Which group has the highest rate of low-birth-weight neonates within the united states?

Overview

An extremely low birth weight (ELBW) infant is defined as one with a birth weight of 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 with a birth weight less than 1500 g are defined as very low birth weight (VLBW) infants.

Approximately 3,952,841 US births were reported in 2012. [1] Low birth weight (< 2500 g) was noted in 7.99% of the births, and VLBW was noted in 1.42% of all births. Over the last 2 decades, there has been a consistent downward shift in the US birth weight distribution, driven by a steady increase in births with weights less than 3500 g and a relative decrease in births with weights over 3500 g.

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

ELBW survival has improved with the widespread use of exogenous surfactant agents, maternal steroids, and advancements in neonatal technologies. The minimum age of viability is currently considered to be 23 weeks' gestation, with scattered reports of survivors born at 21-22 weeks' estimated gestation.

Morbidity and Mortality

Survival correlates with gestational age for infants who are appropriate for gestational age (AGA). In 2010, infant mortality rates were 24 times higher for infants with low birth weight (< 2500g) and 100 times higher for those with very low birth weight (VLBW) (< 1500g) than for infants with birth weights of 2500g or more. First year survival was 15.5% for infants with a birth weight less than 500g. [2] Infants with extremely low birth weight (ELBW) are more susceptible to all complications of premature birth, both in the immediate neonatal period and after discharge from the nursery.

Although the mortality rate has greatly 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 improved as significantly. Despite reports of improved neurodevelopmental outcomes in a few small studies, such improvement has not been seen on a global scale.

A study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network was undertaken to relate other known risk factors with the likelihood of survival and impairment. [3] The study reported that 83% of infants born at 22-25 weeks' gestation received intensive care (consisting of mechanical ventilation). Of the infants whose outcomes were known at 18-22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. Similarly, a 2018 retrospective study (2005-2011) of 210 extremely preterm infants (< 27 weeks' gestation) at a level IV neonatal intensive care unit (NICU) revealed 35% were on intermittent positive pressure ventilation (IPPV) for at least 56 days. [4]

The report suggested other factors be considered in addition to gestational age when determining the likelihood of favorable outcome with intensive care. [3] A web-based outcome calculator was developed for ELBW infants and includes the following 4 factors [5] :

• Sex: Female sex has a more favorable outcome

• Antenatal corticosteroid use: Exposure has a favorable effect

• Single or multiple birth: Single birth has a favorable effect

• Birth weight: Increasing increments of 100g each add to a favorable outcome potential

According to data from a 2011 cohort study, infants born at 23-25 weeks' gestation who received antenatal exposure to corticosteroids had a lower rate of mortality and complications compared with those who did not have such exposure to corticosteroids. [6] More recently, chorioamnionitis has been linked to preterm birth and neonatal infection; additionally, in a longitudinal observational study that included 2,390 extremely preterm infants (gestational age < 27 wk), Pappas et al reported antenatal exposure to chorioamnionitis appeared to increase the odds of cognitive impairment as well as death/neurodevelopmental impairment. [7]

A meta-analysis by Laswell et al indicated that VLBW infants and very preterm infants have increased odds of death when not born in level III hospitals. [8] In addition, the rates of significant intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), which are associated with less than optimal neurodevelopmental outcome, also increase.

A study of 1064 infants born at 28 weeks’ gestation or less found that unless it is accompanied or followed by a white matter lesion, low-grade IVH was associated with a modest and possibly no increased risk of adverse developmental outcome during infancy (age 24 mo). [9]

In a longitudinal study of 1279 extremely premature children (gestational age ≤28 wk; birth weight < 1250g), Robertson et al found permanent hearing loss in 3.1% and severe to profound loss in 1.9%. [10] Among affected children, hearing loss was delayed in onset in 10% of them and was progressive in 28%. Prolonged supplemental oxygen use was the most important marker for predicting hearing loss.

In a study that evaluated the 11-year outcomes in 247 infants born in Sweden at less than 26 weeks' gestation between 1990 and 1992, investigators found that in infants who survive to a postmenstrual age of 36 weeks, brain injury and severe retinopathy of prematurity (ROP) — but not bronchopulmonary dysplasia (BPD) — may predict the risk of death or major disability at age 11 years. [11]

More recently, a prospective longitudinal study of 165 Australian adults aged 25 years who were born extremely preterm or extremely low birth weight (1991-1992) that compared their cardiovascular health profile to 127 control persons aged 25 years found that those born extremely preterm or extremely low birth weight had an overall greater cardiometabolic risk and in specific parameters (abdominal visceral fat, blood pressure, exercise capacity, fasting glucose, particularly predicted by male sex). [12]  Less favorable profiles of exercise capacity and visceral fat were predicted by greater increases in weight Z scores between age 2 and 8 years, and age 8 and 18 years.

