Section N: Newborn Medicine

BACKGROUND

In order for a normal transition from fetal to newborn physiology to occur, a complicated and well-orchestrated sequence of physiologic changes must transpire. While the majority of newborns transition from fetal to postnatal circulation without significant difficulty, it is estimated that 10% require some degree of resuscitation in the delivery room and about 1% require significant resuscitation.¹ Birth asphyxia accounts for approximately 23% of the 4 million neonatal deaths per year.¹ Delays in establishing effective cardiorespiratory function may increase the risk for hypoxic-ischemic cerebral injury, pulmonary hypertension, and systemic organ dysfunction. Some of these injuries may be preventable with prompt resuscitation. However, some of these outcomes are related to events or exposures that precede the birth process, such as prenatal injuries, abnormal development, and insults to the intrauterine environment.

PATHOPHYSIOLOGY

The adaptation from intrauterine life to extrauterine life starts during the process of labor.² Labor not only increases oxygen consumption in the transitioning fetus but also causes brief periods of asphyxia during contractions as umbilical venous blood flow is briefly interrupted. The fetus tolerates this interruption in blood flow because fetal tissue beds have greater resistance to acidosis than adult tissue beds do. The fetus responds to bradycardia with the “diving reflex” whereby blood preferentially flows to the brain, heart, and adrenal glands. Finally, the fetus is capable of switching to anaerobic sugar production, provided that liver glycogen stores are adequate.

During labor and delivery, catecholamine levels surge and increase lung fluid resorption, release of surfactant, and stimulation of gluconeogenesis. This surge also helps direct blood flow to vital organs such as the heart and brain. With clamping of the umbilical cord, the low-resistance placental circuit is removed from the newborn’s circulation. Systemic blood pressure increases, and transition to the postnatal circulation begins.²

As a newly born infant takes the first few breaths, negative intrathoracic pressure is generated, which helps the lungs expand and become filled with air. Alveolar oxygenation increases as air replaces the fetal lung fluid. The negative intrathoracic pressure, however, is countered by lung compliance, lung fluid viscosity, and surface tension forces. Because these factors need to be overcome to establish adequate alveolar expansion, the infant must take deep enough breaths to create the large transpulmonary pressure initially required after birth. Surfactant, a phospholipid-protein complex that is produced by type II pneumocytes and is deposited along the alveolar surfaces, also helps counteract alveolar surface tension and promote alveolar stability. As a result of the increasing effect of surfactant, less transpulmonary pressure is needed for subsequent breaths, and functional residual capacity is soon established. Pulmonary blood flow increases as the lungs expand, and pulmonary vascular resistance declines under the influence of oxygen-mediated relaxation of the pulmonary arterioles. This increase in pulmonary blood flow in turn allows the patent foramen ovale and the patent ductus arteriosus to functionally close, thereby allowing further blood flow to the lungs. The postnatal circulation is now that of a low-resistance pulmonary circuit and high-resistance systemic circuit, and the lungs assume the responsibility of gas exchange and oxygenation.²

Asphyxia is defined as failure of gas exchange leading to a combination of hypoxemia, hypercapnia, and metabolic acidemia. If adequate ventilation and pulmonary perfusion are not rapidly established, a progressive cycle of worsening hypoxemia, hypercapnia, and metabolic acidemia ensues. Initially, blood flow to the brain and heart is preserved, whereas blood flow to the intestines, kidneys, muscles, and skin is sacrificed. However, maintenance of blood flow, even to vital organs, cannot be sustained endlessly. Ultimately, ongoing ischemia, hypoxia, and acidosis result in myocardial dysfunction and impaired cardiac output. Inadequate blood flow, perfusion, and tissue oxygenation result in brain injury, multiorgan injury, and even death.

CLINICAL PRESENTATION

Clinical signs and symptoms of disrupted fetal-to-neonatal transition include cyanosis, bradycardia, hypotension, decreased peripheral perfusion, depressed respiratory drive, and poor muscle tone. Apgar scoring is an objective method of quantifying the infant’s status and to convey information about response to resuscitation, depicted in Table 123-1. The newborn is assessed at 1 and 5 minutes, and if the 5-minute score remains less than 7, additional scores should be assigned every 5 minutes for up to 20 minutes.¹ Because resuscitation must be initiated before a 1-minute score is assigned, Apgar scores should not be used to determine need for resuscitation or to guide steps of resuscitation. However, changes in Apgar scores at sequential time points after birth can reflect how well the infant is responding to resuscitation.

DIFFERENTIAL DIAGNOSIS

Multiple maternal, placental, mechanical, and fetal problems may occur at any point in the process of pregnancy, labor, or delivery and can jeopardize a smooth fetus-to-newborn transition. The fetoplacental circulation can be compromised for a variety of reasons, all of which may cause deceleration of the fetal heart rate and result in hypoxia and ischemia. In the case of maternal hypotension, the maternal side of the placenta is inadequately perfused. In placental abruption, gas exchange between the fetus and mother is impaired. Blood flow from the placenta or through the umbilical cord (or both) may be compromised, such as with cord compression. A fetus with intrauterine growth restriction may be intolerant of even brief and intermittent interruptions of umbilical blood flow during contractions.

Insufficient respiratory effort as a result of respiratory distress syndrome, maternal narcotic administration, or anesthesia will hamper lung expansion and replacement of fetal lung fluid with air. Other disturbances to normal tissue function can also lead to fluid retention. Foreign material such as meconium or blood may obstruct the neonate’s airway and prevent adequate lung inflation. The end result of any of these situations is inadequate alveolar oxygenation, which in turn sets the stage for the development of persistent pulmonary hypertension of the newborn (PPHN). In this condition, which is also known as persistent fetal circulation, the pulmonary arterioles remain constricted, thereby preventing adequate blood flow to the lungs and resulting in hypoxia and acidosis. Hypoxia and acidosis mediate sustained constriction of the pulmonary arterioles, and a vicious cycle ensues as progressively deoxygenated blood circulates. Transitional physiology does not occur normally, and unoxygenated blood is shunted away from the high-pressure lung circuit. Systemic organ dysfunction and, more importantly, long-term neurologic compromise may result. Other causes of PPHN include problems that cause systemic hypotension, such as excessive blood loss or hypoxia-induced cardiac dysfunction.

MANAGEMENT

OPTIMIZING DELIVERY ROOM RESUSCITATION

Anticipation, adequate preparation, accurate evaluation, and prompt initiation of support are critical for successful neonatal resuscitation. Well-trained personnel must be immediately available in any setting in which an infant might be delivered. Every birth should be attended by at least one person whose primary responsibility is the newly born infant and who is able to initiate resuscitation if needed. Resuscitation equipment should be readily available for each and every birth and lists exist to help this preparation.¹ Personnel attending deliveries should be familiar with the organization of the equipment so that resuscitation can be promptly initiated and support provided. Equipment should be checked at regular intervals and immediately before any delivery. Expiration dates of medications should be monitored regularly.¹

Significant maternal medical history, gestational age, prenatal complications, medications, illicit drug use, and prenatal laboratory values should be recorded. Risk factors for sepsis, including group B streptococcus carrier status, length of rupture of membranes, maternal fever, evidence of chorioamnionitis, and use of intrapartum antibiotics, should be assessed. Specific indicators of fetal condition such as heart rate monitoring, lung maturity, and antenatal ultrasound findings should be communicated. Many conditions exist that place newly born infants at risk for disrupted transition.¹ If a high-risk delivery is anticipated in which significant resuscitative intervention may be necessary, a prenatal consultation by the pediatric team should be performed if time permits, and additional skilled personnel should be present at delivery.¹

INITIAL STEPS OF DELIVERY ROOM RESUSCITATION

Three primary questions about the newborn should be asked at the time of birth when assessing need for intervention: (1) Is the infant born at term? (2) Is he breathing or crying? and (3) Does he have good tone? If the answer to any of these questions is “No,” resuscitation of the infant should be initiated.¹ The first step after birth of the infant is to provide warmth under a pre-heated radiant warmer and rapid drying with warm blankets. Next, the infant’s head should be positioned in a neutral or “sniffing” position, which allows alignment of the posterior pharynx, larynx, and trachea for maximal airway patency. Either a bulb syringe or a suction catheter should be used to clear the airway of any potential obstructions. The mouth should be suctioned first because suctioning the nose and nasopharynx may cause gagging and aspiration of oral secretions. Vigorous suctioning of the posterior pharynx should be avoided. In addition to drying and airway clearance, respirations can be further encouraged by briefly providing tactile stimulation to the infant with gentle rubbing of the back or flicking of the heels. These initial steps of neonatal resuscitation should take less than 30 seconds, at which point the infant’s respirations and heart rate should be evaluated.

VENTILATION ASSISTANCE

As shown in Figure 123-1, if after the initial steps of resuscitation the infant is apneic or has gasping respirations, or if the heart rate is below 100 bpm, positive pressure ventilation (PPV) should be initiated at a rate of 30 to 60 bpm. If the baby is breathing, has a heart rate greater than 100 bpm, but demonstrates persistent respiratory distress, many clinicians would administer continuous positive airway pressure (CPAP).¹ After 30 seconds of CPAP or PPV, the newborn should be reevaluated to ensure ventilation is adequate. Assurance of adequate ventilation is critical before moving on to any of the next steps of resuscitation. For most infants, the heart rate will appropriately increase to above 100 bpm with adequate ventilation.

ASSESSMENT OF SUPPLEMENTAL OXYGEN REQUIREMENT

Central cyanosis caused by low oxygen will appear as a blue hue to the lips, tongue, and torso. However, studies have shown that clinical assessment of skin color is not very reliable.¹ Therefore, an oximeter probe should be placed in a preductal location (right wrist or right palm) to confirm perception of central cyanosis and to determine need for supplemental oxygen whenever PPV or CPAP are initiated. For infants born at term, resuscitation should be initiated using room air and then be guided by oximetry to titrate supplemental oxygen to achieve saturations that approximate normal transitioning from in utero to extrauterine values. Table 123-2 demonstrates the time course for targeted oxygen saturation values after birth, which range from approximately 60% at 1 minute of life to approximately 90% at 10 minutes of life.¹

BAG-MASK VENTILATION

The first breath must be large enough to ensure alveolar expansion such that functional residual capacity is established. This sometimes requires initial breaths with a pressure of 20 to 40 mmHg. Once functional residual capacity is established, less pressure is likely to be necessary. A tight seal between the infant’s face and the mask is essential to provide adequate ventilation. The mask should cover the nose and mouth but be clear of the eyes. Masks with air-filled cushions help maintain a tight seal without inflicting facial or ocular injury. Care should be taken to prevent overdistention and hyperventilation during resuscitation. Overdistention from bag-mask ventilation using high airway pressure—and therefore applying large tidal volumes—may impair venous return to the heart and may also lead to air leak syndrome.

Three types of devices are available for PPV of the newborn. A self-inflating bag (Ambu) inflates automatically without a compressed gas source, and should be available as a backup wherever resuscitation may be needed, in case of other equipment failure. CPAP cannot be delivered reliably with this device, and maximal oxygen delivery is only 40% unless an oxygen reservoir is attached. A flow-inflating or “anesthesia” bag inflates only when there is continual flow from a compressed gas source and when the outlet of the bag is sufficiently occluded with a tight mask seal against the infant’s face. CPAP can be delivered with a flow-inflating bag. For both the self-inflating bag and the flow-inflating bag, the use of a pressure gauge is recommended to monitor peak inspiratory pressure and to help maintain consistency of each assisted breath.⁴ Finally, a T-piece resuscitator (Neopuff) provides flow-controlled and pressure-limited breaths using gas from a compressed source (see Figure 123-2).

ENDOTRACHEAL INTUBATION

Endotracheal intubation is required when adequate ventilation is not achieved using bag-mask ventilation. The procedure for endotracheal intubation is detailed in Chapter 197, which gives specifics regarding correct endotracheal tube (ETT) sizes and insertion depth based on infant gestational age and weight. A CO₂ detector will assist in confirming tracheal placement of an ETT. However, a CO₂ detector may not change color if adequate circulation has not been established despite proper ETT placement, such as in the case of a patient in cardiopulmonary arrest. Moreover, a CO₂ detector will not indicate whether an ETT is in the correct position along the trachea. Therefore, it is recommended that a CO₂ detector be used during initial intubation but that the ETT position ultimately should be confirmed with a chest radiograph.¹

CIRCULATORY SUPPORT

Chest compressions are indicated if the heart rate is absent or remains less than 60 bpm after 30 seconds of effective ventilation. Two techniques may be used to administer compressions, either the two-finger method or the two thumb-encircling method. Although either method is acceptable, the two thumb-encircling method is preferred because it results in better peak systolic and coronary perfusion pressure.¹ However, care should be taken to avoid limiting chest expansion during ventilation with this method. Chest compressions are performed on the lower third of the sternum immediately above the xiphoid process to a depth of one third of the anteroposterior diameter of the chest, with the goal of generating a palpable pulse. Chest compressions are performed in coordination with ventilations at a 3:1 ratio such that 90 compressions and 30 ventilations occur in 1 minute. As depicted in Figure 123-1, the infant should be reassessed 30 seconds after initiation of chest compressions to determine the next steps in the resuscitation algorithm.

VASCULAR ACCESS

If the infant’s response to resuscitative measures continues to be poor, vascular access should be obtained for administration of medications and volume expansion as needed. Peripheral intravenous access can be difficult and time consuming, especially if hypoxia or acidosis is present. Emergency vascular access can be achieved via the umbilical vein as described in Chapter 193. If the umbilical vein cannot be cannulated and peripheral access is unsuccessful, intraosseous access, described in Chapter 192, can be used as an alternative route for medications or volume expansion.

MEDICATIONS

Drugs are rarely, but sometimes, necessary in resuscitation of a newly born infant. Epinephrine is indicated when the heart rate remains lower than 60 bpm after 30 seconds of effective ventilation with cardiac compressions. The α-vasocon-strictive properties and the positive cardiac chronotropic effects of epinephrine aid in improving spontaneous circulation. A 1:10,000 solution is administered in a dose of 0.1 to 0.3 mL/kg intravenously. Epinephrine may be administered intratracheally; however, the intravenous route is preferred.¹ If administered via the endotracheal tube, the 1:10,000 solution can be given at a higher dose of 0.5 to 1 mL/kg. The dose should be administered rapidly and can be repeated every 3 to 5 minutes as needed.

Correction of metabolic acidosis with sodium bicarbonate may increase pulmonary blood flow and enhance the effect of epinephrine. Adequate ventilation and circulation must be established prior to administration of sodium bicarbonate, as blood pH will not improve significantly in the absence of adequate ventilation.¹

Naloxone administration is indicated for severe respiratory depression that persists despite a normal heart rate and color after delivery of positive-pressure ventilation in the setting of maternal narcotic administration within 4 hours of delivery. Naloxone has a rapid onset of action within 1 to 2 minutes, but it also has a short duration of action; repeated doses may therefore be needed. The dosage of naloxone is 0.1 mg/kg, and it can be administered via the endotracheal tube, subcutaneously, intramuscularly, or intravenously. If given to an infant of an opioid-addicted mother, naloxone may precipitate acute withdrawal, including severe seizures and long-term sequelae, and it is therefore contraindicated in this setting. Naloxone is ineffective for respiratory depression due to magnesium sulfate exposure.

Volume expansion should be considered in situations in which hypovolemia progresses to hypovolemic shock. This may occur as a result of inadequate supply, as with umbilical cord compression, or increased loss of blood. Significant hemorrhage may be due to placenta previa or placental abruption, fetomaternal bleeding, internal hemorrhage, or twin-twin transfusion syndrome. Options for volume resuscitation include normal saline or lactated Ringer’s solution, 5% albumin, or type O-negative packed red blood cells. Any of these solutions should be administered slowly and in increments of 10 mL/kg, as cardiac function may be compromised during shock and may be exacerbated by an acutely expanded preload volume. Intracranial hemorrhage is a potential consequence of rapid volume expansion, especially in preterm infants. Reassessment, including blood pressure, perfusion, and oxygenation, is essential before additional doses.

ADMISSION CRITERIA AND CONSULTATION

Transfer from the delivery room to a neonatal intensive care unit or consultation with a neonatologist (or both) is recommended in the following circumstances:

• Existence of or suspicion of a significant fetal anomaly, including Down syndrome, ambiguous genitalia, or cardiac or gastrointestinal malformation

• Respiratory distress/tachypnea

• Infants requiring respiratory or cardiac support

• Prolonged resuscitation or delivery of infants requiring cardiac compressions

Of note, many infants with minor concerns can remain in a mother’s room to facilitate parent-infant bonding. Infants with simple anomalies such as supernumerary digits, hypospadias, or a cleft lip or palate may not require admission to the neonatal intensive care unit.

SPECIAL CIRCUMSTANCES

MECONIUM-STAINED AMNIOTIC FLUID

Meconium-stained amniotic fluid (MSAF) is caused by a reaction to fetal hypoxemia, acidemia, stress, or any combination of these precipitants. If in utero stress is significant, the meconium may be aspirated into the airways before birth. Clinical presentation of meconium aspiration ranges from mild tachypnea after birth to severe pneumonitis and pulmonary hypertension. Pulmonary disease is more likely if MSAF occurs before the second stage of labor, if the meconium is thick with particulate material, or if meconium is present below the vocal cords. After delivery, in the setting of MSAF, infants who are vigorous or crying require routine resuscitation only; endotracheal intubation and tracheal suctioning is not indicated as it is not associated with improved outcomes and may result in esophageal or tracheal injury.^1,3,4 However, if the infant is nonvigorous or depressed after delivery, endotracheal intubation and tracheal suctioning should be performed before any stimulation or positive-pressure ventilation.¹ The endotracheal tube (ETT) should be large enough to remove thick copious meconium yet fit easily into the infant’s trachea. A meconium aspirator should be placed directly onto the end of the ETT and connected to suction at 80 to 100 cm H₂O pressure. The entire apparatus, including the ETT, should then be withdrawn slowly. Repeat intubation and tracheal suctioning with a clean ETT may be necessary. Suctioning should be performed until other resuscitation priorities take precedence or the return is clear. Once the infant has been resuscitated, the stomach should be suctioned as well to avoid the potential aspiration of swallowed meconium.

PNEUMOTHORAX

Infants requiring positive pressure ventilation are at risk for developing pneumothorax, which is identified clinically by asymmetry of chest movement or breath sounds. If a tension pneumothorax develops, venous return and cardiac output are compromised and cardiac arrest may occur. Transillumination may be helpful in diagnosis; a light placed next to the newborn’s chest on the affected side will illuminate the air pocket of the pneumothorax more brightly compared with the unaffected side. A chest radiograph is diagnostic, but thoracentesis should be considered in life-threatening cases, even before a radiograph is available. This procedure is described in Chapter 163.

MULTIPLE GESTATIONS

Separate teams of skilled personnel are required for each infant of a multiple gestation. Multiple gestations are associated with an increased incidence of preterm labor and delivery, as well as an increased risk for intrauterine growth retardation in at least one fetus. Postnatally, there is a risk of higher sensitivity to asphyxia, hypoglycemia, or polycythemia in each infant. Monozygotic twins are especially at high risk not only because of the potential for twin-twin transfusion syndrome, possibly with hydrops in either twin, but also because of the increased incidence of congenital anomalies.

