Elisabeth L. Raab, MD, MPH
Lisa K. Kelly MD
Delivery of a high-risk fetus requires multidisciplinary prenatal decision making to ensure the best outcome for the newborn and mother. Obstetricians, neonatologists, and, in appropriate cases, pediatric medical and/or surgical sub-specialists must work together to determine an appropriate plan of care for the fetus and delivery of the newborn and provide counseling for the family. Discovery of a significant complication during pregnancy often warrants referral of the mother to a perinatologist for further evaluation and possible treatment. When circumstances allow, the mother of a high-risk fetus should be transferred to a tertiary care center with experience in high-risk obstetric and neonatal care prior to delivery. Numerous studies have shown improved outcomes for low-birth-weight (LBW) infants (<2500 g) who are delivered at a center with a higher level of neonatal care.
Successful transition from fetal to ex utero life involves a complex series of hormonal and physiologic changes, many of which occur or begin before birth. Events such as cord compression, placental abruption, meconium aspiration, and premature delivery or the presence of infection or major congenital malformations may alter or prevent the essential postnatal transition. Any process that prevents or hinders the newborn from inflating the lungs with air and establishing effective ventilation, oxygenation, and/or circulation will result in a depressed newborn in need of resuscitation for survival.
RESUSCITATION OF THE HIGH-RISK INFANT
The American Academy of Pediatrics (AAP) guidelines mandate that at least 1 skilled person capable of carrying out resuscitation of a newborn be present at every delivery. When a delivery is identified as high risk, 2 or more skilled people may be required to provide adequate care. Often it is useful to assign roles to the resuscitation staff to ensure that the resuscitation flows as smoothly as possible. The equipment required for resuscitation, such as the bag and mask used for ventilation, the blender for oxygen and air delivery, the suction equipment, the radiant warmer, and the monitors, should be checked prior to the delivery. Communication between the obstetric and neonatal staff about the maternal medical and obstetric history as well as the prenatal history of the fetus is essential to ensure that the neonatal team can anticipate and interpret the problems the newborn may have in the delivery room.
Delivery Room Management
Although the expectations may be different and the need for resuscitation more common, the same principles apply to a high-risk delivery as to a routine delivery: The newborn should be kept warm and rapidly assessed to determine the need for intervention.
The initial evaluation and resuscitation may take place in the delivery room or, in centers with a high-risk delivery service, preferentially in an adjacent room specifically designed for high-risk resuscitations. Typically the newborn is brought immediately to a radiant warmer, although some institutions weigh extremely premature infants prior to transfer to the warmer bed in order to determine the birth weight if viability is in question. The infant is dried with prewarmed towels to prevent heat loss. At some centers, LBW newborns are put into polyurethane bags or wrapped with polyethylene occlusive wrap after delivery; these measures have been shown to significantly improve temperature stability during stabilization and transport to the neonatal intensive care unit (NICU). In addition, a knit hat is used to prevent heat loss from the head. Preterm infants are at increased risk for thermal instability given their greater body surface area to weight ratio, thinner skin, and relative paucity of subcutaneous fat compared to term infants. Hypothermia (body temperature <36°C) can occur rapidly in the preterm infant and may cause complications such as hypoglycemia and acidosis.
After rapidly drying the infant and removing the wet towels, the resuscitation team should position and clear the airway. The team then assesses the newborn’s respiratory effort, heart rate, color, and activity to determine the need for intervention. Drying the patient and suctioning the airway usually provide adequate stimulation for the newborn to breathe. Rubbing the back or flicking the soles of the feet may be done to provide additional stimulus if initial respirations are irregular.
Positive-pressure ventilation (PPV) should be started if the newborn is apneic or has a heart rate less than 100 bpm. Figure 22–1 shows the correct positioning of the neck and placement of the mask. PPV will not be effective if the airway is not extended slightly and the mask is not applied to the face in the correct manner, with a tight seal around the nose and mouth. In addition, sufficient pressure must be given to produce adequate chest wall movement. A pressure manometer should be attached to the bag to monitor the amount of pressure that is being delivered. Overdistention of the lung causes significant trauma to the lung parenchyma and may cause complications such as a pneumothorax or lead to development of pulmonary interstitial emphysema (PIE), especially in the very-low-birth-weight (VLBW) neonate (birth weight <1500 g). Inability to move the chest wall with high pressures may indicate the lack of a good seal between the mask and the face, an airway obstruction, or significant pulmonary or extrapulmonary pathology compromising ventilation, such as pleural effusions, a congenital chest or abdominal mass, or a congenital diaphragmatic hernia (CDH). If the infant’s respiration is markedly depressed, endotracheal intubation should be considered.
Figure 22–1. Technique of bag and mask ventilation of the newborn. The neck should be slightly extended. An anesthesia bag should have a manometer attached; a self-inflating bag should have an oxygen reservoir attached.
Chest compressions should be initiated if the heart rate is less than 60 bpm after 30 seconds of effective PPV. Figure 22–2 shows the acceptable methods for administering compressions to a neonate. Pressure should be applied to the sternum to depress it one-third of the anteroposterior diameter of the chest. Compressions should be coordinated with breaths: A single cycle should consist of 3 compressions followed by a single breath, and each cycle should last for 2 seconds. Compressions should be continued until the heart rate rises above 60 bpm. PPV should be continued until the heart rate is >100 bpm and the patient is showing adequate respiratory effort. If the heart rate remains <60 bpm after 30 seconds of compressions, administration of epinephrine is indicated. Failure to respond to PPV and chest compressions is a clear indication for endotracheal intubation; intubation should be attempted at this time if it has not already been performed. Figure 22–3 shows the landmarks used to guide placement of the endotracheal tube (ETT) between the vocal cords.
Figure 22–2. A: Thumb technique for performing chest compressions on an infant. The two thumbs, placed either side by side or overlapping one another, are used to depress the lower third of the sternum, with the hands encircling the torso and the fingers supporting the back. B: Two-finger method for performing chest compressions on an infant. The tips of the middle finger and either the index finger or ring finger of one hand are used to compress the lower third of the sternum.
Figure 22–3. Landmarks for placement of the laryngoscope.
Epinephrine can be given via an ETT or an umbilical venous catheter. The standard dose of epinephrine in neonates is 0.01–0.03 mg/kg. The 2010 AAP guideline recommends giving epinephrine via the intravenous (IV) route and only giving endotracheal epinephrine if IV access cannot be obtained. If using the ETT, a dose of 0.05–0.1 mg/kg of the 1:10,000 concentration solution is recommended. The dose can be repeated every 3–5 minutes until the heart rate rises above 60 bpm.
When the infant’s response to resuscitation is poor, other factors that may be complicating successful resuscitation of a newborn should be considered. Previous recommendations from the AAP have stated that the use of naloxone (Narcan) may be considered in cases of recent (<4 hours prior to delivery) administration of narcotics to the nonsubstance-using mother. However, the 2010 AAP recommendations do not recommend the use of naloxone under any circumstances and recommend only appropriate support of respiratory depression and oxygenation. Hypovolemia should be suspected if there is a perinatal history consistent with blood loss (eg, placental abruption, placenta previa) or sepsis and the baby is hypotensive and pale, with weak pulses and cool extremities. A 10 cc/kg IV infusion of normal saline, lactated Ringer’s solution, or O-negative blood, if available and anemia is suspected, can be given to treat the suspected hypovolemia. The dose can be repeated if there is minimal improvement with the initial bolus. Metabolic acidosis may be present at birth if the baby was significantly distressed in utero or may develop after birth if oxygenation and/or perfusion are compromised. Although use of bicarbonate in resuscitation is not included in the AAP recommendations, significant acidosis will cause pulmonary vasoconstriction and poor myocardial contractility and should be treated. The umbilical artery can be catheterized to provide ongoing access to blood samples for determination of the extent of acidosis and the response to treatment during resuscitation. If bicarbonate is used, the dose is 2 mEq/kg IV of a 0.5 mEq/mL (4.2%) solution. Bicarbonate should be given slowly via an IV line and should be used only after ventilation is established so that the carbon dioxide (CO2) produced with bicarbonate administration can be removed. Otherwise, bicarbonate administration may result in a significant increase in intracellular acidosis.
Apgar scores are assigned at 1 and 5 minutes of life and continued at 5-minute intervals for up to 20 minutes as long as the score remains below 7. The Apgar score is a means of communicating the newborn’s status during resuscitation; it should not be used to determine the need for resuscitation. The initial assessment of the newborn and assignment of the Apgar score are discussed in further detail in Chapter 9.
In the past, 100% oxygen has been the standard for neonatal resuscitation; however, 2 recent meta-analyses have demonstrated increased survival when resuscitation is initiated with air as compared to 100% oxygen. Therefore, the 2010 AAP recommendations now recommend beginning resuscitation with room air. There have been few studies looking at the use of blended oxygen and target oxygen saturations in either preterm or term infants. However, given the known toxicities of oxygen, the recent recommendations are to use blended oxygen when available and to target arterial saturations in the interquartile range for each gestational age (Fig. 22–4). If blended oxygen is not available and the baby remains bradycardic after 90 seconds of resuscitation, it is recommended to increase the oxygen to 100% until recovery of a normal heart rate.
Figure 22–4. Heart rate and blood pressure changes during apnea.
Specific Considerations in the Delivery Room
A. Meconium
Meconium-stained fluid is present in 10–20% of deliveries. It is extremely rare if delivery takes place prior to 34 weeks’ gestation. Passage of meconium in utero usually indicates fetal distress, and those personnel present at the delivery should be alerted by the presence of meconium to the possibility that the newborn may be depressed at birth.
It is no longer recommended by the AAP that all meconium-stained babies receive intrapartum suctioning. An active, crying, well-appearing infant does not require endotracheal intubation regardless of the presence of meconium staining or the thickness of the meconium. If the newborn is in distress or has depressed respiratory effort, the appropriate intervention is to intubate and suction the trachea before stimulating the baby in any way. If no meconium is suctioned from the airway, resuscitation should proceed according to the standard algorithm. If meconium is suctioned from the trachea, another attempt should be made to intubate the patient and suction the trachea again. However, if the patient has significant bradycardia, it may be appropriate to defer repeated suctioning and provide PPV.
