Extremely premature newborns (sometimes called extremely low gestational age newborns, or ELGANs), those born before 28 weeks gestational age (GA), represent a uniquely challenging patient population. These patients suffer high morbidity and mortality.1, 2, 3, 4 Much of this morbidity and mortality arises from the patient being forced to transition from the intra- to extra-uterine environment at a time when they are not developmentally prepared for this transition. Management of these patients therefore requires providers to consider their physiology a cross between neonatal and fetal. This complexity can be daunting to pediatric surgeons when they become involved in their care. The goal of this review is to summarize the challenges posed by ELGANs to pediatric surgeons across multiple organ systems, so that surgeons can provide the best possible care and avoid the potential unique pitfalls inherent to these fragile patients.

Neurologic complications are unfortunately common in ELGANs. These stem from a combination of incomplete anatomic development at birth, trauma or insults related to early delivery, and the consequences of medical interventions, such as blood transfusion and mechanical ventilation, on the delicate cerebral blood flow. In order to understand the neurologic risks in these preemies, it is important to review normal fetal brain development.

Development of the fetal brain proceeds by interconnected but distinct steps. The first of these is neural induction, which takes place between weeks 3 and 4 of gestation. This results in neural plate formation, which subsequently gives rise to the central nervous system, and the neural crest, which eventually becomes the peripheral nervous system. Disruptions of this crucial phase of development can often lead to fetal demise. The second step is neuroblast proliferation, which occurs during gestational weeks 8-25. Around the same time, neurons migrate to their final topographic destinations during weeks 8-34. Once they arrive, they aggregate to form either nuclear groups or cortical layers. Neuronal differentiation is a complex process that starts at 5 weeks of gestation and continues through 4 years of age. During this time, synaptic transition modes and specializations are formed. Myelination, which starts at 25 weeks gestation, also continues well beyond gestation and finalizes around 20 years of age.5

Developmental deviations or insults at any of these stages can result in severe neurologic pathology. Intracranial hemorrhage (ICH) is one of the most common neurologic complications associated with prematurity. Risk increases significantly with lower gestational age, especially at less than 30 weeks gestation.6 The most common form of ICH in this population is intraventricular hemorrhage (IVH). This occurs at the site of the geminal matrix which is rife with immature vessels and unsupportive connective tissue that make it prone to bleeding. The delicate germinal matrix starts slowly involuting at 20-26 weeks GA and is absent in term infants. Its presence in ELGANs is a significant risk factor to IVH.7 Additional contributing factors include the premature baby's fluctuating and immature hemostasis, frequent episodes of hypoxia, and potential need for blood transfusions as well as mechanical ventilation which raises intrathoracic pressure and alters cerebral blood flow.7,8

The Papile classification is most often used to grade IVH in premature newborns, with Grade I being a subependymal hemorrhage, Grade II being intraventricular hemorrhage without ventricular dilation, Grade III being IVH with ventricular dilation, and Grade IV consisting of IVH with associated parenchymal hemorrhage (Figure 1).9 Grade III to IV hemorrhage is associated with substantial immediate and long- term negative outcomes, including increased mortality. Seizures arise in 5-10%, and 50% experience post-hemorrhagic hydrocephalus.10 Although Grade I – II IVH is not considered as severe, it has been found that preterm newborns with Grade I – II IVH do have an increased risk of moderate to severe neurosensory impairment.11 If the ELGANs survive the perinatal period, there are long term sequela of IVH which mostly relates to motor and developmental delay. Among premature infants with Grade III-IV IVH, between one-half and three-fourths have debilitating cerebral palsy and three-fourths have been reported to have learning disabilities requiring substantial educational assistance prior to age 9.10

Management of IVH mostly consists of screening and early diagnosis as well as optimizating of hemodynamic status and respiratory regulation.10 The American Academy of Neurology recommends screening ultrasounds for all neonates born prior to 30 weeks gestational age: the first ultrasound is to be done within 7 to 14 days of life and is to screen for the existence of IVH. The second is done around 36-40 weeks corrected gestational age in order to identify associated CNS lesions such as periventricular laukomalacia.12