PRETERM INFANTS

The incidence of perinatal depression is markedly increased in infants less than 37 weeks gestation because of their physiologic and anatomic characteristics. Risk factors in this population include lungs deficient in surfactant, which can make ventilation difficult, immature brain development, and weak respiratory muscles, which can decrease respiratory effort, thin skin and lower fat stores, contributing to rapid heat loss and fragile cerebral blood vessels that are more prone to bleeding under stress.¹ Additional resources required at delivery for preterm infants include additional personnel to perform complex resuscitation. The temperature in the delivery room should be increased and the radiant warmer pre-heated. If the infant is anticipated to be very preterm (i.e. less than 29 weeks gestation), a recloseable, food-grade polyethylene bag and a chemically activated warming pad should be used. An oxygen blender, an oximeter, and a transport incubator should always be available for preterm births.¹

For infants at the threshold of viability (22 to 23 weeks), it is especially important to provide antenatal counseling as well as maintain an ongoing dialogue with the family. Assessment of gestational age both antenatally by ultrasound, and postnatally by a gestational age examination such as the Ballard Score, which is accurate only to within 1 to 2 weeks. Therefore, if there is any question of gestational age, it is reasonable to provide aggressive resuscitative support, which allows ongoing assessment of the infant. The infant’s response to therapy is an important factor in assessment, and if response to resuscitation is poor or if severe complications develop, withdrawal of support may be offered.

DISCONTINUING RESUSCITATION

Indicators of a poor outcome in terms of both survival and subsequent neurodevelopment include Apgar scores of less than 3 at 5 and 10 minutes, cord or newborn blood pH less than 7.0 in the first 2 hours of life, absence of a heartbeat at 5 minutes of life, and seizures in the first 24 hours of life. The occurrence of seizures within the first 12 hours of life is particularly ominous. Resuscitation should rarely be continued longer than 15 to 20 minutes in an infant with an initial Apgar score of 0 who does not respond rapidly to resuscitation. In these infants, the incidence of death or severe, irreversible neurologic damage is very high.

REFERENCES

BACKGROUND

The majority of full-term newborns have an uneventful postnatal course. Once the newborn transitions from the intrauterine to extrauterine environment, management centers on routine care and parental anticipatory guidance. However, certain clinical conditions may not manifest in the immediate newborn period, and their early detection may prevent long-term morbidity or even death. Therefore, proper parental education not only makes the mother’s and father’s transition into parenthood easier but also prevents potential adverse outcomes for the infant.

CLINICAL PRESENTATION

Assessment of the newborn begins with review of the maternal history, the pregnancy, and the delivery (Table 124-1). A physician must perform a thorough head-to-toe examination of the newborn infant within 24 hours of birth and daily while the infant is in the hospital. Every examination should start with a review of the vital signs; the range of normal values for newborns is provided in Table 124-2. The initial examination should also include measurements of birth weight, length, and head circumference. These are plotted on standard growth curves to determine whether they are proportional and appropriate for the gestational age.

The infant should be completely undressed and observed for any signs of distress, dysmorphology, asymmetry, or abnormal color. Pertinent findings of the newborn examination are summarized in Table 124-3. Abnormalities, including vital signs outside the normal range, often require further investigation or follow-up.

MANAGEMENT

BREASTFEEDING

In a 2012 policy statement, the American Academy of Pediatrics (AAP) reaffirmed its recommendation of exclusive breastfeeding for the first 6 months of life, with continuation of breastfeeding for 1 year or longer as mutually desired by mother and infant.¹ Hospital procedures to encourage and support the initiation of exclusive breastfeeding should be based on the AAP-endorsed “Ten Steps to Successful Breastfeeding” and have been demonstrated to increase breastfeeding success and duration. For healthy infants, it is important for breastfeeding to begin within the first hour after birth (even for cesarean deliveries) and for mothers to have continuous infant access through rooming-in arrangements that facilitate around-the-clock, on-demand feeding. Providers should place emphasis on the numerous health benefits of exclusive breastfeeding. Artificial nipples or pacifiers should be avoided when possible, and mothers should be provided contact information for breastfeeding support after discharge from hospital.

Medical contraindications to breastfeeding in the United States are rare, and include infant galactosemia, maternal human immunodeficiency virus (HIV) infection, active tuberculosis infection, human T-lymphotropic virus type I and II infection, and certain drugs, including drugs of abuse, cytotoxic drugs, and radioactive compounds. Medications taken by the breastfeeding mother should be reviewed to ensure that their transfer via breast milk will not adversely affect the infant. A complete list of drugs compatible with breastfeeding is available from the American Academy of Pediatrics.²

FORMULA FEEDING

Formula-fed infants usually take between ¼ and 1 ounce (approximately 7.5 to 30 mL) per feeding in the first 24 hours of life. This amount increases in subsequent days. At discharge, most infants take 2 to 3 ounces (60 to 90 mL) of formula every 3 to 4 hours. Full-term formula-fed infants can be started on any of the standard 20 kcal/oz formulas. Although there are differences among the various brand-name formulas, they all meet nutritional standards and provide adequate calories and nutrients to full-term infants. Premature infants have unique nutritional needs and may require special formulas. All infants should be fed iron-fortified formula. Although low-iron formulas are available, they provide inadequate amounts of this essential element and there is no medical indication for their routine use.

The use of soy formula should be limited to infants with galactosemia or congenital lactase deficiency.³ Soy formulas may also be fed to infants whose parents want a formula that is free of animal products. However, soy formulas should not be fed to premature infants because of the poor bone mineralization associated with their use. Soy formulas are often used in infants with suspected cow’s milk protein intolerance; however, and hydrolysate formulas should be considered for these infants given a 10% to 30% cross-reactivity between cow milk and soy proteins.³ As signs and symptoms of allergy usually do not become evident until after the newborn is discharged home, standard cow milk-based formula should be routinely offered unless there is a strong family history of milk-protein intolerance.

ELIMINATION

Many infants urinate in the delivery room, and most void within hours of birth. A normal infant should urinate within 24 hours of birth; if no urine output is recorded within that time frame, the cause should be investigated. An infant with decreased urine output may be dehydrated; this is more common in infants who are having difficulty breastfeeding with inadequate oral intake. Other considerations are anatomic or functional abnormalities that prevent normal urination.

Most full-term infants pass meconium (thick, sticky, dark green or black with a “tarry” appearance) in the first 24 hours of life, then transition to yellow, seedy stools in the first 48 hours of life. A delay in the passage of meconium may be a variant of normal or may signal a problem, such as meconium plugging, Hirschsprung disease, or dehydration. When addressing a lack of stool production, it should be noted whether there was meconium staining of the amniotic fluid. An infant who has not produced a stool in 48 hours should undergo investigation for an underlying pathology (e.g. cystic fibrosis, Hirschsprung disease, imperforate anus, anorectal malformations, small left colon syndrome).

WEIGHT

Normal infants typically lose weight in the first few days of life as they diurese the excess fluid not needed for extrauterine life. Weight should be monitored daily in the nursery because a weight loss of more than 7% may indicate a potential problem, usually inadequate intake. Loss of more than 10% of birth weight for an appropriate for gestational age infant should be considered a significant problem that requires exploration and rectification before discharge and close follow-up afterward. Parents should be reassured that infants usually regain their birth weight in the first 10 to 14 days of life.

VITAMIN SUPPLEMENTATION

After delivery, all infants should receive prophylaxis against hemorrhagic disease of the newborn with the intramuscular administration of 1 mg of vitamin K₁ (phytonadione). Breastfed infants should routinely receive an oral supplement of vitamin D, 400 IU per day, beginning at hospital discharge to prevent vitamin D deficiency and rickets.¹

OCULAR PROPHYLAXIS

Prophylaxis against ophthalmia neonatorum with topical antimicrobial application to the eyes is recommended immediately after birth for all infants and is required by law in most states.⁴ Regimens of 1% silver nitrate solution, 0.5% erythromycin ointment, and 1% tetracycline ointment are considered equally effective, although tetracycline ointment is no longer available in the United States. While effective, silver nitrate is associated with a transient chemical conjunctivitis that may temporarily impair vision and affect the appearance of the infant, and is no longer manufactured in the United States.⁴ Although topical agents work well against many of the typical organisms, including Neisseria gonorrhoeae, their effectiveness against Chlamydia trachomatis has not been established.

UMBILICAL CORD CARE

The umbilical stump usually falls off in the first 2 weeks of life. While the most commonly used antiseptics for cord care include chlorhexidine, triple dye, hexachlorophene, and 70% alcohol, recent literature on this topic has prompted reconsideration of what, if anything, should be applied to the umbilical cord after birth.⁵ Several studies have suggested leaving the cord to dry naturally, which may promote earlier cord separation. Varying approaches to cord care have been evaluated in terms of their impact on the timing of cord separation, bacterial colonization, and infection. While the American Academy of Pediatrics supports dry care of the umbilical stump after birth, many recent investigations suggest that staphylococcal colonization rates may be high without application of topical antiseptics.⁵ Whatever method is used, caretakers must be instructed on how to keep the stump clean and dry. Old blood and discharge accumulated between the skin and the base of the stump may serve as a nidus for infection. Omphalitis is uncommon and usually presents with erythema and induration around the umbilical stump and foul-smelling discharge, with or without fever. It usually occurs after the newborn has left the hospital. Parents should be taught to recognize signs of omphalitis and instructed to bring the infant to medical attention immediately if these signs develop.

CARE OF THE MALE GENITALIA

Whether to circumcise a newborn male is a personal choice, and many parents base their decision on religious or cultural factors. In a 2012 policy statement, the AAP stated that the health benefits are not great enough to recommend routine circumcision, however, the benefits are sufficient to justify access to this procedure for families choosing it.⁶ Potential benefits include decreased risk of urinary tract infection in the first year of life, decreased risk of penile cancer, and decreased risk of heterosexual acquisition of syphilis, HIV, and other sexually transmitted infections. The risks of circumcision are minor but include bleeding, infection, poor cosmetic result, surgical trauma, meatal stenosis, skin bridges, and inclusion cysts. Infants undergoing circumcision experience pain, as demonstrated by increased heart rate, blood pressure, and cortisol levels and changes in oxygen saturation. Therefore, all infants undergoing circumcision should receive proper analgesia. Options to reduce pain include topical anesthetic application, dorsal penile nerve block, and subcutaneous ring block, along with sucrose on a pacifier and proper positioning during the procedure. Potential but rare complications of analgesia include methemoglobinemia and hematoma. Infants with penile anomalies, such as hypo- or epispadias, should not be circumcised in the newborn period because the foreskin may be needed during subsequent repair.

Immediately after circumcision, there is swelling and oozing of the glans and subcorona. Depending on the method of circumcision, gauze with lubricant may be applied to the area to prevent adherence to the diaper and repeated trauma to the healing tissue. This should be continued until the area is well healed, usually by the fifth day. The area can then be cleansed with water as needed.

The uncircumcised penis requires little care, but parents need to be warned against retracting the foreskin. Many parents are under the impression that the foreskin is always retractile. However, separation of the skin and glans usually takes several years to develop. In most cases, the foreskin can be retracted by age 4 to 5 years, but in some boys this may not happen until adolescence. Forceful retraction of the foreskin is painful and can lead to scarring and permanent adhesion. Until the foreskin separates on its own, only cleansing the external tissue with warm water and later with mild soap is recommended. If the foreskin is retracted down, parents should be advised to pull it back over the glans to prevent paraphimosis.

CARE OF THE FEMALE GENITALIA

White, mucus-like vaginal discharge, secondary to maternal hormone exposure, is normal and common in newborn female infants. As it resolves, blood streaking from the vagina may be noted due to maternal hormone withdrawal. Hymenal tissue is often hypertrophied and may protrude from the vaginal opening. It regresses as the effects of maternal hormones on the genitalia resolve. Gentle cleaning with water-soaked gauze or a cotton ball between the labia is all that is necessary to keep the area clean.

HEPATITIS B VACCINE

Hepatitis B infection is a worldwide problem, with up to 300 million carriers. It causes acute as well as chronic hepatitis and cirrhosis and is responsible for up to 80% of hepatocellular carcinomas. Although there is an age-specific decline in immunogenicity, the hepatitis B vaccine series is very effective and provides adequate immunity in 90% of adults and more than 95% of children. Routinely, the hepatitis B vaccine is initiated in the nursery.⁷

Perinatal transmission of hepatitis B is very efficient. If the mother is positive for both hepatitis B surface antigen (HBsAg) and hepatitis B envelope antigen, 70% to 90% of exposed infants will become infected if no postexposure prophylaxis is provided. If the mother is positive only for HBsAg, up to 20% of infants will be infected. Among these congenitally infected infants, up to 90% will become chronic carriers; of these, up to 25% will die of secondary liver failure.^7,8

Decisions to provide postexposure prophylaxis to infants are based on the mother’s HBsAg status. If the mother is HBsAg positive, the infant should receive both hepatitis B immune globulin (HBIG) and the first dose of the hepatitis B vaccine administered as soon as possible within the first 12 hours of life, in different extremities. If HBIG is not available, the vaccine alone should be administered. The vaccine alone is 70% to 95% effective, and the combination of hepatitis B vaccine and HBIG is 85% to 95% effective in preventing infection in the infant.

If the mother’s hepatitis B status is unknown, full-term infants with birth weight over 2000 grams should receive the hepatitis B vaccine as soon as possible within the first 12 hours of life and the mother should be tested to determine her status (see Figure 124-1). If the test comes back positive, HBIG should be administered as soon as possible. If the results of the HBsAg test are unavailable when the infant reaches 7 days of age, some experts recommend that the infant receive HBIG. Infants should complete the vaccine series based on the maternal hepatitis B status and current recommendations by the American Academy of Pediatrics. Infants of mothers with positive or unknown HBsAg results should be tested at 9 to 18 months of age for evidence of hepatitis B infection.^7,8

SCREENING FOR HYPERBILIRUBINEMIA

All newborns should be clinically assessed for jaundice prior to discharge, with initial bilirubin measurement occurring at 24 hours of life or earlier if pathological jaundice is suspected; see Chapter 130 for specifics on screening and management of neonatal hyperbilirubinemia.

SCREENING FOR CONGENITAL HEART DISEASE

Congenital heart disease (CHD) is the most common congenital disorder in newborns. Although many newborns with critical CHD, defined as requiring surgery or catheter-based intervention in the first year of life, are symptomatic and identified soon after birth, others are not diagnosed until after discharge from the birth hospital. For those with a critical cardiac lesion, the risk of morbidity and mortality increases with any delay in diagnosis and referral to a tertiary care center. Refer to Chapter 53 for further details on pathophysiology and clinical presentation of CHD.

In 2011, a report from the US Health and Human Services Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children recommended routine pulse oximetry newborn screening, as this improves identification of patients with critical CHD compared with physical examination alone.⁹ The American Academy of Pediatrics currently recommends universal pulse oximetry screening in the right hand and either foot using a motion-tolerant pulse oximeter by trained personnel after 24 hours of life or as late as possible if early discharge is planned. A positive screening test requires either (1) oxygen saturation measurement <90%; (2) oxygen saturation measurement <95% in both upper and lower extremities on three measurements, each separated by 1 hour; or (3) a difference in oxygen saturation >3% between the upper and lower extremities. Each birth hospital should establish procedures to ensure timely evaluation for newborns that screen positive, including echocardiography and interpretation by a clinician with expertise in CHD.⁹

HEARING SCREENING

All newborns should undergo a hearing screen before discharge from the hospital.¹⁰ Between 1 and 3 per 1000 well newborns have some form of hearing loss. Until universal hearing screening was implemented, most of these children were not identified until 14 to 30 months of age. Studies have shown that if medical intervention is instituted by 6 months of age, the child’s language development will be equal to that of normal peers.

There are two accepted and commonly used methods for screening hearing in newborns: the otoacoustic emissions (OAE) test and the auditory brainstem response (ABR) test. The OAE test measures sound waves generated by outer hair cells in the cochlea in response to clicks emitted and recorded by microphones in the outer ear canal. It detects sensory or inner ear hearing loss but not neural hearing loss. It is easy and quick to perform but may produce false failures if there is debris or fluid in the ear canal or effusion in the middle ear. The ABR test measures the activity of the cochlea, auditory nerve, and auditory brainstem pathways. Three electrodes placed on the infant’s scalp measure waves generated in response to clicks emitted in the ear canal. It is not affected by conditions of the middle or external ear but requires a quiet infant and environment.

It is recommended that an infant who fails the initial hearing test have a second test before discharge. An infant who fails the second test should be referred prior to discharge from the nursery for outpatient screening at 1 month of age. For rescreening, a complete screening on both ears is recommended, even if only one ear failed the initial screening. A referral for full audiologic evaluation is warranted for infants who fail this series of tests, and this referral should take place before the infant reaches 3 months of age.

METABOLIC SCREENING

Newborn screening for certain metabolic and genetic disorders began in the 1960s when Robert Guthrie devised a test that screened for phenylketonuria (PKU). He also developed a simple and inexpensive way of collecting blood samples from the heel of newborns on filter paper. Since then, screening for other disorders has become possible. The goal of newborn screening is to detect certain disorders early and provide treatment to prevent their clinical manifestations and subsequent morbidity and mortality. Today, all 50 states test for PKU and hypothyroidism; however, because there is no federal law regulating newborn screening programs, there is state-to-state variation in the testing for other disorders. Many states test for medium-chain acyl-CoA dehydrogenase deficiency, congenital adrenal hyperplasia, biotinidase deficiency, cystic fibrosis, maple syrup disease, galactosemia, homocystinuria, and sickle cell anemia. Clinicians must be familiar with the tests performed in the states where they practice and counsel parents appropriately about these conditions. It is important to ensure that the specimen is collected at least 24 hours after birth, because many of the disorders are based on abnormal protein metabolism. Some state laboratories may require specimen collection 24 hours after initiation of feedings. With the development of tandem mass spectrometry and DNA-based testing, it is now possible to screen for a number of other metabolic, genetic, and infectious diseases. Clinicians should be aware of the facilities that offer these expanded screenings so that they can provide that information to parents.

PARENTAL SUPPORT

During the hospital encounter, one must assess not only the health of the newborn but also the bonding that should be taking place between the newborn and the mother. Postpartum “blues” or depression is very common and may manifest in the hospital with a mother who is emotionally labile or withdrawn. A mother may leave her newborn in the nursery while she is resting, but a mother who does not feed or visit her baby may be having difficulty bonding. Breastfeeding is often a challenge, especially for first-time mothers. Feelings of inadequacy may ensue in the first few days and interfere with bonding. Reassurance, professional guidance, and family support should be instituted in the hospital and continued after discharge.

Additional consultation for social services may be indicated in cases of poor prenatal care, drug use during pregnancy, teen pregnancy, maternal mental illness, family violence, or lack of family support or resources.

ADMISSION AND DISCHARGE CRITERIA

The newborn provider is responsible not only for parental anticipatory guidance but also for ensuring that the infant’s caregivers have the necessary resources and support. All newborns should have a designated physician for follow-up care. Infants with feeding issues, significant weight loss, temperature instability, significant jaundice, or social concerns are not candidates for early discharge before 48 hours of life. The 2010 AAP policy statement, Hospital Stay for Healthy Term Newborns, outlines the criteria for discharge of full-term newborns.¹¹ For infants discharged before 48 hours of life, follow-up with a physician should occur preferably within 48 hours, and no later than 72 hours in most cases.

At discharge, parents should be specifically counseled with regard to temperature measurement, how to recognize jaundice, the need for a car seat when transporting the infant in a vehicle, positioning the child on the back for sleep, and when to call the physician. Parents should be provided with a telephone number where they can reach a medical professional if questions arise.