The majority (94–97%) of infants born through meconium-stained fluid will not develop meconium aspiration syndrome, but when it does occur, infants are often critically ill. Meconium can block the airway and prevent the newborn’s lungs from filling with air, a vital step in normal transitioning. Meconium aspiration into the lungs can cause obstruction of the small airways and consequently areas of atelectasis, gas trapping, and overdistention in addition to a chemical pneumonitis. The infant born through meconium may have pulmonary hypertension and inadequate oxygenation and requires close observation and early initiation of treatment when appropriate.
B. Asphyxia
Despite optimal prenatal care, some infants sustain injury prior to or during delivery that results in asphyxia. Perinatal asphyxia is characterized by the presence of hypoxemia, hypercapnia, and metabolic acidemia. It is the result of compromised oxygen delivery and blood flow to the fetus, either chronically or acutely, that stems from processes such as placental insufficiency, cord compression, trauma, and placental abruption.
If significant prepartum or peripartum hypoxic–ischemic injury has occurred, the infant likely will be depressed at birth and may not respond to initial interventions to establish respiration. The initial response in the newborn to hypoxemia is rapid breathing, followed shortly thereafter by a period of apnea, termed primary apnea. Drying the infant and rubbing the back or flicking the soles of the feet is sufficient to stimulate respiration during primary apnea. However, without intervention at this point, continued oxygen deprivation will lead to a series of gasps followed by a period of secondary apnea. It is important to recognize that an infant who does not respond to stimulation is likely exhibiting secondary apnea and requires further intervention. Respiration will not resume with stimulation if secondary apnea has begun, and positive pressure is necessary to reverse the process. Heart rate changes typically begin toward the end of primary apnea, whereas blood pressure typically is maintained until the period of secondary apnea.
Effective resuscitation of an asphyxiated newborn usually requires treatment of acidosis. Perinatal asphyxia may also be complicated by hypoglycemia and hypocalcemia. Myocardial dysfunction may be present, and fluid boluses and continuous infusion of inotrope may be required for adequate blood pressure support. However, in the presence of significant myocardial dysfunction, repeated volume boluses will worsen the cardiovascular status. In these cases, early administration of an inotrope (eg, dobutamine) with or without low to moderate doses of a vasopressor (eg, dopamine) is appropriate. In addition, seizures may occur in the newborn with perinatal asphyxia. Seizures usually are the result of hypoxic–ischemic injury to the cerebral cortex, but hypoglycemia and hypocalcemia also may cause seizure activity in the depressed neonate. In the newborn, phenobarbital (15–20 mg/kg IV) typically is given as the first-line treatment of seizures not caused by hypoglycemia or hypocalcemia. An additional 5–10 mg/kg bolus can be given to control status epilepticus. Asphyxiated infants are at increased risk for persistent pulmonary hypertension (discussed in detail later in the section Pathology & Care of the High-Risk Term Neonate).
The severity of the insult sustained by the newborn can be difficult to assess in the neonatal period. The presence of abnormal findings on the neurologic examination and the severity and persistence of those abnormalities are the most useful measures for assessing the degree of brain injury. Laboratory (umbilical cord and baby blood gases, serum creatinine level, liver function tests, blood lactate level, and cardiac enzyme levels) studies, radiographic (brain magnetic resonance imaging [MRI]) studies, and electroencephalographic (EEG) findings provide additional information to help predict the likelihood and anticipated extent of an adverse neurodevelopmental outcome. Early onset of seizure activity has been shown to increase the likelihood of a poor outcome. Infants with severe hypoxic–ischemic encephalopathy, which is characterized by absent reflexes, flaccid muscle tone, seizures, and a markedly altered level of consciousness, either die within several days of birth or have significant neurologic sequelae. It is a misconception that perinatal asphyxia is the cause of cerebral palsy. A minority of cases of cerebral palsy are actually attributable to intrapartum complications.
Several randomized, controlled studies have shown that induced hypothermia is protective in babies with mild-moderate asphyxia. Both selective hypothermia (ie, head cooling) and total body cooling have been shown to be effective. Devices are now available to regulate and safely cool neonates to a core temperature of 33.5–34.5°C. Therefore, it is now recommended that infants with moderate asphyxia should be cooled. Ideally the therapy should be initiated within 6 hours of the event (ie, birth). Timely transfer to a center that provides therapeutic hypothermia is of the utmost importance.
C. Shock
The newborn who fails to respond to initial attempts at resuscitation may be in circulatory shock. A number of different pathophysiologic processes can result in shock in the delivery room. Circulatory collapse can result from absolute (hemorrhage, capillary leak) or relative (vasodilatation) hypovolemia, cardiac dysfunction (asphyxia, congenital heart disease [CHD]), abnormal peripheral vasoregulation (prematurity, asphyxia, sepsis), or a combination of these factors. The peripartum history often helps elucidate the etiology. The presence of risk factors for sepsis (prolonged rupture of membranes, maternal fever, chorioamnionitis), hemorrhage (placenta previa, placental abruption, trauma), or perinatal asphyxia may be informative. Pallor or peripheral hyperemia, weak pulses with tachycardia, and cool or warm extremities are present on examination. Hypotension in the newborn immediately following delivery is commonly defined as a mean arterial pressure that is equal to or less than the gestational age. It is worth noting that blood pressure is normal in the early (compensated) phase of shock; hypotension may only develop as the process progresses.
As mentioned earlier in Delivery Room Management, a 10 cc/kg normal saline bolus typically is given to the newborn with hypotension. An additional 10–20 cc/kg is often given if the improvement in circulation is inadequate. Unmatched O-negative blood can be transfused in 10–15 cc/kg aliquots if severe anemia from blood loss is suspected. Volume should be administered slowly and judiciously to preterm infants who lack the mechanisms to autoregulate cerebral blood flow and protect the brain against reperfusion injury. Excessive volume may worsen the patient’s status if cardiac dysfunction is the cause of hypotension. As discussed earlier, administration of sodium bicarbonate or THAM (tromethamine) may be indicated to treat metabolic acidosis in the newborn in shock. Vasopressor/inotrope infusions should be initiated in neonates who do not respond to volume resuscitation.
D. Cyanosis
Although acrocyanosis (cyanosis of the hands and feet) is often normal in the newborn, central cyanosis is not. Cyanosis is due to inadequate oxygen delivery to the tissue, either as a result of poor blood flow (peripheral vasoconstriction in acrocyanosis or low cardiac output in cardiogenic shock) or insufficiently oxygenated blood (pulmonary hypertension or severe parenchymal lung disease). Free-flow oxygen can be administered if a newborn has central cyanosis despite regular respirations. Free-flow oxygen can be delivered by holding a mask or oxygen tubing that is connected to a flowing source of 100% oxygen close to the baby’s nose and mouth. Oxygen can be gradually withdrawn when the newborn turns pink. PPV is often indicated if the baby remains cyanotic despite free-flow oxygen. Lack of improvement of central cyanosis with administration of free-flow oxygen necessitates an evaluation of the cause of cyanosis. As discussed earlier, provision of 100% oxygen may have significant side effects if it is used for newborn resuscitation.
E. Prematurity
The delivery of a preterm infant requires a skilled multidisciplinary resuscitation team that has an understanding of the myriad problems associated with preterm delivery and has experience handling VLBW newborns. The presence at delivery of physicians, nurses, and a respiratory therapist trained in newborn resuscitation will optimize the early care of the newborn. Details of the delivery room care of the preterm infant are discussed in the section Delivery Room Management earlier in this chapter.
The neonatal team should meet with the family prior to delivery whenever possible. The parents should be informed about the prognosis for the fetus and need for intensive care admission if appropriate. It is critical that the family understand the plan for resuscitation in the delivery room and the anticipated short- and long-term problems the newborn may face. Often it is helpful to families to discuss the emotional impact of the admission and the possibility of a prolonged stay of their newborn in the intensive care unit. If the fetus is at the limits of viability, currently considered 23–24 weeks’ gestation and/or weight <500 g, it is essential that the parents understand the considerable risk of death and the serious cognitive, motor, and pulmonary complications that may occur if the newborn does survive. The neonatal team must have a clear conversation with the parents about the possible options for postnatal management. Unfortunately, it often is difficult to make definitive plans given that the margin of error for prenatal determination of birth weight and gestational age is wide enough to have a significant impact on the viability of the fetus. Although many physicians have strong feelings of their own, it is vital that the course of resuscitation of a newborn at the limits of viability incorporates the family’s wishes. Nevertheless, parents should understand that the fetus’s viability will be reassessed after delivery, and that the maturity of the newborn, the newborn’s condition at delivery, and the response to the resuscitative efforts made, in combination with available outcomes data, ultimately will determine the management in the delivery room.
F. Abdominal Wall Defects
Gastroschisis is the herniation of abdominal contents through an abdominal wall defect. The defect in gastroschisis usually is small and to the right of the umbilicus, and the intestines are unprotected by the peritoneal sac. Omphalocele also involves the herniation of abdominal contents through the abdominal wall, but the defect is in the umbilical portion of the abdominal wall, and the herniated viscera are covered by the peritoneal sac. Both defects require emergent care in the delivery room. Current delivery room recommendations suggest positioning the baby right side down to avoid kinking the mesenteric blood vessels and compromising blood flow to the intestines. The baby’s lower body, including the defect and externalized organs, should be placed in a “bowel bag,” which is then secured at the mid-thorax. This allows for direct visualization of the intestines while also limiting fluid losses. A nasogastric tube (at least 10 French) should be placed to allow for adequate decompression of the stomach and intestines.
Despite these measures, patients will still have increased heat and insensible fluid losses, and IV fluid should be started promptly at 1.5 times normal maintenance requirements to prevent dehydration and hypernatremia. Electrolytes and fluid status must be monitored closely. A surgical consultation should occur prenatally if the defect is diagnosed in utero. An urgent surgical evaluation should be obtained upon admission of the newborn to the NICU.
Kattwinkel J, Perlman JM, Aziz K, et al. Neonatal resuscitation: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Pediatrics2010;126:e1400–e1413. PMID: 20956432.
Paneth N. The evidence mounts against use of pure oxygen in newborn resuscitation. J Pediatr 2005;147:4–6. PMID: 16027683.
Saugstad OD. Oxygen for newborns: how much is too much? J Perinatol 2005;25(Suppl 2):S45. PMID: 15861173.
Spector LG, Klebanoff MA, Feusner JH, et al. Childhood cancer following neonatal oxygen supplementation. J Pediatr 2005; 147:27–31. PMID: 16027689.