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 weight (ELBW) 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 weight in following 4 ways:

• Conduction - 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 - The similar loss of thermal energy to an adjacent gas

• Evaporation - Evaporative heat loss is the total heat transfer by energy-carrying water molecules from the skin and respiratory tract to the drier environment

• Radiation - 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 essential for survival, and it is typically achieved with the 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, as the scalp is a site of large heat loss. Studies have shown that placing a plastic film over the baby immediately after drying or placing the infant on a warming mattress can further minimize evaporative and convective heat losses. [13, 14]

For transport to the neonatal intensive care unit (NICU) from the delivery room, the infant should be covered with either warmed blankets or cellophane wrap, or the top of the warmer should be lowered to prevent heat loss. To transport the infant to other hospital areas, he or she 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; therefore, such pads are not recommended. Caution is due when using any of the currently available methods to prevent hypothermia; frequent monitoring of temperature is necessary to prevent overheating given any combination of approaches.

Hypoglycemia

Fetal euglycemia (maintenance of normal blood glucose levels) is maintained during pregnancy by the mother via the placenta. Infants with ELBW have difficulty maintaining normal glucose concentrations 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 they have insufficient levels of glycogen stores. Preterm infants are generally considered hypoglycemic when plasma glucose levels are lower than 45 mg/dL. [15]

Because symptoms of hypoglycemia (seizures, jitteriness, lethargy, apnea, poor feeding) may be less obvious in preterm infants, hypoglycemia may be detected only on routine sampling.

One form of accepted treatment consists of an immediate intravenous (IV) dextrose infusion of 2 mL/kg of 10% dextrose-in-water solution (200 mg/kg), followed by a continuous IV 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 of greater than 10% should be avoided because of the hyperosmolarity of the solution and the 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). [16]

Compared with full-term newborns, infants with extremely low birth weight (ELBW) 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. In ELBW infants, the serum creatinine peak is higher, and the subsequent decline is slower, than that of term equivalents. In ELBW infants, sustained high creatinemia correlates with immaturity and morbidity. [17]

Fluid status is commonly monitored with daily (or sometimes twice daily) body weight measurement, strict monitoring of fluid intake and output, including estimated insensible water loss, and frequent monitoring of electrolytes.

Hyperkalemia

These infants are prone to nonoliguric hyperkalemia, defined as a serum potassium level greater than 6.5 mmol/L, due to a shift from the intracellular to the extracellular compartment following delivery. [18] Normal potassium concentration is recovered in 4–5 days, with an eventual increase in glomerular filtration rate and increased diuresis. However, nonoliguric hyperkalemia has been associated with cardiac arrhythmias and death. [19] There is no current guideline for the most effective treatment of hyperkalemia in ELBW infants; suggested therapies include insulin with glucose, albuterol inhalation, calcium, diuresis with furosemide, kayexalate and, rarely, exchange transfusion. [20]

Hypernatremia and hyponatremia

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 ELBW 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 salt-poor fluid to replace the free water loss. Some infants may require as much as 200-250 mL/kg/day to maintain adequate hydration. Such large amounts of fluid can potentiate a PDA and increase the risk for the development of BPD. However, free water losses may be decreased by early use of double-walled incubators and further mitigated by providing adequate humiditification. [21]

Alternatively, 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. [22] Again, close monitoring of fluid and salt balance can minimize these complications.

Nutrition

Initiating and maintaining the growth in ELBW infants is a continuing challenge. These infants should be 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, which may compromise the ability to provide optimal nutrition.

The most common factor contributing to poor growth is inadequate caloric and protein intake. Concern that early feeding may be a risk factor for necrotizing enterocolitis (NEC) often deters initiation of enteral feeding, although nutritional management of such infants is marked by a lack of uniformity of practice. Starting with trophic feedings within 24-48 hours of life and regularly increasing the volume of enteric nutrition along with appropriate total parenteral nutrition (TPN) will result in optimal growth.

Insufficient and delayed nutritional support results not only in significant postnatal growth failure [23] but also directly impacts neurodevelopmental outcome [24]  as well as contribute to BPD during the first 14 days of life. [16] Hence, nutritional goals in ELBW infants should aim to quickly establish caloric and protein intake that is equivalent to, or at least very similar to, the in utero delivery rate with early introduction and maximization of both parenteral and enteral nutrition. [25]

Parenteral nutrition

Parenteral nutrition may provide the primary source of energy and protein in infants with ELBW in the first few weeks after birth. Optimal parenteral nutrition of approximately 80-100 kcal/kg/day is achieved by the use of a specialized solution consisting of amino acids, dextrose (sugar), minerals, and electrolytes, called TPN. A 20% lipid emulsion is provided to complete the nutrition of the infant. Lipid intake should be given, even initially, at approximately 3 g/kg/day in the first 24 hours of life for optimal nutrition. [26]

Theoretical concerns regarding infection, hyperlipidemia and hyperbilirubinemia frequently lead to a delay in the initiation of lipid supplementation; however, given the safety of current 20% intralipid formulation, as well as the recommended rate of infusion to not exceed 0.2g/kg/hr, and lack of scientific proof, should encourage earlier optimization of lipid suppmentation. [27]

