Impact of Maternal–Fetal Environment on Mortality in Children With Single Ventricle Heart Disease

Abstract

BACKGROUND Children with single ventricle heart disease have significant morbidity and mortality. The maternal–fetal environment (MFE) may adversely impact outcomes after neonatal cardiac surgery. We hypothesized that impaired MFE would be associated with an increased risk of death after stage 1 Norwood reconstruction. METHODS AND RESULTS We performed a retrospective cohort study of children with hypoplastic left heart syndrome (and anatomic variants) who underwent stage 1 Norwood reconstruction between 2008 and 2018. Impaired MFE was defined as maternal gestational hypertension, preeclampsia, gestational diabetes, and/or smoking during pregnancy. Cox proportional hazards regression models were used to investigate the association between impaired MFE and death while adjusting for confounders. Hospital length of stay was assessed with the competing risk of in‐hospital death. In 273 children, the median age at stage 1 Norwood reconstruction was 4 days (interquartile range [IQR], 3–6 days). A total of 72 children (26%) were exposed to an impaired MFE; they had more preterm births (18% versus 7%) and a greater percentage with low birth weights <2.5 kg (18% versus 4%) than those without impaired MFE. Impaired MFE was associated with a higher risk of death (hazard ratio [HR], 6.05; 95% CI, 3.59–10.21; P <0.001) after adjusting for age at surgery, Hispanic ethnicity, genetic syndrome, cardiac diagnosis, surgeon, and birth era. Children with impaired MFE had almost double the risk of prolonged hospital stay (HR, 1.95; 95% CI, 1.41–2.70; P <0.001). CONCLUSIONS Children exposed to an impaired MFE had a higher risk of death following stage 1 Norwood reconstruction. Prenatal exposures are potentially modifiable factors that can be targeted to improve outcomes after pediatric cardiac surgery.

Understanding the Maternal‐Fetal Environment and the Birth of Prenatal Pediatrics

“…Pregestational diabetes is itself associated with increased risk of CHD, including impaired diastolic function or diabetic cardiomyopathy, even in the absence of major structural defects. Together, these widespread injurious influences could reasonably be expected to further increase the mortality risk of infants with critical CHD, as demonstrated by Savla et al 2 …”

“…In this issue of the Journal of the American Heart Association (JAHA) , investigators from the Children’s Hospital of Philadelphia, one of the leading centers for fetal medicine, pediatric cardiology, and cardiac surgery, extend their investigation into the factors associated with adverse outcome in children with critical congenital heart disease (CHD). 1 In their article, 2 Savla et al report on a retrospective cohort study that examines the association between prenatal factors in the maternal‐fetal environment and mortality after the stage 1 Norwood procedure in children with single‐ventricle cardiac lesions. In recent years it has become increasingly recognized that population‐based predictors of outcome in these children fail to account for much of the variability in individual patient‐based outcomes.…”

“…The role of the placenta in the development of CHD and its outcome has become an area of increasing interest. 9 , 10 Savla et al 2 included preeclampsia, a complication of impaired placentation, as an environmental variable in their risk model. The rationale for this is several‐fold as there are a number of ways in which preeclampsia might be implicated in the causal pathway to adverse outcome in infants with critical CHD.…”

“…The multitude of potential risk factors add a daunting complexity to the challenge of identifying risks most hazardous to survival and well‐being. The approach taken by Savla et al 2 is logical as it starts with associated maternal‐placental factors known in general to be the best to start with additional factors that affect fetal well‐being. Looking ahead, this important line of inquiry needs to extend beyond survival (as a primary outcome) to elucidate the role of maternal‐placental influences on the long‐term health and wellness in survivors of CHD across the lifespan.…”

“…The article 2 by Savla et al underscores the need to consider the complex interactions between the maternal, placental, and fetal environments, especially in high‐risk fetal conditions, such as critical CHD. Developing precise and personalized care is a major “next frontier” for medicine, in general.…”