Tan A, Schulze A, O’Donnell CP, Davis PG. Air versus oxygen for resuscitation of infants at birth. Cochrane Database Syst Rev 2005;2:CD002273. PMID: 15846632.
PATHOLOGY & CARE OF THE PRETERM INFANT
In 2008, 12.3% of all births in the United States were preterm, a slight decrease from 12.8% in 2006. Advances in obstetric and neonatal care have markedly increased the survival of premature infants and improved outcomes. However, prematurity continues to account for a significant percentage of neonatal and infant mortality in the United States. As tinier and less mature infants survive, we face new ethical and medical challenges to continue improving the long-term and societal impact of the care provided in the NICU.
Respiratory Distress Syndrome
In 1959, Mary Ellen Avery and Jere Mead reported data showing that the severe respiratory disease seen in preterm infants, then known as hyaline membrane disease, was due in part to a deficiency of surfactant. Surfactant, a complex of phospholipids and protein secreted by type II pneumocytes, reduces surface tension in the alveoli of the lung. Its absence, or deficiency, results in diffuse microatelectasis and decreased functional residual capacity leading to the presentation of a “ground-glass” pattern and poor expansion of the lungs on chest radiograph (CXR). The lung disease of the preterm infant, now known as respiratory distress syndrome (RDS), also is a consequence of the immature architecture of the lung at the time of birth.
RDS presents as tachypnea and increased work of breathing that develops shortly after birth. Both oxygenation and ventilation are impaired, and blood gas analysis typically reveals hypoxia and a respiratory acidosis. Although most commonly seen in premature infants, RDS is associated with other conditions as well. Infants of diabetic mothers are at risk, even at term, because high levels of insulin in the fetus suppress lung maturation, including surfactant production. Without intervention, RDS typically worsens over the first few days of postnatal life. Historically, improvement was often heralded by a marked increase in urine output (“diuretic phase” of RDS).
The likelihood of RDS is inversely proportional to gestational age. It now is standard to give corticosteroids to mothers at risk of delivery before 32–34 weeks’ gestation to hasten maturation of fetal organs, including the lungs, and to decrease the incidence and severity of RDS. Some larger preterm infants may require supplemental oxygen by nasal cannula or no respiratory assistance whatsoever. Babies with significant RDS typically require assisted ventilation. Ventilatory support can be given with continuous positive airway pressure (CPAP), a pressure- or volume-limited ventilator, or a high-frequency ventilator. A recent analysis concluded the data are not sufficient to recommend any mode of mechanical ventilation over the other as standard therapy for RDS. Provision of positive end-expiratory pressure (PEEP) (either as CPAP or PEEP) quickly after delivery is vital in order to prevent collapse of the lungs. If the lungs are allowed to collapse, oxygenation and ventilation will be compromised further and higher pressures will be required to reinflate the lungs, causing avoidable barotrauma and volutrauma to the lungs.
Exogenous surfactant administration has significantly reduced morbidity and mortality from RDS since its routine use began in the early 1990s. Prophylactic administration of surfactant to the preterm infant (ie, before 15 minutes of age) has been shown to reduce neonatal morbidity (pneumothorax and pulmonary interstitial edema) and mortality compared to rescue therapy (ie, waiting until after the diagnosis of RDS is made). Proposed explanations of this finding include a more homogeneous distribution of surfactant in the fluid-filled lung and the delivery of surfactant after a minimal period of PPV minimizing barotrauma and volutrauma to the lung. However, it is very important to ensure correct placement of the ETT prior to surfactant administration in the delivery room. If the ETT position cannot be determined, it may be better to delay surfactant until CXR has confirmed placement. If the degree of RDS is significant, an additional 2–4 doses of surfactant can be given every 6–12 hours depending on the surfactant preparation used. The newborn should be monitored closely after receiving surfactant because rapid changes in respiratory status usually occur, necessitating aggressive weaning of the ventilator settings. If the ventilator support is not weaned appropriately, the improving lung compliance will result in high tidal volume ventilation leading to volu-trauma and hypocapnia. Complications such as obstruction of the ETT, pneumothorax, or pulmonary hemorrhagic edema may occur with surfactant. Pulmonary hemorrhagic edema likely is due to the surfactant administration-associated rapid decrease in pulmonary vascular resistance and the resulting pulmonary overcirculation through the ductus arteriosus. Blood gases should be checked frequently to prevent hypocapnia, which is associated with an increased incidence of periventricular leukomalacia (PVL) in the preterm neonate.
Despite the advances attributable to prenatal steroids, surfactant, and newer modes of ventilation, RDS continues to carry significant morbidity, including the risk of chronic lung disease, which is defined as the need for supplemental oxygen or ventilatory support at 36 weeks’ postmenstrual age. New strategies have evolved over recent years to improve outcomes of newborns with RDS. Given the toxicities of oxygen, as discussed earlier, efforts are being made to limit exposure of preterm infants to hyper-oxia. Many centers now aim to keep the oxygen saturation percent in the 80s or low 90s for preterm babies to prevent periods of hyperoxygenation and free-radical production. Although the data are scant and not well controlled, no current evidence suggests adverse neurologic effects of the lower saturations. However, it is recommended that saturations be kept in the high 90s once an infant’s corrected gestational age reaches near-term. Future studies must be designed to investigate the potential side effects of lower saturations, including the development of pulmonary hypertension and subsequent cor pulmonale during infancy or early childhood.
Another recent change in neonatal practice has been the adoption of permissive hypercapnia. Permissive hypercapnia involves allowing CO2 levels in the blood to rise above the normal value of 40 mm Hg in order to minimize the pressures required for ventilation and thereby reduce the lung injury caused by ventilator-induced barotrauma and volu-trauma. This practice allows for infants to remain extubated who might have been reintubated in the past because of CO2 retention. Although the procedure differs, CO2 levels of 45–55 mm Hg are generally accepted, with some centers allowing higher CO2 levels without a change in ventilatory management. The side effects of this approach are unknown, but hypercapnia may decrease the autoregulatory capacity of cerebral vessels, resulting in a more or less pressure-passive cerebral circulation. Therefore, the potential long-term neurodevelopmental effects of hypercapnia-associated pressure-passive cerebral circulation require investigation.
Encouraged by data from nonrandomized studies at Columbia University, many neonatologists are now trying to avoid intubation and/or mechanical ventilation, even in the tiniest babies. Using CPAP with nasal prongs for newborns with respiratory distress soon after birth (regardless of gestational age or birth weight) and a strategy of permissive hypercapnia, physicians at Columbia University reported a low incidence of bronchopulmonary dysplasia (BPD) compared to other tertiary care centers, without any significant increase in mortality. Because these findings require confirmation in appropriately designed randomized clinical trials, some centers have chosen an intermediate approach: VLBW infants are intubated for surfactant administration, but the ETT is removed shortly after and the period of mechanical ventilation is brief. Although approaches differ, early extubation is now a widely shared goal among neonatologists.
Dexamethasone was a key part of efforts to prevent and/or treat BPD for many years. However, a number of studies have shown a worse neurodevelopmental outcome in preterm infants who received dexamethasone treatment compared to controls with a similar degree of illness in the neonatal period. Many studies are still in progress, and data on long-term outcomes are not yet available, but the routine use of dexamethasone is no longer recommended. Dexamethasone is now reserved for those patients with the most severe lung disease, although, in general, no data support a better pulmonary outcome with its use. The available data suggest that there may be a window for dexamethasone use at 7–14 postnatal days, categorized as “moderately early” treatment, which has not been seen to cause any adverse outcomes. However, as mentioned earlier, a significant direct benefit associated with the use of dexamethasone is not available. Steroids also are now usually given in lower doses and shorter courses than in the past. The AAP currently recommends that neonatologists counsel parents about the risks and benefits of dexamethasone prior to initiating treatment. Future studies are needed to evaluate the effect, if any, of the newer treatment regimens on neurodevelopment outcome.
Nutrition
Providing optimal nutrition is an essential and challenging part of the care of the premature baby. Preterm infants are born with minimal nutrient stores and high metabolic demands, and growth failure is a frequent complication of prematurity. Supplying adequate nutrition for growth and development is complicated by the fact that many preterm newborns are too unstable to receive enteral nutrition in the first few days of postnatal life. There may be clear contraindications to enteral feeding, such as hypotension and vasopressor requirements, or factors can arise that can raise concerns about early initiation of enteral feeds, such as cocaine exposure in utero, indomethacin administration, the presence of a patent ductus arteriosus (PDA), or respiratory instability. Parenteral hyperalimentation is used to meet the newborn’s initial fluid and nutritional requirements, but the ultimate goal is to meet those needs with enteral feedings given as early as safely possible.
An IV infusion of 10% glucose typically is started soon after birth to maintain glucose homeostasis. Extremely low-birth-weight (ELBW) babies (birth weight <1000 g) may require lower concentrations of dextrose because of higher total fluid requirements. Calcium supplementation in the dextrose infusion is standard for VLBW babies because transfer of calcium from mother to fetus primarily occurs during the third trimester, so VLBW babies are born with inadequate stores. The infusion rate of fluids typically is begun at 80–120 cc/kg/d depending on the immaturity and severity of illness of the neonate. Excessive fluids should be avoided because they have been associated with an increased risk for RDS, PDA, intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). Electrolytes and fluid status must be closely monitored over the first few days of life to determine appropriate fluid management. Depending on the level of immaturity, prenatal steroid exposure, and ambient humidity, ELBW infants may have enormous insensible losses and may develop hypernatremia if fluid needs are not met.
Protein breakdown can begin within the first postnatal days in preterm infants receiving only dextrose-containing fluids as nutrition. As a result, protein supplementation should be started as soon as possible to prevent a catabolic state. Parenteral hyperalimentation containing amino acids can be safely initiated immediately after delivery without development of acidosis, hyperammonemia, or uremia. The amino acid infusion should be started at 1.5–2.5 g/kg/d and advanced over several days to a goal of 3–4 g/kg/d.
Preterm newborns typically require a glucose infusion rate (GIR) of 6–8 mg/kg/min. The GIR is advanced in small increments to provide additional calories. Carbohydrate should account for approximately 40% of the 90–120 kcal/kg/d provided to the neonatal patient receiving parenteral nutrition. (Caloric requirements are higher with enteral feeding, typically 120–150 kcal/kg/d.) The need for GIR in excess of 15–18 mg/kg/min for adequate caloric support is rare. Glucose levels should be monitored and the dextrose infusion adjusted to maintain normoglycemia (ie, plasma glucose concentration 60–160 mg/dL). An insulin infusion can be started in the unusual event that hyperglycemia persists despite restricting the GIR to 4–6 mg/kg/min to continue to provide adequate calories for growth.
