Beatriz Larru, MD, PhD and Theoklis E. Zaoutis, MD, MSCE

Developmental Immunology

Except in the case of congenital infection, all pathogen encounters in the neonatal period are first-time encounters. For those first-time exposures to pathogens, neonates are dependent on the innate immune system. The innate immune system comprises cells and mechanisms that defend in a nonspecific manner. T- and B-cell responses are part of the specific (adaptive) immune system. The adaptive immune response allows the immune system to remember specific pathogens. ¹²³

There are two types of effector CD4⁺ helper cells: T_h1 and T_h2. Each of these is responsible for eliminating a specific kind of pathogen. The T_h1 response leads to cell-mediated immunity (important defense against viruses and intracellular pathogens.) T_h1 responses are considered proinflammatory. T_h2 responses activate B cells to make antibodies, leading to humoral immunity (important defense against extracellular bacteria, parasites, and toxins). T_h2 responses are antiinflammatory. T_h2 inflammatory responses are favored in the fetus, dampening the fetal immune response and preventing alloimmune reactions between mother and fetus (e.g., miscarriage). Decreased production of T_h1 cytokines increases the susceptibility to infection and contributes to the poor response to vaccines. ⁴

The nonspecific innate immune system includes host defense mechanisms that operate effectively without prior exposure. It includes the following:

The vernix caseosa is a waxy coating in newborns that is secreted by fetal sebaceous glands. It contains antimicrobial peptides that act as a microbicidal shield. The lipids and acid pH of the neonatal skin inhibit microbial growth and reach maturity by week 2 to 4 in term neonates (later in premature infants). Small breaks in the integrity of the skin can serve as entry points for infection. ⁶⁷⁸

Complement components are synthesized as early as 6 to 14 weeks of gestation. However, neonatal plasma concentrations of complement components are diminished, ranging from 10% to 70% of adult levels. A relative deficiency in complement might contribute to the inability of newborns to limit the replication of many bacterial strains in the blood because opsonization is impaired; these differences are greater in preterm than in term neonates.

Overall activity and components of the alternative pathway are more consistently decreased than those of the classical pathway. This finding is especially problematic for neonates who are exposed to organisms with polysaccharide capsules, such as Escherichia coli K1 and group B Streptococcus (GBS) and who cannot rely on classical pathway activation owing to the lack of specific antibodies. ⁹

CRP is a soluble protein that facilitates clearance of infected cells and microorganisms by phagocytes. It is produced by the liver and is part of the acute-phase response. It does not cross the placenta. Neonates can produce CRP, and levels reach concentration similar to that of adults in the first days of life in term neonates.

The pluripotent hematopoietic stem cells are generated from embryonic para-aortic tissue, fetal liver (by 4 weeks’ gestation) and bone marrow (by 11 weeks’ gestation). The yolk site is a major site of production of erythrocytes and phagocytes (by 3 weeks’ gestation). Liver hematopoiesis ceases by week 20 and continues only in bone marrow. All major lineages of the hematopoietic cells that are part of the immune system are present in the fetus by the beginning of the second trimester ( Fig. 13-1). ¹⁰¹¹

Circulating monocytes first appear in the fetal blood at 18 to 20 weeks’ gestation; by week 30 they increase to 3% to 7% of the circulating formed blood cells. By birth values exceed 500/mm³, which is higher than in most adults. Monocytes undergo tissue-specific differentation into mononuclear macrophages, which utilize a respiratory burst (biosynthesis of O₂^– and H₂O₂) to kill organisms.

The microbicidal activity of macrophages can be regulated by cytokines (interferon gamma [IFN-gamma], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-alpha]). The ability of mononuclear phagocytes to generate reactive oxygen intermediates is normal in neonates. However, IFN-gamma production and response to exogenous IFN-gamma are diminished in newborns. ¹²

T-cell precursors differentiate into immunocompetent T cells within the thymus. Before entering the thymus, stem cells lack antigen receptors and do not express CD3, CD4, or CD8 on their surface. Prothymocytes do not initially express CD4 or CD8 (double negatives); however, during the process of differentialtion they express both CD4 and CD8 (double positives) and then proceed to express either CD4 or CD8. A double-positive cell will differentiate into a CD4-positive one if it comes into contact with a cell bearing class II major histocompatibility complex (MHC) proteins but will differentiate into a CD8-positive cell if it comes into contact with a cell bearing class I MHC proteins.

