Impaired Maternal-Fetal Environment and Risk for Preoperative Focal White Matter Injury in Neonates With Complex Congenital Heart Disease

Abstract

Background Infants with congenital heart disease (CHD) are at risk for white matter injury (WMI) before neonatal heart surgery. Better knowledge of the causes of preoperative WMI may provide insights into interventions that improve neurodevelopmental outcomes in these patients. Methods and Results A prospective single-center study of preoperative WMI in neonates with CHD recorded data on primary cardiac diagnosis, maternal-fetal environment (MFE), delivery type, subject anthropometrics, and preoperative care. Total maturation score and WMI were assessed, and stepwise logistic regression modeling selected risk factors for WMI. Among subjects with severe CHD (n=183) who received a preoperative brain magnetic resonance imaging, WMI occurred in 40 (21.9%) patients. WMI prevalence (21.4%-22.1%) and mean volumes (119.7-160.4 mm³) were similar across CHD diagnoses. Stepwise logistic regression selected impaired MFE (odds ratio [OR], 2.85 [95% CI, 1.29-6.30]), male sex (OR, 2.27 [95% CI, 1.03-5.36]), and older age at surgery/magnetic resonance imaging (OR, 1.20 per day [95% CI, 1.03-1.41]) as risk factors for preoperative WMI and higher total maturation score values (OR, 0.65 per unit increase [95% CI, 0.43-0.95]) as protective. A quarter (24.6%; n=45) of subjects had ≥1 components of impaired MFE (gestational diabetes [n=12; 6.6%], gestational hypertension [n=11; 6.0%], preeclampsia [n=2; 1.1%], tobacco use [n=9; 4.9%], hypothyroidism [n=6; 3.3%], and other [n=16; 8.7%]). In a subset of 138 subjects, an exploratory analysis of additional MFE-related factors disclosed other potential risk factors for WMI. Conclusions This study is the first to identify impaired MFE as an important risk factor for preoperative WMI. Vulnerability to preoperative WMI was shared across CHD diagnoses.

Keywords: congenital brain injuries; heart defects; maternal fetal environment; placenta; risk factors; white matter injury.

Figure 1. Probabilistic maps of preoperative WMI volumes in 40 patients.

WMI lesions were manually traced and overlayed on a study subject template. F indicates frontal; I, inferior; L, left; P, posterior; R, right; S, superior; and WMI, white matter injury.

Figure 2. Odds ratios of WMI for the 4 features remaining in the final stepwise model.

Red indicates risk factors, and blue indicates a protective factor. An odds ratio of 1.0 indicates no association. Horizontal lines are 95% CI. The final model had an area under the receiver operating curve of 0.71 (95% CI, 0.62, 0.80). All 183 subjects were included in the analysis. MFE indicates maternal‐fetal environment; MRI, magnetic resonance imaging; TMS, total maturation score; and WMI, white matter injury.