Epidemiology, Risk Factors, and Presentation
The fetus and the newborn are extremely susceptible to infections. This susceptibility stems from maternal risk factors, obstetrical complications, the postnatal environment, and the immature host defenses of the newborn. Neonatal sepsis is defined as a systemic inflammatory response syndrome secondary to infection. The age of onset of sepsis reflects the likely mode of acquisition, microbiologic features, mortality rate, and presentation of the infection. Meningitis is usually a sequela of sepsis. The incidence of neonatal sepsis ranges from 1 to 8 cases per 1000 live births, whereas meningitis may occur in 1 of every 6 septic infants. Epidemiologically, neonatal sepsis is divided into the following categories: early-onset sepsis, late-onset sepsis, and very late-onset sepsis.
Early-onset sepsis (EOS) is a systemic, multiorgan disease that presents in the first week of life and usually on the first day of life. Infection is most often acquired before delivery. Obstetrical complications contribute to the development of infection and include rupture of membranes prematurely (before onset of labor) or a prolonged period (>18 hours) before delivery, chorioamnionitis, maternal fever, maternal urinary tract infection, and infant prematurity or low birth weight. These infants have a fulminant onset of respiratory symptoms, usually due to pneumonia; shock or poor perfusion; and temperature instability. Mortality may be as high as 30% to 50%. The microbiologic features of EOS reflect maternal genitourinary and gastrointestinal colonization. Before the adoption of intrapartum antibiotic prophylaxis (IAP) against group B Streptococcus (GBS), this pathogen caused the overwhelming majority of EOS. Today, GBS still causes most cases of EOS; however, enteric bacilli such as Escherichia coli have become more prevalent in term infants and are as likely as GBS to cause EOS in very low-birth-weight premature infants. Although GBS and enteric bacilli cause the preponderance of EOS, a third pathogen, Listeria monocytogenes, can cause EOS. Unlike GBS and the gram-negative pathogens, which usually are acquired through asymptomatic maternal colonization, L. monocytogenes generally causes a flulike or gastrointestinal illness in the mother. This organism is mostly acquired from animal products: unpasteurized milk, cheese, delicatessen meats, and hot dogs. The importance of this organism will become clear in the discussion of empiric antibiotic therapy.
Late-onset sepsis is defined as the infections that occur beyond the first week of life but before 30 days of life. Very late-onset sepsis occurs beyond 30 days of life. Although obstetrical complications may be identified, these are not typical. Late-onset disease is more likely to reflect infection with gram-positive organisms acquired in the nursery: coagulase-positive staphylococci, Staphylococcus aureus, and enterococci. Very late-onset disease includes infections caused by GBS, gram-negative bacilli, and Streptococcus pneumoniae.
The high incidence of gram-positive infection in the hospitalized infant reflects the combination of usually lower gestational age and low-birth-weight, and the consequent need for the insertion of central venous catheters for supportive care. Although many of these infants will manifest poor feeding, temperature instability, and lethargy, they are more likely to have localized disease: urinary tract infection, osteoarthritis, or soft tissue infection. Meningitis is common. Presentation may be slowly progressive or fulminant. Mortality is lower than with EOS but may still be 20% to 40%.
The widespread use of IAP in the United States has been shown to have decreased the incidence of EOS by 70%, to 0.44 cases per 1000 live births, an incidence equivalent to that of late-onset sepsis. Of importance is that the improved survival of very low-birth-weight infants has put them at increased risk of systemic nosocomial infection. In a multicenter trial of prophylactic intravenous immunoglobulin administration involving more than 2400 very low-birth-weight infants, 16% of the infants developed sepsis at a median age of 17 days. Compared with the infants who did not develop sepsis, these infants not only had increased morbidity, but their mortality rose from 9% to 21% (not always directly due to sepsis) and their average length of hospital stay increased from 58 to 98 days.
The most important risk factors for the development of neonatal sepsis are low birth weight and prematurity. Sepsis conversely is also the most common cause of death in infants under 1500 g. The incidence of sepsis is inversely proportional to the gestational age or birth weight of the infant. Other risk factors include immature immune function, exposure to invasive procedures, hypoxia, metabolic acidosis, hypothermia, and low socioeconomic status—all factors associated with low birth weight and prematurity. In a multicenter survey of GBS disease carried out by the Centers for Disease Control and Prevention (CDC), 13.5 cases per 1000 live births were diagnosed among black infants compared with 4.5 cases among 1000 white infants, and EOS was twice as common among black infants as among white infants. Although males have a higher incidence of sepsis, once respiratory distress syndrome is accounted for, they are not at a significantly higher risk of sepsis, contrary to the results of older studies. It is generally felt that sepsis is more common among the firstborn of twins. Infants with galactosemia are more likely to become infected with gram-negative organisms, in particular E. coli. The administration of iron for anemia appears to increase risk because iron may be a growth factor for a number of bacteria. Finally, the widespread use of broad-spectrum antibiotics may cause a shift in the nursery to a higher prevalence of resistant bacteria that are also more invasive.
Evaluation and Management of Neonatal Sepsis
Definitive diagnosis of bacterial infection is predicated on the recovery of a pathogen from a normally sterile body site such as blood, urine, or cerebrospinal fluid (CSF). Although many indirect indices of infection have been identified and studied, including total white blood cell count, absolute neutrophil count, C-reactive protein level, procalcitonin level, and levels of a variety of inflammatory cytokines, these tests are nonspecific and are not adequately sensitive to confirm or exclude systemic infection.
In any infant with suspected EOS cultures of blood should be drawn and, if the infant is in hemodynamically stable condition, spinal fluid should be obtained, and the infant should be started on intravenous antibiotics. The need for lumbar puncture in the first 24 to 72 hours of life has been a topic of some controversy. Data suggesting that lumbar puncture is unnecessary in these infants comes primarily from retrospective studies of asymptomatic infants. The poor correlation between the results of neonatal blood cultures and CSF cultures underscores the need for lumbar puncture. Several studies report that bacterial meningitis would be missed in approximately one third of neonates on the basis of blood culture results alone. Antibiotic regimens should cover GBS, gram-negative bacilli, and L. monocytogenes. The most commonly used regimens are ampicillin and cefotaxime or ampicillin and gentamicin. Both regimens are quite effective against GBS. Unfortunately, E. coli has increasingly become resistant to ampicillin. In many institutions, more than half of the E. coli isolates are resistant to ampicillin. A search of the Cochrane database for evidence suggesting that one regimen is superior to another does not yield a conclusion. Regardless of the regimen used, ampicillin should be included, because the cephalosporins have no activity against L. monocytogenes, and gentamicin monotherapy would be ineffective.
The data for empirical therapy in late- and very late-onset disease are not definitively in favor of any one regimen. Given the prevalence of staphylococcal species, many clinicians would include vancomycin in the empiric treatment of a hospitalized neonate with signs of sepsis beyond the seventh day of life. If the infant is being admitted from the community, the regimen should include coverage for GBS, E. coli, and S. pneumoniae. Commonly cited guidelines for the evaluation of febrile children without a focus of infection who are between 30 and 60 days of life include obtaining blood and urine samples for culture and performing a lumbar puncture before administration of antibiotics.
Group B Streptococcus Infection
Streptococcus agalactiae, or group B Streptococcus (GBS), is the most common cause of vertically transmitted neonatal sepsis, a significant cause of maternal bacteriuria and endometritis, and a major cause of serious bacterial infection in infants up to 3 months of age. Nine serotypes of GBS have been identified on the basis of differing polysaccharide capsules: Ia, Ib, II, and III through VIII. Traditionally, neonatal disease is considered early onset (EOGBS) if it occurs in the first 7 days of life and late onset if it occurs from 8 days through 3 months of life. Epidemiologically, the serotypes responsible for neonatal disease shifted significantly in the 1990s. Type Ia, type III, and type V cause 35% to 40%; 25% to 30%; and 15% of cases of EOGBS, repectively. Type III still causes the majority of late-onset disease and neonatal meningitis. Antibodies against specific serotypes of GBS are protective but not cross-reactive.