Periventricular leukomalacia (PVL) is another severe lesion that is associated with prematurity and is a harbinger of significant long term neurologic impairment. PVL consists of focal or diffuse lesions that affect the white matter peripheral to the lateral ventricles. PVL affects up to 10% of all neonates born at or before 33-35 weeks gestational age who live at least three days.13 It is thought to be caused by hypoxic-ischemic insults or by infection that lead to inflammation and necrosis.14 Among infants with PVL who survive, 60%-100% will have cerebral palsy.15

In addition to the specific pathologies described above, prematurity in general is associated with impaired neurologic development. All infants born prior to 26 weeks GA have a 50% chance of demonstrating mild to severe neuromotor or sensory disability which will become apparent by age of 2 years. Mild disabilities include intellectual and learning delays, attentional deficit, and executive functional impairment. The number effected improves to only 10% for those infants born between 27 and 31 weeks GA.16 Overall, neurologic screening and monitoring is key in identifying any lesions while in the NICU and it should be expected that any neurologic pathology that is identified will long-term, and potentially life-long, consequences.

Pulmonary morbidity in ELGANs can be both acute (e.g. respiratory distress syndrome, RDS) and chronic (e.g. bronchopulmonary dysplasia, BPD). Pathophysiology is largely rooted in incomplete lung development.

Fetal and neonatal lung development is divided into five stages, orchestrated by complex molecular mechanisms.17,18 These stages are as follows:

Embryonic stage (4-7 weeks gestation): The initial lung bud develops from the ventral aspect of the future esophagus, then subsequently branches to form the 2 primordial lungs. Lobar and segmental branching occurs by the 7th week.

Pseudoglandular stage (7-17 weeks gestation): Continued bifurcation produces a highly branched airway system (up to 20 generations), with the most distal being the terminal bronchioles. Pulmonary vascular development proceeds in the mesenchyme, and is considered complete by 20 weeks.

Canalicular stage (16-25 weeks gestation): Respiratory bronchioles and early alveolar airways form, with thinning of the mesenchyme and closer approximation of the vascular beds to the epithelium. Distal epithelial cells differentiate into Type 1 and 2 alveolar cells, the latter of which produce surfactant. Lamellar bodies, which will become the source of pulmonary surfactant, can be identified as early as 20 weeks gestation, though true surfactant production will not be observed until 26 weeks.19The result of the canalicular stage is airway-blood gas exchange units with the potential for surfactant production, making 22 weeks gestation the currently accepted threshold for viability.

Saccular stage (24-38 weeks gestation): Terminal saccules generate from respiratory bronchioles, which then septate to form true alveolar sacs. Surfactant production begins around 26 weeks, with secretion by 30 weeks.

Alveolar stage (38 weeks to several years post-natal age): Early alveoli continue to septate and mature, with continued angiogenesis to maintain appropriate ventilation-perfusion matching. Though postnatal alveolar development is most rapid during the first 2 years of life, evidence now supports alveolar development through the entire period of linear growth.20,21

The predominant acute pulmonary pathophysiology in extremely premature newborns is respiratory distress syndrome (RDS). RDS is nearly ubiquitous in the extremely premature neonatal population, with 93% of newborns born < 28 weeks gestation affected.22 The cause is surfactant deficiency. Since the primary role of surfactant is to decrease alveolar surface tension, RDS is characterized by high alveolar surface tension and resulting atelectasis and decreased compliance. This is often exacerbated by pulmonary edema, likely related to impaired lung fluid resorption, as the immature lungs demonstrate decreased expression of epithelial sodium channels.23 ELGANs also have a compliant chest wall, incomplete alveolarization (as they remain in the canalicular to saccular stage of lung development), and collapsible airways, all of which contribute to atelectasis and decreased surface area for gas exchange.

The diagnosis of RDS is clinical, and it should be suspected in any preterm neonate with signs of respiratory distress, including retractions, head bobbing, nasal flaring, and grunting. FiO2 required will generally be at least 30-40%. A chest radiograph will often support the diagnosis, showing low lung volumes, ground glass opacities and air bronchograms (Figure 2).