SPECIAL CONSIDERATIONS

DEVELOPMENTAL DYSPLASIA OF THE HIP

Developmental dysplasia of the hip (DDH) is defined as an abnormal relationship of the femoral head and acetabulum. It includes frank dislocation (luxation), partial dislocation (subluxation), femoral head instability, and any malformation of the acetabulum. Screening for DDH should start after birth and continue at each scheduled well-child visit until age 18 months. By that age, normal children should be walking well, and any hip abnormality will manifest as an abnormal gait. The earlier the diagnosis is made, the sooner proper treatment can be instituted to prevent long-term morbidity. The true incidence of DDH is unknown, but it is estimated that 1 in 100 newborns has hip instability and 1 to 1.5 per 1000 has dislocation. The left hip is involved three times more often than the right hip. Factors that increase the risk for DDH include female gender, breech position, positive family history, and incorrect lower-extremity swaddling.¹²

Physical Examination

The hip examination should be carried out in a systematic manner while the infant is quiet and relaxed. Although no physical examination signs are pathognomonic for a dislocated hip, findings that should raise the examiner’s suspicion include asymmetry of thigh or gluteal folds, apparent limb length discrepancy, and restricted mobility of the hip, especially abduction. The Barlow, Ortolani, and Galeazzi tests are physical maneuvers that suggest hip dislocation and should prompt the physician to undertake further action. It is not unusual for hip “clicks” to be elicited during the initial newborn examination; these usually represent ligamentous laxity that tends to resolve by 2 weeks of age.

Management

If a “clunk” is obtained during the examination, the infant should be referred to an orthopedic surgeon. There is no need to confirm the dislocation by radiographic studies; the physical examination should guide treatment. The infant will likely be placed in a Pavlik harness and followed with ultrasound studies and physical examinations by the orthopedic specialist. Double and triple diapering of infants to stabilize the hip is not recommended. A “click” present after birth should be re-evaluated at 2 weeks of age. If the finding persists or there are other suspicious findings (e.g. unequal gluteal folds) but no evidence of true hip dislocation, the physician may refer the patient to an orthopedist or perform ultrasonography of the hip at 3 to 4 weeks of age.

If the examination is normal at 2 weeks of age, routine periodic examinations should be continued. Certain risk factors may prompt the physician to pursue further evaluation, even when the examination is normal. Boys with a positive family history of DDH have a newborn risk of 9.4 in 1000 and may be followed clinically; girls with a positive family history have a newborn risk of 44 in 1000 and may benefit from an ultrasound study at 6 weeks of age or radiographs of the hips at 4 months. Boys and girls with breech presentation in the third trimester (regardless of delivery mode), those with a positive family history, those with parental concerns or an inconclusive examination, and those with a history of improper swaddling, may benefit from imaging by 6 months of age.¹²

When imaging pediatric hips, one must remember that because the femoral head is mostly cartilaginous in the first weeks of life, plain radiographs are not useful. Ultrasonography is a reliable method of evaluating hips in the first 4 months of life. After age 4 months, the femoral head should be well ossified, and plain radiographs can be obtained. Between 4 and 6 months of age, either method is acceptable. Table 124-4 summarizes the evaluation and management of DDH.

REFERENCES

BACKGROUND

Birth injuries are an uncommon complication of vaginal and cesarean delivery. Injuries range from those that are minor and require no further diagnostic evaluation or treatment to those that are life threatening or associated with long-term morbidity. Risk factors for injury include macrosomia, precipitous or prolonged delivery, breech presentation, cephalopelvic disproportion, shoulder dystocia, and the use of forceps or vacuum to assist extraction. However, birth injuries also occur in infants with no identifiable risk factors, making prediction difficult.

FRACTURES

BACKGROUND

Fractures as complications of the delivery process most commonly occur in the clavicle, humerus, and femur. Skull fractures are also reported, usually in association with forceps delivery. Long bone fractures generally require evaluation by an orthopedic specialist, whereas skull fractures are usually simple linear fractures that do not require intervention. Infants rarely have more than one fracture; for those with multiple fractures, diagnoses such as osteogenesis imperfecta should be considered.

Pathophysiology

Clavicle fractures occur as a complication of the delivery process in approximately 0.5%¹ to 1.7%² of all live births. Historically, clavicle fractures were thought to be a result of obstetric mismanagement. Recent studies, however, have shown that little can be done to prevent this complication. Clavicle fractures are most commonly reported with vaginal deliveries, but they are also reported with cesarean sections. Risk factors include fetal macrosomia, instrumented delivery, and a prolonged second stage of labor, but predictive models based on these factors have a high false-positive rate and have not been clinically useful.

The humerus is occasionally fractured during the delivery process, typically with a difficult vertex delivery of the shoulder or a breech delivery. The fracture may result from direct pressure or traction. A greenstick fracture is most common, but displaced fractures may also occur. Breech deliveries may also result in a femur fracture; most are complete fractures that result in obvious deformity.

CLINICAL PRESENTATION

Clavicular fractures are sometimes overlooked, particularly in the case of a nondisplaced fracture. Acutely, the examiner may feel crepitus, and irritability may be noted with pressure over the bone. In displaced fractures, a bony ledge may be palpated. The infant may have decreased movement of the ipsilateral arm with an asymmetric Moro response. This pseudoparalysis is typically related to pain but may also be the result of associated nerve damage. Frequently, the fracture is first diagnosed as normal healing occurs and the callus forms, which may be noted as early as the second week of life.

Humerus fractures may present clinically with swelling and pain; in the case of a displaced fracture an obvious deformity will be noted. The infant may refuse to move the affected arm, thereby resulting in an asymmetric Moro reflex and pseudoparalysis; however, nerve involvement may also occur. Most femur fractures will present as an obvious deformity.

DIAGNOSTIC EVALUATION

The diagnosis of neonatal clavicle fracture may be made clinically either at the time of delivery or in the first month of life. A single anteroposterior radiograph of the chest is sufficient to confirm the fracture if the diagnosis is in question. Plain films are also usually sufficient to confirm the diagnosis of humerus or femur fractures.

MANAGEMENT

Clavicular fractures usually heal without sequelae or deformity. Management is conservative and involves keeping the infant off the affected side; immobilization of the arm may help decrease pain. Healing should occur within 2 weeks, and callus formation may be seen radiographically in several weeks. Parents may complain of a bony irregularity as the clavicle heals, but it will become less prominent as the child grows.

Treatment of humerus fractures is generally limited to immobilization for 2 to 4 weeks in the adducted position, and the prognosis is excellent. Treatment of femur fractures is 3 to 4 weeks of traction and suspension of both lower extremities. Immobilization with a Pavlik harness may also be effective in treating femur fractures. The prognosis is excellent.

ADMISSION AND DISCHARGE CRITERIA

Admission to the neonatal intensive care unit for management and consultation with a pediatric orthopedic surgeon is indicated for infants with concerns for humerus or femur fracture, including focal pain, edema, erythema, or deformity. Infants with clavicular fracture can generally be managed on the routine postnatal ward. Discharge criteria include adequate pain control and nutritional intake as well as timely access to primary care and orthopedics follow-up if indicated.

PERIPHERAL NERVE INJURIES

BACKGROUND

Nerve damage is an infrequent, but important complication of the birthing process. In some cases, injury may be traced to traction on the neck and thus on the brachial plexus during delivery. Severity can range from mild stretching of the nerve, to nerve root avulsion. Brachial plexus injury is documented in 0.038% to 0.2% of all live births.^3,4 A large retrospective analysis from the United States concluded that the risk of brachial plexus injury was 1 in 1000 live vaginal births.⁵ Incidence rates rise with birth weight; in one study of infants weighing more than 4500 g and born vaginally, the incidence of brachial plexus injury was 3.6%.⁶ Risk factors include macrosomia, shoulder dystocia, breech presentation, and instrumented delivery. However, because many cases of brachial plexus injury occur without these risk factors, an effective predictive model has not been established.

CLINICAL PRESENTATION

Injury to the fifth and sixth cervical (C5 and C6) nerve roots is the most common nerve injury (Figure 125-1) and results in partial paralysis of the upper extremity, known as Erb-Duchenne paralysis. Affected infants have unilateral arm weakness and an asymmetric Moro response. The hypotonic extremity is adducted, internally rotated, and pronated at the forearm. Additional involvement of the seventh cervical (C7) root results in paralysis of the wrist and finger extensors, which causes unopposed flexion of the hand. Together, this is described as the “waiter’s tip” position (Figure 125-2).

Klumpke paralysis is very rare and involves isolated injury to the seventh and eighth cervical (C8) and first thoracic (Tl) nerve roots. These infants have normal shoulder and elbow position but a weak or paralyzed hand. If the sympathetic fibers of Tl are also affected, miosis, ptosis, anhidrosis, and enophthalmos (Horner syndrome) are additional findings.

Infants may also have injury to the third and fourth cervical nerve roots (C3 and C4), which results in unilateral diaphragmatic paralysis from phrenic nerve involvement. These infants may present with respiratory distress, hypoxia, asymmetric chest wall movement, and diminished breath sounds on the affected side.

Total plexus injury (C5-T1) accounts for approximately 20% of all plexus injuries and results in a flaccid upper extremity. Involvement of C4 with or without C3 may accompany this severe form of plexus injury.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes a clavicular or humeral fracture that may cause the infant pain and result in a pseudoparalysis that is not associated with nerve root damage. Pseudoparalysis of Parrot involving the upper extremity caused by a painful osteochondritis secondary to congenital syphilis can also mimic a brachial plexus injury. However, in this condition multiple long bones are generally involved and other features of congenital syphilis are often present.

DIAGNOSTIC EVALUATION

The diagnosis of nerve root injury is usually made clinically and based on the finding of an upper extremity with abnormal tone and movement. Plain radiography can rule out an associated fracture of the clavicle or humerus. Electromyography and nerve conduction studies may help clarify the injury in anticipation of surgical repair, but they are rarely necessary otherwise. These studies are typically performed several weeks after birth. When required, magnetic resonance imaging (MRI) can define the anatomy and extent of injury.

The diagnosis of diaphragmatic paralysis is made by demonstrating an elevated hemidiaphragm on the same side as the affected arm on an inspiratory radiograph. Real-time visualization with ultrasound or fluoroscopy will reveal paradoxical movement.

MANAGEMENT

There is some debate about how many infants have complete resolution of their injury without surgical intervention. Full recovery occurs in 66%⁶ to 92%⁷ of affected infants, with the rest displaying varying degrees of residual weakness. Among 80 infants with brachial plexus injury examined monthly, complete recovery occurred in 53 (66%) while the remaining infants had mild (n = 9, 11%), moderate (n = 7, 9%), or severe (n = 11, 14%) permanent weakness with a mean follow-up of 4 years.⁸ Infants with upper arm paralysis do better than those with lower arm involvement. Other features associated with a less favorable outcome include diaphragmatic paralysis and Horner syndrome. Early signs of recovery, which may be noted by 2 weeks of age, favor complete resolution. Permanent weakness is likely if significant weakness is still present at 4 to 6 months.⁸

Initial management is rapid initiation of physical therapy. Therapy needs to include range-of-motion, stretching, and strengthening exercises. The therapist also needs to educate the parents of the infant in appropriate exercises at home. These exercises decrease the risk for contractures. Additionally, early involvement of an occupational therapist and a brachial plexus surgeon may be helpful.

CONSULTATION

Nerve reconstruction is an emerging technique that has shown promise in improving function in certain patients. The best timing for the procedure is still not clear, but several studies suggest that early repair may have a better long-term outcome. If the infant has no detectable muscle strength of the biceps by 2 to 3 months, surgical evaluation is indicated.

ADMISSION AND DISCHARGE CRITERIA

Admission to a neonatal intensive care unit is indicated for infants presenting with respiratory symptoms concerning for C3 and C4 nerve root injury. Prior to discharge of all infants with brachial plexus injury, rapid follow-up should be ensured with a team specializing in brachial plexus injury care.

EXTRACRANIAL INJURIES

BACKGROUND

Injuries to the scalp, subcutaneous tissue, and skull usually result in swelling that is apparent at birth or shortly thereafter. These extracranial injuries may occur from soft tissue swelling or hemorrhage and often resolve without treatment. However, the clinician needs to be able to accurately recognize these entities and be aware of the complications that may occur with each.

CLINICAL PRESENTATION

Caput Succedaneum

Pressure applied to the scalp by the uterus, cervix, or pelvis during vaginal delivery results in a localized swelling outside the cranial aponeurosis known as caput succedaneum (Figure 125-3A). It appears as a circular boggy area of edema with indistinct borders that typically crosses cranial suture lines. There may be overlying ecchymosis. Vacuum extraction can cause a more pronounced caput as the presenting region of the scalp receives negative pressure in addition to the positive pressure from below. A chignon is a vacuum-induced caput succedaneum.

Cephalohematoma

It is estimated that up to 2.5%⁹ of infants present with a subperiosteal hemorrhage known as a cephalohematoma. It represents hemorrhage between the cranial periosteum and the bony skull and presents as a fluid-filled mass that does not cross suture lines (Figure 125-3B). Cephalohematoma is often not present at the time of delivery but develops over the first few hours of life. Most commonly it appears in the parietal bone, but more than one cranial bone may be involved. Risk factors for cephalohematoma include a primiparous mother, forceps- or vacuum-assisted delivery, and prolonged labor. In one study, 90% of infants with cephalohematoma had an occiput anterior presentation. In the same study, 7% of cephalohematomas were associated with an underlying skull fracture, with all these injuries being related to the use of forceps.⁹

Subgaleal Hemorrhage

Bleeding that occurs beneath the aponeurosis of the scalp but outside the cranial periosteum is termed a subgaleal or subaponeurotic hemorrhage. Similar to a cephalohematoma, a subgaleal hemorrhage is fluctuant because of the fluid collection that is present, but it extends over suture lines (Figure 125-3C). Unlike a cephalohematoma, the bleeding into the subgaleal space is not restricted by the boundaries of the sutures. Extensive bleeding may occur and the infant may present with signs of hypovolemic shock.

DIFFERENTIAL DIAGNOSIS

Other entities to consider in the differential are subarachnoid cyst, meningocele, or leptomeningeal cyst.

DIAGNOSTIC EVALUATION

The diagnosis is based on the feel and location of the scalp swelling. Ultrasonography is helpful when the clinical examination is not definitive. Because fractures are only occasionally associated with cephalohematoma and the majority of these fractures are benign linear skull fractures, routine skull radiographs are not generally necessary.

MANAGEMENT

Caput succedaneum resolves spontaneously over a period of several days; no management is needed other than parental reassurance. Cranial molding and prominent bony ridges as a result of overriding sutures may become more apparent as the soft tissue swelling improves. Parents can be reassured that these bony changes will improve over the next few weeks.

Cephalohematoma takes weeks to months to resolve. As resorption proceeds, the additional red cell destruction may cause or contribute to indirect hyperbilirubinemia. As the hematoma resolves, a firm calcified ring may form around the hematoma and cause the illusion of a depressed skull fracture. As previously noted, cephalohematomas are uncommonly associated with skull fractures, and they are almost always linear skull fractures that require no specific management.

Subgaleal hemorrhage requires prompt recognition because it is a much more serious entity with mortality estimated at up to 20%. Rapid bleeding can occur and may lead to hypovolemic shock. Serial hemoglobin and bilirubin levels as well as coagulation studies are indicated. Volume replacement or red cell transfusion may be needed. Surgical management is rarely indicated because the source of bleeding is typically not identifiable.

Aspiration of these fluid collections is discouraged because the procedure is rarely therapeutic or diagnostic. Imaging studies can determine the anatomic level of the bleeding and do not have the attendant risk of introducing infection.

Infection of the fluid collection can occur, especially when there is an overlying laceration or puncture secondary to forceps, scalp probes, or aspiration attempts. The area becomes erythematous and warm, and fever often develops. When infection is present, aspiration for Gram stain and bacterial culture and sensitivity studies is warranted while empirical antibiotic therapy is initiated. Coverage of skin flora and newborn pathogens is recommended.

ADMISSION AND DISCHARGE CRITERIA

Admission to the neonatal intensive care unit is indicated for infants with cephalohematoma who develop significant hyperbilirubinemia requiring exchange transfusion. Infants with subgaleal hemorrhage also may warrant admission to the neonatal intensive care unit for close vital sign monitoring, serial laboratory studies, and volume replacement or red cell transfusion as needed. Routine postnatal care and discharge can be anticipated for infants with caput succedaneum.

INTRACRANIAL HEMORRHAGE

BACKGROUND

With advances in obstetric practices, hemorrhage within the bony skull is an increasingly uncommon occurrence in full-term infants. Risk factors are similar to those for other birth injuries, including macrosomia and precipitous or instrument-assisted deliveries. Intraventricular hemorrhage is a significant consideration in premature infants, but not in full-term infants.

CLINICAL PRESENTATION

Subdural Hemorrhage

Although often associated with vacuum-assisted deliveries, subdural hemorrhage is now known to occur in spontaneous vaginal deliveries as well as in utero before delivery. Clinical manifestations range from asymptomatic infants with no long-term sequelae to serious neurologic injury. The location of the hemorrhage can alter the presentation, but the most common locations are tentorial and intrahemispheric. Apnea or cyanotic episodes are the most common initial symptoms, although seizure, focal neurologic deficits, lethargy, or other global nonspecific findings may be the presenting early symptoms. Commonly, infants become symptomatic on the first day of life, but sometimes the findings are not apparent until several days after birth.

Epidural Hemorrhage

Bleeding into the epidural space is the least common form of intracranial hemorrhage. The cause is injury to the middle meningeal artery, which is almost uniformly associated with an overlying fracture of the temporal bone and cephalohematoma. Focal or generalized neurologic symptoms are present shortly after birth, and evidence of raised intracranial pressure may be demonstrated by a bulging fontanelle.

Subarachnoid Hemorrhage

In older children and adults, subarachnoid hemorrhage is most often due to aneurysms or arteriovenous malformations. By contrast, subarachnoid hemorrhage in newborns is due to rupture of small bridging veins of the subarachnoid space and is more common with vacuum- or forceps-assisted deliveries than with vaginal deliveries. The typical presentation in newborns with subarachnoid bleeding is seizure activity that starts on the second day of life, with normal neurologic findings between seizures. The prognosis is very good, with complete resolution of the hemorrhage and no neurologic sequelae, although children with asphyxia or underlying cortical injury are at risk for permanent deficits. Posthemorrhagic hydrocephalus may develop in the first few weeks of life and can be detected by routine monitoring of head circumference.

DIAGNOSTIC EVALUATION

For subdural, epidural, and subarachnoid hemorrhages, computed tomography (CT) of the head is the diagnostic tool of choice. This may also demonstrate any associated skull fracture in the case of epidural hemorrhage. For infants with subdural hemorrhage, MRI may be needed to clearly visualize bleeding in the posterior fossa. Because of the possibility of an underlying coagulopathy with subdural hemorrhage, a prothrombin time and partial thromboplastin time should also be obtained.

MANAGEMENT

In the case of subdural hemorrhage, surgical intervention is usually reserved for infants with evidence of brainstem compression. Surgical drainage for epidural hemorrhage is necessary for most newborns. Most infants with subarachnoid hemorrhage do not require surgical intervention unless the hemorrhage is very extensive.

ADMISSION AND DISCHARGE CRITERIA

Admission to the neonatal intensive care unit is indicated for infants presenting with neurologic symptoms consistent with intracranial hemorrhage, including apnea or cyanotic seizure, focal deficits, and lethargy. Discharge criteria should be determined in consultation with a neonatologist.

PNEUMOTHORAX

BACKGROUND

Spontaneous pneumothorax in full-term newborns has a reported incidence of 1% to 2%, although many are asymptomatic.¹⁰ It is thought to be the result of the intrathoracic pressure created by the infant during the first few attempts at respiration. Pneumothorax may also be seen in infants with meconium aspiration or pneumonia and in those with a history of receiving positive-pressure ventilation at delivery.

CLINICAL PRESENTATION

Most cases of spontaneous pneumothorax in newborns are not clinically apparent. However, if the volume of air in the pleural space is large or under pressure (tension pneumothorax), the infant will display signs of respiratory distress, including grunting, flaring, and retracting, with decreased breath sounds on the involved side. A tension pneumothorax may cause a shift in location of the point of maximal impulse of the heart, deviation of the trachea, or a distended hemithorax.