Although GBS can cross the placenta, the primary mode of transmission is after rupture of membranes and during passage through the birth canal. Approximately 20% to 40% of women are colonized in their genital tract, but the primary reservoir of GBS is the lower gastrointestinal tract. High genital inoculum at delivery increases the likelihood of transmission and the consequent rate of EOGBS. Half of infants born to colonized women will themselves be colonized with GBS. Before the use of IAP targeted against GBS, the incidence of EOGBS ranged from 1 to 3 cases per 1000 live births. By definition, EOGBS presents in the first 6 days of life, and close to 90% of cases present within 24 hours of life. The vast majority of these infants demonstrate systemic illness by 12 hours.
In 1986 Boyer and Gotoff published the first randomized controlled trial showing the effectiveness of IAP in reducing neonatal colonization and EOGBS. In 1996 the CDC published the first set of guidelines for the prevention of perinatal GBS disease. The guidelines endorsed two approaches to IAP: (1) women with vaginal or rectal cultures positive for GBS should receive IAP; or (2) women with any of the following risk factors—delivery before 37 weeks’ gestation, membrane rupture 18 hours or longer before delivery, or maternal fever of 38° C or higher—should receive IAP. In addition, any woman who had a history of GBS bacteriuria or who had previously delivered an infant with EOGBS was to receive IAP. In addition to the administration of IAP, the guidelines provided for the evaluation of the infant after delivery. These strategies reduced the incidence to 0.6 cases per 1000 live births in 1998. Ongoing active surveillance of GBS demonstrated that the screening-based approach was superior to the risk-based approach in preventing EOGBS. In 2002 the CDC published revised guidelines that promoted the universal screening of all pregnant women between 35 and 37 weeks’ gestation using rectovaginal cultures and recommended that all women with positive culture results receive IAP. The guidelines also recommended IAP for mothers who had any history of GBS bacteriuria during the pregnancy, who had suspected amnionitis, or who had previously delivered an infant with EOGBS. These guidelines also clarified the antibiotic dosages for IAP, alternatives for mothers with penicillin allergy, and the management of an exposed newborn ( Fig. 14-1 ).
As of 2003, the incidence of EOGBS was down to 0.3 cases per 1000 live births. Although effective, the screening-based approach incurs the costs of testing, IAP, and management of the exposed infant. Although, to date, no studies have shown an association between penicillin and ampicillin IAP and the emergence of antibiotic resistance in other bacteria, this risk remains a concern. An immunization-based strategy targeting pregnant women has the potential to prevent EOGBS, late-onset disease, and some maternal disease and to be more cost effective. A multivalent protein conjugate vaccine has proved effective in a murine model, and several human trials of individual serotype conjugate vaccines have shown promise.
For documented GBS infection, penicillin is the drug of choice and is the most narrow-spectrum agent. Ampicillin is an acceptable alternative agent. No penicillin resistance has been reported to date. The dosages and intervals depend on the postgestational age of the infant. The duration of therapy is 10 days for bacteremia without a focus, 14 days for uncomplicated meningitis, and up to 4 weeks for septic arthritis, endocarditis, or ventriculitis.
Coagulase-Negative Staphylococcus Infection
For several decades, coagulase-negative staphylococci have been the most common cause of nosocomial blood stream infections in the neonatal intensive care unit and are responsible for the majority of cases of late-onset sepsis in preterm neonates. Infections with these gram-positive bacteria are most often associated with indwelling central venous catheters. These bacteria are part of normal human skin flora. Staphylococcus epidermidis is the most common species of coagulase-negative staphylococci recovered from human skin and mucous membranes. Most infants are colonized within the first week of life from passage through the birth canal and repeated exposure from colonized caregivers.
The major virulence factor for coagulase-negative staphylococci is its ability to adhere to plastic and other foreign bodies by producing a biofilm. The biofilm consists of multiple layers of bacteria surrounded by an exopolysaccharide matrix or slime. This biofilm protects the bacteria from host phagocytic cells and interferes with the ability of many antimicrobial agents to effectively eliminate infection. This affinity for plastic foreign bodies explains the high recovery rate of these organisms from infected catheters, ventricular shunts, endotracheal tubes, and artificial vascular grafts and cardiac valves.
Neonatal infections with coagulase-negative staphylococci typically present without localizing signs with fever, new-onset respiratory distress, or a deterioration in respiratory status. Other common nonspecific signs of coagulase-negative staphylococcus sepsis include apnea, bradycardia, poikilothermia, poor perfusion, poor feeding, irritability, and lethargy. Indolent infection is more common than fulminant disease, with mortality generally under 15%. Coagulase-negative staphylococci infections, however, are a major source of morbidity leading to increased antibiotic exposure, length of stay, and hospital costs.
Treatment of coagulase-negative staphylococci often requires the use of vancomycin. More than 80% of strains acquired in the hospital are resistant to β-lactam antibiotics. Resistance is typically attributable to altered penicillin-binding proteins and β-lactamase production. Unfortunately, these types of resistance can be inducible and therefore may not be detected by routine microdilutional methods. If a strain is reported as penicillin sensitive, consultation with the hospital microbiologist is recommended to confirm testing for inducible resistance. More than 50% of coagulase-negative staphylococci are resistant to clindamycin, trimethoprim-sulfamethoxazole, gentamicin, and ciprofloxacin. Coagulase-negative staphylococci isolated from hospitalized patients show varying rates of resistance to the tetracyclines, chloramphenicol, rifampin, and newer-generation quinolone antibiotics. Some S. epidermidis isolates have been recovered that show resistance to vancomycin; however, these species have been susceptible to the newer agents for gram-positive organisms: linezolid, quinupristin-dalfopristin, and daptomycin. Pharmacokinetic data and clinical experience with these agents in neonates are limited, and these drugs should be used only in consultation with a physician with expertise in infectious diseases.
The most effective management of coagulase-negative staphylococci infections is the combination of systemic antimicrobial therapy and, whenever possible, the removal of the foreign body. When a foreign body cannot be feasibly removed, the combination of vancomycin with rifampin, and/or an aminoglycoside, may be used. In the case of ventricular shunt infections, antibiotics may be administered both systemically and intraventricularly. If an attempt is made to manage an infection without foreign body removal, consultation with an infectious disease expert would be advised to determine the best antimicrobial agents and duration of therapy.
Although many groups have proposed different strategies to prevent neonatal catheter infections, few studies have yielded promising results. Several groups have studied the use of prophylactic antibiotics in neonates with indwelling catheters. The Cochrane Neonatal Group found no evidence to support this practice for neonates with umbilical arterial or venous catheters, nor did they find evidence to support routine use of vancomycin in preterm infants to prevent nosocomial sepsis. The use of a vancomycin-heparin lock solution to prevent nosocomial blood stream infection showed promise in a small randomized, controlled, double-blinded study in critically ill neonates with peripherally inserted central venous catheters ; however, larger studies are needed. The use of antibiotic- or silver-impregnated catheters has not been studied in neonates. In 2002, the CDC recommended against the routine use of antimicrobial prophylaxis for patients with central venous catheters. In 2006, the Cochrane Neonatal Group began a systematic review of the use of systemic antibiotics to reduce morbidity and mortality in neonates with central venous catheters. Results are not yet available.
Staphylococcus Aureus Infection
Staphylococcus aureus is a gram-positive bacteria that is morphologically indistinguishable from the coagulase-negative staphylococci by light microscopy. S. aureus is part of normal skin flora. This organism causes a much wider and potentially more invasive spectrum of disease than that caused by coagulase-negative species. This pathogen is a common cause of superficial pustular disease and localized cellulitis, and is the most frequent cause of surgical site infection in infants and adult patients. The production of numerous toxins, enzymes, and binding proteins facilitates its ability to establish aggressive, life-threatening pyogenic infection. Small-inoculum colonization or infection can produce catastrophic, toxin-mediated disease such as scalded skin syndrome or toxic shock.