Because these infants lose at least 1.2 g/kg/day of endogenous protein, they require at least that amount of amino acid and 30 kcal/kg/day to maintain protein homeostasis. Recommendations advocate for initiation of protein supplementation within the first 12-24 hours to avoid protein catabolism [28] and, to that end, many practices have adopted the use of standardized stock solution of parenteral nutrition containing 3 g/80 mL of amino acids in the critical first few days of life. [29]

Some investigators postulate that total daily need to approximate fetal protein accretion rates in these infants may be as high as 4g/kg/day. Evidence to date suggests that early and higher amino acid provision is well tolerated by most infants with extremely low birth weight. Such provision of amino acids will positively affect the plasma amino acid concentrations during the first postnatal week but does not necessarily translate into a significant difference in postnatal growth in the first 28 days. [30, 31]

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. [32] As such, regular laboratory tests are usually obtained to evaluate liver function, alkaline phosphatase levels, and triglyceride levels. The best means to avoid these complications are provision of early enteral nutrition that is advanced on a regular basis and minimizing exposure to TPN.

Enteral nutrition

Enteral feeding is often begun when the infant is medically stable, using small-volume trophic feeding (approximately 10mL/kg/day) to stimulate the gastrointestinal (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 10-20mL/kg/day, although feeding practices widely vary. [33] 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 their counterparts who are less systematically treated. [34] Although the fear of precipitating necrotizing enterocolitis (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. [33, 34, 35, 36, 37]

Breast milk is considered to be the best choice for enteral feeding and has been shown to have protective effects against NEC. [38] A mother’s own milk is preferred unless known contraindications exist, such as galactosemia, maternal infection with human immunodeficiency virus (HIV) (in the United States), and miliary tuberculosis, or maternal use of illicit drugs. However, when a mother’s milk supply is insufficient, pasteurized donor breast milk is an acceptable alternative. [39] Infants with low birth weight have a high need for macronutrients and micronutrients that approaches intrauterine needs; at the same time, their functionally immature GI 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 phosphorus to support the goals of intrauterine bone mineralization and growth rates in small, premature infants. [40] Consequently, 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. [41, 42]

Human milk may be supplemented by adding commercially available liquid or powder fortifiers, premature infant formulas, modular supplements, or vitamin/mineral supplements. Commercially available multinutrient fortifiers include Enfamil Human Milk Fortifier and Similac Human Milk Fortifier, both of which have liquid and powder formulations. These two formulations have a bovine protein base, but there are some significant differences in their compositions, which may be clinically important. Human milk–based fortifiers also exist (Prolact CR).

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. [43]

Hyperbilirubinemia

Most infants with ELBW develop clinically significant hyperbilirubinemia (jaundice) that requires treatment. Hyperbilirubinemia develops as a result of increased red blood cell (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. [44]

These complications of extreme prematurity, in addition to typical conditions that cause jaundice (eg, ABO incompatibility, Rh disease, sepsis, inherited diseases), are thought to place these infants at higher risk for kernicterus at levels of bilirubin far below those in more mature infants, [45] 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 serum protein levels and the occurrence of acidosis in ELBW infants 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

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 photo-oxidation through the skin. This product can then be eliminated in bile and urine. [46]

The light source is positioned at 50 cm above the infant, with the rate of bilirubin reduction directly proportional to the light intensity. Clinical studies have shown maximum effectiveness when the intensity of the light exceeds 12-15 µW/cm2. [47]

Newer phototherapy lights have been developed 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). [47] Use of prophylactic phototherapy has not been shown to decrease the peak level of total serum bilirubin (TSB) or the duration of phototherapy [48, 49] and, in fact, aggressive phototherapy may increase mortality while reducing impairment and profound impairment among the smallest and most ill infants. [50]

Exchange transfusion

If the level of bilirubin does not satisfactorily decrease with phototherapy, exchange transfusion is the next therapeutic option. Exchange transfusion should be considered if the level of bilirubin approaches 10 mg/dL (or 10 mg/dL/kg). [47] In otherwise healthy term infants, exchange transfusion is not considered until the bilirubin level approaches greater than 20-25 mg/dL and a trial of phototherapy in the infant has failed. [51]

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 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 weight [ELBW] are affected). Common complications of RDS and its therapy include air leak syndromes, chronic lung disease or bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP).