DIAGNOSTIC EVALUATION

If the diagnosis of pneumothorax is suspected and the infant is not clinically stable, intervention should not be delayed to obtain a chest radiograph. Initially, needle thoracostomy may be performed until a definitive chest tube can be inserted (see Treatment). An audible release of air under pressure along with an associated improvement in the patient’s clinical status confirms the diagnosis.

If the diagnosis is in question and the infant is clinically stable, a chest radiograph is appropriate to confirm the presence and severity of the pneumothorax. Pneumothorax appears as a dark (radiolucent) area in the chest, without overlying lung markings (Figure 125-4). A radiograph of an infant with tension pneumothorax also displays a shift of the mediastinum and airway away from the affected side.

MANAGEMENT

A small pneumothorax generally resolves spontaneously in a few days and may be monitored clinically or radiographically. Large pneumothoraces and those under pressure require evacuation of the air and continued drainage with a chest tube and negative pressure. When the air leak has stopped, the tube may be clamped. Without further evidence of reaccumulation, the chest tube may be removed (see Chapter 163 for further details on chest tube insertion).

ADMISSION AND DISCHARGE CRITERIA

Infants with large or symptomatic pneumothoraces should be admitted to the neonatal intensive care unit. Criteria for discharge include resolution of tachypnea, tachycardia, hypoxia, and other vital sign disturbances.

REFERENCES

BACKGROUND

Congenital anomalies have a wide array of presentations, from almost unnoticeable variations to remarkable dysmorphology. They may be detected at first breath of life or several weeks to months later. The causes of congenital anomalies are also as varied as their presentations. Genetic mutations, toxin-induced syndromes, and mechanical in utero effects drive the majority of anomalies; yet in others, the causes remain unknown.

The clinical management of all congenital anomalies involves a multidisciplinary approach to the patient. Due to the altered physiology of congenital anomalies, many different specialties including neonatology, critical care, surgery, and genetics work in concert to provide optimal outcomes for each individual patient. This chapter will examine several of the most common congenital anomalies and address their pathology, diagnosis, and management.

ABDOMINAL WALL DEFECTS

BACKGROUND

Gastroschisis and omphalocele are the most common abdominal wall defects in neonates. In the United States, the incidence of gastroschisis has seen a 10- to 20-fold increase over the past 20 years.¹ Currently, the incidence of gastroschisis is 1 in 4000 live births while omphaloceles have an incidence of 1 in 4000 live births.¹

Pathophysiology

During normal fetal development, the gut protrudes from the umbilical ring and then retracts back into the abdominal cavity by the 11th week of gestation.¹ When the series of events needed to complete this process fail to occur, abdominal wall defects result. Gastroschisis is not commonly associated with other congenital anomalies, with the exception of localized abnormalities such as intestinal atresia (10% to 28%) and cryptorchidism (up to 15%).^1,2

An omphalocele results from failed growth and fusion of the lateral folds early in gestation. This creates a central defect of the umbilical ring and allows the bowel to remain herniated. Over 50% of patients with omphalocele have associated anomalies, which are usually midline.¹ These include cardiac defects (30% to 50% of infants), colonic atresia, imperforate anus, sacral and vertebral anomalies, and genitourinary malformations such as bladder exstrophy or cloacae.¹ Syndromes associated with omphalocele include the Pentalogy of Cantrell (sternal cleft; pericardial, cardiac, and diaphragmatic defects), Beckwith-Wiedemann syndrome (macroglossia, macrosomia, and hypoglycemia), and trisomy 13, 15, 18, and 21; chromosomal abnormalities occur in up to one-third of cases.^1,2,3

CLINICAL PRESENTATION

Patients with gastroschisis are often premature. They commonly present with a defect to the right of the umbilicus and herniation of the abdominal contents through the umbilical ring (Figure 126-1). The bowel is not contained within a sac therefore it is often thickened, with a fibrous peel, due to prolonged intrauterine exposure to amniotic fluid.² Complications of gastroschisis include intestinal macroglossia, volvulus, stenosis, or atresia.²

An omphalocele presents as a central defect in the abdominal wall, commonly inferior to the umbilical ring. The opening is generally greater than 4 cm, and a membranous sac covers the contents, unless it ruptured before delivery. The liver and intestines herniate through the opening in 10% of these patients, resulting in a giant omphalocele.² In contrast to gastroschisis, infants with omphalocele typically have normal gastrointestinal function.

DIAGNOSTIC EVALUATION

These abdominal wall defects can be detected prenatally on ultrasound examination which allows delivery of these neonates at centers that can provide the intensive care needed during the perinatal period. A physical examination should be performed immediately after birth to detect any associated anomalies that require urgent evaluation.^1,2,3 Radiographic studies, echocardiography, renal ultrasound, and chromosomal analysis should be obtained.

MANAGEMENT

The initial management of an infant with either gastroschisis or omphalocele is similar. Treatment is aimed at bowel decompression, replacement of insensible fluid losses, avoidance of hypothermia, and a thorough search for concurrent anomalies. To this end, in gastroschisis, the abdominal contents should be wrapped in warmed, sterile saline-soaked gauze.² Care should be taken to prevent kinking of the mesenteric vessels.² The patient should be wrapped in a large bowel bag to prevent evaporative heat and fluid losses. Intravenous fluids at one and a half times the maintenance rate should be initiated.³ For patients with omphalocele, intravenous fluid replacement and prevention of hypothermia also apply, but due to the sac covering the bowel the risks of hypothermia and evaporative fluid losses are less than those in gastroschisis.³ Nasogastric tube placement aides in bowel decompression and rectal examination coupled with rectal irrigation can aide in the evacuation of meconium.² Parenteral antibiotics that cover bowel flora should be administered (e.g. ampicillin + gentamicin + metronidazole or ampicillin-sulbactam + gentamicin). Once the patient is hemodynamically stable, nutrition is started. While enteral feeding is preferable to parenteral nutrition, these patients often have delayed bowel motility—especially with gastroschisis—and therefore parenteral nutrition is often necessary initially.

ADMISSION AND DISCHARGE CRITERIA

After initial stabilization, newborns with abdominal wall defects require prompt transfer to a neonatal intensive care unit (NICU). Discharge criteria include adequate surgical coverage of the intra-abdominal organs, resolution of any sepsis, and recovery of bowel function with tolerance of full enteral nutrition.

CONSULTATION

Consultation with a pediatric surgeon is indicated for either primary repair of the defect or silo placement with reduction of the bowel and then delayed repair² (Figure 126-2).

CONGENITAL DIAPHRAGMATIC HERNIA

BACKGROUND

Congenital diaphragmatic hernia (CDH) represents one of the most challenging conditions in neonates. Prior management used to include immediate surgical correction of the CDH, but as our understanding of this disease has evolved, initial management now focuses on stabilization of the patient with delayed surgical repair.² The incidence of CDH is 1 in 2000 to 5000 live births, and the majority present on the left side.² Despite recent advances in critical care and surgical interventions the overall survival rates have remained at 70% to 90%.³

Pathophysiology

In utero compression of the developing lung by the bowel may result in pulmonary hypoplasia as well as pulmonary hypertension.

CLINICAL PRESENTATION

Initially, the patients may have a “honeymoon period” with adequate respiratory effort.³ Gradually though, as respiratory function worsens, neonates with CDH present with respiratory distress, which can include tachypnea, grunting, chest wall retractions, cyanosis, and pallor.^2,3 Physical examination reveals a scaphoid abdomen and bowel sounds within the chest. Heart sounds can be heard on the right with breath sounds decreased bilaterally. Persistent fetal circulation may be demonstrated by the difference in pre- and postductal oxygen saturation measurements thus giving an idea of the degree of shunting occurring within the lungs.³ The Oxygenation Index (OI) is the most valuable parameter that can be used to predict survival of patients with significant shunting caused by the pulmonary hypoplasia associated with CDH. The OI is calculated using the preductal partial pressure of arterial oxygen (P_aO₂) with the formula:

An OI less than 6 is associated with a survival of 98%, with higher OI values indicating worse lung hypoplasia and therefore a worse prognosis.²

DIFFERENTIAL DIAGNOSIS

Many neonatal conditions can present with respiratory distress. Some conditions include pulmonary sequestrations, bronchogenic cysts, congenital pulmonary airway malformations (formerly known as congenital cystic adenomatoid malformations), meconium aspiration, pleural effusions, pulmonary consolidations, cystic teratomas, and neurogenic tumors.

DIAGNOSTIC EVALUATION

CDH is frequently diagnosed by fetal ultrasonography.² At birth, radiographs of the chest and abdomen (i.e. “babygram”) reveal multiple gas-filled bowel loops within the chest, mediastinal shifting as well as an intrathoracic gastric bubble² (Figure 126-3). A nasogastric tube, placed for gastric decompression, frequently coils in the chest cavity; this is also identified on x-ray. Echocardiography and renal ultrasonography should be performed to assess for any associated anomalies.²

MANAGEMENT

Initial stabilization, treatment of pulmonary hypertension, and delayed surgical intervention constitute the principal management strategies for CDH. Treatment of respiratory distress includes endotracheal intubation and mechanical ventilation.² Nasogastric tube decompression of the stomach prevents bowel distention which would compromise respiratory function.³ Maintenance of euvolemia and avoidance of acidosis and hypoxemia are paramount in the treatment of the pulmonary hypertension which is found in these patients. Patients with respiratory failure and persistent hypoxemia may require extracorporeal membranous oxygenation (ECMO).²

ADMISSION AND DISCHARGE CRITERIA

After initial stabilization, newborns with CDH require prompt transfer to a NICU. These lesions used to be treated as surgical emergencies but multiple studies have shown that delayed repair results in improved survival rates. As a result, initial care focuses of respiratory management and stabilization of the pulmonary hypertension and repair is often performed once both ventilatory status and pulmonary hypertension has stabilized or improved. Patients are ready for discharge once their CDH is surgically repaired, they are off ventilatory support, and they are able to demonstrate adequate growth on enteral nutrition.

CONSULTATION

Pediatric surgical consultation is necessary for the initiation of ECMO as well as the planning of the eventual repair of the CDH.

ANORECTAL MALFORMATIONS

BACKGROUND

Anorectal malformations are a set of complex congenital disorders that present in the neonatal period with a wide array of presentations. Their specific cause is unknown, and the worldwide incidence is 1 in 5000 live births.³

Pathophysiology

In embryologic development, the cloaca is a cavity into which the intestinal, urinary, and reproductive tracts open. This is formed by 3 weeks gestation. When the septum separating these structures fails to form properly then abnormal connections form between the urinary tract, reproductive tract, and colon. If the membrane covering the cloaca fails to degenerate then variants of imperforate anus will develop.²

CLINICAL PRESENTATION

Patients with anorectal malformations present in the newborn period in various ways. Some present with obvious abnormalities of the perineum such as an absence of an anus or a fistula to the perineum. Others present with meconium staining of the urine.²

DIFFERENTIAL DIAGNOSIS

Almost 60% of patients may have associated malformations including cardiac, gastrointestinal, or spinal anomalies.² Cardiac anomalies include atrial septal defects, patent ductus arteriosus, Tetrology of Fallot, or ventricular septal defects.² GI anomalies include tracheoesophageal fistulas, esophageal and duodenal atresia, and malrotation.² Spinal anomalies found in patients with anorectal malformations include scoliosis, tethered cord, and myelomeningocele.²

DIAGNOSTIC EVALUATION

A detailed physical examination is the most important diagnostic maneuver in patients born with anorectal malformations. Perineal inspection will demonstrate most notably the absence of normal perineal anatomy.² Specifically in female patients, the perineal exam can show a vestibular fistula. If a single perineal opening is present then the patient is diagnosed with a persistent cloaca. Next, the location and presence of meconium should be noted. If meconium staining is noted on the perineum then a fistula to the skin is identified. If the urine is stained with meconium then a fistula to the urinary tract is identified.²

MANAGEMENT

Management of patients with anorectal malformations starts initially with stabilization of the patient. Parenteral nutrition should be provided initially while enteral feedings are withheld. The use of intravenous antibiotics such as ampicillin, gentamicin, and metronidazole should be considered to empirically protect against translocation of gastrointestinal flora; these can be discontinued after surgical colostomy or repair of the anomaly.² A thorough search for associated anomalies includes echocardiography, renal ultrasonography, spinal plain radiography and spinal ultrasounds. Presence of tracheoesophageal fistulas or esophageal atresias would be indicated if there is difficulty placing a nasogastric tube.

ADMISSION AND DISCHARGE CRITERIA

After initial stabilization, newborns with anorectal malformations require prompt transfer to a NICU. Discharge criteria should include restoration of the normal functioning gastrointestinal tract including normal stooling patterns or normal colostomy function after surgical repair.

CONSULTATION

A pediatric surgical consultation should be obtained once an anorectal malformation is suspected. Cross-table lateral x-rays obtained in the prone position may be obtained to aid the surgeons in surgical planning.

NEURAL TUBE DEFECTS

BACKGROUND

Neural tube defects (NTDs) affect approximately 1 in 2000 births in the United States.⁴

Pathophysiology

A neural tube defect is any defect in the morphogenesis of the neural tube, ranging from anencephaly to spina bifida occulta. The etiology of these defects is unknown to date but several teratogens including valproic acid and folic acid deficiency have been linked to the development of neural tube defects.²

CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS

Physical examination of infants with neural tube defects will vary. Patients with meningocele present with a fluid-filled sac containing cerebrospinal fluid (CSF) only and no neural elements. Myelomeningoceles have both CSF and neural elements. These are usually located at the lumbar region but can occur anywhere on the spine. Physical examination in patients with myelomenigocele can demonstrate marked kyphoscoliosis and some degree of neurologic deficit such as bowel or bladder incontinence, sensory deficits, or flaccid paralysis of the extremities.² Patients with spina bifida occulta show no obvious external evidence of spinal abnormalities, although lumbosacral hypertrichosis, sacral dimples, dermal sinus tracts, or subcutaneous lipomas of the gluteal cleft may allude to possible underlying problems.² These patients usually develop neurologic symptoms over time.

DIAGNOSTIC EVALUATION

Prenatal diagnosis can be made by fetal ultrasonography or measurement of α-fetoprotein levels in either the maternal serum or the amniotic fluid via amniocentesis.^2,4 Measurement of α-fetoprotein levels in the amniotic fluid is 98% sensitive for detecting open neural tube defects but is ineffective in detecting closed neural tube defects.² For infants with suspected spina bifida occulta, spinal x-rays and magnetic resonance imaging (MRI) are needed to demonstrate the defects in vertebral formation.

MANAGEMENT

Due to the exposure and damage of neural elements in patients with neural tube defects, patients born with myelomeningocele have many long-term disabilities including bowel dysfunction, bladder dysfunction, and paralysis; and the extent of disability depends upon the level of damage to the nerves.² Management of patients with neural tube defects is undergoing changes as advances in prenatal surgical repairs are being advanced at specialized centers. In 2011, a large randomized controlled trial demonstrated improved motor and neurologic outcomes of myelomeningocele patients treated with prenatal surgery compared with those patients that had postnatal repair. This improvement also came with increased risks to both the fetus as well as the mother, including increased risk of preterm delivery.⁵ Unfortunately, prenatal interventions are limited to centers that specialize in prenatal surgery, thus the postnatal management of patients born with neural tube defects still warrant emphasis.

The initial management of patients born with meningoceles or myelomeningoceles starts with protection of the exposed lesions. The sac should be wrapped with saline-soaked dressings to prevent sac rupture, dessication of the sac, and damage to underlying neural elements.² Plastic wrap should be used to assist in preventing heat loss. Broad-spectrum intravenous antibiotics (i.e. ampicillin + gentamicin) are indicated as prophylaxis against infection of the central nervous system (CNS), especially if there is a leak of cerebrospinal fluid. Antibiotics can be discontinued once complete coverage of the sac and neural elements is obtained and there are no signs of sepsis. Prior to surgery, prone positioning is essential to prevent damage to the neural elements from the patient’s body weight.²

ADMISSION AND DISCHARGE CRITERIA

After initial stabilization, newborns with neural tube defects require prompt transfer to a NICU. Discharge criteria should be determined in consultation with specialists in neonatology and pediatric neurosurgery and includes surgical closure, absence of untreated hydrocephalus (i.e. stable head circumference growth), tolerance of full enteral nutrition, and a stable regimen of adequate bowel and bladder evacuation (including the use of clean, intermittent catheterization as needed).

CONSULTATION

A neurosurgical consultation should be obtained as these lesions are typically closed within 72 hours of birth unless comorbidities prevent the patient from undergoing surgery.

CLEFT LIP AND PALATE

BACKGROUND

One in every 700 infants has cleft lip or palate, or both.² Patients with these anomalies have a 30% to 50% chance of other associated anomalies.²

Pathophysiology

Failure of the facial prominences to fuse leads to cleft lip; failure of the palatal shelves to fuse leads to cleft palate.^2,6

CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

Patients who have cleft lip are easily identified at birth, which should prompt the examiner to check for an associated abnormality of the palate. Visualization can also identify isolated cleft palate; however, because palatal defects may exist despite a normal appearance, palpation of the anterior and posterior palate is required to detect submucosal abnormalities. These defects are either partial or complete lesions. The extent of these lesions affects the eventual surgical repair but not the initial medical management of these patients. In addition, an assessment of hearing is important because there may be associated auditory abnormalities.⁶ Furthermore, approximately 10% of cleft deformities are associated with the 22q deletion associated with the velocardiofacial syndrome. In patients with cleft palate, if there is associated micrognathia with glossoptosis, a diagnosis of Pierre-Robin syndrome should be considered.

MANAGEMENT

Feeding is a major concern in the postnatal period.⁶ A physician should evaluate the infant’s cough and gag reflex before attempting the various methods available for oral feeding. Although some infants may be able to breastfeed, many infants with cleft lip and palate cannot generate enough suction to draw milk from the breast or from a standard bottle.⁶ A special nipple with an enlarged slit-like aperture and a squeezable bottle (Haberman bottle) are often effective. Surgical repair is not emergent in these patients. There are varying opinions as to the optimal timing for a repair of a cleft deformity. As such, consultation with a plastic surgeon or pediatric ear, nose, and throat (ENT) specialist is warranted to determine the best timing for surgical repair.

ADMISSION AND DISCHARGE CRITERIA

It is possible for infants with cleft lip and/or palate to be managed in the routine postnatal ward. Transfer to a NICU is indicated for difficulty with oral feeding or respiratory difficulty due to airway obstruction. Criteria for discharge home includes establishment of a safe and adequate feeding regimen as well as scheduled subspecialty follow-up.

CONSULTATION

A speech therapist should be involved early to assist in assessing and implementing safe and effective feeding regimens.⁶ The patient should be referred to a center that can provide the multidisciplinary services required by these children and their families. Repair usually occurs by 3 to 6 months ² and involves a multidisciplinary approach including plastic surgery, otolaryngology, oral and maxillofacial surgery, speech pathology, and audiology.⁶

VACTERL ANOMALIES

BACKGROUND

The VACTERL association describes a spectrum of vertebral, anorectal, cardiac, tracheoesophageal, renal, radial, and limb malformations that occur in association with each other. The incidence has been estimated at 1 in 10,000 to 40,000 live births.⁷

Pathophysiology

Vertebral anomalies are present in 60% to 80% of patients and include malformations of the vertebrae, myelodysplasia (myelomeningocele, meningocele, lipomeningocele), rib, or even central nervous system disorders.⁷ Flaccid paralysis or anesthesia beyond the spinal lesion may be evident.

Anorectal malformations are present in 50% to 90% of patients with the most common abnormality being imperforate anus.⁷

Cardiac defects present in 40% to 80% of patients and can include the Tetralogy of Fallot, atrial septal defects, ventricular septal defects, truncus arteriosus, patent ductus arteriosus, and coarctation of the aorta.⁷

Tracheoesophageal malformations occur in 50% to 80% of patients and include tracheoesophageal fistula and esophageal atresia.⁷ Polyhydramnios, resulting from the inability to swallow amniotic fluid, may be noted prenatally if renal agenesis does not exist. After birth, patients present with excessive salivation from pooling of secretions in the posterior pharynx and esophageal pouch.² Feeding leads to regurgitation, choking, and cyanosis. Inspired air enters the gastrointestinal tract, causing abdominal distention. The inability to pass a nasogastric tube is an important finding.

