Diagnosis

Seizure manifestations in newborns differ from those in older children in that newborns generally do not have well-organized, tonic-clonic seizures due to the immaturity of synaptic connections (Volpe, 2008). Table 80.1 summarizes the common types of neonatal seizures. The basis for classification should be a combination of clinical and electroencephalographic (EEG) abnormalities (Clancy, 2006). These seizure types are not specific for cause, but some are seen more often with certain underlying conditions. Tonic seizures, which may represent nonepileptic decerebrate posturing, occur in up to 50% of premature newborns with severe intraventricular hemorrhage (IVH). Focal clonic seizures in the term newborn are most commonly associated with focal cerebral infarction or traumatic injury, such as cerebral contusion.

Table 80.1 Types of Neonatal Seizures

Differentiation of Seizures from Nonconvulsive Movements

Simultaneous monitoring with EEG and video display in newborns with movements suggestive of “subtle seizures” have not shown consistent electrographic discharges concomitant with the movement. This suggests that the abnormal movements may represent nonictal brainstem release phenomena rather than seizures. Similarly, epileptiform discharges rarely accompany tonic extensor posturing in newborns with severe IVH, and the posturing responds poorly to anticonvulsant therapy. Myoclonic seizures, which may evolve into infantile spasms, often have a dismal outcome and must be distinguished from benign neonatal sleep myoclonus, which occurs in healthy newborns.

Jitteriness, an exaggerated startle response, is often confused with clonic seizures, especially because both jitteriness and clonic seizures occur in conditions such as hypoxic-ischemic or metabolic encephalopathies and in drug withdrawal. The absence of associated ocular movements and autonomic changes (e.g., tachycardia, increase in blood pressure, apnea) and the presence of stimulus sensitivity distinguish jitteriness and seizures. The predominant movement is tremor that stops when passively flexing the affected limb.

Determination of the Underlying Cause

Diagnosis of the underlying cause allows specific treatment and a more precise prediction of outcome (Glass and Wu, 2009; Tekgul et al., 2006). Table 80.2 summarizes the major causes of neonatal seizures, their usual times of onset, and prognosis. Sometimes, several factors cause seizures (e.g., the combination of intracranial hemorrhage, metabolic derangement, and hypoxic-ischemic injury). Benign genetic epilepsies rarely have their onset in the neonatal period; the only example is benign familial neonatal epilepsy, an autosomal dominant trait for which two gene loci, KCNQ2 and KCNQ3, have been identified, which encode for voltage-gated potassium channels (Bellini et al., 2010).

Electroencephalography

EEG, particularly continuous EEG monitoring when available, is a valuable aid in the diagnosis of neonatal seizures, especially in newborns paralyzed to assist ventilation and in those with suspected subtle seizures. Amplitude-integrated EEG is a more recent technique that may assist in detecting subtle and subclinical electrographic seizures (van Rooij et al., 2010). Concern exists that use of amplitude-integrated EEG criteria alone may lead to an overdiagnosis of neonatal seizures, so confirmation by standard EEG is advisable prior to treatment with anticonvulsants (Koh et al., 2010). EEG correlates of neonatal seizures are focal or multifocal spikes or sharp waves and focal monorhythmic discharges. Sharp transients are normal in premature newborns and should not be confused with seizure activity. Similarly, the trace alternant pattern of quiet sleep in normal term infants, in which normal low-amplitude reactivity is preserved between bursts, must be distinguished from the abnormal burst-suppression pattern, in which long periods of voltage suppression or absence of activity are recorded between bursts of high-voltage spikes and slow waves (Lamblin et al., 2010).

Interictal EEG may have prognostic value. Severe suppression of the background activity, whether or not interrupted by high-amplitude bursts, is associated with an abnormal outcome in more than 90% of patients. In contrast, normal background activity is associated with good outcome.

Management

Neonatal seizures require urgent treatment. Once adequate ventilation and perfusion are established, the blood glucose concentration is measured. If the glucose concentration is low, 10% dextrose should be administered in a dose of 2 mL/kg. In the absence of hypoglycemia, immediate treatment should be started with anticonvulsant medication, as outlined in Table 80.3. Studies for other underlying causes should proceed concurrently and specific treatment initiated whenever possible.

Table 80.3 Treatment of Neonatal Seizures

IM, Intramuscularly; IV, intravenously; PO, orally.

* Fosphenytoin is an alternate form of phenytoin that may be used.

Phenobarbital alone controls seizures in most newborns after administering adequate dosages (up to a maximum of 40 mg/kg loading dose). Give phenytoin, 20 mg/kg, if seizures continue. Evaluation of fosphenytoin in the newborn, which is converted to phenytoin, is presently unknown, but initial data suggest that the rate of conversion is identical to that shown for older infants. Unfortunately, seizures are often incompletely controlled by phenobarbital and phenytoin (Jensen, 2009). When these drugs fail, other anticonvulsants (benzodiazepines: midazolam, lorazepam, levetiracetam, and topiramate) may be effective. These are not recommended as first-line drugs (Bassan et al., 2008; Jensen, 2009; Rennie and Boylan, 2007).