The double-negative and double-positive cells are located in the cortex of the thymus, whereas the single-positive cells are located in the medulla, from which they migrate out of the thymus into the blood. The thymic education of T cells includes negative selection; self-reactive cells are removed to prevent autoimmune reactions and positive selection; CD4-positive and CD8-positive cells bearing antigen receptors that do not react with self MHC proteins are eliminated.

In healthy neonates the number of eosinophils increases postnatally, reaching a maximum at 3 to 4 weeks, when it represents a larger percentage (10% to 20%) of total granulocytes than in adults. This physiologic eosinophilia does not suggest the presence of allergic diseases or helminthic infections as strongly as they do in adults and is not associated with increased amounts of circulating immunoglobulin (Ig) E. ¹³

By week 12 of gestation, lymphocytes obtained from the human thymus respond to mitogens and foreign histocompatibility antigens. Furthermore, fetal cells stimulated with alloantigens exhibit normal antigen-specific cytotoxicity. In contrast, the phenotypic appearance and proportion of circulating cells are diminished, and the production of some cytokines such as interleukin (IL)-12 is reduced in neonates. The most significant defect appears to be a deficiency of memory T cells, which may be responsible for the deficient production of IFN-gamma in the neonate. The mother does not transfer T-cell–specific immunity to the fetus. ¹⁴

Immature polymorphonuclear neuthrophils (PMNs) (metamyelocytes and band forms) and mature bone marrow PMNs constitute a reserve pool of cells that may be rapidly mobilized into the circulation in response to inflammation. The rate of proliferation of neuthrophil precursors in the human neonate seems to be near maximal, and therefore their capacity to increase numbers in response to infection might be limited. As a result, rather than develop neutrophilia, as might occur in the septic adult, the neonate will rapidly develop neutropenia as a result of exhaustion or depletion of the storage pools. ¹⁵

Circulating PMNs increase dramatically after birth, peak at 12 to 24 hours, and then decline slowly by 72 hours in a neonate without complications. The fraction of immature forms remains constant at about 15%. A limited ability to accelerate neutrophil production in response to infection and impaired migration of PMNs to areas of microbial invasion in tissues contribute to the higher risk of developing overwhelming sepsis in neonates (especially premature infants). However, phagocytosis and microbial killing by PMNs seem not to be greatly impaired unless the neonates are critically ill. ¹⁶

The IgG content of the fetus and the newborn infant is mainly maternal in origin and is predominantly transferred during the latter third of pregnancy. Levels of all classes of IgG fall rapidly after birth, and the respective concentrations derived from maternal placental transfer and active production by the young infant are approximately equal by 2 months’ postnatal age. By 10 to 12 months of age, catabolism of passively acquired IgG is complete, and the infant produces all the circulating IgG ( Fig. 13-2).

In humans the antigens can be divided into three groups depending on the nature of the immune response: (1) thymus-dependent (TD) antigens, which include most protein antigens; (2) thymus-independent type 1 (TI-1) antigens, which bind directly to B lymphocytes and do not require T cells for antibody production; and (3) thymus-independent type 2 (TI-2) antigens, which are mostly polysaccharides composed of multiple identical subunits and require small numbers of T lymphocytes for antibody production to occur. The response to TI-2 antigens appears last chronologically at approximately 6 months of age, accounting for the poor neonatal response to polysaccharide vaccines and to the higher risk of infection with encapsulated organisms such as GBS. ¹⁷

The defenses against viral infections involve numerous mechanisms, including antibody neutralization of extracellular virus, direct cytolysis of infected cells by natural killer (NK) cells, antibody-dependent cellular cytotoxicity and specific cell-mediated cytotoxicity through T lymphocytes. Neonates have deficits in virtually all of these components. Infants infected with herpes simplex virus (HSV) at the time of delivery depend on the presence of passively acquired maternal antibodies, which are low in mothers with primary infection. This is the scenario in which the most severe neonatal infection occurs.

