Invited commentary: the hidden population in perinatal epidemiology.

Several recent papers have argued that understanding of pathologic perinatal processes may be advanced by considering, in varying ways, the population of fetuses still in utero. Initially invoked by Yudkin et al. (Lancet 1987;1:1192-4) as the optimum denominator for intrapartum stillbirths, fetuses in utero (or "fetuses at risk") have also been of interest because of their patterns of growth, especially in comparison to infants born after varying durations of gestation. The paper by Hutcheon and Platt (Am J Epidemiol 2008;167:786-792) extends work that compares growth in infants born prematurely with that in infants continuing in utero and investigates the biases in analyses that can emerge from failure to consider the selection for impaired fetal growth characteristic of many prematurely born infants. Although the conceptual basis of this perspective is sound, in-utero fetal growth standards from serial ultrasonographic measurements in pregnancy are often based on small and highly selected samples. Some authors have proposed "fetuses at risk" as the appropriate denominator for postnatal phenomena related to premature birth, such as neonatal mortality and cerebral palsy. This application is problematic; in such situations, the denominator population differs from infants with the outcome in not having experienced adjustment to postnatal life, a potentially important determinant of outcome, especially in premature infants. The fetuses-at-risk concept is important in perinatal epidemiology and has implications for obstetric practice, but it must be handled with caution.