RE: "A PROPORTIONAL HAZARDS MODEL WITH TIME-DEPENDENT COVARIATES AND TIME-VARYING EFFECTS FOR ANALYSIS OF FETAL AND INFANT DEATH"

Gordon C. S. Smith

Department of Obstetrics and Gynaecology, Cambridge University, Cambridge, United Kingdom CB2 2QQ

I read with interest the recent series of Journal papers on gestational-age-specific mortality (14). I agree with Platt et al.’s statement: "Research to date on perinatal outcomes has all but ignored the fact that gestational age is a time-to-event variable" (1, p. 200). Given the paucity of such studies, it is odd that they ignored my first description of time-to-event methods in assessing stillbirth risk (5) and a recent practical application, which included both Cox modeling and the Grambsch and Therneau test of the proportional hazards assumption (6).

All papers in the series ignore the clinically crucial distinction between stillbirths determined before labor and those determined during labor. Approximately 15 percent of stillbirths at term are due to intrapartum death of the fetus (5). The fetuses at risk of intrapartum stillbirth because of, for example, shoulder dystocia are clearly only those delivered in the given week of gestation.

I am not convinced that incorporating all causes of perinatal death into a single model to obtain a summary hazard ratio, as described by Platt et al. (1), is likely to be useful. Even within categories of death, such as antepartum stillbirth, the event of stillbirth is the endpoint of multiple pathways, which differ in their determinants. Different maternal characteristics are associated with perinatal death due to different causes (6). Our own approach has been to use well-established classification systems of different types of perinatal death to define the event and then relate the event to the appropriate denominator. We use time-to-event analysis with gestational age as the time scale for antepartum stillbirth (6) and logistic regression for intrapartum stillbirth and neonatal death, with the denominator being all births excluding antepartum stillbirths (7).

Finally, the "paradox" that babies born to smokers are at decreased risk of neonatal death if they weigh less than 3,000 g but are at greater risk of neonatal death if weighing more than 3,000 g reflects two facts: 1) gestational age is a greater determinant of neonatal death than growth restriction, and 2) smoking is more strongly associated with growth restriction than prematurity. Therefore, among smokers, small babies are likely to be at more advanced gestational ages since more will be small because of poor growth, predicting that the interaction would disappear when adjusted for gestational age. I addressed this issue by studying 559,733 livebirths, including 992 neonatal deaths not due to congenital abnormality, from a previous linkage of Scottish databases (6). Logistic regression yielded an odds ratio for an interaction term between smoking and weight less than 3,000 g of 0.69 (95 percent confidence interval: 0.50, 0.96) unadjusted for gestational age and 1.00 (95 percent confidence interval: 0.71, 1.40) when adjusted for week of gestation. This approach seems much clearer to the "paradox" than the model of Platt et al. (1).


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  1. Platt RW, Joseph KS, Ananth CV, et al. A proportional hazards model with time-dependent covariates and time-varying effects for analysis of fetal and infant death. Am J Epidemiol 2004;160:199–206.[Abstract/Free Full Text]
  2. Cheung YB. On the definition of gestational-age-specific mortality. Am J Epidemiol 2004;160:207–10.[Abstract/Free Full Text]
  3. Klebanoff MA, Schoendorf KC. Invited commentary: what’s so bad about curves crossing anyway? Am J Epidemiol 2004;160:211–12.[Free Full Text]
  4. Wilcox AJ, Weinberg CR. Invited commentary: analysis of gestational-age-specific mortality—on what biologic foundations? Am J Epidemiol 2004;160:213–14.[Free Full Text]
  5. Smith GCS. Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 2001;184:489–96.[CrossRef][ISI][Medline]
  6. Smith GCS, Pell JP, Dobbie R. Caesarean section and risk of unexplained stillbirth in subsequent pregnancy. Lancet 2003;362:1779–84.[CrossRef][ISI][Medline]
  7. Smith GC, Pell JP, Cameron AD, et al. Risk of perinatal death associated with labor after previous cesarean delivery in uncomplicated term pregnancies. JAMA 2002;287:2684–90.[Abstract/Free Full Text]




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