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eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Extremely Low Birth Weight Infant

KN Siva Subramanian, MD, Professor of Pediatrics and Obstetrics/Gynecology, Chief of Neonatal Perinatal Medicine, Director of Nurseries, Georgetown University Hospital
Aimee M Barton, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, Georgetown University Medical Center; Sepideh Montazami, MD, Assistant Professor, Department of Pediatrics, Section of Neonatal-Perinatal Medicine, Georgetown University School of Medicine

Updated: Jun 18, 2009

Introduction

Extremely low birth weight (ELBW) is defined as a birth weight less than 1000 g (2 lb, 3 oz). Most extremely low birth weight infants are also the youngest of premature newborns, usually born at 27 weeks' gestational age or younger. Infants born at less than 1500 g are termed very low birth weight (VLBW). Low birth weight (<2500 g) was noted in 8.3% of all births in the United States in 2006, and very low birth weight was noted in 1.48% of all births; approximately 63,137 US births were reported in 2006.1

Infants whose weight is appropriate for their gestational ages are termed appropriate for gestational age (AGA). Infants who are heavier than expected are large for gestational age (LGA); conversely, those smaller than expected are considered small for gestational age (SGA) and are also usually found to be intrauterine growth restricted (IUGR) prior to birth.

Extremely low birth weight survival has improved with the widespread use of surfactant agents, maternal steroids, and advancements in neonatal technologies. The minimum age of viability is now as young as 23 weeks' gestation, with scattered reports of survivors born at 21-22 weeks' estimated gestation.

Mortality and Morbidity

Survivability correlates with gestational age for infants who are appropriate for gestational age (AGA). In 2002, the first-year survival rate was 13.8% for infants with birth weights less than 500 g, 51% for infants with birth weights of 500-749 g, 84.5% for infants with birth weights of 750-1000 g. Infants with extremely low birth weights (ELBWs) are more susceptible to all of the possible complications of premature birth, both in the immediate neonatal period and after discharge from the nursery.

Although the mortality rate has diminished with the use of surfactants, the proportion of surviving infants with severe sequelae, such as chronic lung disease, cognitive delays, cerebral palsy, and neurosensory deficits (ie, deafness and blindness), has not. Although improved neurodevelopmental outcomes have been reported in a few small studies, such improvement has not been seen on a global scale.

A study by the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network was undertaken to relate other known risk factors with likelihood of survival and impairment.2 The study reported that 83% of infants born at 22-25 weeks' gestation received intensive care (consisting of mechanical ventilation). Of all study infants whose outcomes were known at 18-22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. The report suggested the following 4 factors should be considered in addition to gestational age when determining the likelihood of favorable outcome with intensive care:

  • Sex: Female sex has the more favorable outcome.
  • Exposure to antenatal corticosteroids (with favorable effect)
  • Single or multiple birth: Single birth has a favorable effect.
  • Birth weight: Increasing increments of 100 g each add to favorable outcome potential.

In a longitudinal study of1279 extremely premature children, (gestational age ≤28 wk; birth weight <1250 g), Robertson et al found permanent hearing loss in 3.1% and severe-to-profound loss in 1.9%.3 Among affected children, hearing loss was delayed in onset in 10% and progressive in 28%. Prolonged supplemental oxygen use was the most important marker for predicting hearing loss.

Clinical Features

Thermoregulation

As a result of a high body surface area–to–body weight ratio, decreased brown fat stores, nonkeratinized skin, and decreased glycogen supply, infants with extremely low birth weights (ELBWs) are particularly susceptible to heat loss immediately after birth. Hypothermia may result in hypoglycemia, apnea, and metabolic acidosis.

Heat loss can occur in infants with extremely low birth weights in 4 ways: conduction, convection, evaporation, and radiation. Conduction is the transfer of energy from the molecules of a body to the molecules of a solid object in contact with the body, resulting in heat loss. Convection is the similar loss of thermal energy to an adjacent gas. Evaporative heat loss is the total heat transfer by energy-carrying water molecules from the skin and respiratory tract to the drier environment. Radiant loss is the net rate of heat loss from the body to environmental surfaces not in contact with the body. Extremely preterm infants are especially prone to these losses secondary to the poor barrier provided by their thin, poorly keratinized skin.

Temperature control is paramount to survival and is typically achieved with use of radiant warmers or double-walled incubators. Hypothermia (<35°C) has been associated with poor outcome, including chronic oxygen dependency. Immediately after birth, the infant should be dried and placed on a radiant warmer and a hat or another covering should be placed on his or her head. Studies have shown that placing a plastic film over the baby immediately after drying can further minimize evaporative and convective heat losses.

For transport to the neonatal ICU (NICU) from the delivery room, the infant should be covered with either warmed blankets or cellophane wrap. For transport of more than very short distances, the infant should be placed in a double-walled, heated incubator. The delivery room and NICU should be kept warm to aid in the prevention of hypothermia in the preterm infant. Architectural designs should facilitate adjacent location of delivery rooms and NICUs or at least provide separately heated resuscitation rooms. Although chemical heating pads are commonly used to provide a warm surface on which to place the baby, the unregulated heat source may burn the very fragile skin of the infant and are not recommended.4

Hypoglycemia

Fetal euglycemia (maintenance of normal blood glucose levels) is maintained during pregnancy by the mother via the placenta. Infants with extremely low birth weights have difficulty maintaining glucose levels within reference range after birth, when the maternal source of glucose has been lost. In addition, these infants are usually under increased stress compared with their term counterparts and have insufficient levels of glycogen stores. Preterm infants are generally considered hypoglycemic when plasma glucose levels are lower than 45 mg/dL.

Because symptoms of hypoglycemia (seizures, jitteriness, lethargy, apnea, poor feeding) may be less obvious in preterm infants, hypoglycemia may only be detected on routine sampling. One form of accepted treatment consists of an immediate intravenous dextrose infusion of 2 mL/kg of 10% dextrose-in-water solution (200 mg/kg) followed by a continuous intravenous infusion of dextrose at 6-8 mg/kg/min to maintain a constant supply of glucose for metabolic needs and to avoid further hypoglycemia. Rapid infusion of glucose concentrations greater than 10% should be avoided because of the hyperosmolarity of the solution and risk of cerebral hemorrhage. Increased insulin secretion that leads to a "rebound" hypoglycemia is a concern when the insulin is administered through an umbilical artery catheter.