Respiratory management in extremely premature newborns is directed at preventing atelectasis and addressing surfactant deficiency. Therefore, the mainstays of treatment are 1) continuous positive airway pressure (CPAP), and 2) surfactant replacement. The American Academy of Pediatrics Committee on Fetus and Newborn published guidelines on respiratory support of RDS, and on surfactant administration, in 2014.24,25 Based on numerous clinical trials, these recommendations are:

Early administration of CPAP. This can be non-invasive (via nasal prongs or mask) or invasive (endotracheal intubation). Early use of non-invasive CPAP may decrease the need for endotracheal intubation and the duration of mechanical ventilation.

Administration of exogenous surfactant as an early rescue therapy (as opposed to prophylactic use based solely on gestational age). In a 2012 Cochrane review, the approach of CPAP with selective use of surfactant was found be associated with less chronic lung disease and mortality than an approach of intubation with prophylactic surfactant administration.26 This recommendation is further supported by the United Kingdom national consensus, who recommends rescue surfactant following CPAP initiation if an FiO2 > 30% is still required, as this predicts CPAP failure and conversion to intubation and mechanical ventilation.27

Between 43% and 88% of extremely premature newborns < 29 weeks gestation will fail non-invasive CPAP and surfactant alone and require endotracheal intubation.2,28 Not surprisingly, the odds of requiring invasive mechanical ventilation increase with decreasing gestational age. Perhaps the most important consideration with mechanical ventilation in the premature population is that this support can be simultaneously life-saving and injurious. High tidal volumes (volutrauma), pressures (barotrauma), and inspired oxygen (oxytrauma) all have potentially deleterious effects. Therefore, the overarching goal of mechanical ventilation is to provide only the support that is needed to support the physiology of the newborn, and not more.

Conventional mechanical ventilation is most often employed when intubation is required. Ventilation modes that allow for supported spontaneous breaths, such as synchronized intermittent mandatory ventilation (SIMV) or assist-control ventilation (A/C) are generally preferred for improved ventilatory synchrony, gas exchange, and patient comfort.29 Positive end-expiratory pressure (PEEP) is initially set at 5 cm H2O, and can be increased to prevent atelectasis. Tidal volumes are limited to 4-6 ml/kg to prevent volutrauma. Volume control ventilation is generally favored over pressure control ventilation as it more consistently delivers breaths within this desired range, and it has been associated with lower rates of bronchopulmonary dysplasia, pneumothorax, and intraventricular hemorrhage, as well as with shorter duration of mechanical ventilation.30,31 Respiratory rates as high as 50 are tolerated; if these are unable to provide adequate carbon dioxide clearance, permissive hypercapnia up to PCO2 of 65 mmHg with pharmacologic alkali therapy can be judiciously employed.

At times, transition to high frequency ventilation must be considered, whether that be via high frequency jet ventilation (HFJV) or high frequency oscillatory ventilation (HFOV). An in-depth discussion of the mechanisms and management of these strategies is outside the scope of this article. In short, both employ small volume “breaths” at multiple cycles per second (HFJV: 240-660 breaths/minute; HFOV: 3-15 Hz), and are thought to rely on laminar inspiratory flow down the center of the airways, and peripheral, more turbulent expiratory flow. Settings using jet ventilation include PEEP, peak inspiratory pressure (PIP), and mean airway pressure (Paw) as well as rate/frequency and FiO2. Those involved with HFOV include Paw, frequency, inspiratory time, and amplitude (or delta P). There is little evidence to suggest a strong benefit of either elective HFJV or HFOV. HFOV has been associated with modest decreases in rates of bronchopulmonary dysplasia; neither has shown a mortality benefit.32,33

Bronchopulmonary dysplasia (BPD) is the hallmark chronic lung pathology associated with extreme prematurity. The simplest and perhaps most widely used definition in clinical trials is the requirement of supplemental oxygen at 28 days postnatal age or 36 weeks post-conceptual age.34 This definition has been revised, with the 2001 consensus guidelines providing a more relevant, staged depiction of the disease, breaking BPD into mild, moderate, and severe and accounting for the use of positive pressure ventilation.35 According to the NICHD Neonatal Research Network 2010 report, the overall incidence of BPD in extremely premature newborns (using the simplified definition) was 42%. When breaking this down by gestational age, this ranged from an 85% incidence for those delivered at 22 weeks, to 23% incidence at 28 weeks.22 Though gestational age at delivery is the predominant predictor of BPD, other risk factors exist, including being small for gestational age,36 maternal smoking,37 aggressive mechanical ventilation (as observed by lower arterial PaCO2),38 high oxygen concentrations,39 and sepsis.40