Intralipids provide the essential fatty acids required for multiple physiologic processes. Ideally, 40–50% of the daily caloric intake for a preterm infant receiving parenteral nutrition should come from fat. Usually a continuous 20% infusion at 0.5–1 g/kg/d is started on the first or second day of life, with the ultimate goal of providing 3 g/kg/d. Triglyceride and cholesterol levels must be monitored closely; elevated levels may require lower levels of lipid supplementation. Lipid infusion of 0.5–1 g/kg/d is required to prevent essential fatty acid deficiency.
In addition to providing protein, glucose, and fats, parenteral hyperalimentation provides electrolytes, vitamins, and minerals for the preterm infant unable to tolerate enteral feeds. Electrolyte levels must be monitored periodically to ensure appropriate levels. Particular attention must be paid to providing maximal amounts of calcium and phosphorous to VLBW infants who are at risk for developing osteopenia of prematurity.
It is important to begin enteral feeds as soon as possible in preterm infants. Delayed enteral feeding has adverse effects on the gut, such as mucosal atrophy, decreased digestive enzyme activity, and altered intestinal motility. In addition, long-term parenteral nutrition can cause cholestasis and presents an increased risk of infection because of the prolonged need for central venous access. Regimens for initiation of enteral feeding in VLBW infants vary but usually involve starting volumes of 10–20 mL/kg/d. Feeds are given via an orogastric or nasogastric tube for all but the most mature infants. The infant is monitored carefully for signs of feeding intolerance, such as abdominal distention, emesis, or large-volume gastric residuals while the feed volume is increased daily by 10–20 mL/kg. Some centers continue small-volume feeds for 5–10 days before advancing the volume toward the ultimate goal of 140–160 mL/kg/d.
Mothers of preterm infants should be encouraged to provide breast milk for their babies. Although infants are not typically developmentally ready to coordinate oral feeding until they reach 34 weeks’ gestation and thus are unable to breastfeed initially, preterm infants can receive expressed breast milk via a gavage tube. The advantages of breastfeeding on everything from the appropriate function of the immune system to developmental outcomes and IQ are well documented. The caloric value of human milk clearly has proven to be superior to formula. Many NICUs now use pasteurized human breast milk banks to provide these benefits to infants whose mothers are unable to breastfeed. Human milk fortifiers are used to increase the protein, calories, calcium, phosphorous, vitamins, and minerals of mature human milk in order to meet the needs of the growing premature infant. Breast-fed infants should receive iron supplements once they reach the goal volume of enteral feeds.
Special formulas have been designed to better meet the nutritional needs of preterm infants receiving formula. Premature infant formulas contain 24 kcal/oz and provide higher amounts of protein, medium-chain triglycerides, vitamins, and minerals (eg, calcium and phosphorous) than standard formulas. If needed for adequate growth, the caloric content of preterm formula can be increased with any of a number of commercially available supplements, the majority of which provide additional calories as carbohydrate or fat. Although term infants gain an average of 30 g/d, 15–20 g/d is considered sufficient growth in the preterm infant.
Necrotizing Enterocolitis
NEC is a significant cause of morbidity and mortality in neonates. Although gastrointestinal in origin, NEC may lead to septic shock, respiratory failure, and death. Only 10% of cases occur in term newborns. The most premature and smallest infants are disproportionately affected; NEC occurs in 5–10% of all VLBW infants.
The presentation of NEC is highly variable. Signs and symptoms often are specific to the gastrointestinal tract, such as abdominal distention and/or erythema, emesis, bilious gastric residuals, and bloody stools; however, they may be nonspecific, such as apnea, temperature instability, and lethargy. Findings may be subtle initially, or the onset may be fulminant. Acidosis and thrombocytopenia are worrisome findings that may indicate necrotic bowel. Hyponatremia, due to upregulated sodium transport into the gut, and edema, due to increased capillary leak, often develop. Respiratory distress develops from abdominal competition due to inflammation and distention. The pathognomonic feature of NEC is the presence of intestinal pneumatosis on abdominal x-ray. Pneumatosis results from the production of hydrogen from bacteria in the bowel wall. Serial x-rays are obtained to follow disease progression. Air in the portal venous system or free air in the abdominal cavity indicates intestinal perforation, warranting surgical intervention for either an exploratory laparotomy to resect the necrotic bowel or placement of a right lower quadrant drain to decompress the abdomen if the patient is very small or unstable. Whether or not perforation has occurred, treatment of NEC typically includes 10–14 days of broad-spectrum antibiotics and discontinuation of enteral feeds. Many infants require fluid resuscitation and vasopressor/inotrope support. Seventy-five percent of infants with NEC survive, but half sustain long-term complications such as intestinal strictures and short gut syndrome.
Prematurity and enteral feeds have been clearly linked to NEC, but the pathogenesis of NEC is not well defined and is widely considered to be multifactorial. An infectious component is suggested by the association of certain organisms with outbreaks of NEC and the immature immune function of the preterm gastrointestinal tract. Mucosal injury as a result of altered intestinal and/or mucosal blood flow, either during periods of ischemia from hypotension or vascular spasm or during reperfusion and free-radical production, is believed to make the infant vulnerable. The presence of bacteria, ischemia and reperfusion, formula, and other unknown factors may all work together to trigger the inflammatory cascade responsible for the pathologic findings of NEC.
Risk factors for NEC include ELBW, polycythemia, umbilical catheters, enteral feeding, formula feeding, low Apgar scores, cyanotic heart disease, in utero cocaine exposure, and the presence of a PDA. Data on whether or not the rate of advancement of enteral feeds contributes to the development of NEC are conflicting. However, a recent study showed a decreased incidence of NEC in VLBW neonates who received small-volume feeds for 10 days before advancement compared to those who received daily 20 cc/kg advancement of feeds. The incidence of NEC has also been shown to decrease when standardized feeding regimens are instituted within a unit. The effect may be due to heightened awareness of signs and symptoms of feeding intolerance rather than to the actual specific regimen, but the effect has been reproduced and is dramatic.
NEC occurs less frequently in infants who receive breast milk. The protective effect of breast milk is speculated to result from the transfer of components of breast milk such as cytokines, immunoglobulins, growth factors, and probiotics to the infant. The protective effects of breast milk appear to occur even in those infants who are fed pasteurized donor breast milk. Other studies have shown a decreased incidence and severity of NEC in VLBW neonates who received supplementation with probiotic bacteria such as Lactobacillus acidophilus, Bifidobacterium spp., and Streptococcus thermophilus. However, further studies are needed to examine the safety of probiotics given recent reports of sepsis due to supplemented probiotic organisms. Antenatal steroids also have a protective effect against NEC, likely due to a demonstrated effect on gastrointestinal maturation and PDA closure.
Patent Ductus Arteriosus
During fetal life, close to 90% of the blood that leaves the right ventricle flows from the pulmonary artery to the aorta through the ductus arteriosus. After birth the pulmonary pressure falls, blood flow to the lungs increases, and the ductus arteriosus, primarily as a response to the increased oxygen tension in the blood and decreased circulating levels of prostaglandin E2 (PGE2), begins to close. Functional closure of the ductus arteriosus occurs within the first 1–2 days of postnatal life in the vast majority of term neonates, and definitive anatomic closure of the ductus usually is complete by the end of the first postnatal week. However, in neonates born prematurely, this process takes longer and may not always occur. In preterm neonates, failure of the ductus arteriosus to close is the result of several factors, including persistent hypoxia as a result of RDS and the continued presence of PGE2. A PDA may be asymptomatic initially, but as the pulmonary pressure continues to fall, the left-to-right shunt of blood through the ductus arteriosus increases. Increasing left-to-right shunt produces pulmonary overcirculation (often with >50% of the left ventricular output shunting back into the lungs), worsening respiratory distress and gas exchange, an increasing oxygen requirement, and systemic hypotension. The presence of a PDA is suggested on physical examination by a hyperdynamic precordium (left ventricular overload), bounding palmar and brachial pulses, and a holosystolic precordial murmur. The pulse pressure usually is wide, and CXR typically demonstrates cardiomegaly and pulmonary congestion. Unless contraindications such as renal insufficiency, active bleeding, or thrombocytopenia are present, indomethacin, a nonselective inhibitor of the cyclooxygenase enzyme, is the first-line treatment of PDA because indomethacin effectively decreases prostaglandin synthesis. Indomethacin also has certain actions not directly related to inhibition of prostaglandin synthesis, such as a drug-induced decrease in global cerebral blood flow. This action may contribute to the indomethacin-induced decrease in severe IVH observed in ELBW neonates given indomethacin shortly after birth. However, there appears to be no significant long-term neurodevelopmental benefit of prophylactic indomethacin administration. In neonates with a PDA, fluids should be restricted to prevent worsening of pulmonary edema. Indomethacin may fail to achieve closure of the ductus, particularly in those who were born most prematurely or who received therapy later in postnatal life (beyond 10–14 days). Persistent patency of the ductus typically requires a repeat course of indomethacin followed by surgical ligation of the ductus, depending on the patient’s age and clinical status. It should also be noted that the combination of indomethacin and postnatal steroid use has been shown to increase the likelihood of a spontaneous intestinal perforation. Therefore, care should be used when considering the use of those 2 drugs in combination.
Intraventricular Hemorrhage
IVH is one of the most feared complications of prematurity; severe IVH is a major risk for adverse long-term neurodevelopmental outcome. The incidence of IVH (approximately 20% in VLBW infants) is inversely proportional to gestational age. A number of factors combine to put the preterm neonate at risk. The blood vessels in the periventricular germinal matrix are abundant, immature, and fragile. These vessels may bleed when exposed to changes in blood flow. Sick newborns often experience periods of hypotension and hypertension, and they lack effective autoregulatory mechanisms to protect the brain during these variations in perfusion pressure. Changes in carbon dioxide levels in the blood also play an important role in regulating cerebral blood flow, and VLBW newborns may swing from hypocarbia to hypercarbia and back, particularly during the first few hours of life. In addition, bleeding may be aggravated by abnormal coagulation, particularly in the septic newborn.