Fluids and electrolytes

Maintenance of fluid and electrolyte balance is essential for normal organ function. Disturbances may result in or exacerbate morbidities, such as patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and chronic lung disease, which is also known as bronchopulmonary dysplasia (BPD). Compared with full-term newborns, infants with extremely low birth weights have proportionally more fluid in the extracellular fluid compartment than the intracellular compartment, and a larger proportion of their body weight is attributable to water. During the first days after birth, diuresis may result in a 10-20% weight loss, which can be exacerbated by iatrogenic causes (eg, radiant warmers, phototherapy).

These infants also have compromised renal function stemming from a decreased glomerular filtration rate and a decreased ability to reabsorb bicarbonate. Immature renal tubular function results in decreased ability to secrete potassium and other ions with a relative inability to concentrate urine. In addition, they reabsorb creatinine via the tubules following birth; thus, serum creatinine levels are elevated for at least the first 48 hours of life and do not reflect renal function for the first few days following birth. Fluid status is commonly monitored with daily (or sometimes twice daily) body weight measurement, strict recording of fluid intake and output, and frequent monitoring of electrolytes.

These infants are prone to nonoliguric hyperkalemia, defined as a serum potassium level greater than 6.5 mmol/L, which has been associated with cardiac arrhythmias and death. Hypernatremia and hyponatremia, reflecting disturbances of free water relative to total body sodium, are often disorders of water rather than sodium. As an infant with extremely low birth weight is exposed to radiant heat, phototherapy, and the relatively dry environment, substantial amounts of free water may be lost, causing a relative increase in sodium concentrations.

Management of hypernatremia in these infants consists of administration of hypotonic fluid to replace the free water loss, perhaps requiring as much as 200-250 mL/kg/d to maintain adequate hydration. Such large amounts of fluid can potentiate a PDA; free water losses may be decreased by early use of double-walled incubators. On the other hand, hyponatremia in the first few days of life may be due to excess free water that results in a dilutional hyponatremia, and restriction of fluid and sodium supplementation may be the appropriate treatment.

Nutrition

Initiating and maintaining growth of these infants is a continuing challenge. Infants are commonly weighed daily, and body length and head circumference are usually measured weekly to track growth. The growth rate often lags because of complications such as pulmonary disease and sepsis. An additional contributing factor is inadequate caloric and protein intake.  Concern that early feeding may be a risk factor for necrotizing enterocolitis (NEC) often defers initiation of enteral feeding, although nutritional management of such infants is marked by a lack of uniformity of practice. Parenteral nutrition may provide the primary source of energy and protein in infants with extremely low birth weights in the first few weeks after birth.

Optimal parenteral nutrition is achieved by use of a specialized solution consisting of amino acids, dextrose (sugar), minerals, and electrolytes, called total parenteral nutrition (TPN). A 20% lipid emulsion is often run separately to complete the nutrition of the infant. Lipid intake may vary from 1-4 g/kg/d (as tolerated) and should be started in the first 24 hours of life for optimal nutrition.

Theoretical concerns regarding infection and hyperbilirubinemia frequently lead to delay in initiation of lipid supplementation. Because these infants lose at least 1.2 g/kg/d of endogenous protein, they require at least that amount of amino acids and 30 kcal/kg/d to maintain protein homeostasis. Recommendations advocate for initiation of protein supplementation within the first 12-24 hours to avoid protein catabolism.

Some investigators postulate that total daily need to approximate fetal protein accretion rates in these infants may be as high as 4 g/kg/d. These infants also need essential amino acids, such as cysteine, and may require glutamine, found in human breast milk but not always present in parenteral nutrition mixtures. Trace minerals, such as iron, iodine, zinc, copper, selenium, and fluorine, are beneficial as well. Early evidence suggests that chromium, molybdenum, manganese, and cobalt may need to be added to the nutritional regimen, especially in infants who require long-term parenteral nutrition. Some centers also add L-carnitine. Prolonged use of parenteral nutrition may result in cholestasis and elevated triglyceride levels. To reduce these complications, regular laboratory tests are usually obtained to evaluate liver function, alkaline phosphatase levels, and triglyceride levels.

Enteral feeding is often begun when the infant is medically stable, using small-volume trophic feeding (approximately 10 mL/kg/d) to stimulate the GI tract and prevent mucosal atrophy. Bolus feedings every 2-4 hours may begin as early as day 1. If tolerated, as evidenced by minimal gastric residuals and clinical stability, feeding may increase by as much as 10-20 mL/kg/d, although feeding practices widely vary. Although bolus feeding may appear to be more physiologically appropriate, infants who do not tolerate the volume of the bolus may be continuously fed.

Clinical studies have consistently demonstrated that infants who are fed earlier and are advanced according to a feeding plan have less incidence of infection and achieve full enteral feeds sooner than counterparts who are less systematically treated. Although the fear of precipitating NEC remains widespread, randomized controlled trials have repeatedly failed to show any relationship between feeding practices (ie, age at initiation, rapidity of advancement, caloric density) and the occurrence of NEC.

Breast milk is considered to be the best choice for enteral feeding and has been shown to have protective effects against NEC. Infants with low birth weights have a high need for macronutrients and micronutrients that approaches intrauterine needs; at the same time, their functionally immature gastrointestinal tract precludes adequate enteral intake. Despite its many immunologic and nutritional advantages, an exclusive diet of unfortified breast milk may provide insufficient quantities of energy, protein, calcium, and phosphorous to support the goals of intrauterine bone mineralization and growth rates in small premature infants. To facilitate this, breast milk must be fortified to provide additional calories, protein, and minerals to promote proper growth. Failure to provide adequate amounts of these essential nutrients, especially calcium and phosphorus, may result in protein malnutrition, hyponatremia, osteopenia of prematurity, or rickets.

Human milk may be supplemented by adding liquid or powder commercially available fortifiers, premature infant formulas, modular supplements, or vitamin/mineral supplements. Commercially available multinutrient fortifiers include Enfamil Human Milk Fortifier (Mead Johnson Nutritionals; Evansville, Indiana) or Similac Human Milk Fortifier (Ross Products, Abbott Laboratories; Columbus, Ohio), both of which are powders. The two formulations have some significant differences in their compositions, which may be clinically important. Similac Natural Care Liquid Fortifier (Ross Products) is also available.