Phenobarbital may suppress seizures caused by hypocalcemia, and a favorable response does not exclude that diagnosis. Approximately 50% of newborns with hypocalcemia also have hypomagnesemia, which requires specific treatment.

Pyridoxine deficiency, a rare cause of neonatal seizures, should be considered whenever no other cause is determined. Most infants have an unusual paroxysmal pattern on EEG, with generalized bursts of synchronous high-voltage activity of 1- to 4-Hz intermixed spikes and sharp waves. The diagnosis of pyridoxine deficiency is not excludable based on lack of response to a single large dose of intravenous (IV) pyridoxine with concurrent EEG recording; rather, large doses (50-100 mg daily) should be given orally for several days (Mills et al., 2010).

Specific metabolic disorders require specific therapeutic considerations with rapid intervention to maximize the chance of a good outcome (Pearl, 2009). Glut-1 deficiency syndrome is another rare cause of seizures and major developmental delay associated with hypoglycorrhachia, which may have implications for treatment in that the ketogenic diet may be most effective for control of seizures (Moers et al., 2002).

Duration of Treatment and Outcome

The optimal duration of maintenance therapy for neonatal seizures is unknown. The duration of maintenance treatment for neonatal seizures depends on the risk for recurrence, underlying cause (see Table 80.3), results of the neurological examination, and EEG findings (Glass and Wirrell, 2009). Phenytoin should be discontinued when stopping IV therapy because adequate serum levels are difficult to maintain with oral phenytoin in the newborn. If seizures have stopped and the neurological examination and EEG are normal, phenobarbital should be discontinued before discharge from the hospital. If continuing phenobarbital after discharge, discontinuation should be considered as early as 1 month later based on the neurological status and EEG. Discontinuing zphenobarbital should be considered in an infant whose examination is not normal if EEG does not show epileptiform activity. The potential deleterious effects of phenobarbital on brain development are a concern. Infants should be treated with phenobarbital for the briefest possible time.

Diagnosis

Because asphyxia is mainly an intrauterine event, careful documentation of maternal risk factors and abnormalities of labor and delivery are important. An accurate history also may provide precise information about the type of insult as well as its severity, duration, and timing, which in turn determines in large part the specific pattern of brain injury. Acute, total, or near-total asphyxia may cause disproportionate injury to thalami, basal ganglia, and brainstem nuclei, whereas prolonged partial asphyxia causes injury principally to the cerebral cortex and subcortical white matter (Miller et al., 2005; Roland et al., 1998).

The initial clinical features of severe hypoxic-ischemic encephalopathy include depressed level of consciousness, periodic breathing (due to bilateral hemisphere dysfunction), hypotonia, and seizures. When the hypoxic-ischemic insult is of the acute/near-total type, brainstem dysfunction may be a prominent feature. Between 24 and 72 hours of age, the level of consciousness, seizures, apnea, and other brainstem abnormalities become more prominent, which also correspond to the timing of maximum intracranial pressure. After 72 hours, infants who survive show continued (although diminishing) stupor, abnormal tone, and brainstem dysfunction, with disturbances of sucking and swallowing. Specific patterns of weakness related to the distribution of neuronal injury may become evident (Table 80.4). Table 80.5 summarizes the temporal profile of clinical features of severe hypoxic-ischemic encephalopathy in the term newborn.

Table 80.4 Neuropathological Patterns of Neonatal Hypoxic-Ischemic Brain Injury and Clinical Correlation

The classification of hypoxic-ischemic encephalopathy into mild, moderate, and severe is useful for prediction of outcome. Characteristics of mild encephalopathy are increased irritability, exaggerated Moro and tendon reflexes, and sympathetic overreactivity. Recovery is usually complete within 2 days, and long-term sequelae do not occur. Moderate encephalopathy with lethargy, hypotonia, diminished reflexes, and possibly seizures is associated with a 20% to 40% risk for abnormal outcome. Infants with severe encephalopathy with coma, flaccid muscle tone, brainstem and autonomic dysfunction, seizures, and possible increased intracranial pressure either die or survive with severe neurological abnormalities.

Other clinical features that provide corroborative evidence for significant hypoxic-ischemic brain injury include prolonged low Apgar scores, metabolic acidosis, and involvement of other organs.

Electroencephalography and Cortical Evoked Responses

Hypoxic-ischemic encephalopathy is the single most important cause of seizures in term and premature newborns. Seizures associated with moderate or severe encephalopathy most commonly begin during the first 24 hours after the original insult and may be notoriously difficult to control. The pattern of background activity on EEG may have prognostic implications. Thus, infants with normal EEG findings 1 week after the initial insult usually have a favorable outcome.

