The fetuses-at-risk approach: survival analysis from a fetal perspective

Several phenomena in contemporary perinatology create challenges for analyzing pregnancy outcomes. These include recent increases in iatrogenic delivery at late preterm and early term gestation, which are incongruent with the belief that stillbirth and neonatal death risks decrease exponentially with advancing gestational age. Perinatal epidemiologists have also puzzled over the paradox of intersecting birthweight-specific and gestational age-specific perinatal mortality curves for decades. For example, neonatal mortality rates among preterm infants of women who smoke are substantially lower than neonatal mortality rates among preterm infants of non-smoking women, whereas the reverse pattern occurs at term gestation. This mortality crossover is observed across several contrasts (for example, women with hypertensive disorders of pregnancy vs. normotensive women, older vs. younger women, twins vs. singletons) and outcomes (stillbirth, neonatal death, sudden infant death syndrome and cerebral palsy), and irrespective of how advancing "maturity" is defined (birthweight or gestational age). One approach proposed to address and explain these unexpected phenomena is the fetuses-at-risk model. This formulation involves a reconceptualization of the denominator for perinatal outcome rates from births to surviving fetuses. In this overview of the fetuses-at-risk model, we discuss the central tenets of the births-based and the fetuses-based formulations. We also describe the extension of the fetuses-at-risk approach to outcomes into and beyond the neonatal period and to a multivariable adaptation. Finally, we provide a substantive context by discussing biological mechanisms underlying the fetuses-at-risk model and contemporary obstetric phenomena that are better understood from that model than from one based on births.