Over the last two decades, S. aureus has shown an increasing resistance to β-lactam antibiotics, as documented by methicillin susceptibility testing ; these methicillin-resistant strains (MRSA) are resistant to all penicillins, penicillin–β-lactamase inhibitor combination drugs, cephalosporins, and carbapenems. Most hospital-acquired strains are resistant to clindamycin. Until recently, these resistant strains were not inherently more virulent. Unfortunately, however, over the last several years community MRSA strains have acquired an additional virulence factor, Panton-Valentine leukocidin. This factor has contributed to a significant increase in invasive, pyogenic infection by MRSA. Several outbreaks in preterm and term neonates, as well as nosocomial transmission from caregivers, equipment, and toys in neonatal intensive care units, have been reported. In an ill, hospitalized neonate who develops suspected or documented infection with gram-positive cocci, vancomycin should be included in the empirical antibiotic regimen. As discussed earlier, blood stream infections caused by coagulase-negative species are much more prevalent than bacteremias from S. aureus; however, many clinicians would elect to start vancomycin for any gram-positive blood stream infection in a hospitalized neonate because of the high rate of resistance to β-lactam antibiotics in the coagulase-negative strains and the potential consequences of not treating MRSA. Other drugs are available with activity against MRSA, including older drugs like tetracyclines and trimethoprim-sulfamethoxazole, but these drugs are typically avoided in neonates. Several newer drugs—quinupristin-dalfopristin, linezolid, and daptomycin—have activity against MRSA. MRSA infections in neonates should be managed by an individual with expertise in the pharmacodynamics and pharmacokinetics of these drugs.
The survival of fragile, very low-birth-weight neonates has led to increased infections due to candidiasis in the nursery. Candida species are responsible for 2.4% of early-onset infections in newborns but, more importantly, they cause 10% to 12% of late-onset infections. Overall, infections with these fungi are among the three most common infections in the neonatal intensive care unit.
Although Candida albicans once caused 75% of invasive candidal infections, infections involving non-albicans species are now becoming more common, approaching 40% to 45% of infections. The incidence of Candida parapsilosis infection, unique to the newborn, has risen more than tenfold, and this species now causes 25% of fungal infections in the newborn. Also of note, the incidence of Candida tropicalis and Candida glabrata infection has nearly doubled during the same time period. The reported mortality attributable to C. albicans infection varies widely but may be as high as 20% to 40%. The mortality from C. parapsilosis is certainly significant but tends to be lower than that attributable to C. albicans.
Vertical transmission from mother to infant usually occurs during passage through the birth canal, especially in the presence of vaginitis. This is most often seen with C. albicans and C. glabrata. Congenital infections may rarely be seen and have been attributed both to ascending infection from the vagina and transplacental infection. C. parapsilosis, however, is frequently transmitted horizontally and is the most common fungal organism isolated from the hands of health care workers. This fungus is not commonly found in the genitourinary tracts of mothers. Colonization appears to occur more readily among very low and extremely low-birth-weight infants than among term infants and occurs in up to 25% of these infants in the first week of life. One fourth of intubated infants demonstrate respiratory colonization.
A large number of predisposing factors have influenced the rate of dissemination. One of the primary factors is the prolonged and frequent use of broad-spectrum antibiotics that suppress the growth of bacteria in the gastrointestinal tract and allow candidal overgrowth. Eventually, penetration of the epithelial barrier leads to disseminated disease. Mucosal penetration and dissemination are more likely the denser the colonization, and C. albicans has been shown to adhere to the mucosa of the preterm infant better than to that of the term infant. In particular, the use of third-generation cephalosporins seems to increase the risk of gastrointestinal colonization and subsequent candidemia. Dense colonization of the gastrointestinal tract increases the chances of translocation of the yeast across the mucosa. Intestinal ischemia, necrotizing enterocolitis, and spontaneous perforation of the intestine, common in the preterm infant, are all highly associated with candidemia. Delayed enteral feeding has also been associated with infection. The use of histamine 2 blockers raises the pH of the stomach and increases colonization, particularly of C. parapsilosis. Abdominal and cardiac surgeries are greater risks in term infants. In a similar fashion, candidal organisms readily penetrate the relatively poor barrier provided by the immature skin of the preterm infant, and that skin also readily breaks down during ordinary care. Colonized infants are more likely to be delivered vaginally than by cesarian section. The use of topical petrolatum for skin care of extremely low-birth-weight infants may increase the risk. Catheters, as well as all other indwelling tubes (endotracheal, chest, urinary, ventriculoperitoneal), may become infected. The longer the duration of an indwelling catheter, particularly if used for total parenteral nutrition or infusion of intravenous lipids, the greater the risk is to the infant. Immature immune defenses provide yet another set of risk factors. Neutrophils ingest and kill Candida intracellularly, but neutropenia is also common in very low-birth-weight infants. Theophylline, frequently used in preterm infants, may inhibit the candidacidal activity of neutrophils. Steroids inhibit the immune response, induce hyperglycemia, and, in the mouse, increase the adherence of the yeast to the intestinal mucosa.
Congenital candidiasis is extremely rare. In the term infant, infection results in an erythematous, macular eruption that then becomes pustular and desquamates. These same skin infections become burnlike in the preterm infant and then develop either a branlike or sheetlike desquamation, becoming superficial erosions. Intrauterine infection is highly associated with the presence of genital tract foreign bodies, in particular, cerclage, but have not been associated with maternal diabetes or urinary tract infections. The diagnosis in the newborn can be made with skin scrapings and blood and cerebrospinal fluid cultures. In the term infant with only cutaneous infection, survival is the rule. These infants do not require treatment, although many will administer topical therapy to relieve symptoms and to decrease the mass of organisms the infant has to clear. In contrast, in the preterm infant weighing less than 1500 g, or in any infant with respiratory symptoms signifying aspiration and pneumonia, mortality is the rule unless systemic treatment is begun.
Mucocutaneous infection (thrush or a monilial diaper rash) is the most likely infection after birth, seen in 4% to 6% of newborns and occurring as early as 4 to 5 days after birth but peaking at 3 to 4 months. Thrush manifests as white, curdlike, pseudomembranous plaques on the oropharynx or posterior pharynx, whereas the diaper dermatitis produces an erythematous, scaly lesion with satellite papules or pustules in the intertriginous areas. The latter may be repetitively reinfected by a gastrointestinal tract reservoir. Therapy in those areas is local. Oral nystatin may be given to treat the thrush. Gentian violet works as efficaciously, but its propensity to stain makes it less popular. For the skin lesions, topical nystatin alone works well, although occasionally it should be combined with oral nystatin to reduce the gastrointestinal tract reservoir and to prevent spillage onto the groin. Once the rash starts spreading beyond the usual area in the diaper, systemic therapy must begin.
Invasive candidiasis is a leading cause of morbidity and mortality in infants of less than 1000 g. Incidence in neonatal centers ranges from 2% to 28%. Systemic disease in these infants, unlike in adults, results in multiple foci of infection. Onset is delayed, usually occurring at several weeks of life, and the duration of candidemia, even with treatment, averages 7 days. Most infants have several positive blood culture results, and 10% experience candidemia for longer than 14 days. Infants have a multitude of signs and symptoms including, in order of frequency, respiratory deterioration, apnea and bradycardia, hyperglycemia, a necrotizing enterocolitis–like picture without pneumatosis, skin involvement, temperature instability, and hypotension. Meningitis, once reported in half of infants with systemic candidiasis, now occurs in only 5% to 9%, probably due to more aggressive diagnosis and treatment. Roughly half of infants with meningitis will have negative blood culture results and half will have normal CSF parameters. Endophthalmitis, once seen in half of infants, again is now relatively uncommon, occurring in fewer than 1%. Prognosis is excellent if the infection is treated. However, fungal sepsis in extremely low-birth-weight infants may be associated with increased frequency of threshold retinopathy of prematurity. Endocarditis, which may be the source of infected thromboemboli, is associated with the presence of central venous catheters. The prognosis for osteoarthritis or osteomyelitis is also good with treatment. Cutaneous manifestations may include a generalized erythema or subcutaneous abscesses. Infants may be neutropenic or have an extreme leukocytosis. Continued thrombocytopenia is often an indication of ongoing disease. Pneumonitis presents with respiratory deterioration and a bronchopulmonary dysplasia–like picture on chest radiograph. Other infants may develop abdominal distension, guaiac-positive stools, and feeding intolerance but no pneumatosis intestinalis. A few will have hepatic abscesses, diarrhea, or perforation. Mortality is extremely high in those with candidal peritonitis. Urinary tract involvement is found in over half of infants with systemic candidiasis and ranges from a bladder infection to renal abscesses or renal papillary necrosis to a mycetoma or fungal ball in the renal pelvis, possibly resulting in a flank mass. Disease of the urinary tract may be entirely silent or present with hypertension or acute renal failure with oliguria or anuria. Mortality is usually in the range of 20% to 50%, but death or disability ensues in as many as 73% of extremely low-birth-weight infants. Compared with age-matched controls, there is a higher incidence of periventricular leukomalacia, chronic lung disease, severe retinopathy of prematurity, and adverse neurologic outcome at 2 years corrected age.
