title: Controlled direct effects of preeclampsia on neonatal health after accounting for mediation by preterm birth.
abstract: BACKGROUND
  Preeclampsia is characterized by alterations in angiogenic factors that may increase neonatal morbidity independent of preterm birth.
  
  
  METHODS
  We estimated the controlled direct effect of preeclampsia on neonatal outcomes independent of preterm birth among 200,103 normotensive and 10,507 preeclamptic singleton pregnancies in the Consortium on Safe Labor (2002-2008). Marginal structural models with stabilized inverse probability weights accounted for potential confounders in the pathway from preeclampsia to preterm birth to neonatal outcomes, including mediator-outcome confounders related to preeclampsia status, such as cesarean delivery. Controlled direct effects of preeclampsia on perinatal mortality, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, respiratory distress syndrome, transient tachypnea of the newborn, anemia, apnea, asphyxia, peri- or intraventricular hemorrhage, and cardiomyopathy were estimated for the hypothesized intervention of term delivery for all infants.
  
  
  RESULTS
  When delivery was set at ≥37 weeks, preeclampsia increased the odds of perinatal mortality (odds ratio = 2.2 [95% confidence interval = 1.1-4.5], SGA = (1.9 [1.8-2.1]), NICU admission (1.9 [1.7-2.1]), respiratory distress syndrome (2.8 [2.0-3.7], transient tachypnea of the newborn (1.6 [1.3-1.9]), apnea (2.2 [1.6-3.1]), asphyxia (2.7 [1.5-4.9]), and peri- or intraventricular hemorrhage (3.2 [1.4-7.7]). No direct effect of preeclampsia at term was observed for anemia or cardiomyopathy. Our results appear robust in the presence of moderate confounding, and restriction to severe preeclampsia yielded similar findings.
  
  
  CONCLUSIONS
  Preeclampsia was directly associated with adverse neonatal outcomes beyond morbidity mediated by preterm birth. Although severe neonatal outcomes were less common at later gestational ages, marginal structural models suggested elevated neonatal risk due to preeclampsia even if it was possible to deliver all infants at term.
authors.affiliation: From the aDivision of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD; bDiabetes Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Oulu, Finland; cNaval Medical Center Portsmouth, Department of Pediatrics, Portsmouth, VA; and dDivision of Extramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD.
authors.forename: Pauline
authors.initials: P
authors.lastname: Mendola
authors.forename: Sunni L
authors.initials: SL
authors.lastname: Mumford
authors.forename: Tuija I
authors.initials: TI
authors.lastname: Männistö
authors.forename: Alexander
authors.initials: A
authors.lastname: Holston
authors.forename: Uma M
authors.initials: UM
authors.lastname: Reddy
authors.forename: S Katherine
authors.initials: SK
authors.lastname: Laughon
mesh_terms: D000328:Adult; D001238:Asphyxia Neonatorum / Q000453:epidemiology*; D002543:Cerebral Hemorrhage / Q000453:epidemiology*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007363:Intensive Care Units, Neonatal / Q000706:statistics & numerical data*; D008297:Male; D054238:Perinatal Mortality; D011225:Pre-Eclampsia / Q000453:epidemiology*; D011247:Pregnancy; D047928:Premature Birth / Q000453:epidemiology*; D012127:Respiratory Distress Syndrome, Newborn / Q000453:epidemiology*; D012307:Risk Factors; D047929:Term Birth; D059245:Transient Tachypnea of the Newborn / Q000453:epidemiology*; D014481:United States / Q000453:epidemiology; D055815:Young Adult