Comparisons of the nutrient content and source of macronutrients of these fortifiers have been published. Potential complications of human milk fortifiers include nutrient imbalance, increased osmolarity, and bacterial contamination. Numerous specially formulated preterm formulas are available that have been shown to promote proper growth when breast milk is not available.

Balance of nutrients is very important in early nutrition. Studies suggest that a high carbohydrate neonatal diet is linked to greater weight gain and reduced insulin sensitivity in extremely preterm infants, making them at risk for metabolic syndrome later in life.

Hyperbilirubinemia

Most infants with extremely low birth weights develop clinically significant hyperbilirubinemia (jaundice) that requires treatment. Hyperbilirubinemia develops as a result of increased RBC turnover and destruction in the context of an immature liver that has physiologically impaired conjugation and elimination of bilirubin. In addition, most preterm infants have reduced bowel motility due to inadequate oral intake, which delays elimination of bilirubin-containing meconium, coupled with increased enterohepatic circulation of conjugated bilirubin that enters the intestinal tract. These complications of extreme prematurity, in addition to typical conditions that cause jaundice (eg, ABO incompatibility, Rh disease, sepsis, inherited diseases), is thought to place these infants at higher risk for kernicterus at levels of bilirubin far below those in more mature infants, although specific serum bilirubin levels that are safe versus toxic have never been elucidated.

Kernicterus occurs when free, unconjugated bilirubin crosses the blood-brain barrier (BBB) and stains the basal ganglia, pons, and cerebellum; diminished protein status and the occurrence of acidosis in infants with extremely low birth weights may potentiate the proportion of unbound bilirubin available to cross the BBB. Infants with kernicterus who do not die may have sequelae such as deafness, mental retardation, and cerebral palsy.

Phototherapy is used to decrease bilirubin levels to prevent the elevation of unconjugated bilirubin to levels that cause kernicterus. Special blue-green lamps with wavelengths of 420-475 nm are used to break down unconjugated bilirubin to the more water-soluble product lumirubin via photoisomerization and photooxidation through the skin. This product can then be eliminated in bile and urine. The light source is positioned at 50 cm above the infant with the rate of bilirubin reduction being directly proportional to the light intensity. Clinical studies have shown maximum effectiveness when the intensity of the light exceeds 12-15 µW/cm2.

Newer phototherapy lights have been developed in recent years that decrease the amount of insensible water loss due to photo-induced vasodilatation. In extremely premature infants, insensible water loss can still be significant, and careful attention must be paid to fluid balance. As with the older models, the infant's eyes should be covered with patches to avoid exposure to the blue light. White light phototherapy is not as effective. Fiberoptic blankets may be used, although skin burns from the devices are concerning.

Although phototherapy of these infants is initiated at birth at some institutions, others start phototherapy when the bilirubin value approaches 50% of the birth weight value (eg, 4 mg/dL in an 800-g infant). Use of prophylactic phototherapy has not been shown to decrease the peak level of total serum bilirubin (TSB) or the duration of phototherapy. If the level of bilirubin does not satisfactorily decrease with phototherapy, exchange transfusion is the next therapeutic option. Exchange transfusion should be considered in if the level of bilirubin approaches 10 mg/dL (or 10 mg/dL/kg). In otherwise healthy term infants, exchange transfusion is not considered until the bilirubin level approaches greater than 20-25 mg/dL and the infant has failed a trial of phototherapy.

In exchange transfusions, almost 90% of the infant's blood is replaced with donor blood, and, if correctly performed, the bilirubin level usually falls to 50-60% of the preexchange level. Complications of exchange transfusion include electrolyte abnormalities (eg, hypocalcemia, hyperkalemia), acidosis, thrombosis, sepsis, thrombocytopenia, and bleeding.

Respiratory distress syndrome and chronic lung disease

An early complication of extreme prematurity is respiratory distress syndrome (RDS) caused by surfactant deficiency. Clinical signs include tachypnea (>60 breaths/min), cyanosis, chest retractions, nasal flaring, and grunting. Untreated RDS results in increasing difficulty in breathing and increasing oxygen requirement over the first 24-72 hours of life. Chest radiography reveals a uniform reticulogranular pattern with air bronchograms. As a result of surfactant deficiency, the alveoli collapse, causing a worsening of atelectasis, edema, and decreased total lung capacity. Surfactants decrease the surface tension of the smaller airways so that the alveoli or the terminal air sacs do not collapse, which results in less need for supplemental oxygen and ventilatory support.

The incidence of RDS is inversely proportional to gestational age, with an incidence of 60% at 29 weeks' gestation. RDS affects about 40,000 infants in the United States annually (most infants with extremely low birth weights are affected). Common complications include air leak syndromes, chronic lung disease or BPD, and retinopathy of prematurity (ROP). Surfactant agents may be administered as prophylaxis or as rescue intervention after RDS. Prophylactic use in infants younger than 28 weeks' gestation has been shown to decrease short-term ventilatory needs; neither strategy has resulted in a decreased incidence of chronic lung disease (BPD).

Synthetic surfactants currently on the market lack the proteins found in animal-derived surfactants and may not be as effective as the latter. Newer synthetic surfactants with a synthetic surfactant protein analog are being tested. The incidence of RDS in preterm infants has been significantly reduced with the use of antenatal steroids to promote lung maturity; an additive effect was seen with the use of both antenatal steroids and early surfactant treatment. The use of antenatal steroids also has been linked to a reduction in the incidence of clinically significant PDA and severe IVH; however, concerns have surfaced regarding neurodevelopmental sequelae of repeated antenatal courses of steroids.

In the last decade, surfactants have been widely used to treat RDS, and it was suggested that surfactants should be routinely administered as prophylaxis in infants younger than 30 weeks' gestation. However, this results in unnecessary treatment in some infants. A shift in practice is occurring, and fewer infants are immediately intubated after birth, making prophylactic treatment with surfactant impossible. Infants who are not immediately intubated are usually maintained with nasal continuous positive airway pressure (CPAP), which has been shown to improve endogenous surfactant production. These infants are intubated and given surfactant only if they fail the initial trial of CPAP, as evidenced by increasing PaCO2, increasing respiratory distress, or persistently high oxygen requirement. A study by Geary et al is promising for a reported decrease in incidence of chronic lung disease using this approach (along with lowered oxygen saturation limits and aggressive early nutrition).5

If used as prophylactic treatment, surfactants should be administered as soon after birth as possible. When administered as rescue treatment, a reasonable approach is to treat most infants as soon as clinical signs of RDS appear or if the respiratory picture does not improve after the initial resuscitation.