Surfactant agents and antenatal steroids

Surfactant agents may be administered as prophylaxis or as rescue intervention for RDS. Prophylactic use in infants younger than 28 weeks' gestation has been shown to decrease short-term ventilatory needs; however, neither strategy has resulted in a decreased incidence of chronic lung disease (BPD). [52]

Currently available exogenous surfactants are either natural, derived from animal lung minces or lung lavages, or synthetic. The first synthetic, peptide-containing surfactant was approved by the US Food and Drug Administration (FDA) in 2009. [53]

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 has also been linked to a reduction in the incidence of clinically significant patent ductus arteriosus (PDA) and severe intraventricular hemorrhage (IVH); however, concerns have surfaced regarding neurodevelopmental sequelae of repeated antenatal courses of steroids. [6]

In the last decade, surfactants have been widely used to treat RDS, and mortality from RDS has been reduced by 50%. It had been suggested that surfactants should be routinely administered as prophylaxis in infants younger than 28 weeks' gestation [54, 55] and the earlier the treatment, the better. However, more recent meta-analyses have shown that in the current practice setting of routine antenatal steroids and early continuous positive airway pressure (CPAP) stabilization at delivery, prophylactic use of surfactant is no more superior to early selective treatment as soon as clinical signs of RDS appear. [56, 57, 58, 59]

In addition, a shift in practice toward non-invasive ventilation is occurring, and fewer infants are immediately intubated after birth, making prophylactic treatment with surfactant impossible. InSureE technique of sequential "Intubate – Surfactant – Extubate to nCPAP" was developed to facilitate early surfactant administration. Many studies have replicated the safety and efficacy of InSurE. [60, 61, 62]

Noninvasive ventilation

Infants who are not immediately intubated are usually maintained with nasal CPAP, which has been shown to improve endogenous surfactant production. These infants are intubated and given surfactant only if the initial trial of CPAP failed, as evidenced by increasing PaCO2, increasing respiratory distress, or persistently high oxygen requirement. [63, 64]

A meta-analysis by Schmolzer et a that included four large randomized controlled trials from 2008 to 2011 concluded that one additional infant could survive without BPD for every 25 babies placed on nasal CPAP in the delivery room rather than being intubated and placed on mechanical ventilation. [65] However, although these trials comparing CPAP to intubation at delivery enrolled ELBW infants exclusively, of note is that none of the trials included infants of 23–24 weeks' gestational age; those infants remain at the highest risk of mortality and may continue to have high need for intubation during initial resuscitation.

Following the increasing use of nasal CPAP, other noninvasive forms of ventilation have gained popularity; most notably, nasal intermittent positive pressure ventilation (NiPPV) and high-flow nasal cannula (HFNC) have risen in favor, respectively, to avoid mechanical ventilation via endotracheal tube, [66, 67] and to provide an alternate ventilator delivery mode.

However, studies comparing NiPPV to nasal CPAP have reported inconsistent findings of short-term benefit without significant long-term benefits. A meta-analysis by Meneses et al showed NiPPV reduced the need for invasive ventilation within the first 72 hours of life compared to nasal CPAP, but there was no difference seen in rates of BPD. [68] More recent large trials by Kirpalani et al also did not show any difference in rates of death or BPD when comparing NiPPV to nasal CPAP. [69]

HFNC is well tolerated and can deliver positive end distending pressure, but the delivery pressure is unrequlated, equivalent to nasal CPAP. However, it has yet to replace CPAP in the initial respiratory stabilization of ELBW infants. HFNC has primarily been evaluated as a noninferior, noninvasive alternate mode of postextubation support to nasal CPAP. [70, 71]

Bronchopulmonary dysplasia

A major morbidity of premature birth is BPD, which is defined as a need for supplemental oxygen or ventilatory support at 36 weeks' postmenstrual age. This definition has, to a relative extent, 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 sequela of prolonged ventilation associated with radiographic and pathologic findings; it is the result of abnormal reparative processes in response to injury and inflammation. [72] Unlike the original description of the classic marked fibroproliferative BPD, the histologic face of BPD has changed in the modern postsurfactant and antenatal steroids era to show arrested lung development with impaired alveolarization and compromised vasculogenesis. [73]

In 2000, the definition of BPD was redefined by the National Institute of Child Health and Human Development (NICHD) according to severity, as follows:

• Mild: Oxygen needed at 28 days or older, but not at 36 weeks postmenstrual age (PMA)

• Moderate: Supplemental oxygen needed at 28 days and older, and 30% or less oxygen need at 36 weeks PMA

• Severe: Need for mechanical ventilation and oxygen over 30%

Radiologic findings of BPD were replaced eventually by physiologic testing to determine supplemental oxygen need by an objective criteria. [74]

In an NICHD Neonatal Network study of 9575 ELBW infants at 22–28 weeks' gestation born from 2003 to 2007, 68% of these infants had BPD. [75] The incidence of BPD did not decrease over the 5-year study in this population. In fact, increased survival among low birth weight infants contributed to the overall increase in the incidence of BPD at large. Over the 5-year study period, when BPD was categorized according to severity, the numbers of infants with severe persistent BPD declined. The earliest gestational ages remain at highest risk of developing more severe BPD. [76]  ELBW infants have accounted for more 97% of cases of BPD. [77]

Patent Ductus Arteriosus

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 patent ductus arteriosus (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 up to 80% of infants with extremely low birth weight (ELBW) 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, a decreased systemic blood pressure, bounding pulses, a hyperactive precordium, and an increased respiratory effort due to pulmonary edema.

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.