Candidal species grow readily in cultures of blood or urine or specimens from other normally sterile sites, and yeast or hyphae can be seen on urinalysis. Given the propensity for dissemination, the patient should undergo ultrasonography of the kidneys, echocardiography, and a retinal examination. Fungal stains of skin scrapings can be helpful. A complete blood count and C-reactive protein level may give indirect evidence of infection. A lumbar puncture, together with culture, gram staining and cytologic analysis, is imperative. Overall, it is important to have a high index of suspicion.
Immediate consideration should also be given to the removal of possibly contaminated medical devices, particularly central intravascular catheters. Amphotericin B has been the standard for antifungal therapy for years, but many other agents have been introduced, and few data are available to indicate the advantages of one drug over another, let alone safety, efficacy, dosages, or duration of treatment. CSF penetration of amphotericin B, while better than in adults, is highly variable. This has led a few to suggest the use of 5-fluorocytosine or fluconazole, both of which have good penetration of the CSF, in combination with amphotericin B. Others have successfully treated meningitis with amphotericin B alone. There are three lipid formulations approved by the U.S. Food and Drug Administration for use in adults: amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), and liposomal amphotericin B (AmBisome). Because higher dosages may be used without toxicity, these preparations may be appropriate for the infant with renal disease or severe nephrotoxicity. A few studies have shown fluconazole to be efficacious in the treatment of invasive disease in neonates, equivalent to treatment with amphotericin B. Unfortunately, half of Candida glabrata and Candida krusei isolates are resistant to fluconazole. Fluconazole monotherapy is only recommended in neonates after identification of the fungal organism and determination of its susceptibility. Caspofungin is fungicidal against all candidal species. However, there are only case reports of its use in neonates, and it cannot be recommended at this time.
Prevention is clearly the best treatment for neonatal systemic candidiasis, yet this is also the area of greatest controversy. Treatment of maternal candidal infections may limit vertical transmission to the neonate. Prevention of horizontal transmission is more difficult. Hand washing does not reduce the recovery of C. albicans from medical workers’ hands. Removal of artificial fingernails may help. Careful attention to central lines is of benefit, as is attention to limiting exposure to drugs that increase the risk of disease. No consensus has been reached on the use of fluconazole prophylaxis. Some studies have shown a decrease in the incidence of colonization, invasive disease, or mortality. Finally, concern remains regarding the risk of isolates developing resistance. A recent metaanalysis of three trials involving over 1600 infants found a decrease in the risk of invasive fungal infection in very low-birth-weight infants with oral-topical antifungal prophylaxis but warned about the major methodologic weaknesses in trials to date. Also, one recent trial comparing fluconazole and nystatin oral prophylaxis had to be halted early due to a significant increase in deaths not related to fungal infections among the nystatin-treated infants. Reports do exist of increased resistance among infants with C. parapsilosis infection, a rising form of candidiasis.
Congenital Cytomegalovirus Infection
Cytomegalovirus (CMV) infection is the most frequent congenital infection in humans. The virus is endemic and worldwide and has no seasonal pattern of infection. Typically, after a primary infection, virus is shed for weeks to even years before becoming latent. Periodic episodes of viral shedding occur. The virus consists of three major components: an inner icosahedral or 20-sided capsid containing double-stranded DNA that is similar to that of herpes simplex virus; an amorphous layer consisting of viral proteins and RNA; and an outer envelope. The virus does not code for thymidine kinase, which renders acyclovir ineffective.
Infection with CMV largely depends on socioeconomic status, which reflects crowding. It also increases with parity and number of sexual partners. Finally, seropositivity is much higher among African American and Asian women. Seropositivity occurs in 0.5% to 2.0% of infants in the United States and Western Europe and rises to 50% to 85% among young women, but it is much more prevalent in developing countries and among lower socioeconomic groups, where seropositivity may be as high as 90%. At childbearing age, 2% of women of middle to upper socioeconomic status seroconvert yearly, compared with 6% of those of lower socioeconomic groups. Transplacental transmission of CMV from mother to infant is typical in congenital infection. A primary maternal infection results in transplacental infection in 30% to 40% of infants, with 10% to 15% of them developing symptomatic infection. The later in the pregnancy the seroconversion occurs, the more likely it will result in neonatal infection: 75% of infants are infected in the third trimester. However, the later in the pregnancy the infection occurs, the less likely the infection will be significant in the infant. Recurrent infections in the mother may also occur as a result either of reactivation or reinfection with a different strain. In either instance, transplacental infection still occurs in 1% of infants, but fewer than 1% of the infections are symptomatic. Polymerase chain reaction (PCR) methodology can detect CMV excretion in breast milk in 70% to 90% of women, particularly when the whey portion is tested, and perinatal transmission occurs to 40% to 60% of infants. Excretion occurs among these infected infants from 3 weeks to 3 months after birth. Also, transmission appears to occur readily among young children, and day care is responsible for transmission rates of over 50%, which most likely reflects contamination from saliva on toys and hands. Seroconversion may be as high as 15% to 45% among parents of children attending day care and 11% among women working in day care centers, so that subsequent pregnancies account for nearly one fourth of symptomatic congenital infections in the United States. In contrast, studies of seroconversion among health care workers do not show any risk of nosocomial transmission greater than the risk of acquiring the infection in the community. Yet nosocomial transmission to the infant may occur in the nursery, most likely via contaminated hands or fomites. Finally, infants may be infected as a result of blood transfusion or exchange transfusion. These cases may be largely prevented by using seronegative donors, leukocyte filtration, or frozen, deglycerolized packed red blood cells.
Nearly 90% of congenital infections are asymptomatic and the infants are neither growth restricted nor premature, although 10% to 15% of them are still at risk of later developmental abnormalities, which appear within the first years of life. Among asymptomatic infants, 7.2% will ultimately have hearing loss. Half of these neonates will have bilateral, progressive disease. This progressive loss, however, may be missed by routine nursery screening. A much lower risk (2%) is that of chorioretinitis, which is also usually delayed in onset. A similar number of children may also develop neurologic abnormalities, including microcephaly, neuromuscular motor defects, and mental retardation, or defects in tooth enamel. Cytomegalic inclusion disease is seen in only 5% to 10% of infected newborns and usually occurs as a result of primary infection in the mother around the time of conception ( Table 14-1 ). Mortality, which may reach 20% to 30%, results from liver failure, bleeding, disseminated intravascular coagulation (DIC), and secondary bacterial infection. Some deaths may occur after the neonatal period as a result of the complications of severe neurologic handicap. One half of symptomatic infants have intrauterine growth restriction and one third are prematurely born. Microcephaly may also be seen in half of the infants, along with intracranial calcifications. Hepatomegaly, and even more frequently splenomegaly, are among the most common findings in newborns. Two thirds of the infants develop jaundice, which often persists and becomes increasingly due to a rise in the direct component, and most infants have some rise in liver enzyme levels. Petechiae and even purpura are found in over half. Thrombocytopenia, due to suppression of the megakaryocytes in the bone marrow, may be severe (one third have platelet counts of <10,000). There may also be a Coombs-negative hemolytic anemia. Diffuse interstitial pneumonitis is rare (<1%) and is more commonly seen in perinatally acquired disease. A peculiar defect of the enamel of the primary teeth may be seen in infants. This yellow, soft enamel wears away early, leaving the teeth susceptible to rampant caries. Male infants may also have inguinal hernias. Both the defect in dental enamel and the hernias appear to be teratogenic in nature. A few infants have manifested necrotizing enterocolitis. Sensorineural hearing loss is found in over one third of the infants and, as in asymptomatic infants, may be unilateral or bilateral, profound, and progressive. Chorioretinitis, optic atrophy, and strabismus may be found in 22%, and the retinitis is more likely to present at the macula than in adults. The outcome is grim, with 90% of infants developing at least one neurologic abnormality. Although microcephaly is a strong predictor of intellectual impairment, intracranial calcifications on computerized tomographic images indicate a risk as high as 90% and are often accompanied by progressive, severe, bilateral hearing loss, optic atrophy, and neuromuscular abnormalities. Ultrasonography may accurately demonstrate calcifications, but magnetic resonance imaging may provide additional findings, such as polymicrogyri, hippocampal dysplasia, and cerebellar hypoplasia.
