Case reports
Case A
A male infant was delivered at 32 weeks of gestation with an antenatal diagnosis of transposition of the great arteries with an intact ventricular septum. The infant was born small for gestational age (weight 1342 grams, less than 10th centile) and required ventilatory support at birth. Postnatal echocardiography confirmed the diagnosis. An uneventful balloon atrial septostomy was performed. The infant developed transient systemic hypoperfusion leading to renal compromise that resolved with supportive management.
After discussion with the cardiac surgeons, it was resolved to wait till the infant was at least 2.5 kilograms for an arterial switch operation. It was decided that ductal patency (Prostaglandin E1, 10 nanograms per kilogram per minute) be maintained in order to keep the left ventricular and pulmonary artery pressures at systemic levels, thereby facilitating an arterial switch without the need for a post-operative left ventricular assist device or pre-operative pulmonary artery banding. After 48 hours, the infant developed increasing tachypnoea and high oxygen saturations (greater than 95%), suggesting a substantial left–right shunt. The prostaglandin dose was reduced (5 nanograms per kilogram per minute) and subsequently ceased but with only a mild reduction in duct size. There was significant “ductal steal” present, with reversal of diastolic flow on Doppler imaging of the thoracic aorta, as documented in Figure 1. Feeds – expressed breast milk – were commenced on day 4 and were gradually graded up to full feeds by day 11. The milk was fortified with human milk fortifier, FM 85 (Nestle Nutrition, Munchen, Germany) to 85 kilocalories per 100 millilitres on day 14 to accelerate weight gain. Within 16 hours of commencement of fortified milk, the infant developed clinical and radiological evidence of necrotising enterocolitis. Initially treated conservatively, but following further deterioration, he underwent an exploratory laparotomy on day 23, which revealed extensive necrosis of the small bowel unsuitable for surgical resection. The infant died shortly after.
Figure 1 Two-dimensional colour Doppler view of the patent ductus arteriosus and thoracic aorta showing a large duct with “diastolic steal”.
Case B
A male infant was delivered at 35 weeks following spontaneous premature labour. He was also born small for gestational age (weight 2030 grams, less than 10th centile) and required respiratory support at birth. Antenatal scans had shown multiple anomalies including a ventricular septal defect, bilateral renal hydronephrosis, and ascites. Echocardiography confirmed a large mal-aligned ventricular septal defect with mild pulmonary stenosis. Postnatal scans confirmed bilateral enlarged renal pelvi-calyces with a normal bladder. The ascites had resolved. Renal function was maintained.
Feeds were commenced on day 3 and gradually graded up to full feeds – mostly term formula feeds – by day 8. A high-calorie formula (85 kilocalories per 100 millilitres) was commenced on day 15 to accelerate weight gain, and within 12 hours the infant presented with clinical and radiological evidence of necrotising enterocolitis (Fig 2). He was treated conservatively with nil by mouth antibiotics over the next 2 weeks. There was a recurrence of symptoms when feeds were reintroduced, resulting in a reversion to conservative therapy. The infant eventually tolerated feeds of unfortified expressed breast milk a month later. He underwent surgical closure of his ventricular septal defect at 4 months of age and has done well since.
Figure 2 Abdominal and chest anteroposterior X-ray of patient B on day 16, 12 hours after being commenced on fortified human milk. Note colonic necrotising enterocolitis with pneumatosis intestinalis in the ascending, transverse, and descending colon, including the sigmoid.
Discussion
Prenatal diagnosis of congenital heart abnormalities has led to an increasing number of infants being cared for by neonatal intensive care units before cardiac surgery. Many of these infants are born prematurely, necessitating prolonged hospitalisation before cardiac surgery.
