Candidates at Risk for Postnatal Outcomes

To the Editor: The recent extension of the fetuses-at-risk approach to outcomes originating in pregnancy and diagnosed postnatally remains controversial. Auger and colleagues1 advocate a discussion on extending the fetuses-at-risk approach to neonatal and postneonatal outcomes, whereas Paneth2 argues that such a formulation ignores the “transitions that permit live birth.” Whether fetuses or live births constitute the appropriate denominator for gestational age–specific neonatal mortality or gestational age–specific cerebral palsy hinges on how one conceptualizes the candidates for these outcomes. If the pathogenic process that causes neonatal death or cerebral palsy becomes established in utero, then fetuses constitute the appropriate denominator for these outcomes. Using the fetuses-at-risk approach for neonatal outcomes but not for postneonatal outcomes is a heuristic decision; for most (but not all) neonatal deaths and cerebral palsy, pathogenesis (neurologic injury in the case of cerebral palsy) occurs during pregnancy, whereas for many (but not all) postneonatal deaths, the causes arise postnatally. Thus, it would be appropriate to use the fetuses-at-risk approach for most neonatal outcomes and for cerebral palsy and sudden-infant-death syndrome but not for neonatal tetanus and most postneonatal outcomes. If fetuses are the appropriate candidates for fetal death, neonatal death, and cerebral palsy, then fetuses (not live births) should be sampled for control selection in case–control studies, even if noncase status is ascertained subsequently. The Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE),3 which followed a cohort of preterm infants (<33 weeks), illustrates this issue; the EPIPAGE cohort is complete for predicting the risk of cerebral palsy among preterm infants but incomplete for investigating the etiologic role of maternal smoking, hypertension, etc, on cerebral palsy (because fetuses that went on to deliver at term were not included in the cohort). Also of note is the anchor of the scale of time for assessing the effects of agents. Developmental time windows exist for teratogenic effects, and assessment of exposure to agents within windows of susceptibility requires a time scale anchored to conception. More generally, etiologic time (retrospective) in case–control studies is anchored to the moment of outcome occurrence/classification, and exposure to agents is commonly assessed within mutually exclusive windows of time on such a scale.4 However, the moment of outcome occurrence for postnatally diagnosed outcomes remains a point of contention in perinatology. Cerebral palsy presents the starkest choice—does cerebral palsy occur among fetuses, among infants, or among children in whom the diagnosis is typically made? Sarka Lisonkova Department of Obstetrics & Gynaecology University of British Columbia Vancouver, BC, Canada [email protected] K.S. Joseph Department of Obstetrics & Gynaecology University of British Columbia and the Children’s and Women’s Hospital of British Columbia Vancouver, BC, Canada School of Population and Public Health University of British Columbia Vancouver, BC, Canada

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