Letters to the Editor
767
RE: "VERY LOW BIRTH WEIGHT: A PROBLEMATIC COHORT FOR EPIDEMIOLOGIC STUDIES OF VERY SMALL OR IMMATURE NEONATES" Arnold and colleagues (1) make a persuasive case for organizing studies of small infants around their gestational age and not their birth weight. The problems they discuss derive from the fact that gestational age is causally antecedent to birth weight, and that birth weight is a hybrid variable, constituted by gestational age and rate of fetal growth. Analyses should thus contrast these two constituent variables of birth weight with each other, and not gestational age with birth weight, as is so commonly done. It is particularly important to emphasize, as Arnold et al. do, that extrapolation from samples truncated by birth weight is limited by the gestational ages represented within the sample, which are often incomplete. Gestational age now appears to be more accurately assessed than previously, via the use of ultrasonography during the first half of pregnancy, and it therefore makes sense to try to use gestational age whenever possible to define populations of premature babies. However, even if we accept ultrasonographic findings as the gold standard for the assessment of gestational age, circumstances will continue to occur in which such data are not available, e.g., when the cohort under study had not been assembled early in pregnancy. But is all lost in cohorts assembled by birth weight truncation? I think not. When an outcome such as cesarean section is associated both with fetal growth and with gestational age, both variables must be controlled for in the analysis. For the former variable, Arnold et al.'s recommendation to use the fetal growth ratio is excellent. Alternatively, and following Yerushalmy et al. (2), we have used a measure of gestational age for birth weight (3), which will accomplish the same objective. However, it is also critical to control for gestational age. Arnold et al. provide only one example in which they looked at the effect of growth retardation while controlling for gestational age, and in that example, the odds ratios (for mortality) that emerged from the two differently assembled cohorts were only mildly different (2.72 vs. 3.15). Arnold et al.'s recommendation for design is useful, but a sensible analysis can yield intelligible results, even with data truncated by birth weight. REFERENCES
1. Arnold CC, Kramer MS, Hobbs, CA et al. Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates. Am J Epidemiol 1991 ;134:604-13. 2. Yerushalmy J, Bierman JM, Kemp DH, et al. Longitudinal studies of pregnancy on the island of
Kauai, Territory of Hawaii. I. Analysis of previous reproductive history. Am J Obstet Gynecol 1956;71:80-96. 3. Paneth N, Wallenstein S, Kiely JL, et al. Social class indicators and mortality in low birth weight infants. Am J Epidemiol 1982;116:364-75.
Nigel Paneth College of Human Medicine Program in Epidemiology Michigan State University East Lansing, MI 488241316
THE FIRST AUTHOR REPLIES Dr. Paneth (1) raises two important issues: 1) how to account for fetal growth and 2) the practical importance of working with a cohort truncated by birth weight. We agree that the age-forsize paradigm he suggests as an alternative to the size-for-age paradigm for fetal growth will lead to the same statistical results. However, we feel that this perpetuates the confusion regarding the biological relation of the two variables: growth is size for age, not age for size. We chose mortality as the outcome to illustrate the problems of assessing the effects of growth retardation in cohorts truncated by birth weight because there has been confusion in the literature regarding the "protective" effect of growth retardation on neonatal mortality among very low birth weight infants. Outcomes that might be expected to be confounded in the same way but to a greater extent include intraventricular hemorrhage and bronchopulmonary dysplasia. Likewise, there are exposures that would be expected to be associated with growth status to a greater degree than our example, method of delivery. These include tocolytic therapy and maternal hypertension. That the adjusted odds ratio in the birth weight cohort underestimated the true effect of growth retardation on mortality by 14% is a manifestation of the problem encountered when adjusting for gestational age in cohorts defined by birth weight criteria. Whether the magnitude of this difference is "mildly different" or not is debatable. Because of the greater collinearity of gestational age and growth status in birth weight cohorts, adjusting for gestational age and growth status will always result in a less reliable estimate than would be the case using a gestational age cohort from the same population. The magnitude of the difference will depend on the amount of collinearity in the birth weight cohort, which will vary
