Hypoxic/ischemic hits predispose to necrotizing enterocolitis in (near) term infants with congenital heart disease: a case control study

Abstract

Background Necrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC. Methods 956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses. Results We included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9], P = .011) and (8 [8-9]) vs. (9 [9-10], P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13), P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34–42], vs. 43 mmHg [37–51], P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17–7.35] vs. 7.38 ([7.27–7.43], P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants. Conclusions Our clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC.

Clinical Characteristics and Potential Pathogenesis of Cardiac Necrotizing Enterocolitis in Neonates with Congenital Heart Disease: A Narrative Review

“…Van der Heide et al provided evidence for tissue hypoxia and ischemia in near-term CHD infants subsequently developing NEC. In the few days between birth and the development of NEC, these CHD infants were characterized by lower Apgar scores and increased respiratory support, with a trend toward lower pH and diastolic blood pressure, compared with age-matched CHD infants not developing NEC [ 35 ]. In addition, lower levels of platelets and C-reactive protein (CRP) in term NEC infants with CHD compared with preterm NEC infants without CHD provided further evidence of the ischemic nature of cardiac NEC in comparison with the more acute inflammatory classical NEC [ 18 ].…”

“…Many CHD infants receive RBCTs during or following surgery. A retrospective association between In cardiac NEC infants, mesenteric hypoperfusion or intestinal ischemia may initiate as early as delivery in the transition from shared maternal circulation [35]. Cardiac NEC most frequently involves the colon and distal ileum due to the susceptibility to superior and inferior MA blood supply interruptions in these regions [36], often referred to as 'watershed zones' [35].…”

“…A retrospective association between In cardiac NEC infants, mesenteric hypoperfusion or intestinal ischemia may initiate as early as delivery in the transition from shared maternal circulation [35]. Cardiac NEC most frequently involves the colon and distal ileum due to the susceptibility to superior and inferior MA blood supply interruptions in these regions [36], often referred to as 'watershed zones' [35]. Mechanistically, mesenteric hypoperfusion initiates endothelial inflammation and increases vascular permeability and neutrophil, leukocyte, and platelet accumulation and activation due to endothelial production of adhesion molecules [37].…”

Prediction of High Bell Stages of Necrotizing Enterocolitis Using a Mathematic Formula for Risk Determination

“…A PDA led to left-to-right shunting, resulting in pulmonary overcirculation and diastolic "runoff" in the aorta, contributing to organ hypoperfusion and hypoxia. Changes in oxygen delivery to the gut in the presence of a PDA might initiate the ongoing inflammatory process of severe NEC [24]. We identified CHD as an independent risk factor for higher Bell stages and reduced outcome.…”

Development of necrotizing enterocolitis in full-term infants with duct dependent congenital heart disease

“…In addition, 50% of the infants developed NEC within 7 days after birth (Table 2 ). Mesenteric circulatory insufficiency due to systemic desaturation and decreased cardiac output influences the onset of NEC [ 5 , 7 , 11 , 12 ]. Poor systemic perfusion is caused by systemic-to-pulmonary arterial shunt through PDA, which is believed to cause ischemic injury of the intestine [ 8 , 26 ].…”