NK cells appear early in gestation and reach normal numbers by mid to late gestation; however, they are largely immature in phenotype, consisting of 50% CD56-negative cells. These cells are deficient in their ability to kill virus-infected cells and to produce critical cytokines such as IFN-gamma. Furthermore, virus-specific T-cell–mediated immunity is also diminished or delayed in the neonates with decreased T-cell killing and production of IFN-gamma. Consequently, infection with HSV in the neonate can result in a rapidly progressive, fulminant, and often fatal infection. ¹⁸

An unusually severe course of infection or an unusual pathogen, recurrent pyogenic infections, and recurrent upper and lower respiratory tract infections might be caused by immunodeficiency resulting from a congenital neutropenia or dysfunctional neutrophils. A summary of the most important diseases is shown in Table 13-1. ¹⁹

Neonatal Sepsis Epidemiology

Early-onset sepsis begins at 3 days of age (or even sooner) when organisms ascend from the birth canal after overt or occult rupture of membranes. Early-onset sepsis usually manifests as fulminant systemic illness and is associated with mortality rates of 3% to 50% (highest in premature infants). Infection with gram-negative pathogens and low-birth-weight infants are at higher risk of mortality. ²⁰²¹

Since consensus guidelines were developed in 1996 and subsequently revised in 2002 and 2010, the incidence of early-onset Streptococcus agalactiae (GBS) infections has declined from 1.7 in 1000 live births to 0.28 in 1000 live births, a 70% reduction in the incidence of early-onset GBS sepsis. During the same period, however, intrapartum antibiotic administration has been associated with an increased incidence of drug-resistant neonatal sepsis, particularly ampicillin-resistant gram-negative disease in very-low-birth-weight (VLBW) infants (<1500 g) ( Fig. 13-3). Whether the increase in gram-negative sepsis is due to intrapartum antibiotic prophylaxis remains controversial. ²²²³

Among VLBW infants the incidence of early-onset sepsis increases with decreasing gestational age (15 cases in 1000 live births for preterm versus 2.5 cases in 1000 live births for term infants). Compared with data derived before the inception of guidelines for the prevention of GBS disease, there has been a significant reduction in early-onset GBS disease, from 5.9 to 1.7 cases per 1000 live births, with a concomitant increase in E. coli sepsis from 3.2 to 6.8 per 1000 live births. Approximately 85% of the E. coli isolates have been resistant to ampicillin. When the years 1991 through 1993 were compared with 1998 through 2000, there was also an increase in the incidence of early-onset fungal disease, from 0.1 to 0.4 per 1000 live births. ²⁴²⁵

Low parity, spontaneous labor, longer length of labor and membrane rupture, multiple digital examinations, meconium-stained fluid, internal fetal or uterine monitoring, and presence of genital tract infections. The incidence of chorioamnionitis is inversely related with gestational age. ²⁶

The major risk factors for early-onset neonatal sepsis are preterm birth (the factor most closely associated with early-onset neonatal sepsis), maternal colonization with GBS, prolonged rupture of membranes (>18 hours before labor), and maternal signs or symptoms of chorioamnionitis. Other variables include ethnicity (e.g., African-American women have higher rates of colonization with GBS), low socioeconomic status, male sex, and low Apgar scores. Infant birth weight is inversely related to risk of early-onset sepsis ( Table 13-2).

The presence of any of these factors alone is not an indication for a complete sepsis work-up and antibiotic therapy; however, combinations of risk factors are clearly cumulative and should give rise to the suspicion of sepsis. ²⁷

As a general rule, presence of a major risk factor (e.g., premature rupture of fetal membranes or maternal GBS colonization) leads to an attack rate of about 1% for proven sepsis or 2% for proven or highly suspected sepsis. If a second risk factor is present, the attack rate rises to 4% to 6% for proven and 10% for proven or highly suspected sepsis. Further risk factors are additive; the presence of three risk factors raises the sepsis risk 25-fold over baseline.