BPD, an adverse outcome in itself, is associated with its own morbidity and mortality. A recent 2021 study found a 3% mortality, and nearly 6% with severe BPD.41 Readmissions are common, with one in three admitted within the first corrected year.42 Infants with BPD may suffer serious consequences from respiratory infections such as respiratory syncytial virus,43 and have up to a 25% incidence of pulmonary hypertension.44 Though BPD may be associated with worse neurodevelopmental outcomes, this association is likely multifactorial.45 Overall, for survivors of extreme prematurity, ongoing respiratory issues are common and make these patients challenging even once they leave the NICU.

Even with term delivery, the cardiopulmonary system is forced to undergo abrupt and significant change in order to transition to extrauterine life. This transition is complicated by extreme prematurity, leading to issues such as hypotension, persistent pulmonary hypertension, patent ductus arteriosus and cardiac failure.

The cardiovascular system is the first organ system to form and function in utero. As early as 3 weeks GA the primitive heart has connections to the arterial and venous system and pumping capabilities.46,47 By 8-9 weeks, a 4-chamber heart is formed and by 10 weeks the fetal-placental circulation is established.46, 47, 48, 49 Fetal circulation is defined by low systemic vascular resistance (due to low pressure placental circulation) and high pulmonary vascular resistance. The right and left ventricles work in parallel, with right side dominance, a configuration enabled by three primary fetal shunts: the foramen ovale, ductus arteriosus, and ductus venosus.49,50 This fetal circulation prioritizes oxygen delivery to the brain and heart, and diverts blood from the pulmonary vasculature, with only 10-25% of right ventriclar output going to the lungs.48, 49, 50 At birth, breathing is initiated and the umbilical cord is clamped. The pulmonary vascular resistance drops and systemic vascular resistance rises. As a result, the ductus arteriosus and foramen ovale close, thereby changing the right and left circulations from in-parallel to in-series circuits and leading to left heart dominance.48, 49, 50

In preterm infants, ductus arteriosus patency is frequently prolonged, with lower gestational age correlating with longer peristence.51-53Patent ductus arteriosus (PDA) is the most common cardiac complication in ELGANs and is associated with increased morbidity and mortality.51, 52, 53, 54, 55, 56 Left-to-right shunting increases pulmonary blood flow, which can increase the risk of bronchopulmonary dysplasia. PDA is also associated with increased risks of necrotizing enterocolitis (NEC), IVH, renal failure, and death.48,49,51, 52, 53, 54, 55, 56, 57, 58, 59, 60 However, the links between these phenomena are unclear, and it remains unknown if treating a PDA improves morbidity or mortality.51,52,59,60 There is substantial evidence that routine iatrogenic closure of all PDAs is not beneficial. A more conservative approach to PDA management with treatment in high risk preterm neonates with hemodynamically significant PDAs has become preferred, though defining hemodynamic significance is debated. Closure can be accomplished by medical, surgical, or percutaneous techniques.

Medical Closure: Options include ibuprofen, indomethacin, or acetaminophen. All three have similar efficacy.51,57,58,60 Ibuprofen and indomethacin, both cyclooxygenase inhibitors, constrict the PDA. Ibuprofen, and possibly indomethacin, increases risk of NEC, spontaneous intestinal perforation, and acute kidney injury, and both decrease renal and cerebral blood flow.51,54,57,58,60 Acetaminophen inhibits prostaglandin synthesis leading to PDA closure.51,54,57, 58, 59, 60, 61 It has a more favorable side effect profile than indomethacin and ibuprofen with less thrombocytopenia, renal insufficiency, and gastrointestinal bleeding.62 Acetaminophen is not FDA approved for PDA treatment.

Surgical Closure: Surgical ligation has fallen out of favor. In the past, PDA closure in ELGANs was common and even performed prophylactically, but as less invasive options have become commonplace, surgical closure is often used as last resort.51, 52, 53,55,60,61 Surgical ligation has been linked to increased BPD, ROP and neurodevelopment impairment along with significant post-operative complications and cardiac instability.51,53,55

Percutaneous Placement of Vascular Occluders: Percutaneous transcatheter PDA closure has become more common in premature neonates. Small devices such as the piccolo have made placement feasible in preterm infants as small as 700g.60,63,64 Though promising, robust data and long-term outcomes are lacking, as are consensus guidelines on which ELGANs should be offered the procedure.

