Diagnosis of fetal heart failure depends primarily on fetal ultrasonography assessment. Our recent study demonstrated that plasma
natriuretic peptide levels in umbilical cord blood were correlated with the severity of
heart failure in fetuses with
congenital heart defects or arrhythmias. However, percutaneous umbilical blood sampling is an invasive procedure, and therefore, less or noninvasive
biomarkers reflecting fetal heart failure are required.
OBJECTIVE: This exploratory cross-sectional study was conducted at a tertiary pediatric cardiac center. A total of 50 singletons with fetal
congenital heart defects or arrhythmias and 50 controls who were registered in the National Cerebral and Cardiovascular Center Biobank from 2013 to 2016 were included. Maternal serum samples obtained during the third trimester were analyzed for 2
hormones and 36
cytokines using the Bio-Plex Pro Human
Cancer Biomarker panels 1 and 2. We comprehensively analyzed the association between maternal serum
biomarkers and ultrasonography findings or fetal
arrhythmia status. Fetal heart failure was defined as a cardiovascular profile score ≤7.
RESULTS: Of 37 fetuses with
congenital heart defects,
heart failure was found in 1 case of tricuspid valve dysplasia with moderate
tricuspid regurgitation. Of 13 fetuses with arrhythmias, 5 had
heart failure at 28-33 weeks of gestation. Maternal serum
cytokine and
hormone concentrations were compared between patients with and without fetal heart failure at 28-33 weeks of gestation (n = 6 and n = 61, respectively). Sixty-one fetuses without
heart failure consisted of 10 with
congenital heart defect, 6 with
arrhythmia, and 45 controls. Maternal serum concentrations of
tumor necrosis factor-α,
interleukin-6, soluble
Fas ligand,
transforming growth factor-α, and
vascular endothelial growth factor-D were significantly higher when fetuses had
heart failure than when they did not (P < .05), whereas maternal serum concentrations of
heparin-binding
epidermal growth factor-like
growth factor were significantly lower when fetuses had
heart failure than when they did not (P < .05). Multivariate analysis showed that maternal serum concentrations of
tumor necrosis factor-α,
vascular endothelial growth factor-D, and
heparin-binding
epidermal growth factor-like
growth factor were independently associated with fetal heart failure. The cutoff values were as follows:
tumor necrosis factor-α, 68 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5);
vascular endothelial growth factor-D, 1156 pg/mL (sensitivity of 50.0%, specificity of 93.4%, positive likelihood ratio of 7.6, negative likelihood ratio of 0.5); and
heparin-binding
epidermal growth factor-like
growth factor, 90 pg/mL (sensitivity of 83.3%, specificity of 83.6%, positive likelihood ratio of 5.1, negative likelihood ratio of 0.2). The combination of these 3
cytokines showed sensitivity of 100%, specificity of 80.3%, positive likelihood ratio of 5.1, and negative likelihood ratio of 0. In the absence of fetal heart failure, concentrations of all maternal serum
cytokines and
hormones were similar in cases of fetal
congenital heart defects and controls, while maternal serum soluble
CD40 ligand concentrations were increased only in fetal arrhythmias.
CONCLUSION: