Underlying and Multiple Causes of Death in Preterm Infants

A limited number of studies have utilized multiple causes of death to investigate infant mortality patterns. The purpose of the present study was to examine the risk distribution of underlying and multiple causes of infant death for congenital anomalies, short gestation/low birth weight (LBW), respiratory conditions, infections, sudden infant death syndrome and external causes across four gestational age groups, namely ≤ 23, 24 − 30, 31 − 36,≥ 37, and determine the extent to which mortality from each condition is underestimated when only the underlying cause of death is used. The data were obtained from the North Carolina linked birth/infant death files (1999 to 2003) and included 4908 death records. The findings of this study indicate that infants born less than 30 weeks old are more likely (odds ratio ranging from 1.99 to 6.03) to have multiple causes recorded when the underlying cause is congenital anomalies, respiratory conditions and infections in comparison to infants whose gestational age is at least 37 weeks. The underlying cause of death underestimated mortality for a number of causespecific deaths including short gestation/LBW, respiratory conditions, infections and external causes. This was particularly evident among infants born preterm. Based on these findings, it is recommended that multiple causes, whenever available, should be studied in conjunction with the underlying cause of death data.


Introduction
Infant mortality data have been used to assess disease patterns and long-term trends, develop policies and design public health prevention and intervention programs.In most studies, mortality data analysis is conducted using the underlying cause of death which is defined as "the disease or injury that initiated the train of events leading directly to death, or the circumstances of the accident or violence, which produced the fatal injury" (National Center for Health Statistics, 2003) 1 .Many concerns, however, have been raised over the years about the use of underlying cause of death as means of investigating and evaluating infant mortality.The use of the underlying-cause-of-death model ignores the role of other conditions and their contribution to death, and its reliability may be adversely affected as disease evaluation and coding tend to vary among physicians and other health providers (Nam et al., 1989;Carver et al., 1993).For instance, research has emphasized that the coding of disease classification (International Classification of Diseases, Ninth Revision, 1980) does not adequately measure the impact of short gestation on infant mortality (Carver et al., 1993;Sowards, 1999), while others have suggested that the overall disease burden may have been underestimated due to the exclusive application of the underlying-cause-of-death model (Wall et al., 2005;Redelings et al., 2006).Consequently, researchers have addressed the potential use of multiple causes of death (Wall et al., 2005;Redelings et al., 2006) and recommended that more attention should be given to the mode of identifying cause of death in studies and especially of those of infant mortality (Nam et al., 1989).
Overall, in infant mortality studies, the extent to which the distribution of underlying and multiple causes of death differ across various gestational age groups has not been fully addressed.Given that infants born between 32-36 weeks are at higher risk for death during infancy (Krameret al., 2000) and their higher frequency of occurrence compared to those born at less than 32 gestational weeks (Gould et al., 2000), it would be of interest to examine the frequency distribution and risk for one (underlying cause of death) versus multiple causes of infant death recordings associated with these gestational age groups and determine how they compare to infants born very preterm (≤ 30 weeks ) and full term (≥ 37 weeks).Examining such differences may shed some light on the frequency and under-representation of specific causes of death by gestational age when only the underlying cause of death is utilized, and provide important information on the likelihood of multiple cause recordings for certain preterm infants.
The purpose of this exploratory study is (1) to examine the distribution of underlying and multiple causes of infant death for congenital anomalies, short gestation/low birth weight (LBW), respiratory conditions, infections, sudden infant death syndrome (SIDS) and external causes across four gestational age groups, namely ≤ 23, 24-30, 31-36, ≥ 37, and (2) identify those preterm infants that are at an elevated risk of having multiple cause recordings for a specific underlying cause of death using linked birth/infant death files from 1999 to 2003.Furthermore, to show the extent to which mortality from each condition is underestimated by using the underlying cause of death, frequencies for each of the four causes reported as mentions on the death certificate are compared with listings of these conditions when recorded as the underlying cause only.

