birth/Infant Death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS. TABLE B-9 Gestational Age Specific Infant Mortality 1985–1988 and 1995–2000 Gestatinal Age Categories (wk of Gestation) Infant Mortality Rate 1985–1988 1995–2000 Very Preterm (<33 wks) 198.9 151.3 Moderately Preterm (33–36 wks) 14.0 8.8 Term (37–41 wks) 4.2 2.7 Postterm (>41 wks) 4.6 3.1 SOURCE: 1985–1988 and 1995–2000 Birth Cohort Linked Birth/Infant Death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS. risk births) (10).Preterm birth prevention programs,which often involve social support and patient education,have also been proposed and implemented but have shown little success (28, 30).Lastly,more prenatal care has been touted as a solution,even though it has been argued that little is done in the typical prenatal practice that would prevent preterm birth (26).

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Preterm Birth: Causes, Consequences, and Prevention FIGURE B-16 Infant mortality rates among preterm deliveries, by state, 1995 to 2000. Source: 1995–2000 Birth Cohort Linked Birth/Infant death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS FIGURE B-17 Infant mortality rates among very preterm deliveries, by state, 1995 to 2000. Source: 1995–2000 Birth Cohort Linked Birth/Infant death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS.

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Preterm Birth: Causes, Consequences, and Prevention FIGURE B-18 Gestational age-specific infant mortality rates among U.S. resident African Americans and whites, by state, 1995 to 2000. Source: 1995–2000 Birth Cohort Linked Birth/Infant Death Data Set, CD-ROM Series 20, USDHHS, CDCP, NCHS; 1980–2000 Natality Data Set, CD-ROM Series 21, USDHHS, CDCP, NCHS. Reporting Issues and Their Potential Impact Most of the proposed “causes” of the trends and geographic variations in preterm birth rates are plausible and may operate individually or in combination. What is unclear is the extent to which each potential determinant is associated with observed variations in preterm birth rates and what other possible factors might also be involved. A typical approach for interpreting changes in preterm birth rates involves a systematic assessment of the likely precursors, starting with data reporting, regulations, procedures, processes, training, quality, completeness, etc. Variations and changes in gestational age measurement approaches and data reporting may substantially influence geographic and temporal comparisons of preterm birth rates. Before consideration of the potential roles of changes in maternal demographic and behavioral characteristics (including the age of the mother, substance use and abuse, and multiple births), social and physical environment factors (including violence, poverty, infections, stress, and environmental hazards), and health care service attributes and practices (involving availability, access, utilization, types, and the content and quality of services and programs), reporting considerations must be addressed.

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Preterm Birth: Causes, Consequences, and Prevention Several specific reporting issues may affect trends and variations in preterm birth rates. These include changes or differences in: the reporting of deliveries of infants weighing <500 grams as either a miscarriage, a fetal death, or a live birth; the definition of fetal death involving birth weight and gestational age criteria; the measurement of gestational age, e.g., by the use of LMP and clinical estimates; and reporting regulations, procedures, processes, training, and quality at hospitals and by state and local jurisdictions. Geographic Comparisons Differences in preterm birth rates because of differences in data reporting, validity, accuracy, and completeness are difficult to separate from differences in the high-risk characteristics of the population and environment and the availability of health care and the accessibility and quality of the health care system. As the data included in this appendix have highlighted (Figures B-5a and B-5b, B-8a to B-8d, B-16, and B-17), considerable state variations in preterm birth rates and the survival of infants born preterm are evident. The extent to which population-related and health care system–related risk factors contribute to these variations can be assessed only with a solid understanding of each state’s definitions of a live birth, a fetal death, gestational age, and other reporting attributes. As data are typically collected within hospitals within states, state aggregations of information may obscure what might be significant reporting variations among and within hospitals. Hence, in the United States, where there is considerable similarity in vital statistics reporting regulations, data definitions, reporting procedures, and population characteristics, comparisons among states are still made tenuous by the influence of these myriad confounding factors. The problem of data reporting is magnified at the international level, where substantial differences in the definitions of live births and fetal deaths exist stemming from variations in vital record reporting, laws, and procedures. Infant mortality and low birth weight rates for the United States have repeatedly been indicated to compare poorly with those for other industrialized nations (23, 67). From these data, it is logical to infer that U.S. preterm birth rates are also higher than those in many other countries of similar status, despite potentially higher investments to health care in the United States. The precise delineation of where the United States ranks in preterm delivery is still difficult, as the impacts of different national standards of practice related to the measurement of gestational age are often unclear. For example, it may not be known what measure is typically used

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Preterm Birth: Causes, Consequences, and Prevention to estimate gestational age, e.g., ultrasound or LMP. Some nations may rely on periodic surveys rather than vital records to establish preterm birth rate trends. Hence, observations of marked differences in preterm birth rates between European countries and the United States are fraught with the potential for error. Although there may be an ongoing desire to determine the health care system policies and programs that underlie the preferable preterm birth rates of some nations, such assessments may be flawed and highly speculative if a careful review of potential reporting variations is first performed and then the influences of variations in population and environmental characteristics are taken into account. Often, the confounding effects of these many factors cannot be accurately established to sufficiently assess the contribution of any particular intervention. Currently, the twofold and greater differences in very preterm birth rates among U.S. states are largely unexplained. Establishing which factors underlie similar or greater international variations poses an even more daunting task. The difficulty in making relatively unbiased comparisons in preterm birth rates among countries may underscore the paucity of published international reports (23). International comparisons of low birth weight rates have been made available (67). Nevertheless, such reports emphasize that interpreting international comparisons and trends must be made cautiously and typically tend to shy away from speculating on the range of determinants that may underlie the observed differences in rates. Recognizing the limitations of the available data, recent reports indicate that the U.S. low birth weight percentage is above the average for more developed countries (8 versus 7 percent) (67). However, many low birth weight infants are SGA and not preterm, and the proportion of term low birth weight infants could vary markedly by country. As such, the U.S. standing for low birth weight may not provide an unbiased estimate of its preterm birth rate ranking. Nevertheless, given nutritional levels in the United States, it is unlikely that the United States would fare better in a valid ranking of preterm rates. With a current preterm birth rate of approximately 12 percent, a level notably above the preterm birth rates (≤7 percent) reported for several European countries some years ago, it is a reasonable assumption that preterm birth is a serious problem in the United States that has persisted for some time (23). Understanding the variation in preterm birth rates among states within the United States may be a logical first step that should be taken before an attempt is made to make more global contrasts. For both national and international comparisons, an assessment of the definitions of birth and fetal death and procedures for the reporting of births and fetal deaths are clear starting points. Although some discrepancies in definitions can be taken into account analytically, variations in laws that affect the reporting of preterm births and fetal deaths still remain a challenge. As such work progresses, several documented interventions that have been implemented

