PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1566-1573 (doi:10.1542/10.1542/peds.2006-0860)
ARTICLE |
The Contribution of Preterm Birth to Infant Mortality Rates in the United States
a Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia
b Division of Vital Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland
c Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. Although two thirds of infant deaths in the United States occur among infants born preterm (<37 weeks of gestation), only 17% of infant deaths are classified as being attributable to preterm birth with the standard classification of leading causes of death. To address this apparent discrepancy, we sought to estimate more accurately the contribution of preterm birth to infant mortality rates in the United States.
METHODS. We identified the top 20 leading causes of infant death in 2002 in the US linked birth/infant death file. The role of preterm birth for each cause was assessed by determining the proportion of infants who were born preterm for each cause of death and by considering the biological connection between preterm birth and the specific cause of death.
RESULTS. Of 27970 records in the linked birth/infant death file for 2002, the 20 leading causes accounted for 22273 deaths (80% of all infant deaths). Among infant deaths attributable to the 20 leading causes, we classified 9596 infant deaths (34.3% of all infant deaths) as attributable to preterm birth. Ninety-five percent of those deaths occurred among infants who were born at <32 weeks of gestation and weighed <1500 g, and two thirds of those deaths occurred during the first 24 hours of life.
CONCLUSIONS. On the basis of this evaluation, preterm birth is the most frequent cause of infant death in the United States, accounting for at least one third of infant deaths in 2002. The extreme prematurity of most of the infants and their short survival indicate that reducing infant mortality rates requires a comprehensive agenda to identify, to test, and to implement effective strategies for the prevention of preterm birth.
Key Words: premature birth • infant mortality
Abbreviations: NCHS—National Center for Health Statistics • ICD-10—International Classification of Diseases, 10th Revision
The Healthy People 2010 objectives have identified reduction of the US infant mortality rate as a national priority.1 After years of significant decline, however, there has been minimal progress in recent years; in 2002, national statistics demonstrated the first increase in the infant mortality rate since 1958.2,3 Public health policies aimed at improving infant survival rates must be informed by a thorough understanding of the factors contributing to infant mortality rates. Prematurity is a major cause of infant death, but standard ways of categorizing the underlying cause of death do not fully summarize this relationship.
The National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention uses standard conventions for categorizing and ranking the leading causes of death by using International Classification of Diseases, 10th Revision (ICD-10), codes. The ICD-10 is an international system for classifying disease entities and causes of death that tends to emphasize body system or pathophysiologic criteria. This standardized method allows consistent accurate monitoring of trends over time.4 However, this classification system does not capture adequately the overall contribution of preterm birth (<37 weeks of gestation) to the national infant mortality rate, because the relationship between preterm birth and death during the first 1 year of life is not distinctly identifiable by using available cause-of-death titles. Of the rankable causes, only deaths resulting from "disorders related to short gestation and low birth weight not elsewhere classified" (short gestation/low birth weight, ICD-10 codes P07.0–P07.3) seem to be explicitly attributable to preterm birth. However, if short gestation/low birth weight is listed in conjunction with a more-specific cause of death or an antecedent condition, then typically the other cause is selected as the underlying cause of death. Therefore, many deaths involving preterm births are classified elsewhere, in separate categories. For example, infant deaths attributable to respiratory distress syndrome, which almost always result from incomplete lung maturation in preterm infants, are counted in the category of respiratory distress of the newborn (ICD-10 code P22) instead of the category of disorders related to short gestation and low birth weight not elsewhere classified. Despite the fact that 65% of infants who died in 2002 were born preterm,3 only 17% of infant deaths were reported as being attributable to short gestation/low birth weight. Therefore, preterm birth was ranked as the second leading cause of infant death, following congenital malformations, which accounted for 20% of infant deaths.
Other methods for classifying major causes of infant death in the United States and abroad found that prematurity and related conditions accounted for a substantially greater proportion of infant deaths than conventional leading-cause analyses indicated.5–9 However, those analyses were performed when infant mortality rates were decreasing in the United States and before the use of ICD-10 to code deaths. Moreover, with the exception of the study by Cole et al,7 the analyses preserved certain obstetric conditions that might have led to preterm birth as distinct causes of death.