The pathogenesis of early-onset sepsis has changed over the last decades as intrapartum antibiotic prophylaxis protocols have become widely used. GBS and gram-negative enteric bacilli, predominantly E. coli, are the most common pathogens for early-onset disease. In preterm infants who weigh less than 1500 grams, E. coli is more common than GBS. Coagulase-negative staphylococci (CoNS); Staphylococcus aureus; Enterococcus, Klebsiella, and Enterobacter species; Pseudomonas aeruginosa; and fungi (especially Candida albicans) are the major pathogens for late-onset diseases (onset after 72 hours). ²⁸²⁹³⁰

CoNS have increased as pathogens in the NICU as the survival of extremely-low-birth-weight infants (<1000 grams) has improved. CoNS bacteremia is associated with indwelling vascular lines. CoNS produce a biofilm that facilitates adherence to the catheter and protects them from antibiotic and host immune responses. ³¹

Clinical manifestations of GBS late-onset neonatal sepsis are more insidious, and meningitis is frequently part of the clinical picture. Late-onset disease is associated with GBS serotype III and has a lower mortality rate than early sepsis. With increase survival of extremely-low-birth-weight neonates, very-late-onset disease (>98 days) has also been described ( Table 13-3).

See Table 13-4.

Diagnosis of Neonatal Sepsis

The most sensitive criteria for the clinical diagnosis of chorioamnionitis is maternal fever higher than 38° C (100.4° F). The presence of two or more of the following criteria also supports the diagnosis; maternal leukocytosis (>15000 cells/mm³), maternal tachycardia (> 100 bpm), fetal tachycardia (>160 bpm), uterine tenderness, and foul odor of the amniotic fluid. If maternal fever and two or more of the criteria are present, there is a significant sepsis risk for the neonate, with reported attack rates ranging from 6% to 20%. This issue is further confounded by the use of epidural anesthesia, which is associated with a fourfold increased incidence of maternal fever without increasing the neonatal sepsis rate. ³³

The clinical diagnosis of sepsis in the neonate is difficult because many of the signs are nonspecific. They include fever, respiratory distress, jaundice, lethargy, irritability, anorexia or vomiting, hypotonia, “not looking well,” abdominal distention, hypothermia, hypoglycemia, apnea, seizures, shock, petechiae, and purpura. There is considerable overlap with noninfectious conditions, and some infants may exhibit transiently abnormal clinical signs during the transition to postnatal life.

The temperature of a neonate with sepsis might be elevated; depressed; or, as is frequently observed, within normal limits. Term infants are more likely to have fever than premature infants, whereas the latter are more prone to exhibit hypothermia. Fever is generally considered as a rectal temperature higher than 38° C (100.4° F). Fever can also be due to many other noninfectious causes, such as elevation in ambient temperature.

Diagnostic testing can assist with the decision to discontinue treatment. Isolation of the microorganism from a sterile site, such as blood or cerebrospinal fluid (CSF) remains the most valid method of diagnosis of bacterial sepsis. ³⁴³⁵

Body surface cultures have very limited sensitivity, specificity, and predictive value and do not establish invasive systemic infection. They reveal only colonization and are poorly correlated with pathogens isolated from blood.

In studies of neonates who died, the postmortem diagnosis of sepsis was confirmed by antemortem blood cultures in only 80% of cases. The current extensive use of maternal antibiotics further confounds the reliability of the newborn blood culture. ³⁶

A minimum of 1 mL of blood should be drawn to establish the diagnosis of bacteremia when a single pediatric blood culture bottle is used. Dividing the specimen in half and inoculating the aerobic and anaerobic bottles is likely to reduce sensitivity (0.5 mL of blood will not reliably detect 4 colony-forming units/mL) and is not recommended.

In early-onset sepsis, positive urine cultures are attributable to seeding of the kidneys during an episode of bacteremia unlike the urinary tract infections (UTIs) in older infants, which are usually ascending infections. Therefore urine cultures yield very limited information about the source of infection in early sepsis and should not be part of the sepsis work-up. However, suprapubic aspiration or bladder catheterization should be performed in all infants in whom late-onset sepsis is suspected. ³⁷³⁸³⁹

The decision to perform a lumbar puncture in neonates with suspected early-onset sepsis remains controversial. Infants with clinical signs that can be attributed to noninfectious conditions such as respiratory distress syndrome have a very low likelihood of meningitis. However, up to 23% of infants with bacteremia have concomitant meningitis and often have no clinical signs directly referable to the central nervous system (CNS). Furthermore, up to 38% of infants with meningitis have a negative blood culture. Therefore the presence of a positive blood culture cannot serve as indication to do a lumbar puncture.