Most IVH occurs during the first postnatal day; few cases occur after 5 days of life. Recent findings suggest that, at least in the VLBW neonate, IVH during the transitional period is caused by an ischemia–reperfusion cycle. Although IVH usually occurs without any clear outward signs that the process is occurring, a large bleed may cause a sudden change in mental status, a drop in hematocrit (Hct) level, and/or a full fontanelle. IVH is characterized as grade I when hemorrhage is confined to the region of the germinal matrix. Grade II IVH involves both the germinal matrix and the ventricles but does not fill or distend the ventricles. IVH grades I and II typically resolve and are not associated with a worse neurologic outcome than that expected for babies of the same gestational age without hemorrhages. Grade III IVH fills greater than 50% of the ventricles with blood and causes distention of the ventricles. Grade III IVH carries a significantly increased risk of mortality and adverse neurologic outcome because it more frequently evolves into ex vacuo or obstructive (fibrosis obstructs the ventricular system) hydrocephalus. IVH is classified as grade IV when the hemorrhage involves the brain parenchyma. This hemorrhage historically was considered to be an extension of IVH into the parenchyma but may more accurately represent a distinct process of venous infarction or severe ischemia followed by reperfusion in the periventricular white matter. Irrespective of the etiology, intraparenchymal hemorrhage results in tissue destruction and is associated with neurodevelopmental deficits in a marked majority of affected patients.
Although numerous preventative therapies have been evaluated (indomethacin, phenobarbital, vitamin E, morphine), none is currently recommended for routine prophylactic use. Every effort is made to keep blood pressure and carbon dioxide levels stable and within the normal range and to avoid unnecessary interventions, such as suctioning, which elevate intracranial pressure. Current guidelines recommend routine cranial ultrasound screening for infants less than 30 weeks’ gestation between postnatal days 7 and 14 days and again when the infant reaches a corrected gestational age between 36 and 40 weeks. However, once IVH is detected, serial studies should be done to follow the bleed for progression and the ventricles for further dilation.
Performing an ultrasound study earlier than postnatal day 7 for newborns who are particularly unstable often is useful; the presence of a significant intraparenchymal bleed may help with decisions about direction of care for those whose viability is in question. Many centers advocate brain MRI prior to discharge to evaluate for white matter injury that may go undetected on cranial ultrasound and has been shown to be predictive of significant neurologic sequelae.
Retinopathy of Prematurity
Retinopathy of prematurity (ROP) is a disorder of retinal vascular proliferation that primarily affects premature infants. It is the second most common cause of blindness in children in the United States. Under normal conditions, the retina is completely vascularized by 36–40 weeks of gestation. The earlier in gestation delivery occurs, the larger the avascular region of the retina at birth and the greater the risk for ROP. The pathogenesis of ROP is not completely clear but seems to involve a period of vessel damage (from acidosis, hyperoxia, infection, etc) and cessation of vessel development followed by a period of abnormal proliferation. Hyperoxia and/or fluctuations in PaO2 have been clearly shown to have an adverse effect on retinal development.
VLBW neonates, especially those who are critically ill and were born before 28 weeks’ completed gestation, are at the highest risk for ROP. ROP tends to develop at 33 to 36 weeks’ corrected gestation irrespective of the gestational age at birth. It may resolve spontaneously, as occurs in over 80–90% of cases, or, in rare cases, may progress to complete retinal detachment. Screening ophthalmologic examinations are recommended to monitor the progression of retinal vascularization in infants born at less than 31 weeks’ gestation or weighing less than 1500 g. Screening should also be considered for infants weighing 1500–2000 g or born at 31 weeks’ gestation or greater who have had an unstable course. The initial examination should be performed at 4 weeks of life or 30–31 weeks’ corrected gestational age, whichever comes later. The frequency of repeat examinations is dictated by the findings, with the goal being early detection of ROP that meets criteria for surgical intervention.
American Academy of Pediatrics, Section on Ophthalmology. Screening examination of premature infants for retinopathy of prematurity. Pediatrics 2001;108:809. PMID: 11533356.
American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297. PMID: 15231951.
Askie LM, Henderson-Smart DJ, Irwig L, et al. Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med 2003;349:959–967. PMID: 12954744.
Halliday HL, Ehrenkranz RA, Doyle LW. Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;1:CD001146. PMID: 12535402.
Halliday HL, Ehrenkranz RA, Doyle LW. Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2003;1:CD001144. PMID: 12535400.
Halliday HL, Ehrenkranz RA, Doyle LW. Delayed (>3 weeks) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev 2009;1:CD001145. PMID: 19160189.
Kluckow M, Evans N. Low superior vena cava flow and intraventricular hemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000;82:F188–F194. PMID: 10794784.
Soll RF, Morley CJ. Prophylactic versus selective use of surfactant in preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2001;2:CD000510. PMID: 11405966.
Vohra S, Roberts RS, Zhang B, et al. Heat loss prevention (HeLP) in the delivery room: a randomized controlled trial of polyethylene occlusive skin wrapping in very preterm infants. J Pediatr 2004;145:750. PMID: 85580155.
PATHOLOGY & CARE OF THE HIGH-RISK TERM NEONATE
Persistent Pulmonary Hypertension
During fetal life, oxygenated blood is delivered to the fetus from the placenta. Pulmonary vascular resistance is elevated in utero; consequently minimal blood flow goes to the lungs. Instead, as noted in PDA, close to 90% of the output from the right ventricle passes from the pulmonary artery to the aorta through the ductus arteriosus. However, successful transition from fetal to extrauterine life requires a drop in pulmonary vascular resistance. The fall in pulmonary pressures results from a series of events that begins before birth but accelerates when a baby is born, the baby cries (filling the lungs with air), and the umbilical cord is cut (increasing the systemic resistance). A number of processes can interrupt this process, either by mechanically blocking the airways, thus preventing essential lung expansion and increase in the partial pressure of oxygen, or by preventing relaxation of the pulmonary vascular bed. Meconium aspiration syndrome, asphyxia, sepsis, pneumonia, and CDH are among the most common causes of persistently elevated pulmonary vascular resistance, termed persistent pulmonary hypertension of the newborn (PPHN).
PPHN results in severe hypoxia in the newborn. Blood continues to shunt away from the pulmonary circulation through the foramen ovale, ductus arteriosus, or both, bringing poorly saturated blood to the body. Treatment consists of interventions aimed at lowering the pulmonary vascular resistance. Acidosis and hypoxemia are potent pulmonary vasoconstrictors and are to be avoided. When possible, PaO2 is maintained in the normal range (80–100 mm Hg). Supplemental oxygen is weaned cautiously because even relatively small changes can cause an acute decompensation. Every effort should be made to maintain left ventricular output and blood pressure (thus systemic perfusion) in the normal range and to keep the blood pH in the 7.3–7.4 range. Acidosis is a vasoconstrictor, but aggressive use of bicarbonate or THAM may not be beneficial. Although hyperventilation was used in the past to maintain an alkaline pH, concerns about ventilator-induced lung damage and the effect of hypocarbia on cerebral blood flow have altered this practice. In addition, studies have shown that it is the normalized pH, not the decreased CO2, that improves pulmonary vasoconstriction. Most physicians adjust the ventilator support to target a PaCO2 of 40–50. High-frequency ventilators are often used, allowing for higher mean airway pressures without increasing barotrauma and volutrauma to the lungs. Vasopressors, typically dopamine, are used to maintain systemic blood pressure. If there is evidence of myocardial dysfunction, an inotrope such as dobutamine typically is used, and vasopressor support is adjusted to prevent undesirable increases in systemic vascular resistance. Patients with PPHN are extremely sensitive to noise and tactile stimulation, so infusions of sedatives and analgesia are routinely used to minimize agitation. However, use of neuromuscular blockade is to be avoided because it does not appear to improve clinical outcome and is associated with significant side effects, including sensorineural hearing loss.
Nitric oxide is a selective pulmonary vasodilator. Inhaled nitric oxide (iNO) has been proven to improve oxygenation and decrease the need for extracorporeal membrane oxygenation (ECMO) in term infants with PPHN. iNO is routinely started at 20 ppm, although lower doses may be as effective. iNO is weaned as the patient stabilizes and the supplemental oxygen requirement falls. Despite the dramatic improvement in outcomes since the availability of iNO, a number of patients with PPHN will still require ECMO. Historically the criterion for ECMO has been a greater than 80% estimated risk of mortality with continued conventional medical management. General guidelines for the criteria for ECMO include an oxygenation index greater than 35–60 for between 0.5 and 6 hours, an alveolar–arterial oxygen difference greater than 605–620 (at sea level) for 4–12 hours, or a preductal PaO2 less than 40 for more than 2 hours. ECMO is contraindicated in neonates less than 34 weeks’ gestational age because of technical issues regarding catheter placement as well as the increased risk of intracranial bleeding in the preterm neonate. A preexisting grade II or higher IVH, signs of severe irreversible brain damage, lethal congenital anomalies, and nonreversible pulmonary disease are other contraindications to ECMO. Survival of patients with PPHN treated with ECMO varies depending on the underlying cause of PPHN. The survival rate of patients with meconium aspiration syndrome is greater than 90%, but the survival rate of patients with CDH is only 50%.
Congenital Diaphragmatic Hernia
CDH is a defect that results from incomplete development and closure of the diaphragm, usually at the foramen of Bochdalek at 8–10 weeks’ gestation. The defect in the diaphragm allows the contents of the abdominal cavity to migrate into the chest, resulting in compression of the lungs and, in more severe cases, the heart. The compression leads to pulmonary hypoplasia, abnormal lung development, and potentially underdevelopment of 1 or both ventricles. Ninety percent of CDH involves the left hemidiaphragm. CDH is now generally prenatally diagnosed, but a number of cases still go undiagnosed, even with routine prenatal care.
A number of features should raise suspicion about the possibility of CDH in the newborn with cyanosis and respiratory distress. Breath sounds may be absent on the left side of the chest and the heart sounds shifted to the right. The abdomen tends to be scaphoid, as some of the abdominal organs typically have shifted into the thorax. It may be difficult to effectively ventilate and resuscitate the patient. If a CDH is suspected, mask and bag ventilation must be avoided. The patient should be intubated and a sump/replogle tube placed as soon as possible to prevent air from filling the stomach and bowel and thus compromising ventilation further. Many centers use sedation and sometimes paralysis to minimize activity and prevent competition from swallowed air. CXR observation of bowel loops in the chest confirms the diagnosis.