A major morbidity of premature birth is chronic lung disease (BPD), which is defined as a need for supplemental oxygen or ventilatory support at 36 weeks' postmenstrual age. This definition has relatively replaced the former definition of oxygen dependence beyond age 28 days. BPD is a staged disease that was originally described by Northway et al in 1967 as the clinical sequelae of prolonged ventilation associated with radiographic and pathologic findings; it is the result of abnormal reparative processes in response to injury and inflammation.6

The National Institute of Child Health and Development (NICHD) Neonatal Network reported the incidence of BPD at 36 weeks in all infants who weighed 501-1500 g increased from 19% in 1990 to 23% in 1996.7 This figure remained steady at 22% in 2000. Sixty percent of very low-birth-weight infants requiring prolonged mechanical ventilation were oxygen dependent at age 28 days, and 30% remained oxygen dependent at 36 weeks postmenstrual age. For infants with extremely low birth weights, the overall incidence of BPD was 40%, with as many as 77% of infants requiring mechanical ventilation developing the disease. No further decrease in the incidence of BPD has been observed since 1996.

Inhaled nitric oxide (iNO) has been used in attempts to either rescue extremely ill preterm infants or to help prevent BPD.8 As a rescue, this treatment is linked to an increase in severe IVH. Unfortunately, iNO is also relatively ineffective in preventing BPD. However, it may decrease serious brain injury and improve rates of survival without BPD in mildly ill preterm infants when consistently used. Further studies are currently underway.

A recent study by Wilkinson et al reported changes in Brainstem Auditory Evoked Responses (BAER) in infants with BPD.9  Their results suggested that these infants had "poor myelination and synaptic function of their brainstem, resulting in impaired functional integrity." Their peripheral neural function did not appear to be affected by their lung disease. Additional studies of brainstem function in infants with BPD are needed to further define what neurologic abnormality, if any, is present.

Patent ductus arteriosis

 In the fetus, oxygenation of the blood is accomplished by the placenta, making blood flow through the lungs unnecessary. The ductus arteriosus is a conduit between the left pulmonary artery and the aorta that results in shunting of blood away from the lungs while the infant is in utero. In full-term newborns, the PDA typically closes within 48 hours of birth because of oxygen-induced constriction. However, the PDA in preterm infants is less responsive to this effect of oxygen, and as many as 80% of infants with extremely low birth weights have a clinically significant PDA. This results in a shunt from the systemic circulation into the pulmonary circulation (a so called left-to-right shunt) that causes various symptoms, including a loud systolic murmur, widened pulse pressures, bounding pulses, hyperactive precordium, and increased effort to breathe. A hemodynamically significant PDA has a negative effect on cerebral oxygenation in the preterm infant. Because of a net decrease in systemic cardiac output due to this left-to-right shunting, decreased urine output, feeding intolerance, and hypotension may also occur.

The diagnosis of PDA is typically confirmed using echocardiography, and treatment includes decrease of fluid intake, indomethacin or ibuprofen administration, and surgical ligation, if necessary. Adequate treatment of PDA has long been theorized to prevent diminished cerebral perfusion and subsequent decreased oxygen delivery. However, more recent studies have suggested that aggressive treatment of PDA with surgical ligation may be associated with a higher rate of chronic lung disease.10

Indomethacin is used prophylactically at some institutions and is administered in the first 24 hours of life to close a PDA in anticipation of the deleterious effects of a continued PDA in an infant with extremely low birth weight. Some evidence suggests that prophylactic use of indomethacin has led to decreased symptomatic PDAs and PDA ligations in these infants.11 Concerns regarding indomethacin and its effects on cerebral and renal blood flow have led to the investigation of other drugs, such as intravenous ibuprofen, which is now available as an alternative agent to close PDAs in preterm infants. Use of ibuprofen in premature baboons for PDA closure was shown to improve pulmonary mechanics, decrease total lung water, increase epithelial sodium channel expression, and decrease the detrimental effects of preterm birth on alveolarization in one study.12  However, caution is recommended because the risks associated with indomethacin are also associated with ibuprofen.

Infection
Infection remains a major contributing factor to the morbidity and mortality of infants with extremely low birth weights and can present at any point in the clinical course. Early onset infection (occurring within the first 72 h of life) may present with immediate respiratory distress shortly after birth or after an asymptomatic period. No matter the timing of presentation, the sequence of events leading to early onset infection begins with colonization of the newborn with bacteria from the maternal genital tract. Herpes viral infection in the newborn is transmitted in a similar manner but infants generally do not become symptomatic until after the first week of life. Late infections typically occur after the first week of life and result from endogenous hospital flora (nosocomial).

Signs of infection are myriad, may be nonspecific, and include temperature instability (hypothermia or hyperthermia), tachycardia, decreased activity, poor perfusion, apnea, bradycardia, feeding intolerance, increased need for oxygen or higher ventilatory settings, and metabolic acidosis. Laboratory studies may include CBC count with differential, blood culture, cerebrospinal fluid culture, urine culture, and cultures from indwelling foreign bodies, such as central lines or endotracheal tubes.

The most common causes of early sepsis in the immediate newborn period are group B streptococci (GBS) and Escherichia coli. Nosocomial sources of infection include coagulase-negative staphylococci (CoNS) and Klebsiella and Pseudomonas species, which may be resistant to the antibiotics typically started for early-onset sepsis, necessitating a different treatment regimen. Methicillin-resistant Staphylococcus aureus is also becoming more common. 

Fungi, most commonly Candida albicans, are frequently a cause of late-onset sepsis in infants with extremely low birth weights and may manifest with the above-mentioned symptoms and thrombocytopenia, particularly if the infant has been exposed to broad-spectrum antibiotics. Indolent late-onset sepsis may be related to CoNS, but fulminant late-onset clinical sepsis is more commonly secondary to gram-negative organisms. Late-onset sepsis is especially common in infants with extremely low birth weights who have indwelling catheters and may occur in as many as 40% of these infants.