The usefulness of the visual, auditory, and somatosensory evoked responses in the diagnosis and prognosis of hypoxic-ischemic encephalopathy is more limited (see Chapter 32A), although there may be a role for visual evoked responses in the diagnosis of periventricular leukomalacia (PVL) and for auditory evoked responses in the diagnosis of brainstem injury.

Metabolic Biomarkers

Hypoglycemia, hypocalcemia, hyponatremia (inappropriate antidiuretic hormone secretion), and lactic acidosis may contribute to the neurological syndrome of hypoxic-ischemic encephalopathy. Uncorrected metabolic derangements may worsen the cerebral injury (Hanrahan et al., 1998).

Neuroimaging

Neuroimaging has major value for locating and quantifying cerebral injury. MRI in the term newborn and US and MRI in the premature newborn are especially valuable. Although MRI has superseded CT in many instances, CT still has a role in the assessment of acute hypoxic-ischemic brain injury, especially in term newborns unable to tolerate the prolonged scanning time required with MRI (Chau et al., 2009). CT performed between 3 and 5 days of age may show decreased attenuation. More precise anatomical delineation of mild brain injury or selective involvement of thalamus and basal ganglia or cerebellum may be assessed more accurately by MRI (Rutherford et al., 2010) (Fig. 80.1). More advanced MRI techniques may prove especially useful (e.g., diffusion tensor imaging, functional MRI, diffusion tractography) (Counsell et al., 2010; Miller and Ferreiro, 2009).

Fig. 80.1 A composite of computed tomography (CT) and magnetic resonance imaging (MRI) images from a normal term infant and an infant who sustained an episode of acute/near-total asphyxia. Note the density of the thalami in column 3 (acute/near-total insult) is decreased compared to the cerebral cortex and more closely resembles the attenuation of the white matter. Compare this with the normal thalami in column 1. There is marked restricted diffusion on the ADC maps in column 4, showing involvement of the lentiform nuclei and central lateral nuclei of the thalami, as well as the motor strip superiorly.

Several techniques may also provide additional insight into the functional disturbances of newborn hypoxic-ischemic cerebral injury. For example, positron emission tomography, single-photon emission computed tomography, and near-infrared spectroscopy show disturbances of cerebral perfusion, and magnetic resonance spectroscopy shows decreased brain levels of high-energy phosphates in asphyxiated infants (Barkovich et al., 2006).

Management

Optimal management begins in utero by measures to prevent hypoxic-ischemic injury. Fetuses at risk must be identified early, monitored serially (as discussed earlier), and considered for cesarean delivery when signs of fetal distress persist. An asphyxiated newborn requires immediate intervention and resuscitation to prevent additional hypoxic-ischemic cerebral injury. This includes correction of impaired ventilation, perfusion, and blood glucose concentrations; control of seizures; and maintenance of perfusion and function of other affected organs including the heart, liver, kidneys, and gastrointestinal tract.

Maintenance of Adequate Ventilation

Maintenance of adequate ventilation and minimizing additional postnatal hypoxemia and hypercapnia are critical to outcome. The availability of continuous transcutaneous oxygen and carbon dioxide monitoring facilitates the recognition of hypoxemia and hypercapnia. Deleterious effects of hypercapnia include worsening intracellular acidosis and impaired cerebrovascular autoregulation, with development of a pressure-passive cerebral circulation. Experimental and human data do not support the use of hyperventilation in asphyxiated newborns, except perhaps in those with persistent fetal circulation.

Maintenance of Adequate Perfusion

The maintenance of adequate perfusion is critical to prevent further cerebral ischemia. The basis for management of perfusion is knowledge of normal systemic arterial blood pressure levels in the newborn at all gestational ages. Systemic hypotension should be avoided because cerebral blood flow is not autoregulated in asphyxiated newborns and reflects systemic blood pressure in a pressure-passive manner. Transitory myocardial ischemia, a common cause of hypotension in asphyxiated newborns, may respond to inotropic agents such as dopamine. Other important causes of systemic hypotension that may result in decreased cerebral perfusion are patent ductus arteriosus and recurrent apneic spells with bradycardia. Because of the pressure-passive relationship between the systemic and cerebral circulations in some premature and asphyxiated term newborns, systemic hypertension should be avoided, especially in the premature infant, in whom the presence of vulnerable germinal matrix capillaries predisposes to the development of IVH.

Hyperviscosity due to polycythemia (venous hematocrit > 65%) may further impair cerebral perfusion in asphyxiated newborns, especially in those who are small for gestational age. Jitteriness, apnea, poor feeding, and seizures are concomitant neurological features in approximately 40% of these newborns. All symptomatic newborns with polycythemia require partial exchange transfusion with plasma. Those who are asymptomatic may require the same treatment.

Prevention of Metabolic Derangements

Fluid overload is an important consideration in the maintenance of metabolic homeostasis. Inappropriate antidiuretic hormone secretion is common during the first 3 days after a severe hypoxic-ischemic episode and may lead to hypoosmolality and hyponatremia, which in turn increase brain water content (cerebral edema) and seizures. The role of glucose supplementation in the management of the asphyxiated newborn is unclear. We recommend maintaining blood glucose concentrations in the normal range.