|Type of Maternal Infection|
|% (No.)||% (No.)||P value|
|Sensorineural hearing loss||15 (18/120)||5.4 (3/56)||0.05|
|Bilateral hearing loss||8.3 (10/120)||0 (0/56)||0.02|
|Speech threshold >60 dB ∗||7.5 (9/120)||0 (0/56)||0.03|
|IQ <70||13.2 (9/68)||0 (0/32)||0.03|
|Chorioretinitis †||6.3 (7/112)||1.9 (1/54)||0.20|
|Other neurologic sequelae ‡||6.4 (8/125)||1.6 (1/64)||0.13|
|Microcephaly||4.8 (6/125)||1.6 (1/64)||0.25|
|Seizures||4.8 (6/125)||0 (0/64)||0.08|
|Paresis or paralysis||0.8 (1/125)||0 (0/64)||0.66|
|Death §||2.4 (3/125)||0 (0/64)||0.29|
|Any sequela||24.8 (31/125)||7.8 (5/64)||0.003|
∗ For the ear with better hearing.
† Three of the seven children with chorioretinitis (43%) in the primary infection group had visual impairment.
‡ Four of the eight children (50%) had more than one abnormality.
A perinatal infection may develop in an infant after passage through the birth canal or from breast milk. In the term infant this is usually asymptomatic with little effect on developmental outcome, although such infants may develop a diffuse interstitial pneumonitis. Few require hospitalization and mortality is low. Among preterm infants there is more risk. Transfusion of packed red blood cells may result in a sepsis-like picture with pneumonia, hepatosplenomegaly, thrombocytopenia, and neutropenia, and the mortality may reach 50%. More recently there has been considerable concern regarding breast feeding of preterm infants by seropositive mothers, but most studies have indicated little long-term developmental effect in infected infants.
Viral isolation in tissue culture, usually from urine or saliva, remains the most sensitive and specific test for diagnosis in the infant. To differentiate congenital infection in the neonate from perinatal infection, virus must be isolated in the first 2 weeks after birth. With hyperimmune sera or monoclonal antibodies, detection may occur within 24 hours. Because immunoglobulin (Ig) G is transplacentally transferred, its detection is not helpful without paired sera, and the measurement of serum IgM is associated with many false negatives. However, PCR amplification for detection of viral DNA has been found to be extremely sensitive for diagnosis in a large range of tissues and secretions, particularly blood and saliva. A new technique is the use of nested PCR to detect viral DNA in dried blood spots that are obtained for metabolic tests after birth. These blood spots may be used in screening or can be tested later to determine whether symptoms such as hearing loss are a result of congenital infection. Once the blood is dried it is no longer infectious. The samples can be shipped easily and stored for years.
Maternal and prenatal diagnosis is more complicated. The mother is usually asymptomatic, so infection is not suspected clinically. Screening thus becomes more important. The detection of IgG does not define whether the mother has a primary infection or a recurrent one. The same is true of isolation of the virus. IgM responses are variable and may be detected for 16 weeks or longer after infection. An IgG avidity assay, based on the determination that antibody is of low avidity in the first months of infection, is particularly effective as a negative predictor up to 21 weeks of pregnancy, but is less so later. However, the most important factor is whether or not the fetus is infected and whether or not that infection is symptomatic. Cordocentesis for fetal blood testing will miss many infected fetuses. IgM appears only after 20 weeks’ gestation and is only detected in half of cases. Viral DNA can be detected but the test has a low sensitivity. The standard assay has now become quantitative PCR on amniotic fluid. Ultrasonographic abnormalities may be associated with, but are not diagnostic of, infection and many are transient. These include microcephaly, intracranial calcifications or cysts, intrauterine growth restriction, oligohydramnios or polyhydramnios, pericardial or pleural effusions, hepatic lesions, and hyperechoic abdominal masses.
Because disease is often present for a prolonged period in the fetus and already has deleterious effects, treatment becomes problematic. Clearly the best treatment is prevention of fetal infection. Vaccines are being explored but are not currently available. Recently, hyperimmune globulin was given to 31 women with primary infections in pregnancy and the infant of only one (3%) had disease at birth, developing handicaps by 2 years of age. In contrast, the rate of disease was 50% among the infants of 14 women who did not receive the hyperimmune globulin. Placental thickness, which increases in primary infection, declined after treatment as well. Passive protection after birth is unlikely to be of benefit. In a randomized, controlled trial of intravenous ganciclovir in 100 infants with central nervous system (CNS) disease, the therapy prevented worsening of hearing loss at 6 months and 1 year of age. Fewer developmental delays at 6 and 12 months of age, as measured by Denver developmental tests, were also seen among infants receiving intravenous ganciclovir therapy than among control infants. Treatment of congenital CMV in infants with CNS disease should be considered but needs to be initiated in the first month of life, and the infants need to be closely monitored for toxicity, particularly neutropenia.
Neonatal herpes simplex virus (HSV) disease has really only been recognized in the last 70 years. This double-stranded DNA virus consists of a dense viral DNA core surrounded by an icosahedral protein capsid, which is further surrounded by an amorphous layer of proteins and an envelope. The herpesviruses are known for their ability to enter a latent state after the primary infection from which an active recurrence may arise, despite the presence of humoral and cellular immunity. There are two antigenic types: HSV-1 is usually found above the waist, whereas HSV-2 is found below the waist and is the most common source of genital and neonatal herpes. Infections with either type are usually asymptomatic. HSV-1 may cause gingivostomatitis in young children and a sore throat or a mononucleosis-like infection in an adult. As with other herpesviruses, seroprevalence is related to socioeconomic status. More than three quarters of lower socioeconomic populations have antibody to HSV-1 in their first decade, as opposed to only one third of those of upper middle socioeconomic groups. HSV-2 is responsible for 80% of genital infections and is usually transmitted by sexual intercourse; thus it most often appears after the second decade and is found in 20% to 25% of individuals. African Americans have a higher rate of infection than whites. Higher rates are also seen in women, who have an 80% risk of infection after a single contact with an infected male. From 1988 to 1994 in the United States, the prevalence of HSV-2 infection was 21%, which represented a significant increase over prior years. In the most recent surveys, from 1999 to 2004, the seroprevalence of HSV-2 dropped to 17%. Of note, HSV-1 is now responsible for a larger proportion of both genital and neonatal disease. HSV-1 genital infections are less likely to recur than HSV-2 genital infections and are usually less severe. Both HSV-1 and HSV-2 are found worldwide, and the only reservoir is in humans. Infection occurs year round and is not seasonal. Host defenses begin in 7 to 10 days, with humoral immunity appearing 2 to 6 weeks later, although this does not prevent recurrences.
Transmission to the neonate most commonly occurs from exposure of the infant to contaminated maternal secretions in the birth canal at delivery. Maternal infection is classified as primary if it is the initial infection with either HSV-1 or HSV-2 and there are no preexisting antibodies to either type. A recurrent infection occurs in an individual with latent infection, whereas an initial nonprimary infection occurs in an individual with preexisting antibodies to the other HSV type. All three types of infection are likely to be asymptomatic. Many infections believed to be new infections in pregnant women are actually reactivations of previously acquired asymptomatic infections. Infection does not appear to be associated with an increase in spontaneous abortion or premature rupture of membranes. Cervical shedding of virus has been demonstrated in 0.56% of women with symptomatic infections and in 0.66% of women with asymptomatic infections. Frequent cervical cultures have failed to detect which mothers will be shedding virus at the time of delivery. It is important to note that over 75% of infected neonates are born to women who have no history or symptoms of HSV infection, nor do their sexual partners. Acquisition of HSV-1 or HSV-2 occurs in 2% of susceptible pregnant women and is evenly distributed throughout the pregnancy. There is up to a 60% risk of neonatal infection when the mother is shedding virus at the time of delivery secondary to a primary infection. The risk falls to 30% if the mother is shedding virus at delivery due to an initial nonprimary infection and to 2% if the mother is shedding virus due to reactivation of infection acquired either before pregnancy or during an earlier trimester. This is primarily due to the larger quantity and duration of viral shedding from the cervix during a primary infection. However, some protection is afforded by preexisting neutralizing transplacental antibodies, so that the infants at highest risk are the ones who are infected at birth or after birth and who are born before transplacental transfer of antibodies. Type-specific maternal antibody testing may be useful in determining the risk of infection of the neonate. The use of invasive monitoring provides a site for viral entry into the fetus, and this site is often the location of initial lesions. An additional risk factor is rupture of membranes longer than 6 hours before delivery in a mother with active cervical lesions. For this reason, many experts recommended that infants of such mothers be delivered via cesarian section—before rupture of membranes, if possible, but at least before 6 hours after rupture. Cesarian section reduces the risk of fetal infection from 7.7% to 1.2%, but does not eliminate the risk entirely. In the United States it is estimated that infection occurs in 1 in 1500 deliveries, resulting in 2200 infected newborns per year.