In most institutions, first-line therapy in infants with early sepsis is with ampicillin and gentamicin or a third-generation cephalosporin. Vancomycin should be reserved for proven CoNS infections and organisms resistant to other agents to prevent the emergence of resistant organisms. Vancomycin and a third-generation cephalosporin are often used to treat late-onset sepsis and may be adjusted based on sensitivity patterns of positive cultures. Therapy with amphotericin commonly is initiated in infants with proven or suspected fungal infections, although fluconazole is frequently used as an alternative first-line therapy. Cultures should dictate antibiotic management whenever possible to help prevent increased resistance.

Necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a disease of the premature GI tract that represents injury to the intestinal mucosa and vasculature and is the most common intestinal emergency in the preterm infant. Incidence of NEC is directly correlated with decreasing gestational age, occurring in 1-8% of infants admitted to the NICU and in 1-3 infants per 1000 births. NEC accounts for approximately 2,600 neonatal deaths annually, with a mortality rate of 10-50%. Risk factors include asphyxia or any ischemic insult to the GI blood supply. The role of enteral feeding is controversial. Breast milk has been shown to have a protective effect but cannot prevent NEC. The routine use of antenatal steroids and surfactant therapy has resulted in the survival of more infants with extremely low birth weights, increasing the survival rate in the group at the greatest risk.

Presenting symptoms may be vague and include apnea, bradycardia, and abdominal distention. These symptoms can quickly progress to indicators of sepsis, such as large gastric residuals, metabolic acidosis, and lethargy; the presence or absence of these symptoms forms the basis of Bell's objective criteria for NEC. Radiographic findings include stacked bowel loops, pneumatosis intestinalis (presence of gas in the bowel wall), portal venous gas, and free air indicating perforation of the bowel (an ominous sign of impending deterioration). NEC usually presents close to the time that the infant is taking full enteral feedings, usually between the second and third weeks of life.

Infants with NEC not yet perforated ("medical NEC") are nonoperatively treated. Most infants require some mechanical ventilatory support, and peripheral arterial access is recommended. Major fluid resuscitation is often needed, and blood cultures should be obtained. Appropriate fluid resuscitation is important to compensate for capillary leak and third spacing of fluid in the abdominal cavity. Broad-spectrum antibiotics, elimination of oral intake, gastric decompression by nasogastric tube, and supportive measures to correct complications such as metabolic acidosis, thrombocytopenia, and hypotension are undertaken. Surgical intervention may be necessary if evidence of perforation is observed (presence of free air on radiography) or medical treatment fails ("surgical NEC"). Long-term complications include those related to bowel resection (short gut syndrome), bowel strictures, and risk of abdominal adhesions.

Spontaneous bowel perforation often occurs in the first week of life, presenting earlier than a typical case of NEC and may be associated with administration of indomethacin and/or corticosteroids. These infants are not usually as ill as patients with NEC. Other differential diagnoses for NEC include benign feeding intolerance, septic ileus, inspissated meconium syndrome, Hirschsprung enterocolitis, or severe gastroenteritis.

Intraventricular hemorrhage
A hemorrhage in the brain that begins in the periventricular subependymal germinal matrix can progress into the ventricular system causing IVH. Both incidence and severity of IVH are inversely related to gestational age. Babies with extremely low birth weights are at particular risk for IVH because of vulnerability of the germinal matrix and because the protective cerebral autoregulation present in older babies has not yet developed. Any event that results in disruption of vascular autoregulation can cause IVH, including hypoxia, ischemia, rapid fluid changes, and pneumothorax. Presentation can be asymptomatic or catastrophic, depending on the degree of the hemorrhage. Symptoms include apnea, hypertension or hypotension, sudden anemia, acidosis, changes in muscular tone, and seizures. The most commonly used system classifies IVH into 4 grades, as follows:
  • Grade I - Germinal matrix hemorrhage
  • Grade II - IVH without ventricular dilatation
  • Grade III - IVH with ventricular dilatation
  • Grade IV - IVH with extension into the parenchyma
IVH is diagnosed using cranial ultrasonography. Because most IVHs occur within 72 hours of delivery, neurosonography is usually performed on infants with extremely low birth weights during the first week after birth and serially thereafter, depending on clinical scenario. Use of antenatal steroids decreases incidence of IVH, and treatment consists of supportive care.

Progressive intraventricular dilatation and hydrocephalus may necessitate surgical diversion of accumulating cerebrospinal fluid. Early administration of indomethacin may reduce the incidence of grades III and IV IVH when used prophylactically in infants with extremely low birth weights but may adversely affect urine output and platelet function and has not been shown to improve neurodevelopmental function at age 2 years.

Prognosis is correlated with the grade of IVH. The outcome in infants with grades I and II is good, but these infants require close neurodevelopmental follow-up because uncomplicated IVH was associated with impaired cortical development (as evidenced by reduced cortical volume at near-term age) in a study by Vasileiadis et al.13  As many as 40% of infants with grade III IVH have significant cognitive impairment, and as many as 90% of infants with grade IV IVH have major neurologic sequelae, requiring lifetime care.

Prevention of preterm birth is the most effective method of preventing IVH. The risk of IVH is higher in infants who are transported after birth, underlining the need for preterm births to occur at tertiary centers specializing in high-risk deliveries. Adequate resuscitation is paramount, and hypocarbia and hypoxia should be avoided. Maintenance of adequate mean arterial pressure and avoiding elevations in cerebral blood flow as much as possible are vital. Multiple clinical trials have been undertaken to determine the effect of various medications, either antenatally or perinatally, on incidence of IVH. One trial demonstrated a decrease in the incidence of severe grades of IVH but no difference in neurodevelopmental outcomes at age 18-24 months with the use of postnatal indomethacin. Because of the potentially serious complications of indomethacin, the question of using such an approach remains unanswered.

Periventricular leukomalacia
Periventricular leukomalacia (PVL) is defined as damage to cerebral white matter that can result in severe motor and cognitive deficits in infants with extremely low birth weight who survive; it occurs in 10-15% of these infants. PVL most often occurs at the site of the occipital radiation at the trigone of the lateral ventricles and around the foramen of Monro. The origin of PVL is believed to be multifactorial; the injury possibly results from episodes of fluctuating cerebral blood flow, which are caused by prolonged episodes of systemic hypertension or hypotension. PVL has also been linked to periods of hypocarbic alkalosis and chorioamnionitis.