The blood pressure in premature neonates increases with increasing post-conceptual age.48,49,65, 66, 67, 68, 69, 70 However, normal blood pressure ranges in preterm newborns remain unclear. Many neonatal providers endorse the post-conceptual age as the lower limit of acceptable mean arterial pressure (MAP) in mmHg, while others believe a MAP of 30mmHg should be consider the lower limit, as below this there is loss of cerebral autoregulation. Neither approach has strong clinical evidence. This makes management of hypotension, which is common in extremely premature infants, challenging. At least 40-50% of ELGANs will experience clinically-significant hypotension, and this has been linked to increased risk and severity of IVH, periventricular leukomalacia, ROP, BPD, necrotizing enterocolitis, worse neurodevelopmental outcomes, and death.48,49,65, 66, 67,69, 70, 71 Treating hypotension has been shown to improve neurodevelopment outcomes in some studies, and yield no benefit in others.68 More important than blood pressure alone is signs of systemic end-organ perfusion when deciding to treat. In the setting of hypotension and suspected hypoperfusion, an appropriate differential diagnosis of the etiology is essential. The most common causes of hypotension in ELGANs are cardiac shock, adrenal insufficiency, sepsis and medications.48 Hypovolemic shock is rare in this population.

Dopamine is the most widely used vasoactive medication for hypotension in ELGANs. However, it may increase oxygen consumption, and is known to cause tachycardia, hyponatremia, and thyroid dysfunction.70, 71, 72, 73, 74 Dobutamine is used frequently in the setting of myocardial dysfunction as it increases cardiac output. Epinephrine use has increased, but has not been studied as extensively as dopamine. It is as effective as dopamine for increasing MAP and has better chronotropy with increased side effects of lactic acidosis and hyperglycemia.68,70, 71, 72, 73 Hydrocortisone may be added when adrenal insufficiency is suspected, which is extremely common in ELGANs. It increases MAP, urine output and myocardial function, while decreasing the need for other vasoactive medications.71, 72, 73, 74 Vasopressin is being utilized more frequently and has been shown to treat hypotension in extremely premature neonates, but there is paucity of data on consequences and efficacy.

The kidney is a complex organ that has multiple functions that are crucial in normal body homeostasis including filtration, water and electrolyte balance, acid-base, immune function and blood pressure regulation, bone mineralization, erythropoiesis and drug and toxin metabolism along with many others. The origin of these functions begins with the development of the fetal kidney. Renal organogenesis is complex and is generally broken tino three stages: pronephro, mesonephro and metanephro.75 The first stage begins at approximately 3-5 weeks gestation. The first nephron develops around 8 weeks gestation, after which nephron count grows exponentially until about 28 weeks, and nephrogenesis concludes by 34-36 weeks gestation. At the end of normal fetal kidney development, there are an average of 900,000 to 1,000,000 nephrons to carry out the kidney's multiple functions.76

Premature birth is a significant disruption in renal development. As gestational age and weight decrease, there is thought be a decrease in nephron endowment and maladaptation. This is especially significant in infants born less than 28 weeks GA who are undergoing peak nephron development. With very preterm infants, the glomerular filtration rate (GFR) is lower, sodium reabsorption is limited for 2-3 weeks after birth, and there is decreased ability to concentrate urine.75,77 All these aspects mature with increasing gestational and postnatal age.

The immature renal function of ELGANs is reflected by elevated serum creatinine (SCr). In the immediate postnatal period, SCr correlates with maternal values, but then rises due to increased tubular reabsorption and reduced creatine clearance.78 Eventually SCr declines and reaches equilibrium79, 80, 81. This occurs because of ongoing postnatal renal development, with creatinine clearance and GFR increasing with chronological age. Reference ranges for predicted mean and 95th percentile SCr by chronological age and gestation age group are published and should be used as guidance when evaluating renal dysfunction.80

In utero, the placenta manages fluid and electrolyte balance, but at birth the kidney must take over. For ELGANs this is challenging as the immature kidneys’ ability to compensate for water and electrolyte imbalances is limited. Furthermore, the transition from fetal to neonatal life includes major changes in water and electrolyte homeostasis. Understanding this is important in order to appropriately manage fluids and electrolytes to prevent neonatal morbidities. For instance, excessive fluid restriction puts ELGANs at risk for hypernatremic dehydration and excessive fluid can lead to hyponatremia and volume overload. These issues can then predispose preterm neonates to BPD, IVH, and NEC.