767
RE: "VERY LOW BIRTH WEIGHT: A PROBLEMATIC COHORT FOR EPIDEMIOLOGIC STUDIES OF VERY SMALL OR IMMATURE NEONATES" Arnold and colleagues (1) make a persuasive case for organizing studies of small infants around their gestational age and not their birth weight. The problems they discuss derive from the fact that gestational age is causally antecedent to birth weight, and that birth weight is a hybrid variable, constituted by gestational age and rate of fetal growth. Analyses should thus contrast these two constituent variables of birth weight with each other, and not gestational age with birth weight, as is so commonly done. It is particularly important to emphasize, as Arnold et al. do, that extrapolation from samples truncated by birth weight is limited by the gestational ages represented within the sample, which are often incomplete. Gestational age now appears to be more accurately assessed than previously, via the use of ultrasonography during the first half of pregnancy, and it therefore makes sense to try to use gestational age whenever possible to define populations of premature babies. However, even if we accept ultrasonographic findings as the gold standard for the assessment of gestational age, circumstances will continue to occur in which such data are not available, e.g., when the cohort under study had not been assembled early in pregnancy. But is all lost in cohorts assembled by birth weight truncation? I think not. When an outcome such as cesarean section is associated both with fetal growth and with gestational age, both variables must be controlled for in the analysis. For the former variable, Arnold et al.'s recommendation to use the fetal growth ratio is excellent. Alternatively, and following Yerushalmy et al. (2), we have used a measure of gestational age for birth weight (3), which will accomplish the same objective. However, it is also critical to control for gestational age. Arnold et al. provide only one example in which they looked at the effect of growth retardation while controlling for gestational age, and in that example, the odds ratios (for mortality) that emerged from the two differently assembled cohorts were only mildly different (2.72 vs. 3.15). Arnold et al.'s recommendation for design is useful, but a sensible analysis can yield intelligible results, even with data truncated by birth weight. REFERENCES
1. Arnold CC, Kramer MS, Hobbs, CA et al. Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates. Am J Epidemiol 1991 ;134:604-13. 2. Yerushalmy J, Bierman JM, Kemp DH, et al. Longitudinal studies of pregnancy on the island of
Kauai, Territory of Hawaii. I. Analysis of previous reproductive history. Am J Obstet Gynecol 1956;71:80-96. 3. Paneth N, Wallenstein S, Kiely JL, et al. Social class indicators and mortality in low birth weight infants. Am J Epidemiol 1982;116:364-75.
Nigel Paneth College of Human Medicine Program in Epidemiology Michigan State University East Lansing, MI 488241316
THE FIRST AUTHOR REPLIES Dr. Paneth (1) raises two important issues: 1) how to account for fetal growth and 2) the practical importance of working with a cohort truncated by birth weight. We agree that the age-forsize paradigm he suggests as an alternative to the size-for-age paradigm for fetal growth will lead to the same statistical results. However, we feel that this perpetuates the confusion regarding the biological relation of the two variables: growth is size for age, not age for size. We chose mortality as the outcome to illustrate the problems of assessing the effects of growth retardation in cohorts truncated by birth weight because there has been confusion in the literature regarding the "protective" effect of growth retardation on neonatal mortality among very low birth weight infants. Outcomes that might be expected to be confounded in the same way but to a greater extent include intraventricular hemorrhage and bronchopulmonary dysplasia. Likewise, there are exposures that would be expected to be associated with growth status to a greater degree than our example, method of delivery. These include tocolytic therapy and maternal hypertension. That the adjusted odds ratio in the birth weight cohort underestimated the true effect of growth retardation on mortality by 14% is a manifestation of the problem encountered when adjusting for gestational age in cohorts defined by birth weight criteria. Whether the magnitude of this difference is "mildly different" or not is debatable. Because of the greater collinearity of gestational age and growth status in birth weight cohorts, adjusting for gestational age and growth status will always result in a less reliable estimate than would be the case using a gestational age cohort from the same population. The magnitude of the difference will depend on the amount of collinearity in the birth weight cohort, which will vary