Intrauterine infection is rare and may result from either ascending infection from the birth canal or transplacental infection. It may also occur in either primary or recurrent maternal infection. These infants are severely affected and have a combination of skin vesicles and scarring, hydranencephaly or microcephaly, and keratoconjunctivitis. Antiviral therapy is futile.
The third route of transmission is postnatal acquisition. Virus may be obtained by breast feeding from an infected breast or being kissed by a family member who has orolabial herpes, usually HSV-1. Nosocomial infection in the nursery is also possible. Prospective hospital studies have demonstrated that as many as one third of employees have a history of nongenital herpes and that twice that many have asymptomatic shedding. It remains controversial whether individuals with labial lesions should be removed from the nursery. Currently they are asked to use face masks and to perform careful hand washing. Individuals with herpetic whitlow (finger lesions) should not be providing direct patient care.
In stark contrast to the case of congenital infection of the newborn with CMV, another herpesvirus, asymptomatic infections with either HSV-1 or HSV-2 are rare. Neonatal disease has been classified, for purposes of describing outcome, into localized skin, eye, and mouth (SEM) disease; encephalitis with or without skin, eye, or mouth involvement (CNS); and disseminated disease, with or without CNS involvement. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group reported that 34% of neonates had SEM disease at presentation, 34% had CNS disease, and 32% had disseminated disease. Common presenting signs and symptoms include lethargy, temperature instability, conjunctivitis, pneumonia, hepatitis, and DIC. Skin lesions are the most suggestive of HSV infections, but fewer than 30% of infants ever develop such lesions. Likewise, seizures, focal or generalized, and encephalitis are very indicative.
Symptoms of SEM disease usually appear at 7 to 10 days of life. The most easily recognized skin lesion is the vesicle, which may progress to clusters of vesicles or join with other vesicles to form bullae. Although limited to the skin at first, the lesions tend to progress to more serious disease; this was particularly true before the advent of acyclovir therapy. They are most commonly found on the head of the infant, especially if there was a scalp monitor, but may also be found on the trunk or extremities. Lesions in the mouth presumably are caused by swallowed contaminated amniotic fluid and maternal secretions. Keratoconjunctivitis, chorioretinitis, and cataracts may also develop. Even with antiviral therapy, infants tend to have recurrent skin lesions over several years and some may develop cataracts. Long-term neurologic impairment has also been seen in these infants, probably due to unrecognized CNS disease. This group may experience quadriplegia, microcephaly, and blindness between 6 and 12 months of age. Before the acyclovir era, 30% of these infants progressed to more invasive disease and had neurologic sequelae. With acyclovir therapy, all infants with HSV-1 infection and 95% of those with HSV-2 SEM disease had normal neurologic examination findings at 12 months of age. ,97
Isolated CNS disease in the newborn probably represents retrograde axonal transport of the virus in infants who have acquired transplacental neutralizing antibody, which possibly has not allowed hematogenous spread of the virus. In these infants the infection becomes apparent at a slightly older age, after the first week of life—often in the second or third week, but even as late as 6 weeks of life. Nonspecific signs may include temperature instability, lethargy, irritability, and poor feeding. HSV encephalitis should always be considered in the presence of focal or generalized seizures, especially if they are refractory to treatment; a bulging fontanelle; tremors; pyramidal tract signs; and focal neurologic deficits. Skin lesions or vesicles frequently are not found at presentation. The CSF may be normal initially or show only subtle abnormalities. Many infants will have a bloody tap due to CNS hemorrhage. Most commonly the CSF glucose concentration is low and there is a mononuclear pleocytosis. The protein content may show little elevation at first but rises significantly over time. Computed tomography may show localized or multifocal areas of hemorrhage, edema, and infarct. An electroencephalogram may also help in determining the extent of disease. Brain stem disease results in the death of half of untreated infants. The prognosis of survivors is poor and includes severe psychomotor retardation, blindness, microcephaly, chorioretinitis, and spasticity. Even with antiviral therapy, only 17.5% of infants infected with HSV-2 and 75% of infants infected with HSV-1 have a normal outcome at one year of age.
Most infants with disseminated HSV disease are born to mothers with primary infection and lack transplacental antibody. The resulting viremia in the infant spreads the disease to all organs, usually in the first week of life but also in the first 24 hours. Adrenal hemorrhage and shock with fulminant hepatitis may be prominent. There may be a sepsis-like picture with metabolic acidosis, respiratory distress, DIC, direct hyperbilirubinemia, thrombocytopenia, neutropenia, elevated hepatic enzyme levels, and seizures. A vesicular rash is usually not present at onset, and one third of infants never develop vesicles. Meningoencephalitis develops in the majority of infants. Others may develop an interstitial or hemorrhagic pneumonia or necrotizing enterocolitis with pneumatosis intestinalis. These infants have the highest mortality—more than 80% if untreated, often secondary to DIC or pneumonia—but survivors may have a better neurologic outcome. Although HSV-1 and HSV-2 infection are clinically indistinguishable in disseminated disease, a normal neurologic outcome is more common after antiviral therapy in infants infected with HSV-2 (41%) than in infants infected with HSV-1 (23%).
It is extremely important to have a high index of suspicion for HSV. Enteroviral sepsis is the major differential. Viral isolation by culture remains the standard. Swab specimens for viral isolation should be taken from all skin lesions, the nasopharynx, urine, stool, and conjunctivae. Isolation of the virus from the skin or nasopharynx in the first 24 hours of life may represent transient contamination from birth, so swab specimens should be taken at 24 hours of life in infants born vaginally to mothers with genital lesions or known shedding. Viral typing is important for prediction of survival and neurologic outcome. Analysis as well as viral culture of the CSF is required. The sensitivity and specificity of PCR for viral antigen in the CSF is high. Skin lesions should also be examined by either immunofluorescence or PCR testing. The evaluation should include an ophthalmologic examination, brain imaging, electroencephalography, and audiologic testing. A complete blood count, measurement of hepatic enzyme levels, blood gas analysis, and coagulation studies should also be performed for these infants.
Intravenous acyclovir is the treatment of choice for newborns. Infants should be isolated to prevent nosocomial spread. Oral therapy is not acceptable. Acyclovir is a competitive inhibitor of HSV DNA polymerase and terminates DNA chain elongation. It is activated by HSV thymidine kinase. All infants with HSV disease should be treated with 60 mg/kg/day acyclovir in three divided doses. Infants with SEM disease may be treated for 14 days, but all infants with either CNS or disseminated disease require 21 days of therapy. PCR assessment of the CSF at the end of treatment of encephalitis or meningitis can be used to determine the need for continued therapy in infants whose PCR results remain positive. Adequate hydration is important to prevent nephrotoxicity. Ocular antiviral therapy should be used in the presence of ophthalmic infection, but topical treatment is not necessary for skin lesions because intravenous acyclovir adequately penetrates these lesions. There is no indication that hyperimmune globulin is of benefit. Acyclovir resistance is rare in the non–human immunodeficiency virus–infected newborn.
As discussed, prognosis depends on both the viral antigen type and the location of the infection (SEM disease only, localized CNS infection, or disseminated disease). Further improvements in outcome will require earlier recognition and treatment of infection, but this has not occurred since acyclovir has become available. Poor prognostic signs at the initiation of therapy include prematurity, coma, DIC, and pneumonitis. There is also an association between the frequency of recurrence of skin lesions and the development of late sequelae. A 6-month trial of oral acyclovir suppression did eliminate the recurrence of skin lesions in 81% of treated infants, whereas only 54% of untreated infants escaped recurrence, but whether this will improve the long-term outcome is not known. Serial evaluations should include ophthalmologic and audiologic assessments in addition to neurodevelopmental testing.