Postnatal fluid and electrolyte changes in ELGANs can divided in three phases: prediuretic, diuretic and homeostatic.82, 83, 84 The phases are independent of fluid intake and the onset and duration of each phase varies between each neonates based on gestational age and birth weight. Table 1 summarizes the observations in each phase with appropriate guidelines for management.

Prematurity, along with perinatal and postnatal stressors placed on the developing kidneys, has both short- and long-term implications.85 Reduced nephron endowment, maladaptation, and exposures such as hypoxemia, infection, hypovolemia and nephrotoxic medications increase the risk of acute kidney injury (AKI). This can potentially lead to hypertension, proteinuria, and chronic kidney disease.86, 87, 88 AKI itself has been found to increase morbidity and mortality in low gestational age infants.89, 90, 91, 92 Avoiding nephrotoxic exposure and limiting AKI is therefore critical in managing ELGANs.

Like the other organ systems previously described, the gastrointestinal (GI) system in ELGANs is immature at birth and susceptible to complications. In fact, GI complications – specifically necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) – are perhaps the most common indications for pediatric surgical consultation in these patients.

During normal fetal development, the gastrointestinal system forms from all three germinal layers. Mesoderm becomes connective tissue, while endoderm eventually forms the epithelial lining of the GI tract. Ectoderm, via differentiation into neural crest cells, gives rise to the peripheral nervous system including gastrointestinal neurons. This process begins during week 3 of gestation with gastrulation and differentiation of the digestive tube. Between week 6-10, the midgut herniates outside of the peritoneal cavity, continues developing, rotates and returns to the peritoneal cavity around week 10. Within the mucosa, intestinal villi begin forming at week 9, and crypts by week 12. Absorptive function is first evident during week 24, and is developmentally mature by week 32.93

Even after complete anatomical development of the gastrointestinal system, functionality is severely impaired prior to 26 weeks gestation.94 These infants are at high risk of poor growth and nutrient deficits. Preterm infants often cannot initiate and sustain early enteral feeding, due to intolerance or precluding factors such as NEC or sepsis. In these cases, infants rely on total parental nutrition (TPN). While consensus is lacking, it is generally agreed that TPN is indicated for all ELGANs or for extremely low birth weight (ELBW) infants (<1,500g) to avoid malnutrition and pathologic weight loss. One systematic review and meta analysis showed that early use of TPN in preterm infants improved growth rates with no demonstrated increase in mortality, NEC, IVH, chronic lung disease, sepsis or cholestasis.95 The benefit for infants born after 32 weeks GA is less established, but TPN is often used as a nutritional bridge in these babies to allow the slow advancement of enteral feeds.96

ELGANs have very high energy demands and proper TPN formulation is important to provide for basal energy expenditure and allow for growth. The caloric needs of preterm newborns are roughly 120kcal/kg/day. Dextrose represents the primary carbohydrate and provides 3.4 kcal/g and 30-35% of daily caloric needs. Though hyperglycemia is common, the use of insulin is not supported as it has shown to increase mortality.97 Protein, in the form of amino acids, also provides 3.4 kcal/g and should make up about 10-15% of caloric content of TPN in order to prevent protein catabolism; provision can be as high as 4g/kg/day.98,99 Lipids provide the remaining 25-40% of non-protein calories. Soybean-based emulsions have been found to accelerate the development of TPN-induced cholestasis and liver failure and are not recommended to be used for more than 2 weeks. Emulsions based solely on or including fish oil, such as Omegaven® or SMOFlipid® (Fresenius Kabi, Bad Homberg, Germany), have shown promise in improving liver dysfunction and cholestasis.97

