Neonatal sepsis as a cause of retinopathy of prematurity: An etiological explanation

Abstract

Retinopathy of prematurity (ROP) is a complex neonatal disorder with multiple contributing factors. In this paper we have mounted the evidence in support of the proposal that neonatal sepsis meets all requirements for being a cause of ROP (not a condition, mechanism, or even innocent bystander) by means of initiating the early stages of the pathomechanism of ROP occurrence, systemic inflammation. We use the model of etiological explanation, which distinguishes between two overlapping processes in ROP causation. It can be shown that sepsis can initiate the early stages of the pathomechanism via systemic inflammation (causation process) and that systemic inflammation can contribute to growth factor aberrations and the retinal characteristics of ROP (disease process). The combined contribution of these factors with immaturity at birth (as intrinsic risk modifier) and prenatal inflammation (as extrinsic facilitator) seems to provide a cogent functional framework of ROP occurrence. Finally, we apply the Bradford Hill heuristics to the available evidence. Taken together, the above suggests that neonatal sepsis is a causal inducer of ROP.

Keywords: Infection; Inflammation; Newborn; Prematurity; Retinopathy; Sepsis.

Figure 1.

The concept of “etiological explanation” holds that the term “etiology” (causal history) includes the entire process of disease occurrence, i.e., the etiological process. The etiological process consists of two overlapping sub-processes, i.e., the causation process and the disease process. While the causation process includes causes and the pathomechanism that connects causes with disease, the disease process includes the (subclinical) pathomechanism and the (clinical) disease from start (very first signs or symptoms) to finish (recovery or death). Reprinted from (Dammann, 2017), with permission.

Figure 2.

The proposal of “visuopathy of prematurity” is that both prenatal intrauterine infection and inflammation (IUI) as well as neonatal sustained systemic inflammation (SSI) may contribute to the etiology of both retinopathy of prematurity (ROP) as well as long-term abnormal visual outcomes (AVO) such as structural changes visible on magnetic resonance images, dorsal stream dysfunction, and retinal architecture changes. Reprinted from (Ingvaldsen et al., 2021); with permission.

Figure 3.

Panel A. Rothman’s sufficient-component cause model (Panel A) posits that all diseases are caused by constellations (A-C) of component causes (1–9) where each constellation is sufficient to cause the disease (Rothman, 1976). Note that all three constellations represent a sufficient cause while only component cause 1 is a necessary cause. Panel B. “Combined contribution” (Panel B) is a functional extension of Rothmans model. Causal constellations are made up of initiators, mediators, modifiers, and facilitators. See text for explication of visuals. (Reprinted from (Dammann, 2017) with permission)

Figure 4.

Etiological explanation for the occurrence of retinopathy of prematurity (ROP). Preterm birth is a precondition (not a cause) that provides the background before which the etiological process takes place. Associated (dashed line) with preterm birth are the postnatal causes oxygen (O₂) and sepsis (Sep) which start the causation process by initiating inflammation/oxidative stress-related growth factor aberrations that represent the pathogenetic mechanism that serves as the biological mediator between cause and effect.