Renal anomalies can be found in 50% to 80% of patients and includes renal agenesis, horseshoe kidney, hypoplastic kidney, or ureteric duplication.⁷ Some patients present with early renal failure, requiring kidney transplantation.

Radial and limb deformities include absence of the radius, and absent or displaced thumb, polydactyly, or syndactyly. These are found in under 50% of these patients.⁷

CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION

Diagnosis is confirmed with the presence of at least three of the major anomalies.⁷ The diagnostic workup is aimed at detecting the predicted anomalies, therefore plain radiography is used to evaluate for vertebral malformations and limb defects. Echocardiography evaluates for cardiac defects and renal ultrasonography is used to evaluate the kidneys for abnormalities. Anorectal malformations are evaluated as described above using physical examination and prone, cross-table lateral plain radiography to locate the extent and location of the rectum. Tracheoesophageal malformations are revealed on radiographs of the chest and abdomen, which can demonstrate coiling of a nasogastric tube in the esophageal pouch and the presence of bowel gas in the stomach and small intestine (Figure 126-4).

MANAGEMENT AND CONSULTATION

Management of patients with VACTERL anomalies is aimed at supportive care for each individual anomaly found in these patients. As such, transfer to a NICU is necessary for their care. Patients with tracheoesophageal fistulas and esophageal atresia should be placed on aspiration precautions, with suction to control pooled secretions. Conventional endotracheal intubation should be avoided as the associated gastric distention compromises respiratory function.³ Pediatric surgical consultation is required for eventual surgical treatment. Vertebral and limb anomalies are managed according to their severity and orthopedics and neurosurgical involvement is necessary. As described above, pediatric surgeons should be involved in the management of anorectal malformations. Cardiology and cardiac surgery are necessary for any cardiac anomalies. Finally, urology and nephrology are necessary for the management of renal anomalies.

AMBIGUOUS GENITALIA

BACKGROUND

Ambiguous genitalia is an uncommon birth defect in which the outer genitals do not have either a typical male or female appearance. The incidence of genital ambiguity is estimated to be 1 per 4500, although some degree of male undervirilization or female virilization may be present in as many as 2% of live births.⁸

Pathophysiology

Fetal development of genitalia is influenced by many factors. Male sexual differentiation occurs when müllerian-inhibiting substance and testosterone are produced by the fetal testis and the Y chromosome is present. If these substances are absent, female development ensues. Testosterone stimulates the development of the internal male (Wolffian) structures, and müllerian-inhibiting substance inhibits development of the internal female structures.²

The most common disease leading to intersex anomaly in the United States and Europe is congenital adrenal hyperplasia (CAH). CAH may be due to different enzyme deficiencies in the steroidogenesis pathway, but 90% of cases are due to a deficiency of the 21-hydroxylase enzyme.² The defect in the cortisol pathway leads to increased production of corticotropin and adrenocorticotropic hormone, which results in overproduction of the steroids proximal to the defect—namely, the androgenic steroids and melanocyte-stimulating hormone. Patients with CAH in adrenal crisis present with hyponatremia and hypochloremia along with hyperkalemia.²

CLINICAL PRESENTATION

CAH may present with virilized genitalia in girls, but boys have normal-appearing genitalia at birth. For this reason, girls are more likely to be identified immediately. Clinical manifestations of adrenal insufficiency do not present until after several weeks of life because of the neonatal fat stores of cortisone that crossed the placenta from the mother.² Undetected salt-wasting CAH eventually presents in the first few weeks of life with nonspecific symptoms, including poor feeding, lack of weight gain, vomiting, and lethargy. As adrenal crisis progresses, the infant becomes severely dehydrated and can present in extremis.

DIFFERENTIAL DIAGNOSIS

Many enzyme or receptor defects and chromosomal abnormalities can produce a wide range of abnormalities of the gonads and external genitalia that may be evident in a newborn. In addition to CAH, the differential diagnosis for virilization of XX females includes true hermaphroditism with both testicular and ovarian tissue, exposure to maternal androgens due drugs such as progesterone during pregnancy, and preterm birth, which can be associated with clitoral enlargement.⁸ The differential for unvirilization of XY males includes gonadal dysgenesis, 5-alpha-reductase deficiency, and androgen insensitivity syndromes.⁸

DIAGNOSTIC EVALUATION

A complete history should be performed, including a pedigree, maternal drug use, and assessment of maternal virilization. The physical examination should assess the size of the phallus and the symmetry of the gonads.² Rectal examination may reveal the uterus in females.² Because mineralocorticoids may be deficient or overabundant, chemistries and serum glucose should be rapidly assessed, and vital signs should be monitored. To identify the hormonal abnormalities, serum levels of cortisone, testosterone, dihydrotestosterone, luteinizing hormone, follicle-stimulating hormone, serum 17-hydroxyprogesterone, and dehydroepiandrosterone should be obtained.² The latter two are elevated in 21-hydroxylase-deficient CAH. A rapid evaluation of chromosomes should also be performed. More elaborate testing can be done at a specialized center to look for specific genetic defects.

MANAGEMENT

Patients with salt-wasting CAH develop adrenal crisis with severe dehydration and electrolyte abnormalities. Initial stabilization involves volume expansion with intravenous normal (0.9%) saline.² This fluid resuscitation also corrects the hyponatremia and hyperkalemia caused by the mineralocorticoid deficiency. Hypoglycemia is common and should be treated with intravenous dextrose. If possible, baseline laboratory studies should be obtained before steroid replacement, but steroid administration should not be delayed. Intravenous hydrocortisone (50 mg/m²) should be given as a bolus, followed by an infusion to deliver 50 mg/m² over the first 24 hours; this should provide sufficient glucocorticoid and mineralocorticoid activity.²

ADMISSION AND DISCHARGE CRITERIA

After initial stabilization, infants should be transferred to a pediatric center with a multidisciplinary team who specializes in the evaluation and management of disorders of sexual differentiation. Discharge criteria include stabilization of any fluid and electrolyte imbalances as well as established follow-up with subspecialty care.

CONSULTATION

Multidisciplinary involvement including critical care, endocrinology, pediatric surgery, psychiatry, and urology is necessary for the care of these infants.

REFERENCES

BACKGROUND

Respiratory distress occurs frequently in newborns and can be a presenting symptom of both benign and life-threatening diseases. Failure of any of a complex series of cardiovascular and pulmonary modifications that help the neonate transition to extrauterine life can manifest as neonatal respiratory distress. Clinical features of a newborn in respiratory distress include tachypnea of more than 60 breaths per minute; cyanosis; expiratory grunting; intercostal, subcostal, or supraclavicular retractions; and nasal flaring. Although the causes of respiratory distress are numerous, this chapter focuses on a relatively common cause of respiratory distress known as transient tachypnea of the newborn (TTN) and the identification of a more serious condition, persistent pulmonary hypertension of the newborn (PPHN).

PATHOPHYSIOLOGY

TTN is a benign, self-limited disorder that occurs during the transition from uterine to extrauterine life and results from the delayed clearance of excess lung fluid. TTN was first described in 1966 when it was observed that a subset of newborns exhibited respiratory distress, consisting primarily of tachypnea, at or shortly after birth. Although the tachypnea persisted for several days, it subsequently resolved completely without sequelae.¹

Inadequate or delayed clearance of fetal lung fluid results in TTN. This fluid fills the alveolar space and then moves into the extra-alveolar space subsequently surrounding the perivascular tissue and lung fissures. It remains there until resorption is completed by the lymphatic or vascular circulation. The initiation of gas exchange in the lungs requires onset of breathing, increased pulmonary blood, and decreased systemic vascular resistance and air displacing fetal fluids. Some have suggested that TTN is associated with a relative surfactant dysfunction,² but other studies found no association between TTN and surfactant mutation.³

Delivery via elective cesarean section increases the risk for TTN. Although the physiologic mechanisms are not understood, this risk is significantly decreased if the mother undergoes a trial of labor.⁴ Additional risk factors for TTN include male sex, late prematurity (34 to 37 weeks gestational age) and macrosomia.⁵ Although the mechanism is obscure, being born to an asthmatic mother appears to be a risk factor for TTN. Infants born to women with gestational diabetes also appear to be at increased risk. This observation may be related to a corresponding increase in the rate of cesarean sections among these mothers.

PPHN commonly occurs in full-term and near-term (late preterm) infants (>34 weeks) and has an estimated incidence of 0.2% of live births.⁶ After birth, PPHN occurs when there is an insufficient or delayed decrease in pulmonary vascular resistance, which results in right-to-left shunting of blood through the ductus arteriosus or foramen ovale and severe hypoxemia. PPHN typically arises in the setting of a structurally normal heart, either with or without associated pulmonary disease. Perinatal risk factors that increase pulmonary vasoconstriction include hypoxia, acidosis, alveolar atelectasis, sepsis, direct lung injury, hypoglycemia, and cold stress.^7,8 The most common causes are meconium aspiration syndrome (50%), idiopathic PPHN (20%), sepsis (20%), and respiratory distress syndrome (5%).⁷

Despite the array of conditions associated with PPHN, one common feature is an underlying abnormality of the pulmonary vasculature. This abnormality can be broadly categorized into three groups.^6,7 In the first group, the vasculature is abnormally constricted due to parenchymal lung disease. This group is the most common and includes meconium aspiration syndrome, sepsis, and respiratory distress. The second group is associated with structurally abnormal pulmonary vasculature and includes idiopathic PPHN. The pulmonary vasculature of these infants shows significant thickening and does not appropriately vasodilate in response to birth stimuli (particularly nitric oxide and endothelin-signaling pathways). The vasculature of the third group is hypoplastic, usually due to congenital diaphragmatic hernia or, much less commonly, a rare malformation of lung development known as alveolar-capillary dysplasia.⁶

CLINICAL PRESENTATION

TTN presents within the first few hours of life with respiratory rates greater than 60 breaths per minute. Infants typically have shallow respirations, which may be accompanied by mild cyanosis. Increased work of breathing, including subcostal retractions, expiratory grunting, and nasal flaring, may also be present. Auscultation of the chest generally reveals clear breath sounds without rales, rhonchi, or crackles. Most infants do not require high levels of exogenous oxygen to ensure adequate oxygenation. Although symptoms usually resolve within the first 24 hours, TTN can persist for as long as 72 hours.

Early signs of PPHN may overlap with those of TTN, but there are distinguishing features. As unoxygenated blood is shunted away from the high-pressure circuit of the lungs through the patent ductus arteriosus in PPHN, the blood that reaches postductal areas of the systemic circulation is mixed, or lower in saturation, than the blood that circulates to the preductal regions. Pulse oximeters placed on both a preductal (right upper) and a postductal (left upper, right or left lower) extremity yield discrepancies. If the preductal oxygen saturation exceeds the postductal oxygen saturation by more than 1 or 2 percentage points, a diagnosis of PPHN must be considered. These infants can present with cyanosis and may deteriorate rapidly, with systemic hypotension and severe respiratory distress, if their pulmonary arterioles cannot be dilated.

DIFFERENTIAL DIAGNOSIS

There are many causes of respiratory distress in the newborn (Table 127-1). Infants with TTN generally do not require high levels of oxygen (>60%) or respiratory support such as mechanical ventilation. PPHN is one of the more serious conditions that presents with respiratory distress, but others must also be considered. A newborn exhibiting prolonged, significant respiratory distress or requiring a high level of respiratory support may be suffering from neonatal sepsis, pneumonia, pneumothorax, respiratory distress syndrome, or cardiac disease.

Significant cardiac malformations causing respiratory distress can be differentiated from TTN and other causes of respiratory distress. The initial evaluation should include auscultation for the existence of a pathologic murmur. Chest radiography may also be useful to assess for cardiomegaly or vascular congestion/differentiating these disorders. In infants with significant cyanotic cardiac lesions, blood is shunted away from the lungs through the lesion. Therefore, when these infants receive exogenous oxygen, their oxygen saturation or arterial oxygen tension improves only minimally (or not at all). Measurements of upper and lower extremity blood pressures may reveal a difference between the two, suggestive of coarctation of the aorta. In the presence of critical lung disease or a more subtle cardiac lesion, echocardiography may be necessary to detect or confirm a diagnosis.

DIAGNOSTIC EVALUATION

TTN is a clinical diagnosis. PPHN is also suggested by the clinical presentation, but further diagnostic testing is usually performed to confirm the diagnosis and or assess the severity.

The initial evaluation may include a blood gas, a complete blood count (CBC) and a chest radiograph. If there are clinical features (e.g. temperature instability, lethargy) or risk factors (e.g. maternal fever, chorioamnionitis, untreated or incompletely treated maternal group B streptococcal colonization) for infection, appropriate cultures should also be obtained. In addition, measurement of C-reactive protein (CRP) levels may be helpful, although these results may be unreliable when obtained shortly after birth if there has been insufficient time for an inflammatory response to occur. In TTN, an arterial blood gas evaluation reveals a mild respiratory acidosis due to mild hypoxemia and hypercapnia; the complete blood count and C-reactive protein are typically normal. On chest radiographs, classic findings of TTN include prominent central markings suggestive of vascular engorgement, moderate cardiomegaly, increased lung volume, and increased anteroposterior chest diameter.¹ Among a cohort of 2824 consecutively born infants, ~4% had a clinical picture consistent with TTN but a normal chest radiograph.⁹ This finding suggests that TTN can occur despite normal chest findings. Unless the infant’s clinical symptoms suggest more serious disease, other studies are usually not necessary.

In PPHN, chest radiographs typically reveal a normal or slightly enlarged heart. The arterial blood gas evaluation reflects a low oxygen tension for the inspired oxygen content; carbon dioxide levels may be normal if there is no parenchymal lung disease. The presence of a gradient between preductal and postductal oxygen saturation may also be helpful in the diagnosis (see earlier). However, to diagnose PPHN definitively, an echocardiogram must be obtained to exclude structural heart lesions as the cause of the severe hypoxemia. In PPHN, the echocardiogram reveals normal structural anatomy with evidence of increased right ventricular pressure and right-to-left shunting.

MANAGEMENT

Management of TTN is supportive. Although an infant exhibiting mild tachypnea can usually be observed for a few hours in the newborn nursery, significant tachypnea (>60 to 80 bpm) prevents oral feeding and necessitates transfer to a higher level of care for initiation of intravenous fluids and monitoring. In selected situations, an orogastric or nasogastric tube can be placed for assistance with feeding, but only after determining that the infant is unlikely to require ventilatory support. Because of concerns about gastroesophageal reflux and aspiration, infants with respiratory rates greater than 90 to 100 breaths per minute should not receive oral or gastric feedings. However, placement of an orogastric or nasogastric tube for stomach decompression may be helpful to maximize lung volume expansion. Supplemental oxygen may be needed, and nasal continuous positive airway pressure may be required for infants exhibiting persistent and significant work of breathing. Although some have proposed that furosemide may be useful in the treatment of TTN, studies have not confirmed that it has any role.

Whenever there is concern about PPHN, the infant should be placed on 100% oxygen and transferred to a neonatal intensive care unit. While awaiting transfer, any metabolic abnormalities should be corrected, including metabolic acidosis (although the use of alkalizing agents is controversial), hypoglycemia, hypothermia, hypovolemia, anemia, and hypocalcemia.

ADMISSION AND DISCHARGE CRITERIA

CRITERIA FOR TRANSFER TO A NEONATAL INTENSIVE CARE UNIT

• Suspected or proven PPHN

• Respiratory distress requiring supplemental oxygen

• Significant tachypnea (>60 to 80 bpm) that requires frequent reassessment or precludes oral feeding

• Prolonged tachypnea (>4 to 6 hours)

• Respiratory distress that may require the administration of continuous positive airway pressure or other ventilatory support

• Suspected or proven infection

• Suspected or proven cardiac disease

• Respiratory distress for which there is an unclear diagnosis

CRITERIA FOR DISCHARGE IN THE SETTING OF TRANSIENT TACHYPNEA OF THE NEWBORN

• Resolved respiratory distress

• No exogenous oxygen requirement for at least 12 to 24 hours

• Able to feed adequately by mouth

• Reliable outpatient follow-up

CRITERIA FOR DISCHARGE IN THE SETTING OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

• Management and discharge criteria determined by the neonatologist

CONSULTATION

Consultation with a pediatric cardiologist should be considered in persistent pulmonary hypertension.

REFERENCES

CONGENITAL INFECTIONS

BACKGROUND

Congenital infections acquired in utero are a significant cause of neonatal mortality and childhood morbidity. The original concept of the TORCH acronym was to group five infections with similar presentations: toxoplasmosis, “other” (traditionally referring to syphilis), rubella, cytomegalovirus (CMV), and herpesvirus. However, recent additions have expanded the scope of this term to include infections such as human immunodeficiency virus (HIV), enteroviruses, parvovirus B19, and varicella. The incidence of TORCH infections in the United States is variable, ranging from 0.7% for CMV, the most common congenital viral infection, to ≤1 in 10,000 for rare infections such as rubella and toxoplasmosis. A high index of suspicion for congenital infection and awareness of the prominent features of the most common etiologies will help to facilitate early diagnosis and management.

Pathophysiology

Transplacental spread and invasion of the bloodstream after maternal infection is the primary route for intrauterine infection, though it is also possible for the fetus to be infected by extension from adjacent infections of the peritoneum and the genitalia during the birth process or during invasive procedures such as fetal monitoring and intrauterine transfusion.¹

In order for the maternal immune system to tolerate pregnancy, the placenta serves as a protective barrier that shields the fetus from maternal humoral and cell-mediated immune activity. Without immunologic mechanisms necessary to eradicate an infecting organism, the fetus is susceptible to infection, and a state of immunologic tolerance is often established. The fetus is particularly vulnerable during the first trimester of pregnancy, when the most complex events in embryogenesis occur, including development of sensory organs such as the eyes and ears.

The outcome of fetal infection depends on several factors, including gestational age at the time of infection, organism virulence, degree of associated placental damage, and maternal disease severity.¹ Primary infection is also likely to have more significant effects on the fetus than recurrent infection. Infection during the first few weeks of gestation may cause embryonal death and resorption, prior to recognition of pregnancy. Spontaneous abortion and stillbirth are among the earliest recognizable effects of fetal infection after 6 to 8 weeks of pregnancy. In infants who are live-born, effects of fetal infection may present as preterm birth, intrauterine growth restriction (IUGR), congenital anomalies, or local or systemic signs of infection. Alternatively, fetal infection may present in live-born infants as the complete absence of any clinical signs of disease, with abnormalities becoming obvious only as the child develops and fails to reach appropriate physiologic or developmental milestones.

CLINICAL PRESENTATION

Intrauterine infection with CMV, herpes simplex virus (HSV), syphilis, rubella, toxoplasmosis, and enterovirus may present in the neonatal period with signs of widely disseminated disease caused by microbial invasion and proliferation over weeks or months prior to delivery.¹ In such infants it can be difficult to determine whether infection was acquired in utero, intrapartum, or postpartum. However, if the onset of clinical symptoms after birth occurs within the minimal incubation period for the disease, it is likely that infection was acquired before delivery.