Control of Brain Swelling

Experimental data from animals and human newborns suggest that brain swelling with increased intracranial pressure is a consequence of tissue necrosis rather than a cause of brain damage in severe hypoxic-ischemic encephalopathy, and it is not associated with transtentorial or transmagnal herniation.

Hypothermia

Therapeutic active or passive cerebral hypothermia of 33°C to 35°C initiated early during the “latent phase” of hypoxic-ischemic brain injury (within 8 hours after insult) shows great promise for providing lasting neuroprotection as well as prolonging the latent phases of injury and delaying the onset of secondary energy failure, thereby hopefully lengthening the window of time when additional beneficial interventions may be initiated (Roland, 2008). Despite unanswered questions about the efficacy and safety of specific cooling protocols, therapeutic cooling, which decreased mortality and improved neurodevelopmental outcome in survivors (Jacobs et al., 2007), is emerging as one of the most promising options for neuroprotection in asphyxiated term newborns with moderate to severe hypoxic-ischemic encephalopathy.

Prognosis

Severe hypoxic-ischemic encephalopathy is associated with significant injury. Following a prolonged partial insult, there is often widespread injury involving the cortex and subcortical white matter, and subsequent clinical features are microcephaly, mental retardation, seizures, and spastic quadriparesis (see Chapter 61). When injury is less severe, it affects primarily the parasagittal watershed regions, which may cause shoulder weakness. Acute near-total hypoxic-ischemic insult of brief duration results in injury to the brainstem, thalami, and basal ganglia, often associated with brainstem dysfunction and feeding difficulties and later onset of choreoathetosis (dystonic or mixed cerebral palsy). Unilateral focal lesions result principally in hemiplegia with cognitive difficulties and possibly epilepsy

Selected aspects of the neurological syndrome and neurodiagnostic studies are helpful in determining outcome in hypoxic-ischemic encephalopathy (Box 80.1). Because most instances of hypoxic-ischemic encephalopathy begin before birth, assessment of fetal well-being in utero is useful. Apgar scores at 1 and 5 minutes are notoriously unreliable because of interobserver variability, the effects of drugs given to the mother before delivery, and the stress of delivery, which may be reversible. In contrast, low extended Apgar scores after 10 minutes may suggest that a major prior insult has occurred.

The severity and duration of hypoxic-ischemic encephalopathy is the single most useful prognostic factor. However, if newborns have received sedation or other indications, these may alter the clinical assessment, and more reliance must be placed on adjunctive investigations. Our experience indicates that newborns who may have sustained intrapartum asphyxia but do not develop neonatal encephalopathy will not have major long-term neurological morbidity. The features of encephalopathy that are most predictive are its severity and duration and the occurrence of seizures. Abnormalities on neuroimaging, especially MRI, depending on the location and extent of the lesions, also predict poor outcome.

Diagnosis

The high incidence of PIVH in premature infants has led to the routine use of US scanning at 3 to 4 days in all newborns of less than 32 weeks’ gestation. CT and MRI are also informative, but US is generally considered to be the technique of choice because it can be performed noninvasively in the intensive care nursery, and no ionizing radiation is involved. CT and MRI remain the techniques of choice for demonstration of epidural, subdural, and subarachnoid hemorrhage, as well as most intracerebral and posterior fossa hemorrhages (Dyet et al., 2006).

PIVH is predictable based on clinical features in only 50% of patients in whom the hemorrhages have extended from the germinal matrix into the ventricular system. The spectrum of clinical features associated with PIVH ranges from an asymptomatic state, through stepwise neurological deterioration over several days, to rapid catastrophic deterioration characterized by coma, apnea, generalized tonic seizures, brainstem disturbances, and flaccid quadriparesis. Severe hemorrhage may be associated with systemic abnormalities, which include metabolic acidosis, hypotension, bradycardia, and abnormal glucose and water homeostasis. Bloody or xanthochromic cerebrospinal fluid (CSF) from lumbar puncture also suggests PIVH.

CT has limited value in assessing acute hypoxic-ischemic cerebral injury in premature newborns because the immature brain has high water content, and low tissue attenuation is a normal feature. Routine US scans reveal PVL in premature newborns by increased echogenicity in the periventricular regions during the first days of life and subsequent cyst formation in the same areas after the first several weeks (Fig. 80.2). Although PIVH may be diagnosed with CT, cranial ultrasonography is the technique of choice for diagnosis of intraventricular hemorrhage and PIVH (Fig. 80.3). The ability of US to distinguish between hemorrhagic and ischemic injury (see Fig. 80.3), and to reliably identify mild or diffuse injury in the white matter is limited. MRI performed at term shows increased signal in cerebral white matter on T2-weighted images. Diffusion-weighted MRI may demonstrate diffuse white matter injury even earlier than conventional MRI (Inder et al., 1999). After the neonatal period, PVL is demonstrable by CT or MRI.