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Preterm Birth: Causes, Consequences, and Prevention by other developed countries may well be worth considering simply on the basis of their humane approach to providing services to women and children (68). These include universal health care coverage for women and children and maternal work and parental leave policies. Racial Disparities The factors that underlie the growing racial disparities in infant mortality remain open to speculation (50). Clearly, there have been improvements in survival for both the white and the African American populations in the United States over the last few decades (69). The improvement in preterm infant survival probably reflects technological and practice developments in high-risk obstetric, perinatal, and neonatal care (70–76). In the obstetric area, antenatal corticosteroids and intrapartum antibiotics have been linked to reductions in neonatal morbidity and mortality. Advances in neonatal care include high-frequency ventilation, surfactant, and postnatal steroids. Regionalization of high-risk perinatal services facilitates appropriate access to these obstetric and neonatal intensive care services. Nevertheless, whites have experienced greater improvements in survival for both preterm and term infants, thereby closing the racial disparity found for preterm infants (in which African American infants have long had a survival advantage) and widening the disparity for more mature and postmature births (6). It has been postulated that the development and impact of several therapies, e.g., surfactant and steroids, may have differentially benefited preterm white infants, who may be relatively more immature and who are known to be at greater risk of mortality (7, 8, 72, 77). State variations in the risk of mortality for preterm infants were observed in these data and are largely unexplained. Further investigation is needed to explore how the racial compositions of state populations may partly underlie these variations. With a decreasing racial disparity in the rates of survival of infants born preterm, racial variations in access to tertiary perinatal hospital care may be involved in these observed geographic patterns (78). Although limitations to health care access are typically a concern for more impoverished populations, in some parts of the country, African American women may be more likely than white women to deliver their infants in a tertiary-care center (79). Further investigation will be needed to establish the extent to which racial variations in access to high-risk obstetric and neonatal care exists, has changed over time, and may differ among the states. Although early access to prenatal care does not necessarily have a direct impact on preterm birth rates, early access may facilitate delivery in a risk-appropriate hospital. However, recent investigations of prenatal care use by race groups in the United States have revealed that racial disparities

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Preterm Birth: Causes, Consequences, and Prevention in early, adequate, and intensive use of prenatal care were reduced during the 1990s (80, 81). SUMMARY The current levels of preterm delivery rates in the United States represent a significant health care concern. Preterm birth rates continue to rise, and best estimates suggest that they are elevated in relation to those in other industrialized nations (23). Major geographic and racial disparities in preterm birth rates continue to exist, and these variations offer potential opportunities to better understand the population-based risk factors for preterm birth and the impacts of preterm birth prevention programs and policies. Although progress in the delineation of the risk factors and etiologic pathways for preterm birth has been made, much still needs to be done before cost-effective and efficacious prevention strategies can be implemented at the population level. The general ineffectiveness of current interventions for the prevention of preterm delivery has changed little in the last decade. On the plus side, however, the chances for survival of infants born preterm continue to increase. So long as the medical and support services needed are available to assist these infants and their families, this represents a noteworthy achievement. However, concerns have been voiced that our willingness to support accessibility to these services and the availability of these services for these infants may lag behind our drive to improve survival (82). REFERENCES 1. Centers for Disease Control and Prevention. Infant mortality and low birth weight among black and white infants—United States, 1980–2000. Morb Mortal Wkly Rep 2002; 51:589–592. 2. Carmichael SL, Iyasu S. Changes in the black-white infant mortality gap from 1983 to 1991 in the United States. Am J Prev Med 1998; 15(3):220–227. 3. Demissie K, Rhoads GG, Ananth CV, Alexander GR, Kramer MS, Kogan MD, Joseph KS. Trends in preterm birth and neonatal mortality among blacks and whites in the United States from 1989 to 1997. Am J Epidemiol 2001; 154:307–315. 4. Lee KS, Paneth N, Gartner LM, et al. Neonatal mortality: an analysis of the recent improvement in the United States. Am J Public Health 1980; 70(1):15–21. 5. Philip, AGS. Neonatal mortality rate: is further improvement possible? J Pediatr 1995; 126(3):427–432. 6. Alexander GR, Slay M, Bader D, Kogan M. The increasing racial disparity in infant mortality rates: composition and contributors to recent U.S. trends. In press. 7. Alexander GR, Tompkins ME, Allen MC, et al. Trends and racial differences in birth weight and related survival. Maternal Child Health J 1999; 3(1):71–79. 8. Allen MC, Alexander GR, Tompkins ME, et al. Racial differences in temporal changes in newborn viability and survival by gestational age. Paediatr Perinat Epidemiol 2000; 14:152–158.

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