Recurrent skin lesions can also be a source of infection. Exclusion from day care is not necessary, however, if the lesions are covered to prevent direct contact with others.
Reducing transmission of HSV to neonates is the ideal, but most women shed virus asymptomatically. Delivery by cesarian section may be beneficial in the presence of maternal genital lesions or symptoms but is not indicated in the absence of lesions, because the risk of transmission to the exposed infant in recurrent infection is less than 3%. A primary maternal infection during pregnancy should be treated. Valacyclovir is now commonly being administered to pregnant women with a history of recurrent genital HSV, beginning at 36 weeks’ gestation. Metaanalysis indicates that treatment reduces the risk of HSV recurrences and viral shedding at delivery and the need for cesarean section. It is not known if this therapy also reduces the incidence of neonatal herpetic disease, and its use may give the clinician a false sense of security. The long-term risk to the fetus, particularly the fetal kidney, is not known, although the acyclovir and valacyclovir pregnancy registry has not shown any increase in the rate of birth defects or change in their pattern in infants born to treated women, compared with those born to the general population of pregnant women. The rise of resistant virus in these treated women is also of concern.
Human Immunodeficiency Virus Infection
In the early 1980s, acquired immunodeficiency syndrome (AIDS) was first described in infants and children. Children younger than 13 years infected with human immunodeficiency virus (HIV) account for fewer than 1% of the total number of infected people in the United States. More than 90% of these cases resulted from vertical transmission from infected mothers. Since 1992, the CDC reports a 90% decrease in new infection in children younger than 13 years of age. Only 166 new cases in this age group were reported in 2005. As will be discussed, this nadir was achieved by improved prenatal screening, management of pregnant mothers, and postpartum prophylaxis.
HIV is an RNA retrovirus of the genus Lentivirus . The virus primarily targets CD4 + lymphocytes, where it incorporates itself as a provirus into the host cells’ genome and is replicated as part of normal host cell DNA replication. Infection is therefore lifelong. Even with the use of potent combination antiretroviral therapy and reduction in HIV RNA serum levels below detectability, latent virus has been demonstrated in peripheral blood monocytes. In active infection, virus can be isolated from a variety of cells, organs, and bodily fluids; however, epidemiologic studies have only demonstrated infectivity from blood, breast milk, cervical secretions, and semen.
Neonatal infection is generally clinically silent. Infants may have nonspecific physical examination findings of hepatosplenomegaly or lymphadenopathy. Oral candidiasis in a neonate does not arouse suspicion for pathologic T-cell dysfunction. Refractory, recurrent oral candidiasis, encephalopathy, developmental delay, poor growth, chronic diarrhea, and parotitis are relatively common findings in infected infants during the first year of life; again, none of these symptoms is particularly specific for HIV infection. Before the improvement in identification of infected mothers, use of highly active antiretroviral therapy (HAART), and initiation of appropriate postnatal prophylaxis for viral and opportunistic infections, pneumonia caused by Pneumocystis jiroveci (formerly Pneumocystis carinii ) accounted for the majority of AIDS-defining illness in the first year of life, with a peak incidence between ages 3 and 6 months. Many infants, however, do not have AIDS-defining opportunistic infection, but rather may experience recurrent serious bacterial infections, including pneumonia, septic arthritis, bacteremia, or meningitis. Although a single occurrence of these infections does not raise suspicion about immunodeficiency, their recurrence should alert the clinician to evaluate the infant’s immune system. In general, the likelihood of serious bacterial infection or opportunistic infection correlates inversely with infants’ CD4 + counts; without HAART, these counts begin to decline around 3 months of age.
Diagnosis of HIV infection in infants can be made in several ways. Serologic testing is not diagnostic in a neonate, because a positive result on an enzyme immunoassay may simply reflect maternal serologic status due to passive transplacental transfer of IgG antibody. Antibody tests may yield false-negative results if the mother was infected late in pregnancy and had not yet undergone seroconversion. In infants born to HIV-infected mothers, blood should be sent for either HIV DNA PCR testing or HIV RNA PCR assay during the first 48 hours of life. If results are positive, a second sample should be sent for PCR assay to confirm the diagnosis. Once infection has been established, HIV RNA PCR testing is used to monitor the efficacy of therapy, because this test reports back a quantitative result or viral load in copies per milliliter. There are several ways to rule out infection. A negative result on two PCR samples obtained after 1 month and 4 months of life rules out infection. Two negative antibody test results separated by 1 month obtained after 6 months of life or a single negative antibody test result after 12 to 18 months of life excludes infection.
As noted earlier, interruption of vertical transmission has greatly reduced the number of infected children in the United States. Currently, the CDC recommends universal screening of all pregnant women in the first trimester with repeat testing in the third trimester for women felt to be at high risk of infection. In 1994, the Pediatric AIDS Clinical Trials Group Protocol 076 trial demonstrated a 67% reduction in perinatal HIV transmission with use of a zidovudine regimen for mother and infants.
Numerous subsequent studies have looked at a variety of simple and complex regimens testing different antiretroviral agents, timing, and duration, and have examined their efficacy and side effects in pregnant women and their offspring. The routine use of HAART starting in 1996 has enabled physicians to greatly suppress viral burden in infected patients. Several studies have demonstrated the benefit of viral suppression in mothers in preventing vertical transmission to their infants. The CDC currently recommends that pregnant women receive HAART, containing zidovudine if possible, if they require it for their own health or if they have HIV RNA levels of more than 1000 copies/mL. There is no absolute viral threshold that reduces the risk of transmission to zero, and therefore the CDC urges consideration of this regimen for pregnant women even if they have HIV RNA levels of less than 1000 copies/mL. Several studies have shown that elective cesarean delivery in HIV-infected women who have not received HAART and who have not begun labor or had rupture of membranes reduces the rate of vertical transmission by 50%. The role of cesarean section in women receiving HAART who have RNA viral loads of less than 1000 copies/mL is controversial, and therefore cesarean section is not recommended for those women. Breast feeding has been a major vehicle of vertical transmission. Studies estimate that between 15% and 40% of vertical transmission worldwide occurs through breast milk. Since 1985, the CDC has recommended that women with HIV avoid breast feeding if they have access to safe, affordable formula ; the World Health Organization made a similar recommendation in 2000.
Any infant born to an infected mother should receive antiretroviral therapy as soon as possible after delivery. Antiretroviral therapy administered beyond 48 hours of life is not likely to impact the rate of vertical transmission. The therapeutic regimen should be determined with the help of a pediatric infectious disease specialist and should take into account the mother’s viral load and CD4 + count, mode of delivery, and antiretroviral exposure. Exposed infants generally receive antiviral therapy for 4 to 6 weeks unless infection is confirmed. For all exposed infants chemoprophylaxis against P. jiroveci, most commonly trimethoprim-sulfamethoxazole, should be initiated at 4 to 6 weeks of life. Prophylaxis should be continued until HIV infection is excluded. The likelihood of vertical transmission can be reduced to less than 1% with the aggressive use of HAART to reduce maternal viral loads below the limits of detection and the use of neonatal antiretroviral prophylaxis. In the most recent guidelines for testing of pregnant mothers and neonates, the CDC recommends that women in labor whose HIV status is unknown be offered rapid antibody testing. If the results are positive, the woman should be offered antiretroviral therapy and cesarean section without waiting for confirmatory test results. This aggressive approach reflects clinical consensus that the risk of exposing an uninfected mother or child to antiretroviral therapy and/or surgery is outweighed by the ability to prevent vertical transmission of this incurable infection. Infants with documented HIV infection should be evaluated and treated by an experienced pediatric infectious disease physician who can monitor response to therapy as well as medication toxicities. Current guidelines suggest that all children younger than 1 year of age receive HAART regardless of viral load or immune status. Pneumocystis prophylaxis should be continued until the infant is 12 months of age and has CD4 + counts appropriate for age. The need for chemoprophylaxis against infection with other opportunistic agents, including Mycobacterium avium-intracellulare complex, Toxoplasma gondii, and various herpesviruses, will be determined by the patients’ CD4 + counts and clinical conditions. A discussion of specific HAART regimens is beyond the scope of this chapter. HAART has dramatically increased the life expectancy of infants and children with HIV infection. In the absence of a cure, HIV-infected children may require lifelong therapy with drugs that have been associated with premature coronary artery disease, insulin resistance, and bone fragility. The personal and societal costs of prolonged HAART therapy emphasize the importance of HIV prevention.