Treatment

The diagnosis of PDA is typically confirmed with echocardiography, and treatment includes a decrease in fluid intake, administration of indomethacin or ibuprofen, 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. [78, 79] A 2014 meta analysis showed that surgical ligation of PDA lowers mortality, but it is associated with an increased risk of neurodevelopmental impairment. [79]

Indomethacin is used prophylactically at some institutions; it 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 ELBW infant. Some evidence suggests that prophylactic use of indomethacin has led to a reduction in symptomatic PDAs and in PDA ligations in these infants. [80, 81, 82, 83]

Concerns regarding indomethacin and its effects on cerebral and renal blood flow have led to the investigation of other drugs, such as intravenous ibuprofen. A 2013 Cochrane review concluded that ibuprofen is as effective as indomethacin in closing a PDA, and it reduces the risk of necrolizing enterocolitis and transient renal insufficiency. [84] Ibuprofen appears to be the current drug of choice for PDA closure. [84] Investigations are currently under way to refine pharmacotherapy for PDA, such as evaluating orogastric administration of ibuprofen [85] and analyzing alternative agents such as acetaminophen. [86]

Infection

Infection remains a major contributing factor to the morbidity and mortality of infants with extremely low birth weight (ELBW), and it can present at any point in the clinical course. The overall US incidence of early-onset infection is 0.77 to 1 per 1000 live births, but the incidence increases to 8 per 1000 live births in infants with very low birth weight (VLBW) and to 26 per 1000 live ELBW births. [87] 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 the end of the first week of life. Late-onset sepsis typically occurs after the first week of life and results from endogenous hospital flora (nosocomial).

Signs of infection are myriad and may be nonspecific; they include the following:

• Temperature instability: Hypothermia or hyperthermia

• Tachycardia

• Decreased activity

• Poor perfusion

• Apnea

• Bradycardia

• Feeding intolerance

• Increased need for oxygen or higher ventilatory settings

• Metabolic acidosis

Laboratory studies may include complete blood count (CBC) with differential, blood culture, cerebrospinal fluid culture, urine culture, and cultures from indwelling foreign bodies, such as central lines or endotracheal tubes. Molecular methods such as polymerase chain reaction (PCR) and nonspecific markers such as C-reactive protein (CRP) and procalcitonin (where available) have been incorporated into the routine diagnostic workup. [88]

Other nonspecific screening measures for neonatal sepsis are under investigation; in particular, cytokines—including interleukin 6 (IL-6), interleukin 8 (IL-8), gamma interferon (IFN-?), and tumor necrosis factor alpha (TNF-a)—and cell surface antigens, including soluble intercellular adhesion molecule (sICAM) and CD64, are gaining attention.

Causes

The most common causes of early sepsis in the immediate newborn period are group B streptococci (GBS) and Escherichia coli. The rise of maternal GBS prophylaxis has lead to a reduced mortality from GBS, although GBS is still the most common etiology of sepsis in a newborn, and E coli has become the most common cause of mortality in newborns. 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 (MRSA) has also become more common.

Fungi, most commonly Candida albicans, are frequently a cause of late-onset sepsis in ELBW infants, and they 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, whereas fulminant late-onset clinical sepsis is more commonly caused by gram-negative organisms. Late-onset sepsis is especially common in ELBW infants who have indwelling catheters, and it may occur in as many as 40% of these infants.

Treatment

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 is commonly initiated in infants with proven or suspected fungal infections, although fluconazole is frequently used as an alternative first-line agent. Many institutions provide a fluconazole prophylaxis regimen for the duration of indwelling catheters to reduce the fungemia that is associated with central catheters. [89, 90] Culture results should dictate antibiotic management whenever possible to help prevent increased antimicrobial resistance.

Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a disease of the premature gastrointestinal (GI) tract that represents injury to the intestinal mucosa and vasculature; it is the most common intestinal emergency in the preterm infant. The incidence of NEC is directly correlated with decreasing gestational age, occurring in 1-8% of infants admitted to the neonatal intensive care unit (NICU) and in 1-3 infants per 1000 births. NEC accounts for approximately 2,600 neonatal deaths annually, with a mortality rate of 15-30%. [91, 92, 93, 94]

NEC is predominantly a disease of premature infants; risk factors include dysmotility, abnormal microbiota, gut immaturity with a decreased intestinal barrier, increased permeability, as well as reduced immunity, asphyxia, or any ischemic insult to the GI blood supply. [35, 95]

The role of enteral feeding in this disease is controversial. Breast milk has been shown to have a protective effect, but it cannot completely prevent NEC. Exclusive breast milk feedings as well as implementation and adherence to a feeding protocol have demonstrated reduction in NEC rates in many NICUs. [38, 96, 97] The routine use of antenatal steroids and surfactant therapy has resulted in the survival of more infants with extremely low birth weight (ELBW), thereby increasing the survival rate in the group at the greatest risk. [98]

Antenatal antibiotic use as well as prolonged empiric antibiotic use has been correlated to alterations of gut microflora and an increased risk of NEC. [99, 100, 101] Further alterations in the microbial colonization via antacid H2-receptor antagonists have also been associated with an increased risk of NEC. [102, 103]

Presenting symptoms of NEC may be vague; they 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 (which indicates perforation of the bowel, an ominous sign of impending deterioration). Bedside real-time ultrasonography of the bowel is an emerging diagnostic approach to NEC, allowing functional visualization of the bowel walls, perfusion, and peristalsis. [104] NEC usually presents close to the time that the infant is taking full enteral feedings, usually between the second and third weeks of life. The peak incidence of NEC is between 30-32 weeks' postmenstrual age (PMA).