Cytomegalovirus

Congenital CMV infection may present at birth with generalized petechiae, direct hyperbilirubinemia, hepatosplenomegaly, purpuric rash, microcephaly, seizures, focal or general neurologic deficits, retinitis, and intracranial calcifications (usually periventricular) (Figure 128-1A). However, 90% of infants with congenital CMV infection are asymptomatic at birth, and most cases are undetected prior to discharge from the birth hospital. Infants who are symptomatic at birth are at highest risk of long-term neurological sequelae, including sensorineural hearing loss, mental retardation, cerebral palsy, and vision impairment. However, approximately 10% to 15% of asymptomatic, infected infants will also experience later, long-term adverse neurological outcomes.²

Herpes Simplex Virus

Intrauterine infection with HSV is rare (approximately 1 in 300,000 deliveries), compared with the vast majority of neonatal HSV infections which result from exposure during delivery. Intrauterine HSV transmission is highest during the first 20 weeks of pregnancy, resulting in abortion, stillbirth, and congenital anomalies in infants who survive.³ Perinatal mortality is high, and infected infants usually have clinical abnormalities identified at birth. Typical presentation is a triad of clinical findings: cutaneous manifestations (i.e. scarring, active lesions, hypo- and hyperpigmentation, aplasia cutis, and/or an erythematous macular exanthem), ophthalmologic findings (i.e. micro-opthalmia, retinal dysplasia, optic atrophy, and/or chorioretinitis), and neurologic involvement (i.e. microcephaly, encephalomalacia, hydranencephaly, and/or intracranial calcification).³

Clinical presentation for infants infected with HSV during delivery can be divided into three categories, each associated with different outcomes and manifestations. Neonates with infection confined to the skin, eyes, and mucosa (SEM) comprise about 45% of most case series, most often presenting with cutaneous or mucosal vesicular lesions.⁴ By definition, infants in this category have no central nervous system (CNS) or visceral organ involvement, although systemic therapy is required to prevent further disease progression. Infants with SEM HSV disease often have recurrent cutaneous outbreaks in early childhood. The second category is HSV infection with CNS involvement, comprising 30% of cases.⁴ CNS disease can present with lethargy, poor feeding, or seizures, with or without cutaneous lesions. Morbidity with CNS involvement is higher with HSV-2 than HSV-1 infection, with potential long-term sequelae including developmental delay, epilepsy, blindness, and cognitive disabilities. Relapses of CNS infection may also occur during childhood, further increasing morbidity. Disseminated HIV infection is the third category and occurs in 25% of cases. Mortality risk is highest for these infants (approximately 30%), as it is associated with multiorgan dysfunction. Clinical presentation can be indistinguishable from bacterial sepsis.⁴

Syphilis

Congenital syphilis results from fetal infection with the spirochete Treponema pallidum via transplacental transmission. In recent years, the rate of congenital syphilis in the United States has increased, now affecting 10 per 100,000 births.⁵ Untreated syphilis during pregnancy results in fetal or neonatal death in up to 40% of cases. Infected live-born infants are often asymptomatic, with only severe cases clinically apparent at birth. Untreated asymptomatic infants can subsequently develop severe sequelae in the first few weeks, months, or years of life.

Early presentation of congenital syphilis, manifesting within the first few months to first year of life, can include hepatosplenomegaly, jaundice, lymphadenopathy, meningoencephalitis, chorioretinitis, and mucocutaneous findings such as maculopapular erythema, bullae, and desquamation. Infants may fail to thrive and have a characteristic mucopurulent or blood-stained nasal discharge causing “snuffles.” Osteochondritis of the long bones and ribs may cause pseudoparalysis of the limbs with characteristic radiologic changes. Late presentation of congenital syphilis, manifesting after the first 1 to 2 years of life, can include gummatous ulcers of the nose, septum, or hard palate; periosteal lesions resulting in saber shins and frontal and parietal bossing; juvenile paresis and tabes secondary to neurosyphilis; optic atrophy and interstitial keratitis; and progressive sensorineural deafness. Dental abnormalities include Hutchinson incisors (small, widely spaced, peg-shaped, notched upper incisors with thin discolored enamel), hypoplastic enamel, and mulberry molars. “Hutchinson triad” is a pathognomonic constellation of findings that consist of interstitial keratitis, Hutchinson teeth, and sensorineural hearing loss.

Toxoplasmosis

Toxoplasma gondii is a protozoan parasite transmittable through contact with cat feces or consumption of contaminated foods, such as meat containing infective tissue cysts or unwashed produce from contaminated soil. The risk of transplacental infection is lower (10% to 25%) when maternal infection occurs in the first trimester compared with the third trimester (60% to 90%). However, severe sequelae, including stillbirth and neonatal death, are more likely when infection is acquired in the first trimester. Overall risk of congenital infection from acute prenatal infection ranges from approximately 20% to 50%. Most neonates with congenital toxoplasmosis are asymptomatic; however, clinical presentation can include hepatosplenomegaly, lymphadenopathy, maculopapular rash, jaundice, anemia, and thrombocytopenia. A classic triad of clinical findings associated with this disease is chorioretinitis with intracranial calcifications (typically generalized) (Figure 128-1B) and hydrocephalus.

Enteroviruses

Enteroviruses are small, single-stranded RNA viruses belonging to the Picornaviridae family. Congenital enterovirus infection often presents with a maternal history of viral illness including fever, respiratory concerns, or abdominal symptoms preceding or immediately following delivery. There may also be a history of viral symptoms in other family members. Signs of infection in neonates may include temperature instability, irritability, lethargy, jaundice, emesis, abdominal distension, diarrhea, respiratory distress, and macular or maculopapular rash. Most affected neonates have mild disease, however, a small percentage develop severe sequelae including meningoencephalitis, myocarditis, pneumonia, hepatitis, and coagulopathy. Myocarditis in particular confers high-mortality risk for affected infants and has special diagnostic significance for enterovirus infection.

Rubella

Since licensure of live attenuated rubella vaccines in the late 1960s, the number of reported US cases of congenital rubella infection has declined dramatically to <1 case per year. Risk of infection and associated defects is highest during the first 12 weeks of gestation. Severe sequelae including spontaneous abortion and stillbirth are possible outcomes of infection early in pregnancy. Infection in the first trimester is considered to be uniformly teratogenic, while birth defects are very rare among infants infected after 20 weeks of gestation.⁶ Common congenital manifestations include cataracts, congenital heart disease (most commonly patent ductus arteriosus or peripheral pulmonary artery stenosis), hearing impairment, and developmental delay. Affected infants usually present with more than one sign or symptom, however, they may present with a single defect. Eye findings including glaucoma, chorioretinitis, retinopathy, and cataracts have special diagnostic significance for this infection. In some cases, congenital rubella may only be identified years after birth due to isolated hearing defects.

Human Immunodeficiency Virus

Although the transmission rate of HIV from an untreated mother to the fetus is estimated to be about 25%, this risk can be reduced to <2% with use of antiretroviral regimens and obstetrical intervention (i.e. zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy), and by avoiding breastfeeding. Infants with congenital HIV infection are usually asymptomatic at birth and through the first few months of life. The median age of onset for clinical signs is approximately 3 years, but many children remain asymptomatic for more than 5 years. Clinical presentation of congenital HIV infection can include failure to thrive, persistent diarrhea, recurrent suppurative infections, and opportunistic infections that occur weeks to months or years after birth.

Varicella

Varicella-zoster virus (VZV) is one of eight herpes viruses known to cause human infection; primary infection during pregnancy carries significant implications for both maternal and fetal health. Congenital varicella syndrome due to transplacental infection is rare and mostly occurs with infection between 8 and 20 weeks gestation. Characteristic findings in affected neonates may include: low birth weight; cutaneous scars in a dermatomal distribution; eye findings of cataracts, chorioretinitis, microphthalmos, or nystagmus; hypoplastic limbs; gastrointestinal abnormalities including bowel stenosis; and neurological findings of cortical atrophy or seizures. Varicella is not generally associated with spontaneous fetal loss, preterm birth, or stillbirth.

Parvovirus B19

Parvovirus B19 is a single-stranded, DNA virus that preferentially infects rapidly dividing cells and is cytotoxic for erythroid progenitor cells. The risk for transplacental transmission from an infected mother to the fetus is between 10% to 35%, and is highest in the first and second trimesters of pregnancy. Infection prior to 20 weeks gestation is associated with a higher fetal mortality rate (14.8%) compared with infection after 20 weeks (2.3%). Presentation is typically related to severe anemia, high-output cardiac failure, and extramedullary hematopoiesis, resulting in nonimmune hydrops fetalis, ascites, pleural effusion, and pericardial effusions. Persistent anemia due to hematopoietic suppression can also persist for months after birth.

DIFFERENTIAL DIAGNOSIS

As shown in Table 128-1, clinical presentations for infections acquired in utero share many features, including but not limited to IUGR, microcephaly, cataracts, hearing loss, hepatosplenomegaly, cutaneous findings, and thrombocytopenia. Consequently, in the absence of maternal history or prenatal laboratory results that suggest a specific infection (e.g. positive syphilis serology), the differential diagnosis for each TORCH infection includes all of the other TORCH or TORCH-like infections. It is also important to note that neonates with suspected or confirmed congenital HIV or syphilis infection should also be considered at risk for other sexually transmitted infections including gonorrhea and Chlamydia trachomatis.

Noninfectious diseases in the differential include genetic disorders (e.g. pseudo-TORCH syndrome), inborn errors of metabolism, ABO or Rh incompatibility, neoplastic disorders, and prenatal teratogen or drug exposure.

DIAGNOSTIC EVALUATION

Initial evaluation of a neonate with suspected intrauterine infection should begin with a thorough review of maternal history, including routine prenatal laboratory studies, history of HSV, HIV, and other diseases, and potential exposures including contact with cats and persons infected with VZV. A head-to-toe assessment should be performed to identify physical findings that may be more prominent features of a particular congenital infection. Additional helpful studies for initial evaluation are a complete blood count (CBC) with differential and platelet count, liver function tests, long bone radiography, ophthalmologic and audiologic evaluation, neuroimaging, and lumbar puncture.^7,8 Based on initial results, further tailored evaluation for a specific infection or group of infections may follow. Table 128-2 depicts specific fetal and neonatal laboratory studies to guide antenatal and postnatal diagnosis for each infection.

MANAGEMENT

Care of the HIV-Exposed Infant

Because treatment recommendations change over time, consultation with a pediatric HIV expert is recommended in the care of HIV-exposed and infected infants. Care of the HIV-exposed infant is addressed in Chapter 108. Current treatment recommendations are available online at http://aidsinfo.nih.gov. The National Perinatal HIV Hotline (1-888-448-8765) also provides free clinical consultation for providers.

Currently, it is recommended that for HIV-exposed infants, virologic testing should be performed within the first 2 to 3 weeks of life, at 1 to 2 months, and at 4 to 6 months of age. Additionally, some experts recommend virologic testing at birth, particularly in women who have not had good virologic control during pregnancy or if adequate follow-up of the infant is uncertain.⁹ A 6-week regimen of zidovudine chemoprophylaxis is recommended for all HIV-exposed neonates; this should be initiated as close to the time of birth as possible and preferably within 6 to 12 hours of life. HIV-exposed infants who did not receive antepartum antiretroviral (ARV) drugs should receive 6 weeks of zidovudine as well as nevirapine. To prevent opportunistic infection with Pneumocystis jirovecii, all HIV-exposed infants should begin trimethoprim-sulfamethoxazole prophylaxis at 4 to 6 weeks, after completion of ARV prophylaxis. Because of the risk of HIV transmission through breast milk, infants in the United States should not breastfeed. If the infant’s virologic testing is positive at any time, chemoprophylaxis should be discontinued and the infant should be promptly seen by a pediatric HIV specialist for treatment with standard combination ARV therapy.

Congenital Toxoplasmosis

For congenital toxoplasmosis infections, initial therapy is pyrimethamine combined with sulfadiazine (supplemented with folinic acid).¹⁰ Dosage and duration of therapy should be determined in consultation with an infectious disease specialist.

HSV Exposure and Infection

Management of the asymptomatic, HSV-exposed neonate is complex, as risk of infection varies significantly based on whether maternal infection is primary or recurrent. For infants born vaginally or by cesarean to mothers with active genital HSV lesions at delivery, surface cultures should be obtained at 12 to 24 hours of life from the nasopharynx, mouth, urine, and stool or rectum.¹¹ These asymptomatic, exposed infants should be kept in contact isolation and closely observed. Most experts would not administer empiric antiviral therapy, although parents or caregivers should be educated about the signs and symptoms of neonatal HSV infection during the first 6 weeks of life.

For infants with known maternal, recurrent genital HSV infection but no genital lesions at delivery, close observation without contact isolation or surface cultures is indicated.¹¹ As above, parents or caregivers should be educated about the signs and symptoms of neonatal HSV infection at discharge.

Any neonate with a vesicular rash should be evaluated for HSV. Disseminated HSV infection should also be considered in neonates with signs of sepsis, particularly those with negative bacteriologic culture results and/or severe liver dysfunction. For infants with suspected or confirmed HSV infection, parenteral acyclovir is the treatment of choice regardless of manifestations and clinical findings.¹¹ Treatment for infants with CNS involvement or disseminated disease is a minimum of 21 days. Use of oral acyclovir for 6 months following treatment of acute disease has been shown to improve neurodevelopmental outcomes and to prevent skin recurrences. In addition to parental acyclovir, infants with ocular involvement should also receive topical ophthalmic medication (1% trifluridine, 0.1% iododeoxyuridine, or 3% vidarabine).

Evaluation and Treatment of Congenital Syphilis

Parenteral penicillin remains the standard treatment for congenital syphilis. Factors to consider in treatment include adequacy of maternal treatment and response to treatment, infant serologic titers compared with maternal titers, and physical exam findings and other laboratory studies.¹² The approach to diagnosis, evaluation, and treatment of infants with potential congenital syphilis is summarized in Figure 128-2.

Supportive Care

Treatment for the remaining intrauterine infections, including CMV, rubella, varicella, parvovirus, and enterovirus, is primarily supportive. Infants in congestive heart failure require careful fluid management and treatment with inotropic agents and/or diuretics. Bleeding and coagulopathy due to hepatic failure may necessitate frequent replacement therapy with packed red blood cells, platelets, fresh-frozen plasma, and vitamin K. Intravenous immunoglobulin (IVIG) has been used for neonates with life-threatening enterovirus infections, although proof of efficacy is lacking. The use of antiviral drug pleconaril in neonatal enteroviral sepsis syndrome is currently being studied. For congenital CMV, antiviral therapy is not recommended routinely for neonates due to potential toxicity. However, parenteral ganciclovir or oral valganciclovir can be used in symptomatic infants with CNS involvement and may be helpful in protecting against hearing deterioration and developmental impairment. Finally, newborns with severe varicella infection should be treated with acyclovir, as it may reduce mortality risk. Treatment should begin as soon as possible after onset of symptoms.

ADMISSION AND DISCHARGE CRITERIA

Admission to a neonatal intensive care unit should be considered for newborns with

• Severe IUGR

• Preterm birth (between 35 and 36 weeks gestation, this may depend upon clinical assessment and whether the postnatal ward can provide an appropriate level of care)

• Respiratory compromise, including apnea, cyanosis, or requirement for supplemental oxygen or ventilator support

• Hemodynamic instability

• CNS involvement

• Gastrointestinal symptoms, including feeding difficulty or concern for intestinal anomalies

• Requirement for an exchange transfusion

• Physical exam or laboratory findings concerning for disseminated infection

Discharge home is appropriate when

• Infant is clinically stable

• Any necessary diagnostic and hospital-based treatment regimens are complete

• Appropriate primary care and specialty follow-up appointments have been arranged

CONSULTATION

With suspected congenital infections, consultation with a pediatric infectious disease specialist may be warranted to help guide diagnostic workup, interpretation of laboratory results, and treatment. Consultation with an expert in pediatric HIV infection is recommended in the care of HIV-exposed neonates. Treatment of herpes simplex virus ocular infection should involve an ophthalmologist.

SPECIAL CONSIDERATIONS

Prevention

Risk of TTN may be lowered by limiting cesarean sections whenever possible, and planning elective cesarean deliveries, when deemed necessary, at 39 weeks’ gestation or later. All women should be screened serologically for syphilis early in pregnancy with a nontreponemal test (e.g. RPR or VDRL) and preferably again at delivery. HIV screening is also recommended as part of standard prenatal care. Routine serological screening for herpes simplex virus (HSV) in asymptomatic pregnant women is not recommended, as it has not been shown to reduce transmission of HSV to newborns. Pregnant women identified as rubella nonimmune should be immunized in the immediate postpartum period to protect future pregnancies, however, immunization is contraindicated during pregnancy and in the 3 months before conception.

Awareness of congenital viral infections, their potential risks, and appropriate hand hygiene measures to minimize acquired infection are important for pregnant women and women of childbearing age. Current research of an investigational CMV vaccine for use in pregnancy appears promising. Serologic testing for varicella should be considered only for pregnant women who do not have evidence of immunity (reliable history of chickenpox or documented vaccination). There is no single recommendation for monitoring for parvovirus B19 in pregnancy, but serological testing may be indicated when there are potential exposures. Pregnant women whose serostatus for T. gondii is negative or unknown should avoid activities that potentially expose them to cat feces (such as changing litter boxes, gardening, and landscaping), or they should wear gloves and wash their hands if such activities are unavoidable.

PERINATALLY ACQUIRED INFECTION

BACKGROUND

In addition to congenital infections acquired in utero, infections acquired during birth from the maternal genital tract can present as systemic infection in the neonate. An estimated 10% to 30% of pregnant women are rectally or vaginally colonized with group B streptococcal (GBS), the leading cause of neonatal early-onset sepsis and meningitis in the United States. As a result of prevention efforts, including improved antenatal screening and antibiotic prophylaxis, the incidence of GBS early-onset disease has declined dramatically over the past 15 years, from 1.7 cases per 1000 live births in the early 1990s to 0.34–0.37 cases per 1000 live births recently.¹³ However, available GBS prevention strategies will not prevent all cases of early-onset disease and any cases of late-onset disease, and rapid neonatal detection and treatment is necessary to minimize morbidity and mortality for those cases that do occur.

Pathophysiology

GBS is a gram-positive bacterium that primarily infects infants, pregnant women, and older adults, with the highest incidence among young infants. Neonatal infections within the first week of life are designated early-onset disease, while late-onset infections occur in infants greater than 1 week, with most infections evident during the first 3 months. Early-onset infections are acquired vertically through exposure from the colonized vagina; infection occurs primarily when the bacterium ascends to the amniotic fluid after onset of labor or rupture of membranes, although it also can invade through intact membranes. GBS can then be aspirated into the fetal lungs, leading to bacteremia. Infants also can become infected during passage through the birth canal.

Maternal colonization with GBS is the primary risk factor for early-onset GBS disease. Additional factors that increase the risk include preterm birth, longer duration of membrane rupture, intra-amniotic infection, young maternal age, black race, low maternal levels of GBS-specific antibody, and previous delivery of an infant with invasive GBS disease.¹³

The incidence of late-onset disease, at <0.5 per 1000, has not been reduced with implementation of antenatal screening and maternal antibiotic prophylaxis. The pathogenesis of late-onset GBS disease remains obscure, but it is likely that even when vertical transmission at birth does not occur, exposure to either the mother or other colonized family members and caregivers can serve as a source for colonization and subsequent infection.¹

CLINICAL PRESENTATION

Infants with early-onset GBS disease generally present with respiratory distress, apnea, or other signs of sepsis (including temperature instability, tachycardia, lethargy, irritability, abdominal distention, and poor feeding) within the first 24 to 48 hours of life. The most common clinical syndromes of early-onset disease are sepsis and pneumonia; less frequently, early-onset infections can lead to meningitis. Case fatality ratio for early-onset disease ranges between 4% and 6% in recent years, with highest mortality risk in infants born preterm.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis for symptoms of early-onset neonatal sepsis is broad. Critical congenital heart disease should be considered, as many duct-dependent anatomic lesions and tachyarrhythmias manifest early with features that can overlap with sepsis (i.e. tachypnea, tachycardia, and poor perfusion). Hypovolemia resulting from acute perinatal blood loss may also present with nonspecific signs including tachycardia, pallor, and hypotension. Additional conditions include transient tachypnea of the newborn, pneumothorax, pulmonary hypertension, respiratory distress syndrome, congenital anatomic lesions (e.g. congenital diaphragmatic hernia, choanal atresia), neonatal abstinence syndrome, polycythemia, and endocrine and metabolic abnormalities.