Methods
The data were obtained from the North Carolina linked birth/infant death files from 1999 to 2003.This data set was made available by the North Carolina State Center for Health Statistics.The State Center provides a central collection site for birth records and infant mortality statistics.There were 4908 linked birth/infant death records.Infant deaths (defined as death between 0 and 364 days) were classified into six major categories, including congenital anomalies, short gestation/LBW, respiratory conditions, infections, SIDS and external causes (i.e., homicide, injuries, unknown causes, conditions originated in the perinatal period).They were classified according to the International Classification of Diseases, tenth revision (ICD-10) (National Center for Health Statistics, 2002).These causes of death were elected since they constitute some of the leading causes of infant mortality and they are frequently used in mortality data analyses.Gestational age classifications were as follows: ≤ 23, 24-30, 31-36 and ≥ 37 weeks.Classification of gestational age was based on findings and recommendations of previous studies that have examined the high risk of mortality and morbidity among premature infants (Kramer et al., 2000).
Infant deaths were classified into two categories as having multiple causes of death (at least one non-underlying cause or mentions) and only one cause (underlying cause).Furthermore, in order to determine whether a specific condition has been underestimated when the underlying cause of death is used, each mention of the cause was compared to the listing of the condition as the underlying cause only.
Mortality frequencies and proportions were computed across the six causes and classifications of gestational age to compare cases with one underlying cause versus those with multiple causes, and determine the extent to which a specific cause is being underestimated by the use of underlying cause.Binary logistic regression was used and 95% confidence intervals are reported to examine the risk distribution for each gestational age group of having multiple causes versus one underlying cause.The analyses were performed using SPSS 13.0.

Results
Overall, 52.8% of the 4908 infant who died had multiple causes reported in addition to the underlying cause.The average number of causes per individual was 3.52 (lower quartile = 2.00, median = 4, upper quartile = 5).Table 1, which provides information on the frequency distribution and likelihood of cases with one versus multiple causes of death by gestational age, indicates that overall infants born between 24 to 30 weeks were approximately 3 times more likely to die of multiple causes in comparison to full term infants, and they had the highest  2) revealed that infants born at 23 weeks or less were more likely (OR ranging from 2.61 to 4.98) to have multiple causes recorded when the underlying cause was congenital anomalies, respiratory conditions and infections in comparison to infants whose gestational age was at least 37 weeks.Similarly, infants with a gestational age of 24-30 weeks were far more likely (OR ranging from 1.99 to 6.03) to have multiple causes recorded compared to those born term for congenital The underlying-cause-of-death data captured only 8.7% of short gestation/LBW related deaths identified by multiple-cause records (mentions) for those born between 31-36 weeks, and 54.4% for infants with a gestational age of 24-30 weeks (Table 3).Respiratory related deaths were mostly underestimated by the use of the underlying cause which captured only 29.4% of cases reported in multiplecause data for infants born between 31-36 weeks, and 26.0% for term infants.Furthermore, the percentage of deaths due to external causes relative to mentions was found to be moderate for 24-30 weeks (66.5%) and 31-36 weeks (63.4%).Deaths due to SIDS were not recorded as mentions for any of the other conditions or diseases.Congenital anomalies were declared as underlying causes more frequently on these death certificates than mentions.Overall, the underlying cause of death as a percentage of mentions was the highest for term infants compared to preterm across most of these major causes of infant mortality.

