NEC is an inflammatory disease of the intestine affecting neonates, mostly premature infants, with an associated 10% to 50% mortality.1 Fewer than 10% of all cases of NEC occur in full-term neonates.2 The age of onset of NEC varies inversely with gestational age—that is, premature infants present with NEC later and term infants present with NEC earlier. The pathogenesis is still incompletely understood, but in premature infants it is thought to involve dysfunction or immaturity of the gut barrier, with resultant bacterial invasion leading to inflammation and eventual cell necrosis. In full-term infants, different clinical conditions have been identified as risk factors, although they have been not consistently proven. These factors include perinatal hypoxic events/asphyxia, certain congenital heart malformations, polycythemia/thrombotic conditions, endocrinopathies, and perinatal sepsis.3
In general, it is accepted that the pathophysiology of NEC is likely multifactorial. It seems that the pathway is initiated by mucosal damage (eg, secondary to infection or asphyxia). From there, increased bacterial translocation across the damaged intestinal epithelium triggers endogenous production of signals such platelet-activating factor and tissue necrosis factor, which go on to activate inflammatory cascades.4 What remains to be elucidated is where different clinical factors may play a role in this series of events. For example, are enteral feeding, microbes such as bacteria or viruses, or hypoxic injury simply the initiator of this pathway? Studies have focused on these factors, as they may be involved in the etiology of NEC.
The clinical presentation of NEC can be highly variable, although classically, infants demonstrate abdominal distention, bloody stools, and/or gastric residuals. Some infants can progress quickly to fulminant shock and death. Laboratory evaluation may show elevated white blood cell count with shift to immature cells, neutropenia, thrombocytopenia, electrolyte abnormalities, and metabolic acidosis. Radiographs may show subtle signs such as nonspecific disorganized bowel gas patterns, or fixed, dilated loops. However, the pathognomic finding of NEC is pneumatosis intestinalis, or air in the bowel walls. In more severe cases, portal venous gas or pneumoperitoneum may be seen. Staging via Bell’s classification is based on clinical, laboratory, and radiologic signs, varying from the least severe (stage I) to the worst (stage III).5 Findings on histology include mucosal edema, inflammation, hemorrhage, coagulation necrosis, and mucosal ulceration, with the terminal ileum and proximal colon being the most commonly affected sections. The necrosis and inflammation of the intestinal walls seen microscopically correlates with the abdominal distention and sometimes a “bluish” tinge seen on abdominal examination of these infants.
Once diagnosed, initial management includes bowel rest, decompression with a gastric tube, sepsis evaluation, fluid resuscitation, and broad-spectrum antibiotics. Expectant management is appropriate in hemodynamically stable infants. However, severely affected infants often require ventilatory support, vasoactive medications, aggressive fluid resuscitation, and blood product transfusion. Surgical intervention may be required for frank bowel perforation or for worsening clinical status, implying the need for resection of nonviable bowel.
NEC carries significant morbidity and mortality, with 10% to 50% of infants suffering long-term associated morbidities, 15% to 30% suffering mortality, and 20% to 40% of infants requiring surgery.1,6 Survivors suffer gastrointestinal complications in the short term with feeding difficulties, and in the long term with poor growth, potential liver disease from parenteral nutrition supplementation, or short gut syndrome.
One of the most frustrating aspects of NEC for clinicians is the lack of biomarkers to predict and diagnose disease, and the lack of definitive treatment. Therefore, prevention of NEC would be the ideal solution for a disease as devastating as NEC. There has been a recent emphasis in NEC research on how to prevent NEC, focusing on a number of factors that have been suggested as important in the pathogenesis of disease. Probiotics have been promising in several large, well-designed studies, but have not yet gained wide acceptance in the United States due to strict US Food and Drug Administration guidelines. The use of human milk feeding, as opposed to formula feeding, also has been promising and its protective effect is likely due to the immunoprotective factors found in breast milk and its ability to promote intestinal colonization.6
The physiological normal range of fasting glucose at all ages is 70 to 100 mg/dL. However, there is no universally agreed upon threshold level of blood glucose considered to be sufficiently low to diagnose hypoglycemia and prompt further evaluation, especially in neonates.7 Use of a glucometer to test a patient’s blood sugar levels (ie, “accuchecks”) should be verified by serum glucose testing. Generally, a serum glucose level lower than 40 mg/dL in the neonatal period has been used as a specific cut-off for likely pathology, necessitating further evaluation. Hypoglycemia in the neonatal period can be caused by several disease states, including sepsis or other hypermetabolic states, glycogen storage diseases, fatty acid oxidation disorders, disorders of gluconeogenesis, limited glycogen stores, hyperinsulinism, and deficiencies of pituitary hormones. Evaluation should be appropriately tailored based on clinical presentation and laboratory findings (Figure 2).