Surgical repair of the defect usually is delayed until the patient’s condition stabilizes and the reactive component of the pulmonary hypertension has improved. Efforts are made to use the lowest ventilator settings tolerated to minimize ventilator-induced lung injury. Surfactant, iNO, high-frequency ventilation, and, if necessary, ECMO are often used to manage patients with CDH. However, surfactant administration has been shown to be of no benefit, and some studies suggest that it may be associated with an increased need for ECMO, so its routine use cannot be recommended. To date, the evidence also has not shown a clear benefit of iNO for patients with CDH. Additional studies are needed to evaluate the role of each of these interventions in the care of the patient with CDH.
Reported survival rates vary from approximately 35–80%, perhaps reflecting differences between centers and/or bias related to referral patterns. The prognosis depends on the severity of the underlying pulmonary hypoplasia and the degree of reactive pulmonary hypertension, as well as the presence of other anomalies or a chromosomal abnormality. Development of a pneumothorax has been shown to predict a poor outcome. Failure to achieve a preductal PaO2 greater than 100 mm Hg or a PaCO2 lower than 60 in the first 24 hours of life generally indicates a poor prognosis as well. Some physicians argue that infants in whom the PaCO2 level never falls below 80 or who never achieve a preductal oxygen saturation of at least 85% for at least 1 hour have severe pulmonary hypoplasia and are not appropriate candidates for ECMO. However, the outcome of the individual patient is hard to predict, and every measure must be made to provide gentle ventilation and accept higher PaCO2 and lower PaO2 levels as long as systemic oxygen delivery is appropriate.
Transient Tachypnea of the Newborn
The differential diagnosis for the newborn with tachypnea in the first postnatal hours ranges from RDS to sepsis to CHD. One of the most common causes of tachypnea in the newborn is transient tachypnea of the newborn (TTN). TTN results when fetal lung fluid production fails to cease with the onset of labor. The incidence of TTN is significantly increased when the baby is delivered via caesarean section without labor especially if performed before 39 weeks of gestation.
The newborn presents with tachypnea, increased work of breathing, and cyanosis. Infants with TTN may require moderate supplemental oxygen; some may be sick enough to require intubation. CXR reveals interstitial and alveolar edema; fluid is characteristically seen in the right middle lobe fissure. Symptoms of TTN typically resolve over the first 24–48 hours (fetal lung fluid production ceases in response to stress), and CXR clears by the second or third day of life. However, TTN is a diagnosis of exclusion, and other causes of tachypnea and respiratory distress must be ruled out. An evaluation for sepsis (including initiation of antibiotic therapy pending culture results) as well as other causes of tachypnea is generally warranted.
Congenital Heart Disease
CHD occurs in approximately 1 in 100 live births, and approximately 3 in 1000 have CHD that requires surgical repair or results in death within the first year of life. CHD rarely presents in the delivery room. In fact, the majority of infants with prenatally diagnosed CHD initially appear well. Nevertheless, the newborn with cyanosis who fails to respond to 100% oxygen (hyperoxia test; see below) should be evaluated for structural heart disease. Complex CHD typically presents as cyanosis or congestive heart failure and circulatory shock and only rarely as an asymptomatic murmur in a newborn. Signs such as tachypnea, weak peripheral pulses, or cool extremities may develop quickly with closure of the ductus arteriosus if the lesion has ductal-dependent pulmonary or systemic flow. Right-sided obstructive lesions (eg, pulmonic atresia or stenosis), which are dependent on the ductus for pulmonary blood flow, tend to present with cyanosis due to diminished or absent pulmonary blood flow. Left-sided obstructive lesions (eg, coarctation of the aorta and hypoplastic left heart syndrome) typically present as shock and often are initially misdiagnosed as sepsis. However, statistically the term neonate who develops signs of shock after the first 24–48 hours of life is approximately 5 times more likely to have ductal-dependent CHD than bacterial sepsis.
The initial steps in evaluating a stable patient for suspected CHD include 4-extremity blood pressure measurements, measurement of preductal and postductal saturations, electrocardiogram, CXR, and hyperoxia test. If the PaO2level fails to increase above 100 after exposure to 100% fraction of inspired oxygen (FiO2) for 15 minutes, cyanotic CHD is likely; if the PaO2 level increases above 250, CHD is unlikely. CXR may reveal black lungs that signify diminished pulmonary blood flow (as occurs in right-sided obstructive lesions) or congestion (as occurs with obstructed pulmonary venous return). The diagnosis of CHD usually is established by echocardiogram, although cardiac catheterization is sometimes necessary to clarify the specifics of the abnormal anatomy in complex cases. Low-dose PGE infusion should be started when critical CHD is suspected in order to maintain or reestablish ductal patency. Once the diagnosis of cyanotic heart disease has been made, supplemental oxygen should be used sparingly but as necessary to keep oxygen saturations around 75–85% until surgical repair occurs. This supplementation should provide adequate oxygen delivery to prevent the development of metabolic acidosis without decreasing pulmonary vascular resistance and causing pulmonary overcirculation.
Esophageal Atresia/Tracheoesophageal Fistula
Esophageal atresia occurs when there is an interruption in the separation of the foregut into the trachea and esophagus during the fourth week of gestation. In its most common form, there is a proximal esophageal pouch and a fistula between the trachea and the distal segment of the esophagus. The newborn with esophageal atresia typically presents in the first few hours after birth with copious secretions and coughing or gagging with the first feed. Respiratory distress may develop if secretions or feeds are aspirated. The prenatal istory often is remarkable for polyhydramnios due to the inability of the fetus to regulate amniotic fluid levels by swallowing. The diagnosis usually is apparent when a CXR reveals a nasogastric tube coiled in the proximal esophageal pouch. Absence of a gastric bubble on x-ray usually suggests that a distal fistula is not present. Emergent gastrostomy may be necessary to decompress the stomach. The feasibility of primary repair depends on the distance between the proximal and distal portions of the esophagus. If primary repair is not possible, initial surgery involves ligation of the fistula. Patients typically then undergo serial dilations of the proximal pouch and delayed anastomosis or may require colonic interposition if the gap remains too wide to close. Postoperative complications include leaking or stenosis at the anastomosis site, poor esophageal motility, and gastroesophageal reflux.
Polycythemia
Polycythemia, defined as a central venous Hct greater than 65%, results from either increased in utero erythropoiesis or from maternofetal or twin–twin transfusion. Increased in utero erythropoiesis occurs most often as a response to fetal hypoxia, usually from placental insufficiency. Erythropoiesis in the fetus is also increased with maternal diabetes, chromosomal abnormalities, and endocrine disorders such as congenital adrenal hyperplasia, thyroid disease, and Beckwith-Wiedemann syndrome. Maternofetal hemorrhage most commonly results from delayed cord clamping.
Polycythemia may cause congestive heart failure from volume overload, as in the case of the recipient twin in twin–twin transfusion syndrome. More commonly, the complications attributed to polycythemia arise from hyper-viscosity rather than increased blood volume. Blood viscosity increases as the Hct level rises, placing the polycythemic infant at risk for complications from impaired blood flow and oxygen delivery. Polycythemia may present as hypoglycemia, poor feeding, respiratory distress, pulmonary hypertension, lethargy, jitteriness, or seizures. Infants are at increased risk for NEC, and thrombotic strokes may occur.
Although IV hydration may be useful, a symptomatic neonate with Hct level greater than 65% or an asymptomatic neonate with Hct level greater than 70% should undergo a partial exchange transfusion performed to decrease blood viscosity and ameliorate any symptoms. The volume of blood that should be removed and then replaced with isotonic saline (to lower the viscosity without causing hypovolemia) is determined by the following formula:
Volume to be exchanged = [Blood volume × (Observed hematocrit – Desired hematocrit)]/Observed hematocrit
Blood volume usually is estimated at 80–90 mL/kg in a term infant and 90–100 mL/kg in a preterm infant. The goal Hct usually is 55%. The hope is that partial exchange will prevent symptoms from worsening and further complications from developing, but long-term follow-up studies have failed to show any benefit.
Hyperbilirubinemia
Hyperbilirubinemia is a common problem in the neonatal period, affecting 60–70% of all infants born in the United States to some degree. In most instances, the level of the unconjugated form of bilirubin is elevated. Although the course usually is benign and an increase in serum bilirubin level occurs in all newborns during the first postnatal days, severe unconjugated hyperbilirubinemia can cause kernicterus and long-term neurologic damage.
Bilirubin is produced when heme-containing compounds such as hemoglobin are broken down. The initial unconjugated product is fat soluble but water insoluble, a form that can cross the blood–brain barrier and cause central nervous system toxicity but cannot be excreted. The blood carries bilirubin to the liver, where it is conjugated to a water-soluble and excretable form by the enzyme glucuronyl transferase. The immature hepatic enzyme function in the newborn impairs bilirubin conjugation and thus excretion. The shorter life span of red blood cells and increased red cell mass in neonates further predispose the newborn to elevated plasma concentrations of bilirubin, as does the increased reabsorption of bilirubin that occurs in the sterile newborn intestinal tract.
Hyperbilirubinemia may be severe when other coexisting factors increase hemolysis, decrease the rate of bilirubin conjugation, or impede excretion. Hemolysis is increased by abnormal red cell enzyme function (glucose-6-phosphate dehydrogenase [G6PD] deficiency, less frequently pyruvate kinase deficiency) or morphology (spherocytosis, elliptocytosis) and isoimmunization due to ABO, minor antigen, or Rh incompatibility. Sepsis can increase hemolysis. A number of inborn errors of metabolism and enzyme defects can impair conjugation. Conjugation is impaired when there is delayed maturation of the conjugating enzymes, as is thought to occur in cases of congenital hypothyroidism. Obstructed biliary flow, as in biliary atresia, and gastrointestinal obstruction cause decreased excretion. Many disease states are associated with hyperbilirubinemia.