PVL may be diagnosed using brain ultrasonography in patients aged 4-6 weeks, with MRI providing the definitive diagnosis. Terminology to characterize various patterns of white matter injury is currently in a state of flux, reflecting different pathophysiologic mechanisms thought to underlie the observed abnormalities. The presence of PVL, particularly cystic PVL, is associated with an increased risk of cerebral palsy; spastic diplegia is the most common outcome. With the current ability to use MRI for evaluation of the brain prior to discharge, the incidence of diagnosed PVL and other intracranial pathologies can be expected to increase.

Apnea of prematurity
Apnea of prematurity (AOP) is common in infants with extremely low birth weights and is defined as cessation of respiratory activity of more than 20 seconds, with or without bradycardia or cyanosis. These episodes are usually random and may be difficult to distinguish from the gestationally normal pattern of periodic breathing demonstrated in this age group. Apneic episodes are considered clinically significant if greater than 20 seconds in duration and/or accompanied by bradycardia or change in color or oxygenation. The incidence of AOP is inversely correlated with gestational age and weight, occurring in as many as 90% of infants who weigh less than 1000 g at birth.

Apnea can be caused by decreased central respiratory drive, which causes what is termed central apnea, or by an obstruction in which no nasal airflow occurs despite initiation of respiration (obstructive apnea). AOP in a pure sense is secondary to immature respiratory patterns and may be due to a combination of central and obstructive apnea (mixed apnea) in which a lack of central respiratory stimulation is followed by airway obstruction.

Episodes of apnea may also be induced by hypoxia, sepsis, hypoglycemia, neurologic lesions, seizures, and temperature irregularities. Apnea is clinically diagnosed and can be detected via use of cardiorespiratory monitors and pulse oximetry. Pneumography can be used to illustrate the number and severity of the apneic episodes, with or without bradycardia, in conjunction with a continuous electrocardiography recording.

Treatment of AOP includes nasal CPAP and use of pharmacologic agents, such as theophylline and caffeine. Caffeine appears to be more effective in stimulating the CNS and has a wider therapeutic range while causing less tachycardia than theophylline. Theophylline is more efficacious than caffeine as a bronchodilator and diuretic and is often used as an adjunct therapy for BPD. Studies of long-term effects of caffeine on neonatal outcomes are currently underway by the Caffeine for Apnea of Prematurity Trial Group. Thus far, no long-term ill effects have been noted. The incidence of BPD was decreased at hospital discharge for those infants who received caffeine therapy for AOP, and follow-up studies (age 18-21 mo) suggested a decrease in neurodevelopmental disability.14 Follow-up at 5 years is the next goal of this group.

Premature infants who are believed to have AOP at the time of discharge may be sent home with an apnea monitor, although the use of home apnea monitors in infants with AOP remains controversial. AOP often persists beyond 40 weeks' corrected age, which is longer than was previously believed, although most cases have completely resolved by 43 weeks' postmenstrual age. No association between AOP and sudden infant death syndrome (SIDS) has been proven, and the use of home apnea monitoring has not been shown to decrease the incidence of infant death secondary to SIDS. Home apnea monitoring requires training of caregivers in the use of the monitor and in cardiopulmonary resuscitation for infants.

Anemia
The physiologic anemia, also seen in term infants, occurs earlier and is more profound in preterm infants. Multiple reasons for this increased severity of anemia have been proposed, including physiologic responses to decreased oxygen consumption (compared with term), blood loss secondary to phlebotomy for laboratory studies related to clinical management in the first few weeks of life, a developmentally immature erythropoietic response to anemia, decreased survival of RBCs in preterm infants and deficiencies of folate, vitamin B-12, or vitamin E.

Treatment of anemia in premature infants includes transfusion with packed RBCs (PRBCs). Administration of recombinant human erythropoietin and iron to increase erythropoiesis has not been shown to prevent the need for transfusion in the first few weeks of life. Most transfusions occur in the first few weeks of life to help replace losses secondary to phlebotomy; infants with extremely low birth weights usually receive at least one transfusion at some point during the neonatal stay. Transfusions occurring after the first weeks of life are usually in response to signs and symptoms of severe anemia.

To reduce the risk of infection in preterm neonates, infants are often assigned a "dedicated unit" from which they can receive multiple transfusions until the unit expires. In addition, many NICUs have adopted a policy of minimal blood draws and strict transfusion guidelines to minimize need for transfusion. Arbitrary threshold hematocrits that trigger transfusion are being replaced clinically by delay until the infant develops adverse symptoms from the anemia. Anecdotal reports of NEC occurring within 48 hours after transfusion in asymptomatic growing premature infants has served to further discourage the practice of routine transfusion.

Immunization of preterm infants
Preterm infants are at high risk of increased morbidity from vaccine-preventable diseases but are the most likely group to have delayed immunizations. Many parents, and some physicians, regard preterm infants as frail and tenuous, even if they are relatively stable. The American Academy of Pediatrics (AAP) policy states that preterm infants should receive full doses of diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, poliovirus, and pneumococcal conjugate vaccines at the appropriate chronologic age.15 Hepatitis B vaccine is recommended by the age 30 days and may be given at birth or at age 1 month as per individual unit policies.

Some studies have suggested that immunologic response to hepatitis B vaccine is improved if the infant is more than 2000 g at the time of administration, but the AAP does not recommend delaying this immunization beyond 30 days of age. As always, infants of mothers with serology positive for hepatitis B surface antigen should receive the vaccine shortly after birth, along with hepatitis B immune globulin (HBIG). Guidelines for administration in premature infants whose maternal status is unknown recommend HBIG/HBV within the first 12 hours of life.
 
Emotional reaction of parents
The birth of an extremely premature infant or an infant with an extremely low birth weight is associated with a unique kind of stress to a family dynamic. Parents of such infants often experience wide swings of emotion as their time in the care of the NICU progresses. They also often experience all 5 stages of grief from denial to acceptance. The strain on the marriage relationship caused by the birth of such an infant can be tremendous and may result in divorce if not anticipated early in the course of the infant's life. Great care must be taken by caregivers to be considerate of the myriad emotions experienced by parents while giving care to their infants and they should be prepared to provide additional support to the family.