Algorithm for assessment of hypoglycemia. FAO, fatty acid oxidation.
Congenital hypopituitarism is a rare condition, defined as the underproduction of one or more pituitary hormones (Table 1).8 It may occur as a result of birth trauma and/or asphyxia, as part of a number of midline anatomic defects, or secondary to a genetic mutation involving the anatomic development of the pituitary gland.9 Because the clinical presentation can be variable (from none to severe nonspecific symptoms), the diagnosis is often delayed. The most common symptoms include hypoglycemia (which may result in life-threatening seizures, apnea, or cyanosis), prolonged jaundice, or dysmorphic features on examination.10 Dysmorphic features include midline defects, ocular and craniofacial anomalies, and microphallus in males with or without cryptorchidism. Birth size and weight are often normal or moderately reduced. In this patient, hypoglycemia secondary to hypopituitarism may have been an inciting risk factor in her development of NEC,11 although other factors were likely also contributory because the majority of patients with congenital hypopituitarism do not develop NEC.
Schematic of the Hypothalamic-Pituitary Axis
Careful evaluation of these patients is critical, as early treatment prevents the morbidity and mortality associated with untreated hormonal abnormalities. Evaluation should include serum testing for hormone levels, but diagnosis based on laboratory evaluations can sometimes be difficult in the neonatal period as age-normative data are lacking.12 In the newborn period, a growth hormone (GH) level <20 mcg/L during hypoglycemia or after a glucagon stimulation test is definitive. However, with clinical evidence, a single, randomly taken GH level <7 mcg/L in the first week of life can also be diagnostic.13 Thyroid function testing and cortisol function should also be assessed. Pituitary gonadotropin levels and sex steroids, perhaps at birth and then during the “mini-puberty” of infancy at age 2 months, may be helpful to aid in early treatment to minimize medical and psychological complications associated with deficiencies resulting in micropenis in males.
Definitive diagnosis can be made by MRI of the brain and pituitary gland, and MRI may also identify associated structural anomalies. Classical congenital hypopituitarism is characterized by the triad of pituitary stalk interruption syndrome: (1) an interrupted or thin pituitary infundibulum, (2) an absent or ectopic posterior pituitary, and (3) anterior pituitary hypoplasia or aplasia.14 Other associated structural abnormalities may include optic nerve hypoplasia, absent septum pellucidum, agenesis of the corpus callosum, septo-optic dysplasia, and Arnold-Chiari I malformation.15
Although the majority of cases (80%–90%) of congenital hypopituitarism are sporadic,16 specific gene mutations have been found in an increasing number of cases, especially as the identification of genes that are key in pituitary development and hormone production is expanding. A positive family history and significant malformation of the pituitary gland are risk factors that increase the likelihood of finding a specific genetic mutation. Patients with a complex phenotype, including anterior pituitary hormone deficiencies in association with extra-pituitary abnormalities or malformations, generally have defects in transcription factor genes that are expressed in the early development of the forebrain and midline structures. Patients with pure anterior pituitary hormone deficiencies but normal hypothalamo-pituitary morphology often have mutations of pituitary-specific transcription factors that act late in pituitary development.17 This categorization underlies the importance of MRI in diagnostic evaluation, as genetic testing can be recommended on the basis of imaging findings.
Early treatment with hormone replacement therapy is critical to avoid growth impairment (due to growth hormone deficiency), fatal adrenal crisis (due to cortisol deficiency), or cretinism (due to thyroid hormone deficiency). Adequate replacement of both growth hormone and cortisol may be key to avoidance of hypoglycemia and adverse neurologic sequelae that may ensue in the important early period of critical neurocognitive development. Children with GH deficiency that are untreated may be more than 4 standard deviations below mean height by age 1 year, and may only achieve 70% of growth potential.17 Periodic evaluation of thyroid and cortisol function is also important. The need for replacement of sex hormones should be assessed based on the individual patient, and becomes especially important at the age of normal pubertal maturation. A short course of testosterone over a few months in infancy or childhood may address the micropenis that ensues from hypogonadism, and replacement of testosterone, and later follicle-stimulating hormone and luteinizing hormone may optimize penile size and sexual and reproductive function in adulthood.18,19