Hyperbilirubinemia presents clinically as jaundice, a yellow–green discoloration of the skin and mucous membranes. A serum bilirubin level should be checked in all jaundiced newborns. It is standard policy in some nurseries to check a total serum bilirubin (TSB) level in all newborns prior to discharge. Most centers check a level within 24–48 hours of life in all VLBW infants as risk for sequelae from hyperbilirubinemia is believed to exist at lower serum bili-rubin concentrations in preterm neonates. The etiology of the pathologic hyperbilirubinemia must be sought. A blood type, Coombs’ test, Hct level, and reticulocyte count will provide important information, as will the parent’s ethnicity, maternal blood type, and history of jaundice in siblings. It is important to determine whether it is the level of conjugated or unconjugated fraction of bilirubin that is elevated. The differential diagnosis, evaluation, and treatment are markedly different depending on whether or not the elevated portion is conjugated. A conjugated bilirubin level greater than 10% of the total value should prompt an investigation for biliary obstruction or causes of hepatocellular damage such as TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex) infection, galactosemia, and α1-antitrypsin deficiency. A complete sepsis workup is indicated in the ill-appearing patient.
The AAP has established practice parameters to help direct the use of phototherapy and exchange transfusion for hyperbilirubinemia in infants of greater than 35 weeks’ gestation. Phototherapy causes the photoisomerization of unconjugated bilirubin to a water-soluble form that can be excreted by the kidneys and gastrointestinal tract. Phototherapy is contraindicated for conjugated hyperbilirubinemia; it is ineffective and can cause a bronze staining of the skin. Figure 22–5 shows the current AAP recommendations for initiation of phototherapy. A patient should receive phototherapy if the TSB level lies above the line for the appropriate risk group for the patient. A newborn is considered to have risk factors if any of the following are present: isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin level less than 3.0 g/dL.
Figure 22–5. Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation. G6PD, glucose-6-phosphate dehydrogenase; TSB, total serum bilirubin. (Data from the American Academy of Pediatrics, Subcommitte on hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297–316.)
Insensible losses increase under phototherapy, and liberal IV fluids should be given in anticipation of increased daily fluid needs. Infants who appear well, are tolerating enteral feeds, and are not likely to require an exchange transfusion should continue feeding. Enteral nutrition will increase stooling and facilitate bilirubin excretion. IV fluid should be given in addition if oral intake is insufficient or if needed for adequate hydration.
Figure 22–6 shows the AAP guidelines for exchange transfusion. Exchange transfusion effectively removes anti-red blood cell antibodies circulating in the blood and may have an effect on removing circulating bilirubin. Twice the blood volume (estimated at 80–100 cc/kg) is slowly removed from the patient in aliquots of 5–10 cc, with each aliquot followed by transfusion of an equal volume of fresh type O-negative blood, reconstituted with plasma to a hematocrit of 45–50%. The guidelines shown in Figure 22–6 are intended to apply to the newborn who has a continuous rise in TSB level despite intensive phototherapy or to a neonate readmitted to the hospital after discharge who continues to have a TSB above the exchange level for 6 hours after initiation of phototherapy. Immediate exchange is recommended if the TSB is more than 5 mg/dL greater than the exchange threshold or if the patient has abnormal findings on neurologic examination that suggest acute bilirubin encephalopathy. Complications of exchange transfusion include hypocalcemia, hypoglycemia, hypothermia, coagulation abnormalities, apnea, and bradycardia. Many centers delay resuming oral feeds until 24–48 hours after exchange because of the increased risk of NEC after exchange.
Figure 22–6. Guidelines for exchange transfusion in infants of 35 or more weeks’ gestation. G6PD, glucose-6-phosphate dehydrogenase; TSB, total serum bilirubin. (Data from the American Academy of Pediatrics, Subcommitte on hyperbilirubinemia: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316.)
Indications for phototherapy and exchange transfusion in preterm infants are not well established. A reasonable guideline is to begin phototherapy when the bilirubin concentration is equal to 0.5% of the birth weight (in grams) and to consider an exchange transfusion when the concentration reaches 1% of the birth weight. These numbers represent a very general guideline, however, and it is important that treatment decisions take into account the etiology of the jaundice and the patient’s overall clinical status. The presence of significant bruising, hemolysis, sepsis, or acidosis should lower the physician’s threshold for initiating treatment.
Infection
Infection is a significant cause of morbidity and mortality in the newborn. The immature newborn immune system places the neonate at increased risk for infection. The preterm infant, whose immune system is markedly immature and who has diminished levels of immunoglobulin compared to the term newborn, is at particularly high risk. Typically infection is acquired when organisms ascend into the uterine cavity and come into contact with the fetus, but infection can be acquired hematogenously, from the mother’s blood, or at the time of delivery when the newborn passes through the vaginal canal.
A. Sepsis
Neonatal sepsis occurs in 1 in 1000 term infants and 1 in 4 preterm infants. Risk factors for neonatal sepsis include premature delivery, multiple pregnancy, prolonged rupture of amniotic membranes (>18 hours), maternal fever, maternal group B Streptococcus (GBS) colonization, and chorioamnionitis. The most common causes of early-onset (within the first week of life) sepsis are GBS and Escherichia coli. Listeria monocytogenes, enterococci, and several different gramnegative rod species are other identified causes of early-onset neonatal sepsis. Late-onset infection in hospitalized infants is more often due to Staphylococcus spp.
Signs and symptoms of sepsis in the newborn can be very subtle and nonspecific, such as temperature instability, hypoglycemia or hyperglycemia, apnea, poor feeding, or tachypnea. In contrast, some neonates present in fulminant shock. A complete blood count and blood culture should be sent if sepsis is suspected and antibiotics should be started. A decreased or elevated white blood cell count, a predominance of immature white blood cell forms, and thrombocytopenia are suggestive of infection. Although nonspecific, an elevated C-reactive protein (CRP) level indicates the presence of an inflammatory or infectious process, and data support the negative predictive value of a CRP level in the evaluation for sepsis in the neonate. In addition, CXR is indicated to evaluate for pneumonia. Often differentiating an infiltrate from atelectasis, RDS, or retained lung fluid is difficult, but serial films may be useful in differentiating the various processes. There is debate about whether a culture of cerebrospinal fluid (CSF) is necessary in the newborn evaluated for early-onset sepsis. (A CSF culture is clearly warranted in suspected late-onset sepsis because the incidence of coexisting meningitis with late-onset bacteremia is very high.) Unless signs of meningitis (eg, seizure activity or altered mental status) or a documented positive blood culture is present, meningitis is unlikely in the immediate newborn period. However, studies have reported positive CSF cultures with concurrent negative blood cultures in asymptomatic neonates. The issue has been further complicated by the current widespread use of maternal intrapartum antibiotics. Consequently, given the ramifications of failure to diagnose or only partially treat a case of meningitis, CSF culture is a routine part of the newborn sepsis evaluation in many institutions, and if the infant is unable to have a lumbar puncture, meningitic doses of antibiotic should be used. Urine culture, a routine part of the sepsis evaluation for late-onset disease, is rarely useful in the first few days of life.
Antibiotics that provide broad-spectrum coverage, typically ampicillin and gentamicin in the first few days of life, should be continued for 48–72 hours pending the results of all cultures that were sent for analysis. Vancomycin and gentamicin are often used for nosocomial infections. If bacteremia is documented by a positive blood culture or highly suspected based on clinical status or laboratory findings, antibiotics should be continued for 7–10 days. IV antibiotics usually are continued for a minimum of 2 weeks for gram-positive meningitis and 3 weeks for gramnegative meningitis.
The Centers for Disease Control and Prevention (CDC) developed guidelines in 1996 that recommended screening for GBS colonization at 35–37 weeks’ gestation. It was recommended that colonized women and those with other risk factors receive intrapartum antibiotic therapy beginning at least 4 hours prior to delivery. The incidence of early-onset GBS sepsis has been reduced by 65% in communities that have adopted the CDC GBS prevention guidelines. Currently, no evidence suggests an increased incidence of non-GBS early-onset sepsis with adoption of the guidelines, as had been feared.
B. Conjunctivitis
Infection of the conjunctiva may occur within the first few weeks of life. Prophylaxis with erythromycin 0.5% ophthalmic ointment immediately after delivery is now a standard part of newborn care. Conjunctivitis usually presents with injection of the conjunctiva and discharge from the eye, usually bilaterally, in the first week of life. Erythema of the conjunctiva helps differentiate conjunctivitis from lacrimal duct obstruction, a common cause of eye discharge in the neonate.
Chlamydia trachomatis and Neisseria gonorrhoeae are the most notable causes of neonatal conjunctivitis. Maternal treatment of either infection during pregnancy reduces the risk of infection in the neonate. Gonococcal conjunctivitis produces a purulent discharge and may cause serious complications, including blindness. A Gram stain and culture of the discharge should be performed if there is any suspicion of infection to determine appropriate therapy. It is important to recognize that the infant with Chlamydia conjunctivitis may have or may develop Chlamydia pneumonia. Chlamydia pneumonia commonly presents in the first 6 weeks of life with tachypnea and cough. The infant with gonococcal conjunctivitis should receive 7 days of IV or intramuscular treatment with a third-generation cephalosporin such as ceftriaxone. Chlamydia conjunctivitis is treated with oral erythromycin for 14 days.
C. Viral Infection
A number of viral infections can cause disease in the newborn. The infection may be acquired in utero or at the time of delivery. Antibody titers and cultures should be sent when congenital viral infection is suspected. A number of viruses (including cytomegalovirus [CMV], varicella, and parvovirus) and parasites such as Toxoplasma gondii are associated with congenital infection, and the presentation at birth varies significantly depending on the cause. Herpesvirus and enterovirus infections can present acutely with respiratory failure and/or shock. Hepatitis and coagulopathy are often seen in neonates with viral sepsis, even early in the disease process before end-organ damage is even suspected, and should raise suspicion about the possibility of a viral process. There is no maternal history of herpes simplex virus (HSV) in the majority of neonates diagnosed with HSV sepsis or encephalitis. Acyclovir is used to treat herpes viruses such as HSV and varicella.
Transmission from mother to infant at birth is one of the most efficient modes of hepatitis B virus (HBV). Between 80% and 90% of children born to mothers who are both hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive will become infected, and 90% of those infants will become chronic HBV carriers. Transmission falls to less than 25% if HBeAg is negative and to 12% if anti-HBe is present. Babies born to HBsAg-positive mothers should receive hepatitis B immune globulin (HBIg) and the hepatitis B vaccine within 12 hours of delivery. If the mother’s status is unknown at the time of delivery, the newborn should receive the vaccine within 12 hours of life. If the newborn weighs more than 2 kg, HBIg can be deferred for up to 7 days to allow determination of the mother’s status according to the AAP Red Book guidelines. However, given the less reliable immune response to vaccine in the preterm host, HBIg should not be deferred in patients weighing less than 2 kg. Appropriate postexposure prophylaxis in the newborn has been shown to prevent transmission in 95% of exposures.