Follow-up Care

Nearly all infants with extremely low birth weights (ELBWs) require neurodevelopmental follow-up monitoring to track their progress and to identify disorders that were not apparent during the hospital stay. These infants typically have complicated medical courses and often go home with multiple treatments and medications. The goals of the neonatal follow-up clinic are early identification of developmental disability; parental counseling; identification and treatment of medical complications; and provision of feedback for neonatologists, pediatricians, obstetricians, and other providers. Specific evaluations of cognitive development, vision and hearing ability, and neurodevelopmental progress is extremely important.

Most preterm infants are not significantly handicapped but do have a higher incidence of cerebral palsy and mental retardation than the general population. Wilson-Costello and colleagues found the incidence of neurosensory abnormality to be as high as 25% in infants born weighing less than 1000 g; 14% had cerebral palsy, 1% had blindness, and as many as 7% had deafness.16 They also have a higher risk of disorders of higher cognitive function, such as language disorders, visual perception problems, attention deficits, and learning disabilities. Infants with grades III or IV intraventricular hemorrhage (IVH) or infants with periventricular leukomalacia (PVL), which are cysts in brain parenchyma that are typically seen on routine brain ultrasonography in infants aged 4-6 weeks, are at the greatest risk for mental retardation. Other risk factors for developmental disabilities include maternal chorioamnionitis, meningitis, sepsis, asphyxia, delayed head growth, and chronic lung disease.

Marlow et al published a follow-up of the EPICure study in which they found that infants born before 26 weeks' gestation had significant cognitive and neurologic impairment at school age.17 The unique design of this study included comparing these children with their school-aged peers. The study was conducted in the United Kingdom and Ireland and had 241 patients, which were compared with 160 classmates born at full term. They also found that 38% of those infants who showed no disability or mild disability at 30 months progressed to moderate-to-severe disability by school age. These children may not have been classified as severe had they been measured on traditional scales rather than being compared with their healthy peers; this sheds new light on the true incidence of disability in extremely preterm infants.

A study of Australian born very preterm infants with extremely low birth weights published in 2003 by Anderson and colleagues also found that survivors who were followed until 8 years of age had intelligence quotient (IQ) scores in the average range, although the mean values were lower than values seen in normal birth weight controls.18 The parents of the followed infants also reported more behavioral issues those with infants who had normal birth weights. These children also had significantly slower educational progress than their normal birth weight peers, although their formal scores on academic achievement tests for reading and spelling were within the average range. According to the teachers involved with these students, members of the very preterm cohort were lagging in the areas of verbal thinking, speech, reading, writing, handwriting, mathematics, general facts, basic motor generalizations, and social behavior. These differences were still seen when children with neurosensory deficits were excluded and adjustment was made for sociodemographic variables.  

Vision
Retinopathy of prematurity (ROP) is a disease of the premature retina that has not yet fully vascularized. Changes in oxygen exposure have been postulated to cause a disruption in the natural course of vascularization and may result in abnormal growth of blood vessels, which can result in retinal detachment and blindness.

Risk factors for severe ROP include prematurity and exposure to oxygen. All infants with extremely low birth weights should undergo an eye examination by an experienced pediatric ophthalmologist at chronological age 4 weeks (or at 31 weeks' postconceptual age if born prior to 27 weeks' gestation) and, depending on the results, at least every 2 weeks thereafter until the retina is fully vascularized, even if the infant is discharged from the NICU.

If ROP is present, its stage and location dictate management, which can range from frequent repeat examinations to laser surgery or even vitrectomy. The presence of significant plus disease, or tortuosity, of the retinal vessels, is a poor prognostic sign and requires immediate treatment. Infants with ROP are also at greater risk for sequelae, such as myopia, strabismus, and amblyopia. Infants with extremely low birth weights who do not have ROP or who have resolved ROP should have a follow-up eye examination at age 6 months. A study of the effects of human milk on development of ROP failed to yield the hoped-for result.19

Hearing
All infants should undergo hearing examinations prior to discharge, using either evoked otoacoustic emissions or brainstem auditory evoked potentials. Infants with extremely low birth weights are at higher risk for hearing impairment because of their low birth weights. Other risk factors include meningitis, asphyxia, exchange transfusions, and administration of ototoxic drugs such as gentamicin. These infants should have a repeat hearing examination at age 6 months.

Other therapy
All infants with extremely low birth weights should be referred to their local early intervention or similar program. These programs allow for physical, occupational, and speech therapy evaluations as well as providing in-home treatment. In the United States, these programs are available in all states and in most counties. These programs should be coordinated with the infant's pediatrician and with the follow-up care clinic. As an increasing number of babies are born and continue to survive with birth weights less than 1000 g, optimizing their chances for healthy productive lives is important.

Medical and Legal Pitfalls

Questions regarding ethical, economic, and legal dilemmas surrounding the care of infants with extremely low birth weights (ELBWs) continue to grow as the number of infants with this condition continues to increase in the postsurfactant era. The United States is no longer alone in confronting neonatal-perinatal medical, legal, and ethical issues. The physician must recognize these decisions are influenced by his or her own views of what is beneficial and just and must learn to see these issues from all points of view (ie, the parents', siblings', the extended family's, the infant's, and society's as a whole). In this situation, the clinician must fulfill 3 ethical obligations: (1) understanding one's own value system; (2) possessing some knowledge of ethics as a formal discipline; and (3) making the actual clinical decision and implementing it in a morally defensible way.

Management of anticipated delivery of an infant with extremely low birth weight and subsequent care requires the clinician to make decisions "in the moment of clinical truth." As information regarding mortality, morbidity, and prognosis changes with time, clinicians must make the decisions they feel to be right for the patient and the family at the time. Using the best information available, the clinician should manage the situation while taking into account the family's wishes and what is in the best interests of both the infant and the mother. When resolving bioethical dilemmas facing families and clinicians, the physician must address issues of futility, extension of the dying process, and respect for the dignity of life, and pain and suffering. From a legal standpoint in the United States, government regulations are based on child abuse laws and are enforced by individual states.