Fig. 80.2 Cystic periventricular leukomalacia. Coronal ultrasound scan performed 5 weeks after intraventricular hemorrhage and hypoxic-ischemic insult.

Fig. 80.3 Three coronal ultrasound images through the anterior fontanelle in premature infants. A, Left-sided grade I germinal matrix hemorrhage indenting the inferior margin of the frontal horn of the lateral ventricle. B, Bilateral intraventricular hemorrhage in the frontal horns of both lateral ventricles. C, Left-sided hemorrhage filling the frontal horn of the left lateral ventricle and hemorrhage in the brain parenchyma of the angles of the left lateral ventricle, representing periventricular hemorrhagic infarction.

Pathogenesis and Management

Table 80.6 summarizes the current concepts of pathogenesis and management of PIVH. Fluctuations of cerebral blood flow are a major factor in the pathogenesis of PIVH.

Table 80.6 Pathogenesis and Management of Periventricular-Intraventricular Hemorrhage

Neonatal Meningitis

Bacterial meningitis is more common in premature than in full-term infants and generally has a twofold pattern of illness: “early-onset” disease within the first days of life caused by group B Streptococcus, Escherichia coli, and Listeria monocytogenes acquired from an infected birth canal, and “late-onset” disease after several days, which may be acquired from the mother or other contacts in the environment and may be caused by the organisms listed above, as well as by Staphylococcus or Pseudomonas aeruginosa. Maternal genital infection with group B Streptococcus (which is usually asymptomatic) and maternal urinary tract infection during the weeks before delivery are considered to be particularly high-risk situations. Because as many as 20% to 30% of cases of neonatal sepsis are complicated by meningitis, and because early diagnosis and treatment are critical to prevent morbidity and mortality, lumbar puncture must be performed as soon as a newborn appears sick; one cannot wait for the typical clinical features of meningitis such as a bulging fontanelle, neck retraction, seizures, irritability, pallor, and poor feeding. The characteristic CSF profile is pleocytosis, increased protein concentration, decreased glucose concentration, and identification of the organism by Gram stain and culture. Laboratory techniques that allow rapid detection of bacterial antigens also may be useful (e.g., immunoelectrophoresis, latex agglutination, radioimmunoassays). Valuable supporting data regarding the probable bacterial etiology may be derived from isolation of an organism from body fluids other than CSF.

Management

In an attempt to prevent neonatal meningitis, the American College of Obstetrics and Gynecology and the American Academy of Pediatrics recommend IV administration of ampicillin during labor for mothers with rectal or genital cultures positive for group B Streptococcus or other major risk factors for neonatal sepsis (Schrag et al., 2000). The initial empirical treatment of a neonate with bacterial meningitis of unknown cause is a combination of ampicillin, an aminoglycoside such as gentamicin, and possibly cefotaxime administered IV. The precise dosage varies according to the body weight and postnatal age of the affected infant. The optimal selection of antibiotics is determined when definitive bacteriological diagnosis is known and by the resistances of the infecting organism. Repeated sampling of CSF is required to ensure response to treatment. Parenteral antibiotic treatment is usually maintained for 21 days or at least 2 weeks after sterilization of CSF. A repeat CSF examination should be performed 48 hours after discontinuation of antibiotic therapy.

In addition to antimicrobial therapy, supportive measures such as maintenance of fluid and electrolyte balance and control of blood pressure and blood gases are essential. Because the syndrome of inappropriate antidiuretic hormone secretion is common, fluids should be restricted to 30 to 40 mL/kg/day during the first few days of illness. Seizures are a common complication and should be treated with phenobarbital, phenytoin, or both (see Table 80.2). Serial measurements of head circumference and cranial US scans may assist with early diagnosis of potential complications of ventriculitis, hydrocephalus, and subdural effusion.

Ventriculitis commonly causes hydrocephalus, either during the acute phase of the illness or subsequently (Fig. 80.5). Meningitic hydrocephalus may require treatment by external ventricular drainage, often with a reservoir for intermittent draining of CSF, instillation of antibiotics in selected infants if active infection is present, or both. Most newborns require a permanent ventriculoperitoneal shunt after the infection has been eradicated.

Fig. 80.5 Ultrasound scans of a newborn infant with bacterial meningitis and ventriculitis. Note intraventricular strands in both coronal (A) and parasagittal (B) images (arrows).

Cerebral abscess is a rare complication of neonatal meningitis. It occurs most often with Citrobacter infection but may also occur after other virulent gram-negative infections or rarely, gram-positive organisms. Abscess should be suspected when newborns with increased intracranial pressure respond poorly to treatment. Brain imaging confirms the diagnosis. The duration of antibiotic therapy is prolonged, and surgical exploration and drainage are usually considered to be the treatments of choice. The mortality rate is approximately 15%, and survivors often have major neurological impairment.

