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.

Keywords: Stage 1 Norwood procedure; congenital heart disease; fetal development; fetal programming; hypoplastic left heart syndrome; preeclampsia/pregnancy; prenatal exposures.

Figure 1. Framework for causal mediation analysis.

This schematic diagram demonstrates the causal mediation analysis that was performed to estimate the direct and indirect effects of impaired maternal–fetal environment (MFE) on the risk of death after Stage 1 Norwood reconstruction surgery. Indirect effects were considered those mediated by the following 3 intermediate birth factors: gestational age at birth, birth weight, and birth weight percentile.

Figure 2. Adjusted survival curves for postoperative mortality after stage 1 Norwood procedure.

These adjusted survival curves consider the median age at initial surgery (4 days old), non‐Hispanic ethnicity, no genetic syndrome, no unbalanced common atrioventricular canal, the most common surgeon, and birth era (June 2008–May 2013). HR indicates hazard ratio; and MFE, maternal–fetal environment.

Figure 3. Adjusted competing risk model for time to discharge after stage 1 Norwood reconstruction.

These adjusted cumulative incidence curves consider the median age at initial surgery (4 days old), non‐Hispanic ethnicity, no genetic syndrome, no unbalanced common atrioventricular canal, the most common surgeon, and birth era (June 2008–May 2013). HR indicates hazard ratio; and MFE, maternal–fetal environment.