Association of the biomarkers PAPP-A and beta-hCG with cardiac findings in neonates

Background Congenital heart disease (CHD) is the most common birth defect with an estimated prevalence of up to 10 per 1,000 live births. Previous studies have associated abnormal PAPP-A and β-hCG levels with non-chromosomal CHD. PAPP-A and β-hCG are potential markers of placental dysfunction, which may influence fetal heart development and contribute to CHD. As these biomarkers are already included in routine prenatal screening, their predictive value for CHD could provide a cost-neutral diagnostic tool. Purpose To evaluate whether PAPP-A and β-hCG levels are associated with CHD and neonatal cardiac parameters in a large population-based setting. Methods This study is a prospective, population-based cohort study evaluating cardiac structure and function in neonates. Echo- and electrocardiographic data were collected during the first 60 days of life over a two-year period. Maternal blood samples were collected between gestational weeks 8-14. Data on pregnancy, delivery, the nuchal scan, parental health, etc. were obtained from medical records and national health registries. Results A total of 23,576 neonates (52% boys, median age 11 days) with available echocardiography and measurements of maternal PAPP-A and β-hCG levels were included. Electrocardiographic data were available in 16,305 neonates. The median PAPP-A MoM was 1.03 (range 0.05-13.60), β-hCG MoM was 1.01 (range 0.03-9.07), and the median gestational age at sample collection was 74 days. When investigating maternal biomarker levels and presence of CHD we found a significant association between PAPP-A MoM and CHD (0.98 vs. 1.03, p<0.04), but no association for β-hCG MoM (0.98 vs. 1.01, p=0.15). With combined analyses of the biomarkers, we compared the neonates with both maternal biomarker levels <10th percentile (n=467) to those without this combination (n=23,109). We found an association between low biomarker levels and smaller left ventricular internal diameter at end-diastole (19.6 vs. 20.0 mm, p<0.001) and at end-systole (13.2 vs. 13.5 mm, p<0.001). No significant associations for other echocardiographic (ejection fraction, fractional shortening, interventricular septal or left ventricular posterior wall thicknesses) or electrocardiographic parameters (heart rate, PR interval, QRS duration, QTc, or precordial amplitudes) were found (all p>0.05). Conclusion In this study, we found that lower maternal PAPP-A MoM was modestly associated with CHD, and low biomarker levels were linked to reduced left ventricular diameters. PAPP-A MoM may be a potential CHD biomarker in prenatal screening. Further research is warranted to assess its role in risk stratification and early detection.