Neisseria gonorrhoeae is frequently asymptomatic in women and may therefore be unknowingly transmitted to neonates. Endocervical screening samples should be sent for mothers in the first trimester of pregnancy, and for women at high risk, a second culture should be performed late in the third trimester. Gonococcal infection, whether or not overt clinical symptoms are present, may cause vaginitis, cervicitis, salpingitis, and pelvic inflammatory disease. These conditions may result in neonatal morbidity and mortality directly by infection of the neonate or indirectly by precipitation of preterm labor with its consequent complications.
The most common manifestation of neonatal infection is ophthalmia neonatorum, a severe bacterial ocular infection. Before the routine use of silver nitrate, tetracycline, or erythromycin topical eye preparations, an infant born to a mother with N. gonorrhoeae endocervical infection had approximately a 30% chance of developing ocular disease. A premature infant or an infant born a prolonged period after membrane rupture has an even greater risk of developing infection. Signs of infection typically manifest by 48 to 96 hours of life but may occur within hours. Classically, the infant has bilateral lid edema, chemosis, and purulent drainage. Without treatment the infection can result in permanent corneal damage and panophthalmitis with vision loss.
Rarely, disseminated infection with N. gonorrhoeae occurs in neonates secondary to bacteremia. The majority of systemically infected infants in the United States are born to mothers who were inadequately screened and who have asymptomatic infection. The most common presentation of disseminated neonatal N. gonorrhoeae infection is pyogenic polyarthritis. The infant may have a pseudoparalysis of the affected limb. Even in disseminated disease, meningitis has rarely been reported. Interestingly, the hallmark skin manifestations of disseminated N. gonorrhoeae infection seen in adults are not common in bacteremic infants. Localized cellulitis at breaks in the skin, such as pH probe sites, does occur. In the United States, most systemically infected infants do not have ocular disease because of the universal use of topical prophylaxis. The diagnosis of infection at any site is best made by Gram staining and culture of purulent material on appropriate media.
Prevention of neonatal infection is accomplished through appropriate maternal screening, treatment of infected pregnant mothers, and universal ophthalmic prophylaxis. Pregnant women found to have N. gonorrhoeae infection should be treated according to current CDC guidelines. Universal ophthalmic prophylaxis effectively prevents ocular disease in over 95% of infants born to infected mothers; however, as noted, the topical therapy does not prevent systemic illness. Infants born to mothers with known N. gonorrhoeae infection should receive standard ocular prophylaxis and a single dose of 125 mg of intravenous or intramuscular ceftriaxone. In preterm or low-birth-weight infants, the dose should be 25 mg to 50 mg/kg with a maximum dose of 125 mg.
For any infant with suspected infection, cultures should be performed on blood and CSF as well as samples from any exudate—ocular, skin abscess, or articular. Most infants should be hospitalized to ensure evaluation and therapy. Gonococcal ophthalmia neonatorum should be treated with a single dose of intravenous or intramuscular ceftriaxone at 25 to 50 mg/kg up to a maximum dose of 125 mg. In addition, infants should receive frequent eye irrigation with saline until the discharge has resolved. Topical therapy alone is insufficient to treat established infection and is unnecessary with systemic therapy. In infants with bacteremia or septic arthritis, ceftriaxone or cefotaxime therapy should be administered for 7 days. If cultures of CSF give positive results, the duration of therapy should be 10 to 14 days.
Any infant with documented gonococcal disease should also be evaluated for other common sexually transmitted diseases: syphilis, Chlamydia trachomatis infection, HIV infection, and hepatitis B.
Chlamydia Trachomatis Infection
Chlamydia trachomatis is an obligate intracellular bacterium. C. trachomatis infection is the most common reportable sexually transmitted disease in the United States. The high prevalence of maternal infection coupled with the lack of efficacy of the topical agents recommended as universal ocular prophylaxis for neonates makes C. trachomatis the most common cause of ophthalmia neonatorum. A few of the 18 reported serovars are responsible for the majority of genital infections in women and, consequently, in neonates. Transmission is primarily from infected genital secretions but has been reported in infants born via cesarean section to mothers with intact membranes. Infants born to mothers with untreated infection have a 50% likelihood of acquiring infection, with the nasopharynx being the most frequently colonized site. Once infected, infants have between a 25% and 50% chance of developing conjunctivitis and between a 5% and 20% chance of developing pneumonia.
Conjunctivitis typically appears within a few days to weeks after birth, but the timing of infection cannot reliably distinguish C. trachomatis infection from gonococcal disease. The symptoms tend to be similar to, although milder than, those seen in gonococcal disease: lid edema, erythema, and purulent exudate. Treatment results in resolution of symptoms within 1 to 2 weeks without permanent sequelae. No treatment or inadequate therapy can result in symptoms for up to a year with the potential for conjunctival scarring or micropannus formation. Diagnosis is confirmed by culture of cells from conjunctival specimens. The test depends on the collection of epithelial cells, because C. trachomatis is an intracellular pathogen. Consultation with the hospital microbiologist or infectious disease expert to determine the most appropriate collection methods and culture media is recommended. Staining will reveal intracytoplasmic inclusion in more than 90% of neonatal ocular specimens with confirmation of C. trachomatis infection by species-specific monoclonal antibody staining.
Pneumonia caused by C. trachomatis typically presents from the late neonatal period through the first 4 months of life with a mild to moderate respiratory illness characterized by persistent staccato cough, tachypnea, and nasal congestion without fever. Physical examination often demonstrates tachypnea and rales but no wheeze. Half of infants with C. trachomatis pneumonia have evidence of conjunctivitis. Classically, chest radiography demonstrates bilateral interstitial infiltrates with hyperinflation. Diagnosis of C. trachomatis pneumonia is largely clinical. Although in many affected infants cultures of nasopharyngeal specimens will be positive for the organism, the absence of a positive culture finding in samples from this site does not eliminate the possibility of C. trachomatis as the responsible pathogen. Elevation of C. trachomatis –specific IgM to a titer of 1:32 or higher is diagnostic, but this assay is not always readily or rapidly available. Interestingly, IgM levels do not typically increase in infected infants with isolated ocular disease.
Infants with chlamydial conjunctivitis should be treated with oral erythromycin base or ethylsuccinate, 50 mg/kg/day divided into four doses for 14 days. Azithromycin and clarithromycin are likely to be effective; however, not enough data exist about the proper dosing and duration of therapy to allow them to be recommended for neonatal ocular disease at this time. Pneumonia may be treated with erythromycin in the same manner as ocular disease or may be treated with azithromycin 20 mg/kg/day for 5 days. Outside of the period immediately after birth, sulfonamides may be used if the infant cannot tolerate erythromycin therapy. Up to 20% of treated infants will require a second course of antibiotics. In infants younger than 6 weeks of age, erythromycin therapy has been associated with hypertrophic pyloric stenosis. The American Academy of Pediatrics continues to recommend that neonates with chlamydial disease be treated with erythromycin pending further studies of other potentially effective agents and further delineation of the association between erythromycin and pyloric stenosis. If neonates are treated with erythromycin, the physician should inform the parents of this association and its warning signs.
Disease prevention targets screening of all pregnant women, with treatment of those infected and documentation of cure. Despite the high likelihood of neonatal infection for infants born to untreated or inadequately treated mothers, the routine use of systemic erythromycin therapy for exposed infants is not recommended given the association with the drug and hypertrophic pyloric stenosis. C. trachomatis disease, as discussed, is generally not associated with significant morbidity or mortality. Infants should be observed for clinical signs of infection and treated if such signs are present.
After World War II, the number of cases of acquired and, consequently, of congenital syphilis declined steadily until the late 1980s and early 1990s, when an epidemic occurred. This epidemic coincided with an increase in the incidence of HIV infection, crack cocaine use, and the poverty rate. By 1998, aggressive public health measures led to a decline in congenital syphilis cases to the current record low level of fewer than 500 cases per year ( Fig. 14-2 ).