We aimed to assess the association of umbilical catheters placement with pericardial effusion (PCE) in newborn infants after controlling for confounding variables. We analyzed three subpopulations: infants with birth weight (BW) > 2500g, infants with BW < 1500g, and infants with congenital heart diseases (CHD). We utilized the US-National Inpatient Sample dataset (1997–2012). First analysis included a 22,822,931 infants with BW > 2500g with no hydrops fetalis. Of them, 2583 neonates (0.01%) had PCE. PCE was found in 0.33% of infants with UAC only, 0.22% of infants with UVC only and 0.37% of infants with both catheters (aOR = 2.7, CI:2.4–3.2, p < 0.001), aOR = 2.8, CI: 2.3–3.5, p < 0.001), and aOR = 2.8, CI: 2.4–3.2, p < 0.001), respectively. The second analysis included a 200,288 infants with CHD and BW > 2500g. Of them, 1130 (0.56%) had PCE. PCE was found in 1.46% of infants with UAC, 0.78% of infants with UVC and 0.98% of infants with both catheters (aOR = 2.1, CI:1.8–2.6, p < 0.001), aOR = 1.4, CI:1.1–1.9, p = 0.036) and a OR = 1.6, CI:1.3–1.9, p < 0.001), respectively. While, a total of 1,187,727 infants with BW < 1500g were included in the third analysis. Of them, 1667 (0.14%) had PCE. PCE was found in 0.15% of infants with UAC, 0.19% of infants with UVC and 0.26% of infants with both catheters. (aOR = 1.1, CI: 0.9–1.3, p < 0.90), aOR = 1.4, CI: 1.2–1.7, p < 0.001) and aOR = 1.6, CI:1.4–1.8, p < 0.001), respectively. Conclusion: Central umbilical catheters are associated with increased risk for pericardial effusion and they may be independently associated with the occurrence of pericardial effusion in infants with congenital heart disease.