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. 2011 Nov 1;174(9):1062-8.
doi: 10.1093/aje/kwr230. Epub 2011 Sep 26.

On the pitfalls of adjusting for gestational age at birth

Allen J Wilcox  1 , Clarice R Weinberg, Olga Basso
Affiliations

On the pitfalls of adjusting for gestational age at birth

Allen J Wilcox et al. Am J Epidemiol. .

Abstract

Preterm delivery is a powerful predictor of newborn morbidity and mortality. Such problems are due to not only immaturity but also the pathologic factors (such as infection) that cause early delivery. The understanding of these underlying pathologic factors is incomplete at best. To the extent that unmeasured pathologies triggering preterm delivery also directly harm the fetus, they will confound the association of early delivery with neonatal outcomes. This, in turn, complicates studies of newborn outcomes more generally. When investigators analyze the association of risk factors with neonatal outcomes, adjustment for gestational age as a mediating variable will lead to bias. In the language of directed acyclic graphs, gestational age is a collider. The theoretical basis for colliders has been well described, and gestational age has recently been acknowledged as a possible collider. However, the impact of this problem, as well as its implications for perinatal research, has not been fully appreciated. The authors discuss the evidence for confounding and present simulations to explore how much bias is produced by adjustments for gestational age when estimating direct effects. Under plausible conditions, frank reversal of exposure-outcome associations can occur. When the purpose is causal inference, there are few settings in which adjustment for gestational age can be justified.

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Figures

Figure 1.
Figure 1.
Week-specific neonatal mortality of singletons and twins among US livebirths for gestational-age weeks 24–42, National Center for Health Statistics, 1995–2002. Gestational age is based on last menstrual period, replaced by clinical gestation when last menstrual period was implausible (Epidemiology 2010;21(4):521–527 (16)).
Figure 2.
Figure 2.
Directed acyclic graphs corresponding to alternative models A–G for the causal association of preterm birth and neonatal mortality. “X” represents a measured variable of interest to the investigator, and “U” represents unmeasured confounding variables.
See this image and copyright information in PMC

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