Because neonatal meningitis is a low-incidence disease (0.25 in 1000 live births), an informal meta-analysis of published reports showed that it would be necessary to do at least 1000 lumbar punctures to diagnose one case that would be missed by lack of symptoms or a negative blood culture result. A rational approach would be to perform a lumbar puncture in infants with positive blood cultures, those who deteriorate with antimicrobial treatment, and those whose clinical or laboratory data strongly suggest bacterial sepsis if they do not have any contraindication for the procedure.

The cell content and chemistry of neonatal CSF differs from those of older infants. The cell content of CSF particularly in the first week is higher, and polymorphonuclear leukocytes are often present in CSF of normal newborns. In a recent study the upper reference limit of the CSF white blood cell (WBC) count was 12 cells/mm³ in preterm infants and 14 cells/mm³ in term infants. Most well infants will have cell counts lower than 10 cells/mm³. Adjusting the cell count for the number of red cells does not improve its diagnostic utility. Preterm infants have protein concentrations that are inversely correlated with their gestational age. Uninfected term newborns have protein concentrations in the CSF lower than 100 mg/dL, with a physiologic decline with postnatal age reaching values of healthy older infants before the third month of life. CSF glucose concentrations in normoglycemic uninfected neonates are similar to those of older infants (70% to 80% of a simultaneous peripheral blood glucose). Meningitis can occur in neonates with completely normal CSF values. ⁴⁰

Elevated WBC counts or abnormal neutrophil indices (low absolute neutrophil counts [neutropenia], elevated band counts, and high immature-to-total neutrophil [I/T] ratios) have a poor positive predictive value for the diagnosis of early-onset sepsis. They are useful for excluding infants without infections rather than identifying infected ones. Neutropenia is the index with the best specificity. The definition of neutropenia changes with age, type of delivery, site of sampling, and altitude; peak values are reached 6 to 8 hours after delivery. A recent study suggested that the lower limits of normal WBCs at that time should be 7500/mm³ for infants born at more than 36 weeks’ gestation, 3500/mm³ for those between 28 and 36 weeks’ gestation, and 1500/mm³ for less than 28 weeks’ gestation.

The sensitivity of CRP at birth is low because it requires an inflammatory response to increase (with the release of IL-6). Its sensitivity improves dramatically if the determination is made 6 to 12 hours later. Two normal CRP determinations (8 to 24 hours after birth and 24 hours later) have a negative predictive accuracy of 99.7% for proven neonatal sepsis.

A number of inflammatory mediators have been investigated as possible diagnostic tests for neonatal sepsis. IL-6, IL-8, and IL-10 have been found to have a critical role in the inflammatory response during neonatal sepsis; however, none of these mediators has sufficient sensitivity or specificity for the diagnosis of infection in this population. These mediators are currently not available for routine clinical purposes. ⁴¹

Antibiotic Treatment

Once sepsis is suspected in a neonate, antimicrobial treatment should be promptly begun after cultures have been obtained, even when there are no obvious risk factors for sepsis. Because GBS and E. coli are the most common pathogens of early-onset sepsis in the United States, a synergistic combination of ampicillin and an aminoglycoside (usually gentamicin) is suitable for the initial treatment of early-onset sepsis. Ampicillin is the antimicrobial of choice for treatment of GBS, Listeria monocytogenes, and most enterococci. Once the pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). ⁴²

Third-generation cephalosporins such as cefotaxime are associated with rapid development of drug-resistant bacteria in nurseries, and extensive use has been reported to be a risk factor for invasive candidiasis. Furthermore, the third-generation cephalosporins are not active against Listeria and Enterococcus species. Because of its excellent CSF penetration, the use of cefotaxime should be restricted for infants with meningitis attributable to gram-negative organisms. ⁴³

Ceftriaxone can displace bilirubin from albumin and may increase the risk of kernicterus in a jaundiced infant.