In light of the strong connection between preterm birth and infant deaths and the relatively small proportion of infant deaths attributed to preterm birth with standard methods, a new approach that assesses more accurately how preterm birth contributes to infant mortality rates is needed. We report such an approach, taking into account the fact that deaths can be ascribed to conditions that cause preterm birth or to conditions that result from preterm birth, in an effort to assess more accurately the contribution of preterm birth to infant mortality rates in the United States.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The linked birth/infant death data set (linked file) contains information from birth and death certificates for infants born in the United States who died during their first year of life. The data used in our analysis were taken from the death certificates of all infants (<365 days of age) who died during 2002 and from the birth certificates of those infants regardless of whether they were born in 2001 or 2002. This data set on infant deaths therefore had a richer array of variables, including maternal characteristics, estimates of gestational age, and birth weight, than those available from death certificates alone. For the 2002 linked file, 99% of infant death records were linked to the corresponding birth certificates. The linked file was weighted with respect to the sum of linked plus unlinked records with a weighting protocol designed to correct for possible bias attributable to minor variations in match rates according to characteristics. Therefore, all analyses were weighted to account for the small fraction of unlinked records.
Gestational age in the linked file was assigned by using the standard NCHS gestational age algorithm. For most infants, gestational age for the linked file was computed as the interval between the infant's date of birth and the first day of the mother's last menstrual period, as reported on the birth certificate. If the last menstrual period-based gestational age was inconsistent with the birth weight or was not stated, then the clinical estimate of gestational age, as reported on the birth certificate, was substituted when it was consistent with the birth weight.10 If neither the last menstrual period-based age nor the clinical estimate had a value consistent with the birth weight, then gestational age was assigned as not stated.
To understand the relationship between preterm birth and infant death, we used information in the linked file to demonstrate that a cause of death was truly associated with preterm birth, as well as clinical information on specific diseases and conditions that lead to infant death. We focused on the top 20 leading causes of infant death in the linked file, using the conventions outlined for cause-of-death rankings by NCHS in collaboration with other agencies.11 This strategy provided a manageable number of individual ICD-10 codes, provided sufficient numbers of deaths within each category for meaningful analysis, and accounted for 
80% of infant deaths each year. The list of 130 selected causes of infant death was used to derive the 71 rankable causes. The rankable causes were defined by single ICD-10 codes or groups of ICD-10 codes. More information regarding the selection of rankable causes was published elsewhere.4
To decide whether a death was associated with preterm birth in these data, we first looked at the proportion of deaths for each of the individual ICD-10 codes for the underlying cause of death for the 20 leading-cause categories. For an underlying cause of death to be considered attributable to preterm birth, we required initially that 
75% of infants whose deaths were attributed to that cause had been born at <37 weeks of gestation. For ICD-10 codes that met this criterion, we used available literature findings and clinical expertise to designate which causes of death under consideration were direct consequences of preterm birth (or for which prematurity was a major contributor). In some cases, this determination could not be made because the ICD-10 code did not contain sufficient descriptive information. For example, deaths attributable to intrauterine hypoxia and birth asphyxia were difficult to understand in terms of cause, especially when few clinical data were available. As with most infant deaths, the association with prematurity was present, but it was not always clear how hypoxia/asphyxia, prematurity, and death were related to one another. Therefore, we did not consider those deaths to be attributable to preterm birth.