Treatment

Most infants with NEC 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 leakage 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 (evidence of severely damaged or dead bowel). [105, 106] The timing of surgery, conservative peritoneal drainage versus laparotomy, enterostomy versus primary anastomosis, and duration of antibiotics remain unresolved. [107, 108] Long-term complications include those related to bowel resection (short gut syndrome), bowel strictures, and risk of abdominal adhesions.

Differential diagnosis

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

Intraventricular Hemorrhage

A hemorrhage in the brain that begins in the periventricular subependymal germinal matrix can progress into the ventricular system, causing intraventricular hemorrhage (IVH). The incidence and severity of IVH are inversely related to gestational age.

Babies with extremely low birth weight (ELBW) 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 the following:

• Apnea

• Hypertension or hypotension

• Sudden anemia

• Acidosis

• Changes in muscular tone

• Seizures

The most commonly used classification system divides IVH into 4 grades, as follows:

• Grade I: Germinal matrix hemorrhage

• Grade II: Blood in the ventricle without ventricular dilatation

• Grade III: Blood in the ventricle that results in ventricular dilatation

• Grade IV: Blood in the ventricle, with extension into the parenchyma

Diagnosis and treatment

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 weight during the first week after birth and serially thereafter, depending on clinical scenario. The use of antenatal steroids decreases the 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 weight 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. [109] The outcome in infants with grades I and II IVH is good, but these infants require close neurodevelopmental follow-up because uncomplicated IVH may be associated with impaired cortical development (as evidenced by reduced cortical volume at near-term age). [110] Findings have been conflicting in more recent 18-22-month follow-up studies, in which either no difference or neurodevelopmental impairment is seen in ELBW infants with grade I and II IVH, and school-age outcome comparisons are pending. [111, 112]

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 the 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. [82] 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 (ELBW) 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 magnetic resonance imaging (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), which is common in infants with extremely low birth weight (ELBW), 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 they are greater than 20 seconds in duration and/or are 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.

Causes

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 and monitoring

Treatment of AOP includes nasal continuous positive airway pressure (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.

In a randomized controlled trial conducted by the Caffeine for Apnea of Prematurity Trial group from 1999 to 2004 to study the long-term effects of caffeine on neonatal outcomes, the incidence of BPD was decreased at hospital discharge for those infants who received caffeine therapy for AOP. [113] Although the initial 18–21 months of follow-up studies suggested a decrease in neurodevelopmental disability, [114] the 5-year follow-up study did not show the same neuroprotective relationship. [115]

Large multicenter investigations are under way for the optimal dosing and duration of caffeine therapy. 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 completely resolve 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. [116] Home apnea monitoring requires training of caregivers in the use of the monitor and in cardiopulmonary resuscitation for infants.

Anemia

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 red blood cells (RBCs) (PRBCs). An estimated 90% of extremely low birth weight preterm infants receive RBC transfusions, but the timing and risks remain controversial. [117]

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. [118, 119] Most transfusions occur in the first few weeks of life to help replace losses secondary to phlebotomy; infants with extremely low birth weight (ELBW) usually receive at least one transfusion at some point during their 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 transfusion-related complications in preterm neonates, infants are often assigned a "dedicated unit" of blood from which they can receive multiple transfusions until the unit expires. In addition, many neonatal intensive care units (NICUs) have adopted a policy of minimal blood draws and strict transfusion guidelines to minimize the need for transfusion. Arbitrary threshold hematocrit levels that trigger transfusion are being replaced clinically by delay until the infant develops adverse symptoms from the anemia. [120, 121] Anecdotal reports of necrotizing enterocolitis (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 for increased morbidity from vaccine-preventable diseases, but they are the group to most likely have delayed immunizations. Many parents, as well as 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. For extreme low birth weight (ELBW) infants born to seronegative mothers, hepatitis B vaccine is recommended by the age of 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 2000g 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 immunoglobulin (HBIG). Guidelines for administration in premature infants whose maternal status is unknown recommend HBIG/hepatitis B vaccine within the first 12 hours of life. [122]

Emotional Reaction of Parents

The birth of an extremely premature infant or an infant with an extremely low birth weight (ELBW) is associated with a unique kind of stress to a family dynamic. [123] Parents of such an infant often experience wide swings of emotion as their child's time in the care of the NICU progresses. They also often experience all 5 stages of grief, from denial to acceptance.