The question of what to do in the case of extreme prematurity (<23 weeks' gestation) is a difficult one. Gestational age, which is typically based on the mother's recount of her last menstrual period, can differ from the actual gestational age by as much as 2 weeks, even when the latest ultrasonographic technology is used. Most centers do not have minimum birth weight criteria for resuscitation, and often a "trial of life" may be discussed with the parents before the birth so that the infant can be resuscitated and evaluated for viability after birth. Viability is the term frequently used to indicate the possibility for a fetus to be live born and capable of surviving to a specified endpoint (ie, a designated time, reaching a certain age and landmark event, admission to the NICU, or discharge from the hospital).

Many institutions have generated center-specific data to help discuss the probability of survival with families prior to delivery. In this instance, care must be taken to explain that the fetus in question could actually be part of the percentage of nonsurvivors and that survival may come with varied disabilities. Discussions about treatment or withdrawal of support are often necessary when the family and medical team agree that continuation of medical treatment is not in the infant's best interests.

Naturally, these circumstances raise numerous ethical, moral, and legal issues and sometimes generate more questions than answers. Bioethics consultants and multidisciplinary ethics committees often discuss such issues in an attempt to arrive at recommendations for clinicians and families. Pellegrino outlined a 5-step schema for arriving at such decisions: (1) establish the facts, (2) determine what is in the patient's best interests, (3) define the ethical issues and principles, (4) state the decision in concrete terms, and (5) justify the decision.20 Each one of these steps can be a difficult process, yielding new insights into the family and patient needs in addition to the clinician's biases.

In 2003, researchers from Helsinki published data on the costs of care of infants with extremely low birth weights during the first 2 years of life.21 They studied 71 infants with extremely low birth weights and compared them with 60 infants with normal birth weights born in their hospital from 1996-1997. Taking into account costs of hospitalization, outpatient care, medication, rehabilitation and travel, ancillary costs from daily care, cost of parents' accommodation during hospitalization periods, and loss of earnings until the corrected age of 2 years, they calculated the total healthcare cost for surviving infants with extremely low birth weights to be 104,635 Euros (approximately $125,562 US dollars). The average cost for a healthy, term control infant was 3,135 Euros (approximately $3,762 US dollars), with an average of 19,950 Euros (approximately $23,940 US) for nonsurviving infants. Breaking down these costs, a normally developed infant with extremely low birth weight had a 25-fold increase in costs over the term controls, whereas mild disability resulted in a 33-fold increase and severe disability resulted in a 68-fold increase.

In the United States, one must consider the higher overall healthcare costs and the fact that paid maternity leave is usually 6 weeks or less, resulting in a larger proportion of lost wages secondary to birth of an infant with extremely low birth weight, making these figures significantly higher. An article published in 2007 in Pediatrics suggested the hospitalization costs for preterm and low birth weight admissions in 2001 totaled $5.8 billion.22  The average cost for an infant born at less than 28 weeks' gestation or less than 1000 g birth weight in this study was $65,600, the highest of all groups studied. As technology advances, healthcare costs will continue to rise; the care team must take into account the severe emotional and financial stress encountered with the birth of an infant with extremely low birth weight. The family is often confused, angry, and frustrated by resulting issues. In addition, society in general is affected by these infants, many of whom are significantly cognitively or physically impaired and require lifelong public assistance.

Although addressed by revisions in the World Health Organizations (WHO)/American Heart Association (AHA)/AAP–endorsed Neonatal Resuscitation Program (NRP) protocol, no single rule has been written regarding what to do in the impending birth of an extremely premature infant. Both the obstetrician and the neonatologist must talk with the parents regarding what can be expected after delivery. The role of the medical team is (1) to fully inform the parents, based on the expected gestational age and any other pertinent prenatal data, of the most recent local and national statistics describing morbidity and mortality; (2) to describe procedures that may occur after the infant is delivered; and (3) to answer any questions the parents may have regarding their infant's care.

Remember that opportunities to discuss management options are available after the infant is born, allowing better evaluation of the infant and time for the family to fully comprehend the situation. Documentation by the clinician of these encounters helps guide further decisions in the care of the infant and guard against liability in the future.

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Keywords

extremely low birth weight infant, ELBW infant, very low birth weight infant, VLBW infant, neonatal hypoglycemia, hyperbilirubinemia, preterm infants, prematurity, premature infants, neonatal respiratory distress syndrome, RDS, patent ductus arteriosus, PDA, infection in premature infants, neonatal necrotizing enterocolitis, NEC, intraventricular hemorrhage, IVH, periventricular leukomalacia, PVL, nutrition in ELBW infant, large for gestational age, LGA, small for gestational age

intrauterine growth restriction, IUGR, chronic lung disease, cognitive delays, cerebral palsy, apnea, metabolic acidosis, bronchopulmonary dysplasia, hyperkalemia, cholestasis, protein malnutrition, hyponatremia, osteopenia of prematurity, rickets, kernicterus, hypocalcemia, thrombosis, air leak syndromes, herpes, group B streptococci, GBS, Escherichia coli, short gut syndrome, benign feeding intolerance, septic ileus, inspissated meconium syndrome, Hirschsprung enterocolitis, severe gastroenteritis, pneumothorax, hypocarbic alkalosis, chorioamnionitis

Contributor Information and Disclosures

Author

KN Siva Subramanian, MD, Professor of Pediatrics and Obstetrics/Gynecology, Chief of Neonatal Perinatal Medicine, Director of Nurseries, Georgetown University Hospital
KN Siva Subramanian, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Society for Parenteral and Enteral Nutrition, American Society of Law Medicine and Ethics, New York Academy of Sciences, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Aimee M Barton, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, Georgetown University Medical Center
Aimee M Barton, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, and Medical Society of Virginia
Disclosure: Nothing to disclose.

Sepideh Montazami, MD, Assistant Professor, Department of Pediatrics, Section of Neonatal-Perinatal Medicine, Georgetown University School of Medicine
Sepideh Montazami, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, British Medical Association, and Royal College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

George Cassady, MD, Clinical Professor, Department of Pediatrics, Stanford University School of Medicine
George Cassady, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Brian S Carter, MD, FAAP, Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Co-director, Pediatric Advance Comfort Team, Monroe Carell Jr Children's Hospital at Vanderbilt
Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Society for Bioethics and Humanities, American Society of Law Medicine and Ethics, National Hospice and Palliative Care Organization, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

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