With this approach, we excluded the following 9 NCHS leading causes of death from consideration as being attributable to preterm birth: congenital malformations, sudden infant death syndrome, accidents, diseases of the circulatory system, intrauterine hypoxia and birth asphyxia, septicemia, homicide, influenza and pneumonia, and hydrops fetalis. With the aforementioned criteria for considering a death attributable to preterm birth, 6 of the remaining 11 leading-cause categories were designated as being attributable to preterm birth in their entirety, namely, short gestation/low birth weight, respiratory distress of newborn, bacterial sepsis of newborn, atelectasis, chronic respiratory disease originating in the perinatal period, and necrotizing enterocolitis of newborn; the remaining 5 categories were as follows: newborn affected by maternal complications of pregnancy (maternal complications); newborn affected by complications of placenta, cord, and membranes (cord and placental complications); neonatal hemorrhage; birth trauma; and gastritis, duodenitis, and noninfective enteritis and colitis. These 5 categories include multiple ICD-10 codes, some of which do not comply with our "75% rule" or for which the relationships between the cause-of-death code, preterm birth, and death were unclear. Therefore, for these 5 leading-cause categories, we included only the specific ICD-10 codes for underlying causes that met all of our criteria. For example, the category gastritis, duodenitis, and noninfective enteritis and colitis encompasses 32 individual ICD-10 codes, but only that for acute vascular disorders of intestine was associated strongly with preterm birth and also had a plausible pathophysiologic connection to prematurity. A death was considered attributable to preterm birth if 1 of the eligible codes was used to describe the underlying cause of death on the death certificate and the infant was born at <37 weeks of gestation. If there was not sufficient information on the birth certificate to determine gestational age, then the death was classified as not attributable to preterm birth.
We calculated the proportion of infant deaths attributable to preterm birth for each cause of death according to 4 preterm categories, that is, <37 weeks, <37 weeks and birth weight of <2500 g, <32 weeks, and <32 weeks and birth weight of <1500 g. We also examined the distribution of infant deaths for each diagnostic category according to age at death. Finally, the gestational age distribution for deaths designated as attributable to preterm birth was compared with the distribution for deaths that were not attributable to preterm birth.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The top 20 leading causes of infant death in the linked file, with the use of standard NCHS ranking conventions, and the associated ICD-10 codes are displayed in Table 1. There were 27970 infant deaths in 2002 and the 20 leading causes of death accounted for 22273 of those deaths. According to traditional NCHS ranking rules, congenital malformations accounted for 5630 deaths (20% of all infant deaths); short gestation/low birth weight was the second leading cause of death, accounting for 4636 deaths (17% of all infant deaths).
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The 11 leading-cause categories we considered to be either partially or wholly attributable to preterm birth and the associated ICD-10 codes for the underlying cause of death are presented in Table 2. Overall, 93% of the 10372 infants with causes of death we considered to be attributable to preterm birth were born at <37 weeks of gestation; these 9596 infant deaths were designated as attributable to preterm birth (Table 3). The vast majority (95%) of these 9596 infants were born at <32 weeks of gestation and weighed <1500 g at birth.
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The distribution of deaths for infants with causes of death attributable to preterm birth was unimodal, with a peak at 22 to 23 weeks of gestation. In contrast, the distribution of deaths for infants with causes of death not attributable to preterm birth was bimodal, with a small peak at 24 weeks of gestation and a dominant peak at 38 to 40 weeks of gestation (Fig 1).