After initiating TPN, enteral feeds are usually initiated as long as there are no contraindications. This must be done carefuly as extreme prematurity and enteral feeding predispose to development of NEC. Though specific feeding strategies vary, there is substantial evidence to support the use of human breast milk over formula. Human milk alone has been shown to reduce the incidence of NEC by six-fold in infants <1,850 g.100 The use of donor breast milk in lieu of the mother's own milk has demonstrated protective benefits as well, but lacks strong evidence and requires further study.100 The timing of enteral feeding initiation also lacks strong evidence, but starting feeds at or after 14 days of life has been associated with late-onset sepsis.100

The GI tract of premature infants is clearly susceptible to serious pathology. Among the most notable diagnoses are NEC and spontaneous intestinal perforation (SIP). NEC is characterized by intestinal inflammation that can lead to necrosis. One of the most common surgical diseases among preterm neonates, it affects about 1 in 1,000 infants overall and about 7% of infants with a birthweight between 500 and 1500 grams.101,102 It is most commonly seen in preterm infants and has a peak incidence around 31 weeks gestational age.103 Mortality is high – between 15 and 30% - with lower birthweight and gestational age increasing mortality.102 NEC can affect any area of the intestine, though ileal disease is most commonly seen. Its exact pathophysiology remains poorly understood, though it is believed to be related to an abnormal immune response triggered by an intestinal stimulus, such as the initiation of enteral feeds. The epithelium subsequently loses mucosal integrity and results in bacterial translocation and activation of stress pathways. No one bacterial species has been implicated, but studies have found that patients with NEC have a higher proportion of anaerobes and decreased bacterial diversity.104 ELGANs are at particularly high risk for NEC due to their incompletely developed intestinal motility and lack of coordinated peristalsis, as well as immature intestinal barriers which increase mucosal permeability.102

The classic presentation of NEC is a preterm infant who has initiated enteral feeds and, around 1-2 weeks of age, develops feeding intolerance, abdominal distention, and bloody stools. Radiographic signs, when present, include pneumatosis intestinalis with or without portal venous gas (Figure 3).101 In more severe cases, pneumoperitoneum can be seen, signifiying full-thickness necrosis and perforation. It should not be confused with other forms of intestinal diseases such as SIP or intestinal ischemia preceded by severe cardiac dysfunction or secondary to polycythemia and hyperviscosity.103

SIP is another source of GI pathology in ELGANs. It is defined as intestinal perforation in a newborn with no discernable source. Like NEC, the terminal ileum is most often involved, though it can occur anywhere in the intestinal tract. However, unlike NEC, it tends not to be associated with the same degree of intestinal inflammation and ischemia. It is also not frequently associated with the initiation of enteral feeds.101 The exact etiology and pathogenesis are unknown, although it may be related to fetal or neonatal hypoxia combined with the compromised intestinal growth and motility associated with lower gestational ages.105,106 SIP is more common, and outcomes are worse, in lower gestational ages. Overall, it affects 1.6% of infants ≤ 32 weeks gestational age, and almost 90% of these cases are in those ≤ 28 weeks.106

Prevention and treatment of NEC has been the subject of significant research and effort. As mentioned, Grade A/B evidence supports the use of breastmilk rather than formula. There is also evidence that probiotic supplementation in the first week of life can help prevent severe forms of NEC. However, while it is widely accepted that NEC is associated with the initiation of enteral feeds, there is no strong evidence to support delaying the initiation of feeds or slowing the advancement of enteral feeds in the prevention of NEC.107

Once NEC is diagnosed, treatment is larely based on the severity. The most widely-accepted staging system is the Bell's classification, which was first published in 1978 and categorizes NEC into 3 stages (Table 2).108 Stage 1 is suspected NEC in which a premature baby has been initiated on enteric feeding and later presents with distention, feeding intolerance, and possible ileus found on radiographs and occult blood in the stool. Stage 2 is definitive NEC and includes the addition of grossly bloody stools and radiographic evidence of pneumatosis intestinalis and/or portal venous gas. Finally, Stage 3 includes the previously listed signs and symptoms plus clinical deterioration, usually accompanied by pneumoperitoneum.108 Stage I or II NEC can often be managed nonoperatively. This includes bowel rest (usually with addition of TPN), nasogastric tube decompression, and antibiotics. However, septic shock or signs of perforation (Stage III) warrant surgical intervention.101 Though defined by different patholophysiology, the same applies to SIP.