Viral and Parasitic Infections

Viral, protozoan (Toxoplasma gondii), and fungal infections occur in the newborn. The acronym TORCH is used as a reminder of the major nonbacterial neonatal infections: toxoplasmosis, others (such as syphilis), rubella, cytomegalovirus (CMV), and herpes simplex. All of the TORCH infections occur during pregnancy by transplacental inoculation, except for herpes simplex, which usually is contracted by passage of the fetus through an infected birth canal. Although most newborns with TORCH syndromes have clinical features of disease during the first month of life, symptoms can be delayed until later infancy and childhood.

Congenital Rubella

Although the incidence of congenital rubella infection has diminished markedly since widespread use of the rubella vaccination, it remains a significant problem in many parts of the world (Reef et al., 2002; Zerr et al., 2001). The congenital rubella syndrome occurs when the fetus is infected before 20 weeks’ gestation. Clinical features in the newborn include low birth weight, jaundice, hepatosplenomegaly, petechial rash, congenital heart disease, cataracts, sensorineural deafness, microcephaly, bone lesions, and thrombocytopenia (Fig. 80.6). Less severely affected infants appear normal at birth and later show features of neurological and ocular defects, deafness, and congenital heart disease. Infected infants are highly infectious, may shed virus for several years, and must be considered a hazard to nonimmune women. Diagnosis is confirmed by culture of virus (throat swab and urine) and demonstration of rubella-specific immunoglobulin M (IgM) in neonatal plasma. Neuroimaging may reveal periventricular calcifications, subependymal cysts, or PVL. The only effective management is prevention by universal immunization. Antiviral treatment is unavailable. Infants who survive may develop progressive sensorineural hearing loss, behavioral-emotional problems, growth failure, or diabetes mellitus later in childhood.

Fig. 80.6 A, Computed tomographic scan of term newborn with congenital rubella; note calcifications and low attenuation of white matter. B, Abnormal metaphyses (“celery stalk appearance”) in a term newborn with congenital rubella.

Intracranial Hemorrhage

Other types of intracranial hemorrhage such as primary subarachnoid, epidural, subdural, and intracerebellar hemorrhage are usually associated with traumatic delivery or a bleeding diathesis and occur less commonly than PIVH. Subdural hemorrhage occurs in both premature and term newborns and results from laceration of major veins and sinuses. It is often related to excessive molding of the head. MRI or CT are the investigational techniques of choice for diagnosis of subdural hemorrhage. Convexity subdural hematoma, especially if associated with midline shift, may require decompression by craniotomy or subdural tap. Subarachnoid hemorrhage can also be of venous origin but is usually self-limited, originating from small vessels in the leptomeningeal plexus or bridging veins within the subarachnoid space. Infants may be asymptomatic with minor subarachnoid hemorrhage or present with seizures. Diagnosis may be suspected on the basis of uniformly blood-stained or xanthochromic CSF and confirmed by MRI or CT scans. In the absence of severe trauma or major hypoxic-ischemic injury, normal outcome is seen in 90% of patients. Table 80.7 summarizes the clinical features, management, and outcome of these types of intracranial hemorrhage.

Extracranial Hemorrhage

The classification of extracranial hemorrhage is according to the tissue planes involved. Caput succedaneum is superficial bleeding between the skin and the epicranial aponeurosis. Subgaleal hemorrhage, which is often associated with delivery by vacuum extraction, is located between the aponeurosis and the periosteum of the skull, and cephalhematoma occurs in the deepest plane between the periosteum and cranial bones. The major clinical features and the usual outcome for extracranial hemorrhages are summarized in Table 80.8.

Skull Fractures

Skull fractures may be linear or depressed. Linear skull fractures, often associated with direct compressive traumas, usually are parietal in location. Bony continuity is lost without depression. Depressed skull fractures are called ping-pong fractures because the bone buckles inward without loss of continuity, like a depression in a ping-pong ball. Neurosurgical evaluation is required only in a minority of cases, and nonsurgical elevation by digital pressure, use of breast pump, and obstetrical vacuum extractor should be attempted first. Occipital diastasis is not an actual fracture but rather a traumatic separation of the squamous and lateral parts of the occipital bones that is usually associated with breech delivery.

Depressed skull fractures may be suspected clinically by palpation of the skull, but MRI or CT is needed to visualize the relation of the depressed bone to the cerebral surface. CT is also useful to show a linear fracture beneath a cephalhematoma. Occipital diastasis may be associated with posterior fossa subdural hemorrhage, cerebellar contusion, and brainstem compression without hemorrhage or contusion. The importance of recognizing fractures and diastases is that they alert the physician to the possibility of a more serious intracranial disorder.

In the absence of intracranial lesions, treatment is required only when a depressed fracture impinges on the brain. Spontaneous elevation of the bone may occur with skull molding. Nonsurgical methods for elevation are digital pressure or use of a breast pump or an obstetrical vacuum extractor. Surgical intervention usually is reserved for complicated fractures with extradural or subdural blood clot or bone fragments. A leptomeningeal cyst may develop at the site of a skull fracture. This unusual complication may be identified by transillumination of the region or radiographical evidence of a widening bony defect (“a growing fracture”).