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Of the 776 infants (7%) who had cause-of-death diagnoses considered to be attributable to preterm birth but who did not meet the requirement of <37 weeks of gestation, as determined by the NCHS gestational age algorithm, 282 had a gestational age of
37 weeks and 494 (64%) had gestational age coded as not stated (Fig 1); 190 (38%) of those 494 infants had a clinical estimate of gestational age reported, but those estimates were not used in our analysis because they fell outside the NCHS gestational age algorithm. Two clinical estimates were 38 weeks, 188 were <32 weeks, and 186 were 
24 weeks. Among the remaining 304 infants who had neither gestational age nor clinical estimate reported, 208 had a birth weight of <2500 g and 205 had a birth weight of <1500 g. Therefore, despite the fact that we could not confirm that the infant was born preterm and we classified the death as not attributable to preterm birth, the majority of infants with missing gestational age data who died as a result of causes classified as attributable to preterm birth seemed to have been born preterm. The 9596 deaths classified as attributable to preterm birth represented 34% of all infant deaths and 43% of all deaths among the 20 leading causes. With the strictest requirements for gestational age at birth (<32 weeks) and birth weight (<1500 g), deaths classified as attributable to preterm birth represented 33% of all infant deaths and 41% of all deaths among the 20 leading causes of death. More than two thirds of deaths attributable to preterm birth occurred during the first 1 day of life, and only 7% of deaths attributable to preterm birth were postneonatal (>28 days) (Table 4). Deaths attributable to short gestation/low birth weight, atelectasis, maternal complications, and cord and placental complications were the most likely to occur within 24 hours after birth.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The purpose of this analysis was to describe the contribution of preterm birth to infant mortality rates. We found that more infants died because they were born preterm than as a result of any other cause of death. Although they are useful for describing trends, standard procedures for summarizing causes of death that use ICD-10 code-based body system or pathophysiologic criteria are not designed to address this issue. By using the more-inclusive analytic approach outlined here, we found that preterm birth accounted for
34% of all infant deaths, twice the 17% value for cases with the ICD-10 category of disorders related to short gestation and low birth weight not elsewhere classified listed as the underlying cause of death. The alternative analytic approach reported in this article is a valuable complement to the traditional ICD-10 classification scheme, especially as we try to understand more completely the factors that are implicated in the increasing preterm birth rates and stagnant infant mortality rates. Our finding that preterm birth accounted for a greater proportion of infant deaths than indicated with standard methods is similar to the findings of previous analyses. The classification reported by Dollfus et al5 attributed 37% of infant deaths in North Carolina in 1980 to 1984 to prematurity and related conditions; a modification of this classification by Sowards6 resulted in similar estimates for prematurity and related deaths in the United States between 1985 and 1996. Our study was not a direct attempt to replicate these analyses. First, we restricted our analysis to the 20 leading causes among the list of rankable leading causes. Second, we demanded a strong association in these data between preterm birth and death for any single category or diagnosis (our 75% rule). Third, we required that there must be a good biomedical reason to suspect that the reported cause of death was a direct consequence of preterm birth and one rarely seen at term or that the cause of death resulted in preterm birth. Lastly, we insisted that the infant actually be born preterm, according to the gestational age on the birth certificate. The net result of the analysis scheme was that we excluded some causes that were included by Dollfus et al5 and by Sowards,6 because the causes were not among the top 20 leading causes of death. However, similar to the International Collaborative Effort on Perinatal and Infant Mortality grouping,7 we included some causes, such as certain obstetric conditions, because there was little reason to think that the obstetric condition (for example, placenta previa) in and of itself was the primary explanation for the death but the obstetric condition was the reason for the preterm birth. Although other classifications make distinctions on the basis of preventability of causes of death, the poorly understood and potentially overlapping disorders leading to preterm birth are likely not completely reflected in the information available on vital records. However, the consistency of the findings from a variety of attempts to reclassify causes of infant death strengthens the conclusion that preterm birth makes the greatest contribution to infant mortality rates.5–9
Overwhelmingly, infants whose underlying cause of death was ascribed to maternal complications or cord and placental complications died within the first 24 hours of life. Because there was little time for these infants to develop more-specific pathologic conditions, it seems that the underlying cause of death was ascribed to conditions related to the pregnancy, rather than the prematurity of the infant. In addition, health care providers likely varied in how they ascribed causes of death for these infants. Therefore, making distinctions between maternal and infant causes is likely to conceal the true influence of preterm birth on infant mortality rates.
A strength of the linked file for this analysis was that it allowed for the inclusion of information not available on the death certificate (eg, gestational age at birth and birth weight). This data set provided the opportunity to assess the association between a cause of death and preterm birth and provided the information necessary to impose gestational age and birth weight criteria as requirements for designating a death as attributable to preterm birth.