DIAGNOSTIC EVALUATION AND MANAGEMENT

Detection of early-onset GBS infection can be challenging, as neonatal providers must consider multiple factors, including the infant’s clinical appearance, presence of maternal risk factors (i.e. presence of chorioamnionitis, duration of rupture membranes), and exposure to intrapartum antibiotic prophylaxis. In 2010, a revised algorithm for secondary prevention of neonatal early-onset GBS disease was put forth by the Centers for Disease Control and Prevention (CDC) and endorsed by the American Academy of Pediatrics (AAP) (see Figure 128-3). This algorithm guides evaluation and management for all newborns, who can be categorized into one of five groups: (1) neonates with any signs of sepsis, (2) well-appearing neonates whose mothers had suspected chorioamnionitis, (3) well-appearing neonates without suspected chorioamnionitis and without indication for GBS prophylaxis, (4) well-appearing neonates with adequate GBS prophylaxis, and (5) well-appearing neonates with inadequate GBS prophylaxis. Adequate intrapartum antibiotic prophylaxis is defined as ≥4 hours of IV penicillin, ampicillin, or cefazolin prior to delivery.

Neonates with Signs of Sepsis

As shown in Figure 128-3, all symptomatic infants should receive a full diagnostic evaluation, including blood culture, CBC with differential, chest radiograph if respiratory signs are present, and lumbar puncture if stable enough to tolerate the procedure. Antibiotic therapy should be promptly initiated pending laboratory results, and should include IV ampicillin as well as coverage for Escherichia coli and other gram-negative organisms.

Suspected Chorioamnionitis

It is recommended that for infants with suspected chorioamnionitis, a blood culture and CBC should be obtained, and antibiotics initiated pending laboratory results.

ADMISSION AND DISCHARGE CRITERIA

Admission to a neonatal intensive care unit is indicated for any newborn with signs of sepsis. Well-appearing infants undergoing limited evaluation and empiric antibiotic treatment pending results may be appropriate for care in the routine postnatal ward, depending on institution policies and procedures. As shown in Figure 128-3, discharge home of the well-appearing neonate with adequate intrapartum prophylaxis may occur as early as 24 hours, if sufficient follow-up and observation are available. For well-appearing newborns with inadequate intrapartum prophylaxis, observation in the hospital for at least 48 hours is recommended.

CONSULTATION

Consultation with a neonatologist should be considered for infants with symptoms of sepsis, including temperature instability, feeding difficulty, lethargy, abdominal distension, poor tone, respiratory distress, and hemodynamic instability.

SPECIAL CONSIDERATIONS

Prevention

Prevention strategies have substantially reduced the burden of early-onset GBS disease. The 2010 CDC guidelines recommend universal screening of all pregnant women for vaginal and rectal colonization between 35 and 37 weeks gestation. Any woman with a positive screen, a history of GBS bacteriuria during pregnancy, or previous delivery of an infant with invasive GBS disease requires antibiotic prophylaxis at the time of labor onset or membrane rupture; a planned cesarean delivery obviates the need for antibiotics if labor has not begun and membranes have not ruptured. For women with an unknown GBS status, amniotic membrane rupture ≥18 hours, intrapartum temperature ≥100.4° Fahrenheit, preterm delivery (<37 weeks), or intrapartum testing positive for GBS are indications for intrapartum antibiotic prophylaxis.

Neonatal providers should be aware of current recommendations for appropriate intrapartum prophylaxis regimens. As penicillin is the first-line agent for antibiotic prophylaxis, with ampicillin as an acceptable alternative. Penicillin-allergic women without a history of anaphylaxis or other severe allergic reactions should receive cefazolin. For penicillin-allergic women at high risk for anaphylaxis, susceptibility testing should be performed on antenatal GBS cultures. In such cases, clindamycin should be used if the GBS isolate is susceptible. If the isolate is resistant to clindamycin or demonstrates inducible resistance, penicillin-allergic women should receive vancomycin. Erythromycin should not be used as an alternative for GBS prophylaxis.

REFERENCES

HYPOGLYCEMIA

BACKGROUND

Glucose is the preferred oxidative energy source for the central nervous system. At birth, the sudden loss of a continuous maternal glucose supply requires a neonatal response to maintain adequate serum glucose levels throughout the early feeding and fasting periods. The newborn’s plasma glucose level drops quickly after delivery and generally reaches a nadir by 2 hours of age. While otherwise healthy neonates may develop persistent hypoglycemia, up to 50% in high-risk neonates (e.g. small or late preterm infants, infants of diabetic mothers) develop persistent hypoglycemia.¹ If severe, neonatal hypoglycemia may result in systemic effects and have potential neurological sequelae.

Pathophysiology

Adaptive changes in hormonal regulation at birth conspire to maintain the newborn’s plasma glucose concentration, reserve glucose for the central nervous system, and avoid hypoglycemia. Counterregulatory hormones, including glucagon, growth hormone, cortisol, and epinephrine, act together to increase blood glucose via glycogenolysis, gluconeogenesis, ketogenesis, and inhibition of peripheral glucose uptake and insulin release. These regulatory mechanisms support the transition from a continuous transplacental glucose source to an intermittent supply via feeding. The failure of one or several parts of this process can result in hypoglycemia.

Infants at higher risk for hypoglycemia are those with diminished hepatic glucose production, increased metabolic need versus substrate availability, or increased insulin production (Table 129-1). Additional metabolic challenges such as immaturity, low glycogen reserves, and thermal stress may also render the newborn more susceptible to hypoglycemia.

CLINICAL PRESENTATION

In healthy adults, a decrease in blood glucose concentration inhibits the production of insulin and stimulates the production of glucagon. This prevents the blood glucose from dropping to less than 60 mg/dL, thus avoiding the development of typical symptoms of hypoglycemia such as diaphoresis, headache, and dizziness. In neonates there is a weaker clinical correlation between blood glucose concentrations and symptoms of hypoglycemia. Although some newborns may display nonspecific signs and symptoms of hypoglycemia (Table 129-2) others may appear completely asymptomatic despite low blood and cerebral glucose levels.

DIFFERENTIAL DIAGNOSIS

The presence of hypoglycemia is most often the result of a healthy newborn’s inability to quickly and adequately respond to the dramatic loss of maternal sources of glucose. However, hypoglycemia may also be a signal of other stresses, including sepsis, inborn errors of metabolism, hyperinsulinism, polycythemia, and congenital hypopituitarism (see Table 129-1). Symptoms of hypoglycemia are nonspecific and overlap with other systemic conditions (e.g. neonatal abstinence syndrome). In addition, hypoglycemia may be one feature of a syndrome or a multifaceted disorder (e.g. Beckwith-Wiedemann syndrome).

DIAGNOSTIC EVALUATION

No specific glucose value either defines significant hypoglycemia, or predicts neurologic injury in the newborn. Consequently, there is no consensus or numerical definition for neonatal hypoglycemia. Uncertainty exists about where the appropriate lower limit of normal is for newborns, and there are limitations to a single cutoff value. In general, a conservative threshold for defining hypoglycemia is useful to avoid the systemic effects and potential neurologic sequelae of hypoglycemia. An “operational threshold” has been suggested that takes into consideration the unstable relationship between plasma glucose levels and clinical signs of hypoglycemia. The operational threshold has been defined as “that concentration of plasma or whole blood glucose at which clinicians should consider intervention.”² The American Academy of Pediatrics (AAP) notes that the generally adopted level for an operational threshold for neonatal hypoglycemia is less than 47 mg/dL, and suggest a target glucose of >=45 mg/dL prior to feeds.³ The 2011 AAP clinical report provides a strategy that accounts for infant risk factors, symptoms, and age in hours. Screening is recommended in preterm infants, small and large-for-gestational-age infants, and infants of diabetic mothers. Normal full-term infants who are delivered without complications after a normal pregnancy do not require glucose monitoring. Regardless of risk factors, any infant with clinical signs consistent with hypoglycemia requires evaluation (see Table 129-2).

The optimal timing of screening is not known. Hypoglycemia in newborns generally appears at around 2 to 6 hours of life. As shown in Figure 129-1, the AAP recommends that infants at risk for hypoglycemia be screened within the first 1 to 2 hours after birth, with surveillance continuing before feedings for 12 to 24 hours of life.³

Glucose reagent strips may be used as a screening method to evaluate blood glucose, but provide variable results, with differences up to 10 to 20 ml/dL. Therefore, laboratory confirmation of plasma glucose levels is necessary when point-of-care results are low.

MANAGEMENT

Because of the potential risk to the central nervous system, neonatal hypoglycemia is treated aggressively with the early institution of oral feedings. In symptomatic infants with significant hypoglycemia, or in infants who are unable to be fed, an intravenous bolus of 2 ml/kg of 10% dextrose (D10W) is followed by a maintenance infusion of 80 to 100 mL/kg per day of D10W (Figure 129-1). Infants who do not respond may require an increase in the volume of fluid or the concentration of glucose. Infants who require greater than 100 mL/kg per day of D10W to maintain adequate serum glucose levels can be treated with D12.5W via a peripheral intravenous line. Concentrations greater than this require central venous access. Once the neonate’s glucose has stabilized, glucose infusions can be decreased by approximately 2 mL/hour while providing oral feedings. Glucose levels should be assessed before each oral feeding while the intravenous infusion is being decreased.

ADMISSION AND DISCHARGE CRITERIA

Admission or transfer to a neonatal intensive care unit is appropriate in the following circumstances:

• Persistent hypoglycemia despite adequate oral or gavage feeding

• Inability to tolerate an oral or gavage glucose load

• Presence of nonspecific signs of hypoglycemia (see Table 129-2) despite normalized serum glucose

Discharge criteria include:

• Clinically asymptomatic infant with the ability to take breast milk or infant formula by mouth at age-appropriate intervals

• Stable glucose level greater than 50 mg/dL

CONSULTATION

Subspecialty evaluation by a neonatologist or pediatric endocrinologist should be considered in infants with prolonged hypoglycemia, or when persistently high rates of glucose infusion are required to maintain normal glucose levels. Other situations in which to consider consultation include severe hypoglycemia associated with seizures in an otherwise healthy infant, or infants with physical exam findings consistent with underlying etiologies, such as hypotonia, hepatomegaly, omphalocele, or macroglossia.

Prevention

Neonatal hypoglycemia may be prevented with the early initiation of feeds, at frequent intervals of every 2 to 3 hours. Cold stress in the infant should be avoided by maintaining a neutral thermal environment. This may be facilitated by early skin-to-skin contact with the mother. Infants at risk for hypoglycemia should be closely monitored, and observed for symptoms.

INFANTS OF DIABETIC MOTHERS

BACKGROUND

Diabetes is a condition that is seen with increasing frequency worldwide, and is one of the most common complications of pregnancy. It is estimated that gestational diabetes occurs in approximately 2% to 5% of pregnancies, whereas pregestational diabetes is present in about 1% of women.⁴ Diabetes during pregnancy increases the risk of both fetal and neonatal morbidity and mortality.

Pathophysiology

A unique metabolic consequence of pregnancy is a blunting of the effects of insulin in the mother. The normal clearance of glucose is delayed, which helps maintain a consistent level of maternal glucose for the fetus. Pregestational maternal diabetes potentiates these anti-insulin effects and causes an additional increase in glucose in the fetal environment. Fetal hyperglycemia induces fetal pancreatic islet hypertrophy and beta cell hyperplasia. This results in an elevation in fetal, and later, neonatal plasma insulin concentrations which can lead to neonatal hypoglycemia, occurring in up to 50% of infants of diabetic mothers (IDMs). In addition, the normal shift in energy metabolism that allows the infant to use fat and amino acids may be hampered by hyperinsulinemia and may result in other laboratory abnormalities such as hypocalcemia and hypomagnesemia (Table 129-3). Furthermore, insulin acts as an anabolic growth hormone. In the presence of elevated fetal insulin levels, increased growth of insulin-sensitive tissues occurs, resulting in macrosomia and organomegaly. Chronic fetal hyperinsulinemia may also lead to fetal hypoxemia and placental insufficiency, resulting in higher fetal erythropoietin levels and polycythemia. This contributes to the increased risk of hyperbilirubinemia seen in IDMs.⁵

CLINICAL PRESENTATION

Major congenital malformations occur in 5% to 10% of infants born to women with pregestational diabetes (Table 129-4).⁶ The degree of risk is related to the timing and intensity of the teratogenic effects of hyperglycemia and to the level of glycemic control during the first trimester. Although strict glycemic control during pregnancy is thought to be optimal, especially during the period of organogenesis, it does not appear to lower the rate of congenital malformations or the incidence of macrosomia to that seen in pregnancies unaffected by diabetes. Diabetic embryopathy is a major cause of perinatal mortality in diabetic pregnancies; a 4- to 10-fold increase in risk has been described, compared with the general population.⁷

Macrosomia, which occurs in up to 40% of diabetic pregnancies, is characterized by birth weight above the 90th percentile, increased body fat, visceral organ hypertrophy, and increased skeletal growth. Owing to their large size, IDMs are more likely to be delivered by cesarean section and to experience complications of delivery, such as shoulder dystocia and brachial and facial nerve palsies. Although macrosomia is the most common growth abnormality of IDMs, intrauterine growth restriction (IUGR) can occur in the presence of advanced vascular disease and hypertension in the mother. IUGR can lead to significantly reduced hepatic glycogen stores, making IDMs particularly vulnerable and dependent on an exogenous glucose supply. Macrosomic IDMs have adequate glycogen and lipid stores but cannot use them efficiently owing to the antagonistic effects of high insulin levels on glycogenolysis, gluconeogenesis, ketogenesis, and lipolysis.

The association between congenital malformations and gestational diabetes and type 2 non-insulin-dependent diabetes mellitus is more controversial, but it is likely that in women with gestational diabetes who have greater glucose intolerance and poor first trimester glycemic control, the rate of congenital malformations is similar to that in women with pregestational diabetes. Transient hypertrophic cardiomyopathy is an example of the visceromegaly seen in IDMs. Most infants are asymptomatic, and the septal wall hypertrophy spontaneously resolves over several months. Congenital malformations associated with maternal diabetes are listed in Table 129-4.

DIFFERENTIAL DIAGNOSIS

Maternal diabetes is the most common cause of large-for-gestational-age (LGA) infants; however, post-term pregnancies (>42 weeks gestational age), excessive maternal weight gain, multigravidity, and familial genetic factors (large parental size) can contribute to the incidence of LGA newborns.

DIAGNOSTIC EVALUATION

IDMs are considered high-risk deliveries and are more likely to require resuscitation following delivery. Cardiorespiratory status should be assessed, and major anomalies should be identified. If stable, infants should receive routine neonatal care, and remain with their mother for skin-to-skin contact and early initiation of breastfeeding. IDMs should be screened for hypoglycemia.

MANAGEMENT

See Figure 129-1 for the assessment and treatment of hypoglycemia in IDMs.

ADMISSION AND DISCHARGE CRITERIA

Admission or transfer to a neonatal intensive care unit is appropriate in the following circumstances:

• Persistent hypoglycemia despite adequate oral or gavage feedings

• Inability to tolerate enteral glucose load

• Anomalies present

• Respiratory compromise

• Hyperbilirubinemia requiring intensive phototherapy

Discharge criteria include:

• Clinically asymptomatic infant with the ability to take breast milk or infant formula by mouth at age-appropriate intervals while maintaining stable glucose levels greater than 50 mg/dL

• Cardiorespiratory stability

• Resolution of significant hyperbilirubinemia

CONSULTATION

Consultation with a neonatologist should be considered in IDMs that have refractory or severe hypoglycemia or significant respiratory distress. Subspecialty evaluation by a cardiologist may be warranted for suspicion of cardiac anomalies or symptomatic hypertrophic cardiomyopathy. An evaluation by a geneticist may be indicated if there are multiple congenital anomalies.

SPECIAL CONSIDERATIONS

Prevention

Pre-pregnancy care and counseling may influence pregestational glycemic control, which may lower the teratogenic effects of maternal metabolic derangements. Prenatal screening and ultrasounds may detect malformations and influence delivery site and plan. Close surveillance of the pregnancy is warranted to ensure fetal well-being. Careful management of maternal glycemic control, with nutritional support and attention to appropriate weight targets may minimize the risk of neonatal hypoglycemia.

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REFERENCES

BACKGROUND

Kernicterus, or chronic bilirubin encephalopathy, is a permanent and devastating condition associated with significant mortality, morbidity, and intellectual disability. The risk for development of kernicterus in otherwise healthy newborns is increased with severe neonatal hyperbilirubinemia, or total serum bilirubin values >20 mg/dL.¹ A systematic approach to the detection and management of hyperbilirubinemia in newborns is therefore critical for prevention. While kernicterus in the United States is a rare condition, with an estimated incidence of 1.5 per 100,000 full-term newborns, the diagnosis of hyperbilirubinemia is far more common, affecting over 15% of full-term infants and nearly 60% of preterm infants in the first 30 days of life.² Hyperbilirubinemia is the most common neonatal condition requiring extension of the newborn hospital stay or readmission to the hospital after newborn discharge.³

PATHOPHYSIOLOGY

Bilirubin is a breakdown product of heme, which is contained primarily in hemoglobin but also in myoglobin and cytochromes. Microsomal heme oxygenase catabolizes heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase. The resulting unconjugated biliruibin is a non-polar, lipid-soluble molecule that is transported to the liver in plasma bound to albumin. In the endoplasmic reticulum of the hepatocytes, bilirubin uridine diphosphate glucuronosyl transferase (UDPGT) conjugates bilirubin with glucuronic acid. Conjugated bilirubin is a polar, water-soluble molecule that is excreted from the hepatocyte to the bile canaliculi, through the biliary tree, and into the duodenum. In the colon, bacterial β-glucuronidase converts conjugated bilirubin to urobilinogen. A small amount of urobilinogen is absorbed and returned to the liver (enterohepatic circulation) or excreted by the kidneys. The rest is converted to stercobilin and excreted in the feces.

Hyperbilirubinemia is classified as either conjugated or unconjugated (also known as direct or indirect, referring to the van den Bergh reaction used to measure bilirubin). Unconjugated hyperbilirubinemia is caused by increased production, decreased hepatic uptake or metabolism, or increased enterohepatic circulation of bilirubin. Newborn infants are particularly susceptible to unconjugated hyperbilirubinemia because, compared with adults; they have more red cells with a higher turnover and a shorter life span, and a limited ability to conjugate bilirubin. Newborn bilirubin levels typically peak on days 3 to 5 of life at about 5 to 6 mg/dL and then decrease over the next few weeks to adult levels. Exaggerated physiologic jaundice occurs at values above this threshold (7 to 17 mg/dL). Bilirubin levels higher than 17 mg/dL are not generally considered physiologic, and a cause of pathologic jaundice should be sought.⁴

Conjugated hyperbilirubinemia can occur with hepatocellular or cholestatic disease that causes a decreased secretion of bilirubin into the canaliculi or decreased drainage through the biliary tree.