Spinal Cord Injury

Spinal cord injury is uncommon. It is caused by excessive torsion or traction. Injuries associated with breech delivery (75%) involve principally the lower cervical and upper thoracic regions, whereas injuries after vertex delivery more commonly involve the upper cervical and midcervical cord. Injuries of the lower thoracic and lumbar spinal cord are even less common and are usually related to vascular occlusion due to umbilical artery catheterization or air embolus from peripheral IV injection.

The neurological features reflect the segmental level of the lesion. Newborns with high cervical lesions are often stillborn or die quickly from respiratory failure in the absence of rapid ventilatory support. Lower cervical, upper thoracic lesions cause urinary retention, hypotonia, weakness, and areflexia of all limbs, evolving subsequently to spastic paraplegia or quadriplegia. Cord injuries are distinguished from neuromuscular disorders and brain injuries by the demonstration of a distinct sensory level of response to pinprick, urinary retention, and a patulous anus. Autonomic dysfunction may cause wide fluctuations of body temperature.

Spinal cord injury of fetuses in the breech position can be minimized by cesarean delivery of all fetuses with a hyperextended head. Unfortunately, cesarean section does not entirely eliminate the risk because some fetuses sustain injuries in utero, perhaps caused by vertebral artery occlusion. Cord injury after vertex delivery may be a rare complication of forceps rotation. The diagnosis of spinal cord injury is made on the basis of the clinical features. Ultrasonography, radiography, and MRI of the spine are sometimes indicated to exclude surgically correctable lesions such as spinal dysraphism or extramedullary compression. Because the cord injury is a tear or intraparenchymal hemorrhage, surgical decompression and laminectomy generally are not helpful. Supportive management consists of adequate ventilation and prevention of urinary tract infection, decubitus ulcers, and contractures. High-dose corticosteroids have not been used in controlled trials in spinal cord injury in the newborn age group (Brand, 2006).

Facial Paralysis

Facial paralysis occurs more commonly in utero by compression of the facial nerve against the bony sacral promontory than by the pressure of forceps blades during delivery. The clinical features are a unilateral widened palpebral fissure and flattened nasolabial fold with the infant at rest and inability to close the eye completely or grimace when crying. Facial paralysis must be distinguished from asymmetrical crying facies resulting from congenital aplasia of the depressor angularis oris muscle. Congenital facial palsy may also be a feature of several genetic syndromes, and in these instances, chromosomal analysis with fluorescent in situ hybridization (FISH) should be considered (e.g., chromosome 22q11 deletion, molecular testing for CHD7 [CHARGE] mutation).

Facial palsy is managed by the use of artificial tears and taping the affected eye closed at night to prevent corneal injury. Most cases resolve within weeks or months. Many surgical procedures with varying indications may be considered for long-term management.

Brachial Plexus Injury

Brachial plexus injury occurs in 0.5 to 2.6 per 1000 live term births. The injury almost always occurs in large newborns with shoulder dystocia who are difficult to deliver (Fig. 80.7) (Gurewitsch et al., 2006). The upper roots of the brachial plexus are involved most commonly (Erb palsy). In other instances, lesions may involve the lower nerve roots down to the first thoracic root (Klumpke palsy). Approximately 5% of cases have been associated with diaphragmatic paralysis caused by injury of the third to fifth cervical roots. Such paralysis may result in tachypnea and hypoventilation, with consequent cyanosis and hypercapnia. Brachial plexus injury also may be associated with Horner syndrome, a fractured clavicle or humerus, subluxation of the shoulder or cervical spine, cervical cord injury, and facial palsy.

Fig. 80.7 Brachial plexus injury in a newborn. Upper extremity is held adducted, internally rotated, and pronated. Note “waiter’s tip” position of affected wrist and fingers.

The neurological features of brachial plexus injury may be deduced from an understanding of the function of the involved cervical roots. Thus, involvement of the upper cervical roots results in loss of shoulder abduction and external rotation as well as loss of elbow flexion and supination, with variable impairment of wrist and finger extension (see Fig. 80.7). Absence of the biceps reflex on the affected side and an impaired abduction phase of the Moro reflex are demonstrable. With involvement of the lower roots, paralysis extends to intrinsic hand muscles and includes an absent grasp reflex. Horner syndrome occurs in one-third of such patients. Deficits of motor function and reflexes are usually more striking than sensory deficits.

In the majority of infants, diagnosis is based primarily on careful neurological examination and confirmed, if necessary, by showing electromyographic evidence of denervation 2 to 3 weeks after the injury (Joyner et al., 2006). Clinical suspicion of diaphragmatic paralysis requires confirmation by either fluoroscopy or US scanning. This complication necessitates careful surveillance of respiratory status and perhaps ventilatory support or surgical plication of the affected diaphragm. Other traumatic or bony lesions should be excluded by radiography of the cervical spine, clavicles, and humerus (Piatt, 2005).