Perinatal infection with human immunodeficiency virus (HIV) now accounts for almost all new infections in preadolescents in the United States. The risk of perinatal transmission if an HIV-positive mother does not receive antiretroviral therapy during pregnancy is 13–39%. A trial of zidovudine during pregnancy and delivery, with continued treatment for the newborn for 6 weeks after delivery, showed a greater than 60% reduction in transmission. It is currently recommended that HIV-positive women receive zidovudine prophylaxis in addition to the standard current recommendations for antiretroviral therapy for all HIV-positive patients. Zidovudine prophylaxis/treatment of the newborn should be started and analysis for HIV DNA polymerase chain reaction sent when in utero exposure to HIV is recognized before 7 days of life.
Infant of the Diabetic Mother
From 50,000–100,000 infants are born to diabetic mothers every year in the United States. The infant of a diabetic mother (IDM) is at increased risk for congenital malformations, macrosomia, birth injury, and a number of postnatal complications, such as RDS, polycythemia, and hypoglycemia. With improved obstetric monitoring and neonatal care, perinatal mortality has decreased significantly over the past few decades. With decreased losses from stillbirths, perinatal asphyxia, and RDS, congenital malformations now represent the single most important cause of perinatal mortality and severe morbidity in IDMs.
Studies have shown that IDMs have a 2- to 8-fold higher risk of a structural malformation compared to infants born to nondiabetic mothers. The most common malformations in IDMs are neural tube defects, CHD, renal anomalies, and abnormalities of the genitourinary tract. The exact pathogenesis of the malformations is unclear, but various mechanisms, including altered levels of arachidonic acid and/or myoinositol, free-radical damage, and altered gene expression have been proposed. The risk of structural malformations has been clearly shown to correlate with poor glycemic control in the first trimester. Consequently, tight control of glucose levels must begin prior to conception in order to decrease the risk of structural malformations.
Metabolic alterations seen in IDMs are more closely associated with glycemic control later in pregnancy. Elevated maternal glucose levels result in elevated fetal glucose levels that produce hyperinsulinism in the fetus. Insulin is a growth factor, and abnormal exposure to insulin results in fetal macrosomia. After delivery, the hyperinsulinemic state persists, but there is no longer an ongoing supply of glucose coming across the placenta; the newborn is thus at risk for hypoglycemia. IDMs should be closely monitored after birth to ensure that glucose requirements are met. Severe and/or prolonged hypoglycemia can cause significant injury to the developing brain. Poor glucose control during the second and third trimesters is associated with an increased risk for macrosomia and neonatal hypoglycemia. Other metabolic derangements frequently seen in IDMs are hypocalcemia and hypomagnesemia.
IDMs are at increased risk for RDS. Surfactant production occurs later than normal in diabetic pregnancies. Polycythemia also occurs at a higher rate. The greater red cell volume, in turn, increases the risk of hyperbilirubinemia. Hyperglycemia and the resulting hyperinsulinemia in the fetus generate a catabolic state, causing oxygen consumption. Erythropoiesis is believed to occur as a response to fetal hypoxia.
Asymmetric hypertrophic cardiomyopathy is a frequent finding in IDMs. The cardiomyopathy may be asymptomatic, apparent only as cardiomegaly on CXR, or it may be clinically significant, usually as a result of left ventricular outflow tract obstruction and/or poor ventricular filling and cardiac output related to hypertrophy of the ventricular septum. The hypertrophy of the cardiac muscle resolves over time, and the only indicated treatment is supportive care.
Intrauterine Growth Restriction
Intrauterine growth restriction (IUGR) describes a pattern of aberrant and reduced fetal growth that is identified by prenatal ultrasound examinations. The growth restriction is classified as asymmetric if the head circumference, used as a marker for brain growth, is spared. IUGR refers to growth in utero, and IUGR newborns may or may not be small for gestational age (SGA). (The definition of SGA varies, but historically it has been defined as less than the 10th percentile for gestational age at birth.) IUGR can result from a range of processes that may originate with the fetus (chromosomal abnormalities, fetal gender, genetic inheritance, TORCH infection), the placenta (abnormal implantation or insertion of the cord, preeclampsia, placental insufficiency), or the mother (chronic disease such as diabetes, systemic lupus erythematosus, or cyanotic heart disease; smoking; abnormal uterine anatomy; low pregnancy weight gain). The etiology of IUGR in approximately 40% of patients is never determined. CMV and toxoplasmosis studies are sometimes sent for affected newborns to determine an infectious cause. However, given the number of idiopathic cases of IUGR, some have questioned the utility of sending these cultures for infants with no physical examination or imaging study findings suggestive of congenital infection. Prenatal management of the IUGR fetus is impacted by the increased risk of intrauterine demise and perinatal asphyxia with IUGR, but also requires consideration of the fact that gestational age at birth is still a major determinant of outcome in the premature growth-restricted infant. There is currently great interest in the connection between low birth weight and the development of type 2 diabetes, hypertension, and coronary artery disease in adulthood.
The Dysmorphic Infant
It is estimated that 2% of all newborns have a serious congenital malformation. Advances in prenatal care now allow for early diagnosis of many congenital birth defects or diseases, but many are still difficult or impossible to detect in utero. Dysmorphic features and structural abnormalities may be immediately apparent, or they may be subtle and identified only upon close inspection. Every newborn should undergo a thorough examination to identify features suggestive of underlying pathology, genetic abnormalities, or specific syndromes or disorders.
Transfer of the newborn to a referral center where an evaluation by a clinical geneticist or dysmorphologist can be conducted may be warranted if significant abnormalities are present. The remarkable progress in our understanding of human genetics over the past decade has dramatically increased our ability to identify the genetic defects responsible for countless diseases and syndromes. In addition, each year, more is understood about numerous multifactorial disorders, improving the odds that affected patients will be correctly diagnosed. A geneticist can help identify pertinent elements of the family, exposure, and prenatal history and direct a thorough but targeted radiologic and cytogenetic workup for the newborn. It is preferable to avoid making conclusions about the diagnosis (ie, a particular syndrome or sequence) until a complete evaluation has been performed. The emotional impact of an unsuspected defect or syndrome on the new parents should not be ignored, and misinformation can only hinder the process of acceptance (Table 22–1).
Table 22–1. Elements of counseling for developmental defects.
Allan WC, Sobel DB. Neonatal intensive care neurology. Semin Pediatr Neurol 2004;11:119–128. PMID: 15259865.
American Academy of Pediatrics. AAP 2003 Red Book: Report of the Committee on Infectious Diseases. 26th ed. Elk Grove, IL: American Academy of Pediatrics; 2003.
Baltimore RS, Huie SM, Meek JI, et al. Early-onset neonatal sepsis in the era of group B streptococcal prevention. Pediatrics 2001;108:1094–1098. PMID: 11694686.
Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2003;111:529–534. PMID: 12613322.
Bin-Nun A, Bromiker R, Wilschanski M, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005;147:192–196. PMID: 16126048.
Boloker J, Bateman DA, Wung JT, et al. Congenital diaphragmatic hernia in 120 infants treated consecutively with permissive hypercapnia/spontaneous respiration/elective repair. J Pediatr Surg2002;37:357–366. PMID: 11877648.
Centers for Disease Control and Prevention. National Center for Health Statistics. http://www.cdc.gov/nchs/. Accessed May 2010.
Cifuentes J, Bronstein J, Phibbs CS, et al. Mortality in low birth weight infants according to level of neonatal care at hospital of birth. Pediatrics 2002;109:745–751. PMID: 19986431.
Clark RH, Kueser TJ, Walker MW, et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000;342:469. PMID: 10675427.
Dempsey EM, Barrington KJ. Short and long term outcomes following partial exchange transfusion in the polycythemic newborn: a systematic review. Arch Dis Child Fetal Neonatal Ed 2006;91:F2–F6. PMID: 16174666.
Hëller G, Richardson DK, Schnell R, et al. Are we regionalized enough? Early-neonatal deaths in low-risk births by the size of delivery units in Hesse, Germany 1990–1999. Int J Epidemiol 2002;31:1061. PMID: 12435785.
Khan N, Khazzi S. Yield and costs of screening growth-retarded infants for TORCH infections. Am J Perinatol 2000;17:131–135. PMID: 11012137.
Kunz AN, Noel JM, Fairchok MP. Two cases of Lactobacillus bacteremia during probiotic treatment of short gut syndrome. J Pediatr Gastroenterol Nutr 2004;38:457–458. PMID: 15085028.
Lin HC, Su BH, Chen AC, et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005;115:1–4. PMID: 15629973.
Martin JA, Kochanek KD, Strobino DM, et al. Annual summary of vital statistics—2003. Pediatrics 2005;115:619–634. PMID: 15741364.
Ment LR, Bada HS, Barnes P. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002;58:1726–1738. PMID: 12084869.
Patole S. Prevention of necrotising enterocolitis: year 2004 and beyond. J Matern Fetal Neonatal Med 2005;17:69–80. PMID: 15804791.
Patole S, de Klerk N. Impact of standardized feeding regimens on incidence of neonatal necrotizing enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed2005;90:F147-F151. PMID: 15724039.
Polin RA, Sahni R. Newer experience with CPAP. Semin Neonatol 2002;7:379–389. PMID: 12464500.
Schmidt B, Davis P, Moddemann D, et al. Trial of Indomethacin Prophylaxis in Preterms Investigators. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med2001;344:1966–1972. PMID: 11430325.
Toby Study Group. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomized controlled trial. BMC Pediatr 2008;8:17. PMID: 18447921.
Tsao K, Lally KP. Surgical management of the newborn with congenital diaphragmatic hernia. Fetal Diagn Ther 2011;29:46–54. PMID: 20926849.
Van Meurs K. Is surfactant therapy beneficial in the treatment of the term newborn infant with congenital diaphragmatic hernia? J Pediatr 2004;145:312–316. PMID: 15343181.
Wunsch H, Mapstone J, Takala J. High-frequency ventilation versus conventional ventilation for the treatment of acute lung injury and acute respiratory distress syndrome: a systematic review and Cochrane analysis. Anesth Analg 2005;100:1765–1771. PMID: 15920211.