Unconjugated bilirubin that exceeds the binding threshold of albumin (maximum of 8.2 mg bilirubin per gram of albumin) enters the brain and deposits primarily in neurons in the basal ganglia, hippocampus, cerebellum, and brainstem nuclei for oculomotor function and hearing. Bilirubin’s neurotoxicity is mediated through a variety of mechanisms, including impaired mitochondrial function, DNA and protein synthesis, and synaptic transmission. Factors that increase bilirubin neurotoxicity include the concentration of bilirubin and the duration of exposure to it, albumin levels, and conditions that increase blood-brain barrier permeability (e.g. infection, acidosis, hyperoxia, sepsis, prematurity, hyperosmolarity).⁵

CLINICAL PRESENTATION

Jaundice, the yellow discoloration of the skin and sclerae, may be present at birth or appear any time in the first month of life. It generally starts on the face and spreads down the body in a cephalocaudal progression. Unconjugated bilirubin in the skin appears bright yellow or orange, whereas conjugated bilirubin appears more greenish or muddy yellow; these may be difficult to detect in darker-skinned infants. The extent of cephalocaudal jaundice progression has a poor overall accuracy for predicting risk of significant hyperbilirubinemia, and therefore should not be used to estimate bilirubin level; however, complete absence of jaundice is helpful in predicting which infants will not develop significant hyperbilirubinemia.⁶ Infants who are jaundiced secondary to insufficient milk intake may also be dehydrated, appear lethargic, and have significant weight loss (>10% of birth weight), dry mucous membranes, poor capillary refill, sunken eyes and fontanelle, and poor skin turgor.

Signs of acute bilirubin encephalopathy usually appear 2 to 5 days after birth but may occur any time during the neonatal period. In the early phase, infants display lethargy, hypotonia, and poor ability to suck. In the intermediate phase, infants have stupor, irritability, and hypertonia (retrocollis-opisthotonos) alternating with drowsiness and hypotonia. They may also develop a fever and high-pitched cry. Infants who reach the late phase may have increased retrocollis-opisthotonos, cessation of feeding, bicycling movements, inconsolable irritability and crying, seizures, fever, and coma. Many of these infants die, and the survivors are likely to have severe kernicteric sequelae, even after intensive treatment. The rate of progression of clinical signs depends on the rate of bilirubin rise, duration of hyperbilirubinemia, host susceptibility, and presence of comorbidities.⁵

Infants who survive acute bilirubin encephalopathy may have kernicteric sequelae such as extrapyramidal movement disorders (dystonia and athetosis), gaze abnormalities (especially upward gaze), auditory disturbances (especially sensorineural hearing loss with central processing disorders or auditory neuropathy), and enamel dysplasia of the deciduous teeth. Cognitive deficits are unusual. Earlier reports of mental retardation in children with kernicterus probably reflected an inability to accurately assess intelligence in children with hearing, communication, and coordination problems.

DIFFERENTIAL DIAGNOSIS

The distinction between physiologic jaundice and pathologic jaundice relates to the timing, rate of rise, and extent of hyperbilirubinemia, as some of the same causes of physiologic jaundice (e.g. large red blood cell mass, decreased capacity for bilirubin conjugation, increased enterohepatic circulation) can also result in pathologic jaundice. Jaundice appearing in the first 24 hours of life and bilirubin levels that exceed 17 mg/dL or rise more than 5 mg/dL per day should be considered pathologic, and a specific cause should be sought. Direct bilirubin fractions greater than 10% of the total bilirubin should also be considered abnormal.

The differential diagnosis for pathologic jaundice is extensive (Table 130-1). Processes that lead to increased bilirubin production include isoimmune hemolysis (due to ABO, Rh, or other minor blood group incompatibility), extravascular hemolysis (cephalohematoma and skin bruising), polycythemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Genetic and metabolic disorders resulting in decreased uptake, storage, or metabolism of bilirubin include Crigler-Najjar syndrome (I or II), Gilbert syndrome, Lucey-Driscoll syndrome, hypothyroidism, and hypopituitarism. These rare disorders should be considered when bilirubin levels are greater than 10 mg/dL beyond the first week of life. Processes that result in increased enterohepatic circulation, such as breastfeeding and intestinal obstruction, may also cause pathologic jaundice. Breastfeeding is one of the strongest risk factors for significant hyperbilirubinemia. Infants who are breastfed have higher average peak bilirubin levels than do formula-fed infants. The hyperbilirubinemia observed with breastfeeding is likely multifactorial in origin. Decreased milk intake before maternal milk production is established results in dehydration, which hemoconcentrates bilirubin. Poor milk intake results in fewer bowel movements, which in turn increases the enterohepatic circulation of bilirubin.

Breastfeeding jaundice, which occurs in the first week of life, should be distinguished from breast milk jaundice, which refers to the jaundice that persists beyond the first week of life in approximately 2% of breastfed infants. With breast milk jaundice, bilirubin levels can rise as high as 10 to 30 mg/dL in the second to third week and then decrease, but jaundice may persist for up to 10 weeks. Discontinuation of breastfeeding and substitution of formula for 1 to 2 days results in a rapid and sustained decline in serum bilirubin, but this is generally not recommended unless bilirubin levels approach treatment thresholds. The cause of breast milk jaundice is not known with certainty, although β-glucuronidase (resulting in deconjugation of bilirubin and increased enterohepatic circulation) and other factors in breast milk that might interfere with bilirubin conjugation (e.g. pregnanediol and free fatty acids) have been implicated as potential causes.

Causes of conjugated hyperbilirubinemia include extrahepatic biliary atresia, intrahepatic cholestasis, metabolic disorders, urinary tract infections, and congenital viral infections.

DIAGNOSTIC EVALUATION

RISK ASSESSMENT AND SCREENING

The 2004 American Academy of Pediatrics (AAP) Clinical Practice Guideline recommended that all newborn infants ≥35 weeks gestation be assessed before discharge for the risk of developing severe hyperbilirubinemia using either clinical risk factors or bilirubin measurement or both.⁷ Clinical risk factors for severe hyperbilirubinemia include lower gestational age, exclusive breastfeeding, isoimmune or other hemolytic disease, East Asian ancestry, cephalohematoma or significant bruising, and previous sibling with significant jaundice;^2,7-9 evaluation of such risk factors may help guide timing of follow-up as well as need for additional clinical and laboratory evaluation.

However, more recent literature has suggested that combining evaluation of clinical risk factors with bilirubin measurement improves prediction of hyperbilirubinemia risk compared with either bilirubin measurement or clinical risk assessment alone.^8,9 Therefore, 2009 recommendations of an AAP-convened panel of experts are to perform universal screening with predischarge bilirubin measurement and to interpret risk for hyperbilirubinemia using the hour-specific bilirubin nomogram depicted in Figure 130-1 in combination with clinical risk factors.^8,10 In fact, a recent study demonstrated that combining hour-specific bilirubin measurement and only one clinical risk factor—gestational age—was equally predictive of hyperbilirubinemia risk compared with combining hour-specific bilirubin measurement and multiple clinical risk factors.⁹

In addition to universal predischarge screening, bilirubin measurement should be obtained for infants who are jaundiced in the first 24 hours after birth or for those who appear excessively jaundiced for their age in hours at any point during hospitalization. As above, these levels can be interpreted using the hour-specific bilirubin nomogram in Figure 130-1, which quantifies risk for severe hyperbilirubinemia on an age-adjusted percentile basis.¹⁰

TRANSCUTANEOUS VERSUS TOTAL SERUM BILIRUBIN MEASUREMENT

Total serum bilirubin (TSB) measured in a clinical laboratory is considered the gold standard for bilirubin measurement; however, interlaboratory variability in this measurement may result in inaccuracies. Clinicians should be aware of the method of testing used by their clinical laboratory, as the Vitros method in particular has been shown to result in higher bilirubin values compared with traditional methods.¹¹ The Vitros method will generally report total, conjugated and unconjugated bilirubin levels, while traditional methods measure and report total, direct, and indirect bilirubin levels.

Various devices are available for transcutaneous bilirubin (TcB) measurement, which should be measured over the sternum. Transcutaneous bilirubinometers operate by transmitting light that penetrates the blanched skin and transilluminates the subcutaneous tissues. The scattered light returns through a fiber optic filament, and the yellowness of the reflected light is measured in a spectrophotometric module and converted into an estimate of the TSB concentration. Values generally correlate within 2 to 3 mg/d of TSB values, although there is some evidence that transcutaneous instruments are less accurate at higher bilirubin levels (>15 mg/dL) or for infants with darker skin. In addition, there may be inconsistencies in performances across instruments, and quality control is essential to ensure proper function and accuracy. Advantages of TcB measurement include noninvasive testing, instantaneous information, and the possibility of performing multiple measurements over a single day.¹²

Either TSB or TcB measurement (interchangeably) is recommended for screening in the 2004 AAP hyperbilirubinemia guidelines. However, if bilirubin levels are documented as ≥15 mg/dL or rising rapidly, confirmation with TSB measurement is recommended. TSB values should also be measured once infants begin phototherapy, as TcB measurement may falsely underestimate total bilirubin in this setting.

ADDITIONAL LABORATORY STUDIES

As part of routine prenatal care, maternal blood type should be determined; if the mother has not had prenatal blood typing or is Rh-negative, the infant’s cord blood should be tested for blood type and Rh (D). Testing of infant cord blood for blood type and direct (Coombs) antibody when the maternal blood is group O, Rh-positive is an option but not routinely recommended, as long as appropriate surveillance and follow-up for hyperbilirubinemia are performed.

Infants whose TSB levels are rising rapidly (crossing percentiles) or who require phototherapy should have fractionated (conjugated and unconjugated) bilirubin levels checked, as well as blood type, Coombs test, complete blood count (CBC) and smear, reticulocyte count, and G6PD levels (if available), to evaluate for hemolysis and congenital red blood cell membrane defects. Infants with elevated direct bilirubin levels should have urinalysis and urine culture to rule out urinary tract infection. Infants who are jaundiced beyond 2 weeks of age should have total and direct bilirubin levels measured and should undergo evaluation for the cause of cholestasis if the direct bilirubin level is elevated. The results of the newborn screen can be used to evaluate for congenital hypothyroidism and galactosemia as causes of jaundice.

MANAGEMENT

PHOTOTHERAPY

Hour-specific bilirubin thresholds for initiating phototherapy and exchange transfusion have been recommended by the AAP (Figure 130-2 and Figure 130-3, respectively). Clinicians should use the TSB, not the indirect (or unconjugated) fraction, in applying these treatment guidelines. Treatment thresholds are dependent on the infant’s gestational age, appearance (well versus ill), and other clinical risk factors, all of which modify the infant’s susceptibility to bilirubin neurotoxicity.

Phototherapy achieves reduction of hyperbilirubinemia by two mechanisms: (1) reversible photoisomerization of the nonpolar native unconjugated 4Z, 15Z-bilirubin into the polar configurational isomer 4Z, 15E-bilirubin, which is excreted in the bile without need for conjugation; and (2) irreversible conversion of native unconjugated bilirubin into the structural isomer lumirubin, which is excreted by the kidneys. Phototherapy must contain light in the blue range (420 to 470 nm) and be of sufficient intensity to efficiently reduce hyperbilirubinemia. The AAP recommends that hospitals use intensive phototherapy light of at least 30 μW/cm²/nm measured by a radiometer at the infant’s skin directly below the center of the unit. Intensive phototherapy can be expected to decrease the initial bilirubin level by 30% to 40% in the first 24 hours, with the most significant drop in the first 4 to 6 hours. For infants who are discharged after birth and then readmitted, phototherapy should be continued until the TSB is less than 13 to 14 mg/dL. Though uncommon, rebound hyperbilirubinemia requiring another course of phototherapy can occur, particularly in infants with hemolytic disease or those in whom phototherapy was initiated early and discontinued before 3 to 4 days of life. Discharge from the hospital need not be delayed because of the potential for rebound bilirubin; however, these infants should have a follow-up bilirubin measurement within 24 hours after discontinuation of phototherapy.

EXCHANGE TRANSFUSION

Exchange transfusion is the last therapeutic resort if the TSB level does not decrease despite intensive phototherapy or if an infant presents with signs of acute bilirubin encephalopathy. When the TSB level exceeds the recommended threshold for exchange transfusion, intensive phototherapy should be administered, the TSB measurement should be repeated every 2 to 3 hours, preparations for exchange transfusion should be made, and exchange transfusion should be performed if the TSB remains above the recommended threshold after 6 hours of intensive phototherapy. The bilirubin-to-albumin ratio can also be used, together with TSB level, as an additional risk factor in determining the need for exchange transfusion (Table 130-2). For infants with isoimmune hemolytic disease whose TSB is rising despite intensive phototherapy or whose TSB is within 2 to 3 mg/dL of the exchange level, intravenous gamma globulin (0.5 to 1 g/kg over 2 hours) should be administered, because it has been shown to reduce the need for exchange transfusion in these infants.

FOLLOW-UP

Appropriate and timely follow-up should always be provided, as even for infants with a low predischarge TSB or TcB level the risk of subsequent hyperbilirubinemia is not zero.¹³ Infants discharged before 24 hours, between 24 and 47.9 hours, and between 48 and 72 hours should be seen by age 72 hours, 96 hours, and 120 hours, respectively. Earlier or more frequent follow-up may be needed for infants who have elevated hour-specific bilirubin values or clinical risk factors for hyperbilirubinemia. If an infant’s predischarge bilirubin level remains in, or is crossing percentile tracks into, the high-risk zone and appropriate follow-up cannot be assured, a clinician may opt to delay discharge until the bilirubin trajectory is elucidated and a decision can be made about the need for phototherapy or discharge home.

ADMISSION AND DISCHARGE CRITERIA

Jaundiced infants who require intensive phototherapy, exchange transfusion, or management of dehydration should be admitted to the hospital. Infants with profound dehydration or with bilirubin levels approaching or exceeding exchange transfusion thresholds should be admitted to a neonatal intensive care facility, if available. Infants with mild to moderate dehydration and bilirubin levels requiring phototherapy alone can be monitored and treated in a pediatric inpatient ward or newborn nursery setting.

Infants who are discharged and then readmitted should receive phototherapy until the TSB is less than 13 to 14 mg/dL. For infants treated during the initial birth hospitalization, the TSB thresholds for discontinuing phototherapy are less clear, but reducing the TSB level below the 40th percentile can be used as a treatment goal. Before discharge, infants must be well hydrated and feeding well, with frequent wet diapers and stools. For breastfed infants, particularly those whose jaundice can be attributed to lactation or breastfeeding problems, both the parents and the healthcare providers must be confident that the infant will have an adequate milk supply through either lactation interventions (e.g. pumping) or supplemental feedings.

SPECIAL CONSIDERATIONS

PREVENTION

A hospital-based approach to primary prevention of severe hyperbilirubinemia includes the establishment of standing protocols for nurses’ assessment of jaundice, including measurement of TcB and TSB levels, without requiring a physician’s order (similar to the protocols in place for measuring serum glucose levels). Checklists or reminders should prompt providers to consider risk factors and age at discharge, as well as laboratory test results that guide appropriate follow-up. Educational materials concerning the identification of jaundice should be provided to parents.

REFERENCES

BACKGROUND

Approximately 4.4% of women of childbearing years use illicit drugs or abuse prescription medications, including marijuana, cocaine, hallucinogens, heroin, sedatives, painkillers, and stimulants.¹ Infants born to mothers who habitually use opioids (heroin, methadone, morphine, buprenorphine, meperidine, or codeine) can have physical manifestations of opiate withdrawal, termed neonatal abstinence syndrome (NAS). In recent years, the number of infants diagnosed with NAS nationally has increased significantly,² likely in part due to more liberal use of prescription opiates during pregnancy.³ Although NAS refers specifically to opiate withdrawal, similar symptoms can occur in infants with intrauterine exposure to other drugs.

PATHOPHYSIOLOGY

Placental passage to the fetus will vary depending on pharmacokinetic properties of each drug. Highly lipophilic drugs with a relatively low molecular weight are more likely to equilibrate rapidly between maternal and fetal circulation. They may then accumulate in the fetus due to renal and metabolic immaturity. Manifestations of withdrawal after delivery of the infant depend on various factors, including specific drug properties, dose and frequency of exposure, infant metabolism, and the interval between last exposure to the drug and delivery. Withdrawal is generally a function of the drug’s half-life; with a longer half-life being associated with later onset of withdrawal and potentially decreased likelihood of NAS.

Maternal polysubstance use can potentiate or delay neonatal withdrawal symptoms. Infants of mothers who use narcotics and also smoke cigarettes may have heightened symptoms of NAS. Opiate use combined with sedative use during pregnancy may mask infant withdrawal symptoms for up to 2 weeks. Another factor known to cause delayed or protracted infant withdrawal is prolonged maternal use of high-dose methadone; complete withdrawal for these infants may take up to 4 months.⁴

CLINICAL PRESENTATION

Nearly all infants with chronic intrauterine exposure to opioids have some symptoms of NAS, and 25% require pharmacologic intervention.⁴ Infants born to mothers who use opiates usually present with symptoms within the first 72 to 96 hours of life. Withdrawal symptoms can be classified into three areas: central nervous system (CNS), autonomic nervous system, and gastrointestinal (GI) symptoms (see Table 131-1). Skin excoriation on the buttocks (due to excessive stooling) and the elbows and knees (due to friction burns secondary to tremors) is also well described. Additionally, infants with intrauterine opiate exposure are at increased risk of reduced fetal growth parameters, prematurity, and low birth weight.

Mild NAS symptoms may persist until age 4 months, even after successful medical management.⁵ Sleep may continue to be disorganized, and hyperreflexia and hypertonia may continue, but tremor and jitteriness usually resolve earlier. GI disturbances such as loose stools, emesis, and colic also tend to resolve later in the withdrawal process. An increased incidence of sudden infant death syndrome has been reported in this population. In addition, there is a higher incidence of child abuse, possibly associated with maternal isolation, poor parenting preparation and skills, increased infant irritability, and the stresses of ongoing maternal drug use or recovery.⁵

Long-term effects of opioid withdrawal are not clearly defined. In many infants the withdrawal hypertonia changes to post-withdrawal hypotonia. Eye abnormalities such as esotropia, opsoclonus, and nystagmus have been described. There is some evidence that intrauterine opiate exposure leads to problems such as attention-deficit hyperactivity disorder, cognitive deficits, and poorly developed organizational and adaptive skills, although these behaviors may be related to home and social environment rather than drug exposure.⁶

DIFFERENTIAL DIAGNOSIS

Careful consideration needs to be given to the differential diagnosis of NAS. An infant should not be treated for narcotic withdrawal if exposure cannot be confirmed. The differential diagnosis of NAS in an infant less than 2 weeks of age can include electrolyte abnormalities (e.g. hypoglycemia, hypomagnesemia, hypercalcemia, hypocalcemia) or neonatal hyperthyroidism. Infantile colic, formula intolerance, or severe gastroesophageal reflux may present with symptoms similar to NAS. Infants exposed in utero to large amounts of caffeine, antidepressants,⁷ nicotine, or alcohol may also present with NAS-like symptoms.

DIAGNOSTIC EVALUATION

In the case of known intrauterine exposure to opiates or other illicit drugs, urine and meconium or umbilical cord toxicology screens are indicated. This testing may detect polysubstance use that might not have been revealed in the maternal history. If an infant presents with symptoms consistent with NAS and there is no reported history of maternal drug use, maternal drug use is still a possibility. If the mother abstained from drug use just before delivery, both she and her infant may have negative urine toxicology screens in the peripartum period. In the presence of a negative urine screen, a meconium or cord screen may be helpful in defining in utero exposure to narcotics and risk for NAS. If maternal drug abuse is verified, it is important to test the mother for sexually transmitted diseases, such as human immunodeficiency virus, hepatitis B, hepatitis C, syphilis, gonorrhea, and chlamydia, because of their higher risk for infection.

For infants with symptoms concerning for NAS but who have a negative maternal history and negative toxicology studies, maternal history should be explored for the presence of intrauterine growth retardation during pregnancy, nicotine use, caffeine in large quantities, antidepressant medications, or alcohol abuse. These infants should also be screened for electrolyte abnormalities and hyperthyroidism.

MANAGEMENT

NAS SCORING