1 Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
2 Infant and Child Health Studies Branch, National Center for Health Statistics, Centers for Disease Control and Prevention, Department of Health and Human Services, Hyattsville, MD.
Received for publication November 18, 2003; accepted for publication December 15, 2003.
The purpose of science is not to analyse or describe but to make useful models of the world. A model is useful if it allows us to get use out of it.Edward De Bono
When we trained in pediatrics during the era before synthetic surfactant, there was an old saw among neonatologists that African-American infants, when born remote from term, were more likely to survive than White infants born after pregnancies of comparable duration. It was said that African-American infants seemed less likely to develop neonatal respiratory distress syndrome, and, when they did, it was less severe. Old clinical saws are often wrong, but when the Centers for Disease Control linked the birth and infant death certificates for the 1980 birth cohort, the clinical impression of the neonatologists proved correct. Whether maturity was measured by birth weight or by duration of gestation, small or preterm African-American infants were in fact less likely to die than comparable White infants (1). However, within the "normal range" (2,5003,000 g or
37 weeks gestation), African-American infants were substantially more likely to die than their White counterparts (1). The survival advantage of preterm African-American infants has diminished, but is still present, in the era of synthetic surfactant (2).
The "crossing curves" of infant mortality have now been well documented and are generally considered a paradox, a statistical artifact "lacking biological plausibility" (3) to be understood only to the extent that they can be explained away. On these lines, Wilcox and Russell (4, 5) in the 1980s demonstrated that when birth-weight-specific mortality curves for African-American and White infants cross, simple standardization can produce biased results; however, when the birth-weight-specific mortality curves are each standardized to their own internal distribution, the curves become parallel and African-American infants experience higher mortality at each point of relative birth weight. The results were extended to relative gestational age by Hertz-Picciotto and Din-Dzietham (6) in 1998.
In this issue of the Journal, Platt et al. (3), in an extension of previous work by Joseph et al. (7), take a different tack to uncross the curves. They report that a simple change of the denominator from all livebirths at a given gestational age to all fetuses and infants alive at the beginning of that gestational week can eliminate the crossover of gestational-age-specific mortality curves. Their method is also applied to birth-weight-specific mortality, with similar results.
The Wilcox-Russell and the Joseph-Platt et al. approaches both assume that the crossover is not merely a simple artifact of differential errors in reporting or measurement of birth weight or gestational age. More importantly, although totally different, both approaches explicitly assume that uncrossing the curves is important. When that assumption is made, the appropriateness of the underpinnings of each corrective approach is left unquestioned.
The Wilcox-Russell approach assumes that the observed birth weight or gestational age distribution (or at least the "predominant" distributionthe underlying Gaussian distribution that comprises the vast majority of births (4)) is biologically "normal" for that population. That assumption raises several questions. Should different populations have different gestational age or birth weight distributions? What defines a "population"? The answers to those questions are fundamental to determining the appropriateness of the Wilcox-Russell approach. The original Joseph-Platt et al. approach assumes that, contrary to common practice, the population "at risk" for fetal and particularly neonatal death is not just liveborn infants but rather all fetuses and infants alive at the beginning of that gestational week; that approach seemingly ignored the concept and process of birth. Thus, for example, it equates an infant born at 28 weeks gestation who subsequently died at 4 weeks of age with a 32-week stillbirth (7). The model presented by Platt et al. (3) goes a step further in that birth is represented as a time-dependent indicator variable. However, the foundation of their argument continues to rely on consideration of fetuses and infants of similar postconception age as equivalent, regardless of whether they are in utero or ex-utero. The purpose of this commentary is not to provide answers to these essentially philosophical questions but to reopen them for debate.
Perhaps we should not be so quick to model away the crossing curves. In the rush to define the crossing curves as paradoxical, we miss the opportunity to gain information housed in those crossing lines. The causes of preterm birth are by and large unknown. Although current thinking tends to group the proximate cause of preterm birth in singletons into the broad categories of chorioamniotic inflammation/infection and abnormal placental vasculature (8), other schemes have found as many as eight different groups of causes for preterm labor alone (9). This lack of understanding precludes investigation of 1) whether the relative distribution and/or absolute prevalence of various causes of preterm birth differs between African-American and White pregnant women and 2) whether the underlying cause of the preterm birth influences the preterm neonates chances of survival at a given gestational agealthough the latter possibility seems plausible.
Given our ignorance of the causes of early birth and of whether the underlying cause influences survival, it might not be implausible to expect that African-American preterm infants have a better chance of survival than White preterm infants while simultaneously having a worse chance of survival when born at term. The differences at term might reflect differences in access to obstetric care, or in general maternal health status, as a result of poverty and social inequality. The reasons for the survival difference at early gestational ages or smaller sizes are less obvious, but several speculations come to mind. Perhaps African-American fetuses do in fact mature more quickly in utero, possibly as a response to environmentally induced in utero stress, which can down-regulate expression of placental 11 ß-hydroxysteroid dehydrogenase-2 (10). This enzyme inactivates cortisol, the hormone primarily responsible for fetal lung maturation. Differential changes in gestational-age-specific mortality between African-American and White infants since the introduction of surfactant (2) might support this hypothesis, or perhaps the threshold to trigger the parturition process might be lower in certain groups of women. For example, a tumor necrosis factor- promoter polymorphism reduces the threshold for spontaneous preterm birth in the presence of bacterial vaginosis (11). If the cause of the preterm birth influenced the prognosis of the infant, then a lower threshold for triggering preterm parturition might result in a higher overall occurrence of preterm birth in conjunction with preterm infants who were less ill and more likely to survive.
It seems to us that the Wilcox-Russell approach appears to accommodate more readily the neonatologists clear observation that African-American preterm infants are either "more mature" or "less ill" than White preterm infants. As pediatricians, we are bothered by the ease with which the Joseph-Platt et al. approach dismisses this observation and replaces it with the more speculative concept that African-American fetuses are "less healthy" than White fetuses. The Joseph-Platt et al. approach needs to explain, with a biologically supporting rationale, how a presumably "less healthy" African-American preterm fetus can become a "less ill" preterm neonate once born.
We must not lose sight of the fact that our task as epidemiologists is to try to understand the underlying biology of early delivery, with the goal of developing preventive interventions. We believe it would be wrong to judge the means by the end. The true value of these approaches is not whether they can "explain away" the crossing of the curves. We should not focus too much on whether we can uncross the curves but rather on what the crossing curves might teach us about genetic and environmental influences on the rate of maturation in utero, and on what they might teach us about triggers for preterm birth and factors that might influence the sensitivity of those triggers.
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