Necrotising enterocolitis is the most common gastrointestinal emergency occurring in neonates. It is an acute inflammatory disease of multifactorial aetiology, characterised by variable damage to the intestinal tract ranging from mucosal injury to full-thickness necrosis and perforation. A recent large database analysis found an incidence of necrotising enterocolitis of 1.62% in infants undergoing surgery for congenital heart disease – 194 of a total of 11,958 patients,Reference Mukherjee, Zhang, Chang, Vricella, Brenner and Abdullah 1 which is lower than previously reported (3.3–7.8%)Reference McElhinney, Hedrick and Bush 2 , Reference Leung, Chau and Hui 3 but still high overall. For term infants, congenital heart disease emerges as the main risk factor for developing necrotising enterocolitis, with mortality comparable to that of premature infants with necrotising enterocolitis.Reference Ostlie, Spilde and St Peter 4 Increased mortality from necrotising enterocolitis has been shown in premature infants with congenital heart disease as well.Reference Dees, Lin, Cotton, Graham and Dodd 5 In contrast to necrotising enterocolitis in premature infants, a recent large case–control study of infants with congenital heart disease found that the age of onset of necrotising enterocolitis was earlier – 7 days versus 2–3 weeks – and the clinical presentation as less likely to include systemic signs of illness.Reference Lambert, Christensen and Henry 6 In these infants, the increased risk of necrotising enterocolitis is associated with prematurity, hypoplastic left heart syndrome, truncus arteriosus, and impaired systemic perfusion or shock.Reference McElhinney, Hedrick and Bush 2
Episodes of poor perfusion, shock, and diastolic flow reversal in the abdominal aorta have all been associated with the development of necrotising enterocolitis in neonates with congenital heart disease.Reference McElhinney, Hedrick and Bush 2 Harrison et alReference Harrison, Davis and Reid 7 found that superior mesenteric artery flow was impaired in neonates with hypoplastic left heart syndrome, with diastolic flow reversal occurring commonly in the vessel both before and immediately after the modified Norwood procedure. The underlying condition predisposing term or near-term infants to the development of necrotising enterocolitis may be altered mesenteric blood flow rather than gut immaturity.
Human breast milk fortification has been reported as a risk factor for developing necrotising enterocolitis in premature infants in the absence of congenital heart disease.Reference Hallstrom, Koivisto, Janas and Tammela 8 In fact, a study comparing two different types of human milk fortifiers reported an incidence of necrotising enterocolitis of only 5.5% and those of severe necrotising enterocolitis – Bell stage 2 or more – as low as 1%,Reference Berseth, Van Aerde, Gross, Stolz, Harris and Hansen 9 which is comparable to the incidence of necrotising enterocolitis and severe necrotising enterocolitis in very low birth weight babies not receiving milk fortifier.Reference Reis, Hall and Schanler 10 As a result, fortification of human breast milk has been generally accepted as a safe and acceptable treatment for premature infants to increase the intake of protein, calories, and minerals so as to accelerate their growth and weight gain. However, in situations of mesenteric ischaemia, the addition of fortifiers with an increased osmolality may prove injurious to the intestinal mucosa, contributing to the development of necrotising enterocolitis. Human milk fortifier increases the osmolality of breast milk from 297 milliosmoles per kilogram of water to as high as 361 milliosmoles per kilogram of water depending on the concentration of human milk fortification, increasing further to 449 milliosmoles per kilogram of water if stored for a number of hours.Reference De Curtis, Candusso, Pieltain and Rigo 11 There might be a case to consider measuring the osmolality of fortified milk before administration in a high-risk preterm infant.
The paper describes the onset of necrotising enterocolitis in the context of recent fortification of milk to accelerate growth in two preterm infants with cardiac abnormalities awaiting surgery. Whether this was a complication of their disease process over time or as a result of a causal association cannot be established. However, as medical and surgical advances allow for the palliation and correction of complex cardiac lesions at an earlier gestational age and lower birth weight, the already higher risk of necrotising enterocolitis in this population is likely to increase. This will require more aggressive study of its aetiology in infants with cardiac disease together with the development of preventative therapies to decrease the morbidity and mortality. There are few data comparing different regimens of enteral feeding in this high-risk population. There might be a case to justify a trial of different types of milk – unfortified, partially fortified, or fully fortified – in the pre-operative period. Till more evidence is available, it may be prudent to adopt a cautious approach to accelerate growth in these patients with close monitoring of their gastrointestinal tolerance.
Declaration
The authors confirm that the case reports here conform to the hospital ethics committee's guidelines. The authors further declare that there is no financial support provided for the report and no potential conflicts of interests.
