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Does Adjusting for Causal Intermediate Confounders Resolve the Perinatal Crossover Paradox?

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The preeclampsia-perinatal outcome paradox persists despite adjusting for mediators like preterm birth (PTB). Unmeasured confounding remains a significant issue in understanding preeclampsia

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Area of Science:

  • Perinatal epidemiology
  • Maternal-fetal medicine
  • Causal inference in health research

Background:

  • Preeclampsia-perinatal outcome associations show paradoxical findings, with lower adverse outcomes in preeclamptic preterm births.
  • Previous explanations involve unmeasured confounding, treating preterm birth (PTB) as the sole mediator.
  • Intermediate variables like placental abruption, small for gestational age (SGA), and chorioamnionitis are often excluded due to their timing post-preeclampsia.

Purpose of the Study:

  • To investigate whether adjusting for causal intermediates resolves confounding bias in the preeclampsia-perinatal outcome association.
  • To compare different approaches for handling intermediate confounding when PTB is the focal mediator.
  • To assess the impact of unmeasured confounding on interventional effects.

Main Methods:

  • Utilized data from the Consortium on Safe Labor (2002-2008).
  • Employed interventional indirect effects to examine mediation.
  • Compared treating intermediates as exposure-induced confounders versus multiple mediators.
  • Developed bias formulas to quantify unmeasured confounding.

Main Results:

  • When PTB was the sole mediator, preeclampsia showed a protective direct effect (RR=0.60), consistent with paradoxical findings.
  • This protective effect remained even after adjusting for intermediate confounders (abruption, SGA, chorioamnionitis).
  • Sensitivity analyses indicated a strong unmeasured confounder is necessary to resolve the paradox.

Conclusions:

  • Adjusting for intermediates like abruption, SGA, and chorioamnionitis is insufficient to eliminate unmeasured confounding in PTB-perinatal mortality.
  • The paradox of preeclampsia's protective direct effect on mortality remains unresolved.
  • Sensitivity analyses for unmeasured confounding are crucial for strengthening causal mediation conclusions.