Teratogenic Effects and Intrauterine Growth Retardation

Congenital malformations and intrauterine growth retardation often are associated. In general, maternal alcohol abuse causes growth retardation and intellectual deficits, whereas anticonvulsant drugs cause congenital heart disease and cleft lip and palate. Exposure to valproate during the first weeks of gestation is associated with a 5% risk for neural tube defects. This risk may be diminished to some degree by preconceptional and periconceptional maternal folate supplementation. Because neural tube defects originate very early during pregnancy (5-6 weeks’ gestation), folate administered after confirmation of pregnancy is not helpful in this regard. Distinct syndromes of growth retardation, developmental delay, dysmorphism, and distal limb abnormalities are attributed to fetal exposure to phenytoin (Fig. 80.8), barbiturates, alcohol, trimethadione, and valproate (Kaneko et al., 1999; Report of Quality Standards Subcommittee, 1998). Additional studies are needed to fully delineate the teratogenic potential of newer anticonvulsants. Recent reports from animal studies of neuronal apoptosis following exposure to anticonvulsants in utero raises further concerns (Motamedi and Meador, 2006).

Fig. 80.8 Infant with fetal hydantoin syndrome. A, Typical facial appearance with broad, depressed nasal bridge and widely spaced eyes. B, Hypoplasia of nails and distal phalanges.

Microcephaly and mental retardation are the most disturbing teratogenic effects attributed to fetal exposure to toxins. Microcephaly occurs in approximately 40% of infants who are passively addicted to heroin.

Risk for Intracranial Hemorrhage

A hemorrhagic diathesis caused by reduced levels of vitamin K–dependent clotting factors (factors II, VII, IX, and X) may occur in newborns of mothers treated with phenytoin, barbiturates, and primidone, related to prolongation of either prothrombin or partial thromboplastin times. Severe bleeding may take place in the skin and internal organs. All newborns exposed to anticonvulsant drugs during pregnancy should be treated with IV vitamin K immediately after delivery, and those with abnormal clotting factors should be given fresh-frozen plasma. Newborns with hemorrhagic disease require exchange transfusion.

Passive Addiction and Withdrawal Syndrome

Passive addiction occurs in 60% to 90% of newborns of mothers using neuroactive drugs (i.e., drugs that affect the CNS during pregnancy). The clinical features of addiction and withdrawal are similar for most drugs, but the time of withdrawal differs according to the half-life of elimination for the specific drug. Withdrawal symptoms usually start on the first day with heroin, alcohol, short-acting barbiturates, diazepam, tricyclic antidepressants, hydroxyzine, propoxyphene, and pentazocine; at 2 to 3 days of age with methadone and cocaine; as late as 7 days of age with longer-acting barbiturates; and at up to 21 days of age with chlordiazepoxide.

The initial features of withdrawal reflect CNS overactivity: jitteriness, irritability, disturbed sleep/wake patterns, shrill cry, and frantic sucking. These may be accompanied by gastrointestinal disturbances such as poor feeding, vomiting, and diarrhea, and less commonly by sneezing, tachypnea, and excessive sweating. Fever and seizures are uncommon manifestations of the neonatal withdrawal syndrome (see the exceptions listed in Table 80.9) and suggest the possibility of sepsis or other serious neonatal disorders.

The withdrawal syndrome associated with long-acting barbiturates and hydroxyzine may persist for several weeks. Newborns withdrawing from heroin often appear to recover initially, but later experience a significant worsening of symptoms that may persist for as long as 6 months.

Effective management requires early diagnosis. Attention is focused on management of respiratory complications, infection, dehydration, and metabolic derangements. In addition, severe and persistent irritability, vomiting, and diarrhea may require treatment with tincture of opium, paregoric, phenobarbital, chlorpromazine, or diazepam.

Tincture of opium (0.4 mg/mL of morphine equivalent) may be given at a dose of 0.1 mL/kg and increased as needed every 3 to 4 hours by 0.05- to 0.10-mL increments. The usual dose is 0.2 to 0.5 mL every 3 to 4 hours. Other options are oral paregoric (0.8-2 mL/kg/day, given in 6 to 8 divided doses) and chlorpromazine (2-3 mg/kg/day, given in 4 divided doses), which effectively control both the CNS and gastrointestinal symptoms. Paregoric contains camphor, which is a stimulant and may have adverse effects in premature infants. Chlorpromazine may cause extrapyramidal disorders and a lowered seizure threshold. Treatment must be continued for several weeks and tapered gradually to avoid recurrence of symptoms.

Phenobarbital (loading dose of 20 mg/kg, followed by a maintenance dose of 5 mg/kg/day) or diazepam (0.5-1 mg intramuscularly every 8 hours) control only the CNS abnormalities but do not relieve the gastrointestinal symptoms. These drugs also cause sedation that may worsen feeding problems. Therefore, tincture of opium should be used first and phenobarbital added if CNS abnormalities are not controlled by the narcotic agent alone, which is a distinctly unusual situation.