We confined our analysis to the top 20 leading causes of infant death, but additional causes were likely attributable to preterm birth. Exclusion of the causes ranked below 20 resulted in an underestimation of the numbers of deaths attributable to preterm birth. Moreover, by using the leading-cause framework as our starting point, we excluded causes that were not among the causes that were eligible to be ranked according to standard conventions. For example, other perinatal conditions, a category that is not eligible to be ranked for determination of leading causes of death, includes 34 ICD-10 diagnoses and accounted for 1203 deaths in 2002; 85% of those deaths involved infants born at <37 weeks of gestation. Although many of the specific causes in the category of other perinatal conditions contributed minimally to the overall number of infant deaths, neonatal cardiac failure and neonatal cardiac dysrhythmia accounted for 75% of the 1203 deaths, and 88% of infants who died as a result of these 2 underlying causes were born preterm. In addition, the risk for preterm birth is increased for some leading-cause categories in the top 20, such as congenital anomalies,12 and previous studies showed that mortality rates associated with certain defects were higher among preterm infants than among those born at term.13,14 Similar mortality risks among preterm infants were demonstrated for asphyxia-related conditions and sudden infant death syndrome.15 We confined our analysis to the top 20 causes, rankable causes, and causes that met the 75% rule, which resulted in a conservative estimate of the contribution of preterm birth to infant mortality rates.
Missing and misclassified data are limitations for vital records-based studies. Among records with missing gestational age, the recorded birth weights or clinical estimates of gestational age suggested that the majority of the infants were born preterm. However, we decided a priori to adhere to the NCHS algorithm for assigning gestational age and therefore did not consider deaths of infants with missing gestational age data as being related to preterm birth. In addition, there were a small number of diagnoses attributable to preterm birth for which gestational age was reported to be 37 weeks (282 of 10372 diagnoses; 3%). Because some of these diagnoses could be the underlying cause of death for term infants and none of the diagnoses was specific for preterm infants, there were insufficient grounds for deciding which, if any, of these infants had misclassification of gestational age.
To understand infant mortality rates more fully, the complex relationships among stillbirth, preterm birth, and infant death need to be examined. Although the number of fetal deaths at 20 weeks of gestation reported in US vital statistics approximates the number of infant deaths,16 our knowledge about these events is limited by underreporting of fetal deaths and the quality of vital records on fetal deaths.17,18 Increases in medically indicated preterm births may be associated with decreases in stillbirth rates and perinatal mortality rates,19 whereas improved reporting of births at <500 g may contribute to increased infant mortality rates and decreased fetal and perinatal mortality rates.18 Determination of the net effects of the potential shifts from fetal death to birth and survival or infant death requires more-detailed information about fetal deaths, for an understanding of the entire picture of perinatal death.
Although the US infant mortality rate decreased dramatically during the 20th century, changes in recent years have been minimal. Coincident with the recent leveling of the infant mortality rate was a steady increase in the preterm birth rate. Moreover, an increase in the number of the earliest preterm births (infants with birth weights of <750 g and gestational age of <28 weeks) was implicated as the primary contributor to the increase in infant mortality rates observed for 2002. The 2001 to 2002 increase occurred mostly in the neonatal age group, and the deaths we identified as being attributable to preterm birth contributed nearly one half of all neonatal deaths in 2002.20 Considering this context, it becomes critical to understand more completely the role of preterm birth in infant and neonatal death, so that rational interventions for prevention can be developed and tested.
This study found that efforts to reduce infant mortality rates must focus on preterm birth. Infants who died as a result of causes classified as attributable to preterm birth were born overwhelmingly at previable and periviable gestational ages; access to and delivery of sophisticated medical treatments based on current medical technology would have little effect on the survival of these infants. Efforts to prevent infant deaths attributable to preterm birth require safely delaying birth until a later gestational age, when survival is more likely. Therefore, there is an urgent need for an expanded comprehensive agenda to understand the complex social and biological factors that determine susceptibility to preterm birth, to detect women at risk early in pregnancy, and to develop and to evaluate new methods for preventing this important cause of infant death.
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ACKNOWLEDGMENTS |
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We are grateful to Donna Hoyert, PhD (Mortality Statistics Branch, NCHS) for valuable comments on the manuscript.
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FOOTNOTES |
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Accepted May 25, 2006.
Address correspondence to William M. Callaghan, MD, MPH, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 4770 Buford Hwy, MS K-23, Atlanta, GA 30341. E-mail: wgc0{at}cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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