Discussion
Underlying and multiple cause data have been mainly employed to investigate various causes of death recorded on death certificates (Wall et al., 2005;Redelings et al., 2006) such as cancer (Richardson, 2006) and tuberculosis (Santo et al., 2003).These applications clearly indicate that the multiple-cause-of-death model is superior to just using the underlying-cause-of-death data.Only a handful number of studies (Nam et al., 1989), however, have examined multiple cause frameworks of infant deaths.It is essential to indicate empirically any analytical benefits of using multiple causes of death (Nam at al., 1989), and the extent to which the underlying cause-of-death data underestimate mortality from specific diseases or conditions.Furthermore, the assessment of multiple and underlying causes of death in infants has become even more crucial as concerns have been raised over the contribution of preterm birth to infant mortality (Kramer et al., 2000), and the impact of classification systems on the process of finalizing the underlying cause of death.
In this study, the underlying cause of death underestimated mortality for a number of cause-specific deaths including short gestation/LBW, respiratory conditions, infections and external causes.This was particularly evident among infants born preterm.An under-representation of these causes due to the use of underlying cause of death may be problematic in the assessment of infant mortality or applications that utilize infant mortality data to study premature births and LBW (especially for those born between 24-30 weeks) and respiratory related problems.It also can affect prevention programs designed to prevent deaths associated with such causes in premature infants.Furthermore, whenever a respiratory condition was the underlying cause of death, the odds of frequent recording of multiple causes increased with gestational age.It is known that infants born at lower gestational ages have an increased frequency and severity of respiratory illness (Weisman, 2003).However, little is known about the contribution of respiratory illnesses associated with other conditions to mortality for specific gestational age groups such as those born at 31 weeks and above.Further research using multiple causes of death may warrant the relationship between gestational age and respiratory related deaths.
Overall, regardless of the specific cause of death, infants born at or less than 23 weeks of gestation were less likely to have multiple causes reported on their death certificates in comparison to full term infants.Further stratification by specific cause of death, however, revealed that they were more likely to experience multiple conditions compared to their term counterparts.This difference between the cumulative underlying-cause-of-death model (all causes of death) and the stratified one may be explained by the large number of recorded deaths due to external and short gestation/LBW related causes which masked the likelihood of recorded multiple conditions for this specific gestational age group.This indicates that researchers should explicitly select cause-specific-of-death models when investigating infant mortality since the recordings of other contributing causes to death may vary by the underlying cause of death.
Previous research has shown that the vast majority of deaths are attributable to complications of short gestation developed during the neonatal period (Swarz, 1990;Kliegman et al., 1990).This may explain the large number of multiple causes recorded for preterm infants as they are more prone to develop other conditions and diseases which are likely to lead to death compared to term infants.This in turn complicates the analyses of causes of death for premature infants as the underlying cause of death may oversimplify the biological mechanisms of death for these infants.Consequently, researchers should carefully contemplate the analysis of multiple causes for premature infants since the underlying cause of death alone may not adequately reflect the contribution of other important conditions to mortality and morbidity.
There are some limitations, however, in using death certificate data.Death certificates are often imprecise and data are not rigorously evaluated (Nielsen et al., 1991).Variation also exists in opinions among individuals who are responsible for "coding" a condition or a disease and that can impact the accuracy of the classification system (Nam et al., 1989;Carver et al., 1993).Nonetheless, death certificate data are important in studying disease trends and patterns and can be used to prevent death.The few research studies that have been conducted on multiple and underlying causes of death suggest that multiple-causes-of-death analyses can enrich and help define the mode of death more explicitly than the underlying-cause-of-death model.As Nam et al. (1989) indicate it is important for epidemiologists and public health officials to recognize and take into consideration that infant death can be the result of a number of causes rather than one cause.Based on the findings of this study, it is recommended that multiple causes are studied in conjunction with the underlying cause among premature infants and especially for those born between 32 and 36 weeks of gestational age.This can lead to better understanding of morbidity and mortality in infants and can assist in the development of more effective prevention and intervention programs targeting infant mortality.

Table 1 :
Distribution of cases with only one cause (underlying cause) and multiple causes of death by gestational age.

Table 2 :
Underlying and multiple causes of death by gestational age ) and multiple causes of death by gestational age.

Table 2 (
continued): Underlying and multiple causes of death by gestational age ) and multiple causes of death by gestational age.
A further stratification by specific cause of death and gestational age (Table

Table 3 :
Underlying cause of death as a percentage of mentions (multiple causes) by gestational age.