In addition, the strain on the marriage relationship caused by the birth of an extremely premature or extremely low birth weight 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 care is given to their infant; these caregivers should be prepared to provide additional support to the family.

Follow-up Care

Neurodevelopment

Nearly all infants with extremely low birth weight (ELBW) 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 as follows:

• Early identification of developmental disability

• Parental counseling

• Identification and treatment of medical complications

• 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 this group of infants does have a higher incidence of cerebral palsy and mental retardation than does the general population. [124] 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) are at the greatest risk for mental retardation. Other risk factors for developmental disabilities include maternal chorioamnionitis, meningitis, sepsis, asphyxia, growth failure, delayed head growth, and chronic lung disease. [125]

Early recognition of infants at risk for adverse long-term neurologic outcomes is vital to implementing early intervention. [126, 127, 128, 129] 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. [126] The unique design of this study included comparing these children with their school-aged peers. In the report, which was conducted in the United Kingdom and Ireland, 241 patients were compared with 160 classmates born at full term.

Marlow and colleagues 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.

In addition, Vohr et al reported the potential overestimation of standardized neurocognitive development evaluation by the widely used Bayley III scoring system. Compared to the second edition (Bayley II), the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) showed higher mean cognitive scores by 11 points. [127, 128] Caution is advised when employing the standardized scale to identify neurodevelopmental disability, and being cognizant of this potential overestimation, early intervention services at the time of discharge for all ELBW infants is recommended.

A 2003 study of Australian-born very preterm ELBW infants reported that survivors who were followed until age 8 years had intelligence quotient (IQ) scores in the average range but that the mean values were lower than those seen in normal birth weight controls. [130]

The parents of the followed infants also reported more behavioral issues than did those with infants who had a normal birth weight. 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.

More recent studies continue to document executive functioning deficits with increased rates of disorders of attention, behavior self-regulation, and socialization in ELBW children at school age. [131, 132]

In a study of 148 ELBW children, Voss et al found that maternal educational background was the strongest predictor of long-term neurodevelopment, pointing to the need for follow-up care and support for poorly educated parents. [133] Optimizing nutrition to promote and support appropriate growth is also recognized as goals of care to maximize the ELBW infants’ neurodevelopmental outcome, both in the initial neonatal intensive care unit (NICU) stay as well as throughout the first years of life. [134]

Vision

In the disorder retinopathy of prematurity (ROP), the premature retina 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 lead to retinal detachment and blindness.

Risk factors for severe ROP include prematurity and exposure to oxygen. [135, 136] The optimum oxygen saturation target remains controversial. Results from multiple studies, such as the NICHD Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT), Canadian Oxygen Trial (COT), Benefit of Oxygen Saturation Targeting (BOOST) trial suggest that although hyperoxia via higher oxygen target ranges of 91-95% can be harmful, lower oxygen target ranges of 85-89% can increase mortality. [135, 137, 138, 139, 140]

Not only is the target oxygen saturation range elusive, keeping infants within a target oxygen range is also challenging. The number of newborns cared for by a nurse is likely a significant factor that contributes to the precision of accomplishing targeted oxygen-saturation goals in the NICU. [141] The precision and the mode of assisted ventilation may be modifiable factors worthy of attention in the NICU as efforts continue to be made to reduce ROP and other oxygen-related toxicities. [142]

All ELBW infants should undergo an eye examination by an experienced pediatric ophthalmologist at chronologic age 4 weeks (or at 31 weeks' postconceptual age if the infant was born before 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. [143]

Kennedy et al supported adherence to the recommended screening guidelines of 2013 American Academy of Pediatrics (AAP) section on Ophthalmology/ American Academiy of Ophthalmology (AAO)/ American Association of Pediatric Ophthalmology and Strabismus (AAPOS) for 24 to 27 weeks' gestational age infants after analyzing those infants enrolled in the SUPPORT study from 2005 to 2009. [144] In this contemporary cohort, the imperative need for postdischarge follow-up of infants at risk for severe ROP was emphasized, as some infants were eligible for home discharge prior to full retinal vascularization.

If ROP is present, its stage and location dictate management, which can range from frequent repeat examinations to photocoagulation by laser surgery, intraocular injection of vascular endothelial growth factor inhibitor, or even vitrectomy. [145] 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.

ELBW infants who do not have ROP or who have resolved ROP should have a follow-up eye examination at age 6 months.

Earlier studies of the effects of human milk on the development of ROP failed to yield the hoped-for result. In previous reports, an exclusive breast milk diet, while reducing rates of necrotizing enterocolitis (NEC), [146] did not reduce the risk of severe ROP in ELBW infants. [147, 148] However, more recent reports suggest that exclusive maternal breast milk feedings may reduce the incidence of any ROP stage in at-risk infants. [149]

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 weight are at higher risk for hearing impairment because of their low birth weight. [150] 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.

Intervention programs

All infants with extremely low birth weight should be referred to their local early intervention program or something similar. These programs allow for physical, occupational, and speech therapy evaluations and provide in-home treatment. [151, 152] 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 a birth weight of less than 1000g, optimizing their chances for a healthy, productive life is important.