Standard surgical management of both NEC and SIP includes either laparotomy with resection of the perforated and necrotic bowel, or placement of a peritoneal drain. The choice between drain or laparotomy remains controversial. A 2011 Cochrane Review evaluated these options for NEC and SIP and did not demonstrate any significant difference in mortality at 28 and 90 days. However, only two randomized controlled trials met the review's criteria and the resulting sample size was very small.109 A recently published multi-institutional randomized control trial by Blakely et.al. evaluated the outcomes of laparotomy verses drain for ELBW infants with SIP or NEC. The study confirmed that there was no significant difference in death or neurodevelopmental impairment at 18 and 22 months. However, for those with a suspected preoperative diagnosis of NEC, laparotomy appeared to correlate with reduced incidences of death and neurodevelopmental delay when compared with infants with a preoperative diagnosis of SIP.110 Currently, both surgical methods are considered viable options in the setting of bowel perforation in either disease, and choice largely depends on surgeon discretion.

NEC is associated with high mortality and several factors influence survival, including Bell's stage, gestational age, birth weight, comorbidities, and whether or not surgical intervention is required. Mortality of surgical NEC is estimated at 30-50%.111 Survivors of NEC can suffer numeours long-term complications. These infants are much more likely to experience feeding difficulties, show signs of malabsorption, and develop strictures. It is estimated that about 20% of surgically-managed infants will have short gut syndrome.111 Neurologic compliciations are also common, including IVH and retinopathy of prematurity (ROP),106 and 25% of NEC survivors will have significant neurodevelopment delays.101 SIP is also correlated with higher rates of IVH and ROP, though neurodevelopmental outcomes appear less affected than with NEC.106,112

The immune system in the fetus develops much earlier than previously thought. As early as 7 weeks GA, pre-T cells expressing CD34 migrate to the thymus and mature into T cells.113 Natural killer cells are seen as early as 9 weeks and dendritic cells at 13 weeks GA.114 However, the immune system is constantly changing and developing throughout life, and the fetal immune system acts very differently than the fully developed adult immune system. For example, although fetuses are exposed to a variety of proteins and foreign cells that are transferred through the placenta, their dendritic cells do not mark them for destruction, but instead activate regulatory T cells which in turn suppress the immune system. This allows for ongoing exposeure to foreign cells without mounting a significant immune response.114

At birth, neonates mostly rely on the innate immune system, which is mainly composed of neutrophils. However, term neonates possess far fewer neutrophils than adults, and these neutrophils also have fewer receptors, including TLR4 and L-selectin. This predisposes to neonatal sepsis. The innate immune system continues to develop over the first year of life. The complement system reaches adult levels by 12-18 months and it is not until 10 years of age that the adaptive immune system is finally mature.113

ELGANs are at an even higher risk of infectious complictions than term newborns because of the immature cytokine production and anti-inflammatory protein production.115 Furthermore, their immune system has not undergone the normal third trimester development, during which time defense against foreign antigens is enhanced.116,117 It has been reported that 25-60% of ELGANs are diagnosed with clinical sepsis with 15-50% of ELGANs having a confirmed positive blood culture.117 Inflammatory processes that accompany neonatal sepsis are also associated with a cluster of diseases common in this patient population that are often seen together, including BPD, NEC, and ROP. The causes and outcomes are multifactorial and can contribute to sustained inflammation which affects the long term complications of the CNS, lungs and gut described previously.117

It is clear that extremely premature newborns are a complex and fragile patient population. Understanding this is crucial when surgeons must operate on these patients. The room, whether the operating room or the bedside, must be kept warm to prevent hypothermia as these babies have a high surface area to volume ratio and lack adipose tissue to retain body heat. Tissue integrity is poorer than in older children or adults, likely owing to both the small size of structures and the high water content. The coagulation cascade is immature and surgical bleeding, especially from solid organs such as the liver and spleen, can be incredibly difficult to control. Meanwhile, the low total blood volume lends extra urgency to hemostasis in these situations. As described above, sepsis is a particular concern in these patients and can make post-surgical complications especially difficult to manage. Taken together, all these considerations should convince any pediatric surgeon to approach these patients and their surgical care with the utmost respect.