Discussion

In this population of term-born neonates undergoing cardiac surgery within the first 28 days of life, we identified a 2.64 fold increased odds of developing necrotising enterocolitis, if born by caesarean delivery. This information is important given the high prevalence of caesarean deliveries among newborns with prenatally diagnosed CHD. ^{Reference Peyvandi, Nguyen and Almeida-Jones13} While these findings need further evaluation in future studies, the mechanistic foundations for such findings can be postulated (discussed further below). We did not identify an association between increasing gestational age (linked with more developmental maturity) and a reduced risk of necrotising enterocolitis in this term-born cohort. Additionally, this study showed that preoperative enteral feeds did not increase the risk of necrotising enterocolitis.

Whilst the development of necrotising enterocolitis is multifactorial and remains largely ambiguous, this study carries with it clinical importance in identifying the risk associated with the mode of birth. Development of necrotising enterocolitis in a newborn with CHD often occurs in the setting of impaired mesenteric blood flow or cardiogenic shock, likely resulting in mesenteric hypoperfusion. ^{Reference Siano, Lauriti, Ceccanti and Zani14,Reference Kelleher, McMahon and James15} This is unlike the classical necrotising enterocolitis seen in premature neonates, which involves immaturity of the immune system making the intestine vulnerable to necrotising enterocolitis. The implications of caesarean section versus vaginal birth must be considered when evaluating the risk of infants predisposed to necrotising enterocolitis development. There is an approximately 1.5-fold increase in the rate of primary caesarean sections associated with prenatally diagnosed CHD. ^{Reference Ge, Mahle, Burd, Jelin, Sekar and Jelin10} The decision for planned birth is predicated on beliefs that it is safer for the baby or mother to deliver early. With increase in prenatal diagnosis rates globally, it is likely the numbers of prelabour planned caesarean deliveries will increase; in the absence of other maternal or fetal risk factors we suggest every effort should be made to allow spontaneous onset of labour.

Mode of delivery is known to be an important factor that affects the composition of the gut microbiota throughout the neonatal period and into infancy. The role of aberrant bacterial colonisation in disease pathogenesis has long been acknowledged in literature identifying the role of microbiomes in necrotising enterocolitis development. ^{Reference Musemeche, Kosloske, Bartow and Umland16} Caesarean delivery is followed by a considerably altered gut microbiota during the neonatal period and into infancy. ^{Reference Korpela17,Reference Shao, Forster and Tsaliki18} While babies born vaginally are rapidly colonised by organisms from their mother and environment, babies born by caesarean are largely not exposed to the maternal flora. ^{Reference Lawrence, Bates and Gaul19} Caesarean delivery prevents vertical transmission of gut microbes from mother to the infant. Caesarean born infants have low levels of Bifidobacteria, almost total lack of Bacteroides and have high levels of opportunistic pathogens such as Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Enterococcus, Enterobacter, Klebsiella species, and Clostridium perfringens. ^{Reference Korpela17,Reference Shao, Forster and Tsaliki18} Overgrowth of one or more of these pathogenic organisms (several of which produce exotoxins) creates an environment for later development of necrotising enterocolitis when the gut mucosal integrity is further compromised in cardiac neonates. The newborn gut in this setting takes up macromolecules intact and toxic products from the rapidly multiplying pathogenic bacteria may be absorbed leading to further damage, initiating necrotising enterocolitis. ^{Reference Lawrence, Bates and Gaul19} The high risk of necrotising enterocolitis observed in our study in association with caesarean delivery could potentially be related to an increased propensity to gut inflammation, disordered immune and metabolic development related to gut microbial dysbiosis. ^{Reference Korpela17}

Our results showed a non-significant association between preoperative enteral feeds and risk of necrotising enterocolitis. A cardinal trait of necrotising enterocolitis is a compromised epithelial and endothelial barrier between the intestinal lumen and bloodstream, giving cause to associate necrotising enterocolitis with a disease of prematurity. The notion of avoiding enteral feedings preoperatively, which may further deteriorate gastrointestinal permeability, was thus founded. However, as shown previously, ^{Reference Good, Sodhi and Yamaguchi20} the abundance of human milk oligosaccharide in expressed breast milk may be protective. These findings align with those of a study from Sweden (where it is routine practice to feed preoperatively). Among infants with ductal-dependent systemic circulation, 96% (198/206) were enterally fed before cardiac intervention, and only one infant was diagnosed with necrotising enterocolitis. ^{Reference Nordenstrom, Lannering, Mellander and Elfvin21} It is likely that preoperative enteral feeds (particularly mother’s milk) does not contribute to the risk of necrotising enterocolitis but may also be protective against it. Human milk contains several protective bactericidal and bacteriostatic factors, many of which have been shown to reduce the necrotising enterocolitis incidence. ^{Reference Lawrence, Bates and Gaul19} Our study did not show a meaningful association between preoperative feeds and development of necrotising enterocolitis. Previous literature ^{Reference Nordenstrom, Lannering, Mellander and Elfvin21–Reference Willis, Thureen, Kaufman, Wymore, Skillman and da Cruz23} and results from our institution also did not show an association between preoperative enteral feeds and necrotising enterocolitis. ^{Reference Day, Dionisio, Zannino, Brizard and Cheung24} Unless newborns preoperatively have major haemodynamic instability, enteral feeds (atleast small to moderate volumes) using mother’s milk should be encouraged routinely in cardiac neonates. Feeding guidelines to facilitate this are likely to have a meaningful impact.

The primary limitation of this study surrounds its inability to derive a direct causal relationship between necrotising enterocolitis and the variables investigated. The influence of mode of delivery on bacterial populations is not always easy to elucidate, especially when faecal samples, utilised as surrogate for the gut microbiome, were not collected. Future studies in this cohort may benefit from analysis of stool samples as has been shown previously. ^{Reference Neu and Pammi25,Reference Jakobsson, Abrahamsson and Jenmalm26} Another limitation is that we did not capture the use of antibiotics prior to the caesarean section, although it might be reasonable to assume that that antibiotics are commonly given during caesarean delivery. Previous literature has raised the role of antibiotic use and alterations in microbiota diversity. ^{Reference Neu and Pammi25} However, a previous study of gut microbiota diversity has also clearly shown that the microbial diversity did not differ between mothers who were given antibiotics prophylactically and who did not receive those. ^{Reference Jakobsson, Abrahamsson and Jenmalm26}