Ethical, Economic, and Legal Considerations

Questions regarding ethical, economic, and legal considerations surrounding the care of infants with extremely low birth weight (ELBW) continue to grow as the number of infants with this condition continues to increase in the postsurfactant era. Moreover, the United States is no longer alone in confronting neonatal-perinatal medical, legal, and ethical issues. [153]

The physician must recognize that decisions concerning these issues 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', extended family's, infant's, and society's as a whole). In this situation, the clinician has 3 ethical obligations: (1) to understand his or her own value system; (2) to possess some knowledge of ethics as a formal discipline; and (3) to make the actual clinical decision and implement it in a morally defensible way.

Management of anticipated delivery of an ELBW infant 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 the infant and the mother. [154, 155]

When resolving bioethical dilemmas facing families and clinicians, the physician must address issues of futility, extension of the dying process, 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. [156] 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

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 non survivors 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 the following 5-step schema for arriving at such decisions [157] :

• Establish the facts

• Determine what is in the patient's best interests

• Define the ethical issues and principles

• State the decision in concrete terms

• Justify the decision

Each of these steps can be a difficult process that yields new insights into the family's and patient's needs, as well as into the clinician's biases.

Costs

In 2003, Gilbert et al published data on the costs of care for ELBW infants. 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, the investigators calculated the total healthcare cost for surviving ELBW infants to be USD $202,700. [158] The average cost for a healthy, term control infant was USD $1,100.

Concurrently, Tommiska et al from Finland analyzed these comparative costs: A normally developed ELBW infant had a 25-fold increase in costs compared to the term controls, whereas mild disability resulted in a 33-fold increase, and severe disability resulted in a 68-fold increase. [159]

A 2007 article in Pediatrics suggested the hospitalization costs for preterm and low birth weight admissions in 2001 totaled $5.8 billion. [160] 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.

In 2013, Johnson et al analyzed cost impact of 4 main morbidities plaguing very low birth weight (VLBW) preterm infants: There was an incremental increase in direct cost of $10,055 for an infection, $12,048 for brain injury, $15,440 for necrotizing enterocolitis (NEC) and, finally, $43,312 for bronchopulmonary dysplasia (BPD). [161] Each morbidity substantially increased the cost of care, and it also contributed toward rehospitalizations which also independently affected the longer-term cost. [162]

In 2014, Canadian investigators reported the cost per infant over the first 10 years to be $67,467 for ELBW infants, [163] which translates to total Canadian national costs of $123.3 million for early preterm infants based on population size. The highest individual burden was seen in the lowest birth weight and youngest gestational age infants.

In the United States, current cost estimates are over $100,000 for extreme prematurity, between $40,000 and $100,000 for early prematurity, between $10,000 and $30,000 for moderate prematurity, and below $4500 for late prematurity. [164]

In this vulnerable population, resource utilization persists beyond the neonatal period and into childhood years. Furthermore, in young adulthood, there may be societal economic costs incurred by somewhat less productive ELBW survivors. [165]

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 ELBW infant. The family is often confused, angry, and frustrated by resulting issues. In addition, society in general is affected by these infants, many of whom have significant cognitive or physical impairment and require lifelong public assistance.

Considerations while pending and following delivery

Although addressed by revisions in the World Health Organization (WHO)/American Heart Association (AHA)/American Academy of Pediatrics (AAP)–endorsed Neonatal Resuscitation Program (NRP) protocol, no single rule has been written regarding what to do during the impending birth of an extremely premature infant.

The Society for Maternal-Fetal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, the section on Perinatal Pediatrics of the AAP, and the American College of Obstetricians and Gynecologists (ACOG) published an executive summary from their joint workshop on “periviable births.” [166] The panelists recommended a team approach to establish a bidirectional, collaborative and ongoing counseling.

The obstetrician and the neonatologist must discuss with the parents 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. Importantly, gestational age alone and the currently available predictive algorithms may not be accurate or generalizable to individual infants. Therefore, caution is advised when using such models during counseling. [166]

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 to guide further decisions in the care of the infant and guard against future liability.

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Author

Siva Subramanian, MD, FAAP Emeritus Chief of Neonatal Perinatal Medicine, Medstar Georgetown University Hospital; Professor of Pediatrics and Obstetrics, Ethicist, Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center

Siva Subramanian, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Nutrition, American Pediatric Society, American Society for Parenteral and Enteral Nutrition, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Suna Choi Seo, MD Assistant Professor, Fellow in Neonatal-Perinatal Medicine, Department of Pediatrics, Division of Neonatal Perinatal Medicine, Georgetown University Hospital

Suna Choi Seo, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Chief Editor

Acknowledgements

Brian S Carter, MD, FAAP Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Director, Neonatal Follow-up Program, 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 & Ethics, National Hospice and Palliative Care Organization, Society for Pediatric Research, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose. 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.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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