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

Abstract

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.

Towards a unified perinatal theory: Reconciling the births‐based and fetus‐at‐risk models of perinatal mortality

“…It may, therefore, be possible to reformulate the cross‐sectional, births‐based model in terms of the longitudinal, fetuses‐at‐risk model. Note: The time between birth and neonatal death is treated as a latent period and disregarded in both the fetuses‐at‐risk and births‐based calculations of gestational age‐specific neonatal mortality …”

“…Gestational age‐specific perinatal death (including stillbirths and neonatal deaths) rates were calculated for each cohort under the births‐based and extended fetuses‐at‐risk formulations. Rates calculated under the fetuses‐at‐risk model were incidence density rates expressed per 1000 fetus‐weeks . Although the analyses presented focus on perinatal death rates, rates were also estimated for stillbirths and neonatal deaths separately …”

“…Proponents of the fetuses‐at‐risk formulation, which eliminates the intersecting perinatal mortality curves paradox, conceptualise the births‐based paradox as being the product of a non‐causal model . Non‐causal models, which serve an important diagnostic or (non‐causal) prognostic purpose, typically make liberal use of interaction and other product terms.…”

“…Note: The time between birth and neonatal death is treated as a latent period and disregarded in both the fetuses-at-risk and births-based calculations of gestational age-specific neonatal mortality. 5,18 The second proposition is based on the observation that the exponential increase in gestational age-specific (extended fetuses-at-risk) birth rates complements the exponential decline in births-based gestational age-specific perinatal death rates. 5,18 This commonality (of exponential change) suggests that gestational age-specific birth rates could represent an explanatory link between the fetuses-at-risk gestational age-specific perinatal mortality rate and the births-based gestational age-specific perinatal mortality rate.…”

“…Perhaps the most serious challenge to perinatal theory is offered by the paradox of intersecting perinatal mortality curves. [6][7][8][9][10][11][12][13][14][15][16][17][18] This phenomenon was first described over 50 years ago by Yerushalmy, 6 who showed that low birthweight infants of women who smoked in pregnancy had lower neonatal mortality (compared with low birthweight infants of non-smoking women) and the reversal of this mortality difference at higher birthweights. In fact, this mortality crossover is a general phenomenon 18 seen across many contrasts (eg singletons versus twins, infants of women with versus without hypertension [6][7][8][9][10][11][12][13][14][15][16][17][18] ), different outcomes (eg stillbirth, neonatal death, [6][7][8][9][10][11][12][13][14][15][16][17][18] sudden infant death syndrome 19,20 and cerebral palsy 21 ) and irrespective of how maturity is defined (viz., birthweight or gestational age [6]<...>…”