Stopping treatment for bacteremia without an identifiable focus of infection remains controversial, and the final decision requires consideration of antibiotic use during labor and the infant’s clinical course. Three recent observational studies have demonstrated an association between antibiotic use for longer than 5 days in infants with suspected early-onset sepsis (and negative blood cultures) with death and necrotizing enterocolitis. Therefore in a well-appearing infant antibiotics should not be continued for more than 48 hours (72 hours in certain cases).

A recent double-blind control trial of adjunctive therapy with intravenous Ig showed no effect on the outcomes (death and major disability at 2 years) of suspected or proven neonatal sepsis. ⁴⁴

Because Staphylococcus epidermidis is the most common cause of nosocomial sepsis in neonates, empiric therapy should include vancomycin. This antibiotic is generally paired with an aminoglycoside antibiotic to cover gram-negative organisms.

See Table 13-5.

Some studies have shown a higher risk for contracting ascending intrauterine infection in the first twin born, but this risk is modified by delivery mode and other obstetric variables. More intriguing is the observation of simultaneous occurrence of late-onset sepsis among twins, which warrants close observation and consideration of cultures in the asymptomatic twin.

Neonatal Meningitis

See Table 13-6.

A regimen of ampicillin and cefotaxime is recommended for initial empiric therapy. Treatment should be modified according to microbiology results. Meropenem or ceftazidime should be reserved for infections caused by resistant microorganisms.

Two viral infections must be considered. The first is disseminated HSV with CNS involvement. One helpful diagnostic clue is the development of skin vesicles, which can also be used as a source from which to isolate virus for diagnosis. However, about 20% of infants with this form of HSV never develop skin vesicles. Other sources for detection of the virus include respiratory secretions, blood, and CSF. If infection with HSV is strongly suspected, therapy with acyclovir should begin while viral polymerase chain reaction (PCR) and cultures remain pending. The other viral infections associated with a severe neonatal sepsis syndrome are enteroviral infections (especially Coxsackievirus).

Group B Streptococcal (GBS) Infections

Between 10% and 30% of women are colonized with GBS in their birth canal. Chronic, intermittent, or transient patterns of GBS colonization have been described. Pregnant woman with GBS colonization are 25 times more likely to deliver an infant with early-onset GBS sepsis than women whose cultures are negative (though infants with early-onset GBS have been born to women with negative antenatal cultures). Affected infants became infected during labor and delivery. In the absence of intrapartum prophylaxis, 2% of infants will develop early-onset GBS sepsis. ⁴⁶

Universal screening of all pregnant women at 35 to 37 weeks’ gestation has been recommended since 2002. Specimens should be obtained from the lower rectum and vagina and placed in a selective broth media. This enrichment step significantly increases the sensitivity of the test with at least a twofold greater yield of positive culture results than nonselective methods. On the other hand, standard laboratory methods for the isolation of GBS from blood and spinal fluid are fully adequate.

Nucleic acid amplification tests (NAATs), including PCR, for GBS can be used to screen women at term with no other risk factors but should not replace traditional antenatal cultures because they have lower sensitivity. Chromogenic media can facilitate the detection of beta-hemolytic GBS, but may not detect nonhemolytic strains. ⁴⁷⁴⁸⁴⁹

Ten serotypes have been identified on the basis of capsular polysaccharide antigens. Early studies of GBS disease in North America demonstrated a predominance of the type III serotype, thought also to be the most virulent serotype. Currently, type III accounts for approximately 70% of isolates from infants with meningitis and is isolated in almost two thirds of infants with late-onset diseases. Since the 1970s there has been a progressive change in the predominant serotypes, with type Ia now the leading cause of early-onset infection. Types VI, VII, VIII, and IX rarely cause human diseases in the United Kingdom or the United States, but worldwide its distribution varies (e.g., types VI and VIII are the most common isolates from healthy Japanese women). From an immunologic and public health perspective, the recognition of multiple new serotypes has confounded the efforts of investigators to develop an effective multivalent vaccine to prevent this disease in newborns. ⁵⁰

Penicillin (3 g [5 million units] intravenously followed by 1.5 to 1.8 g [2.5 to 3 million units] every 4 hours administered at least 4 hours before delivery) is the first-line agent for prevention of early onset GBS disease. Ampicillin is an effective alternative. Cefazolin (first-generation cephalosporin) is preferred for penicillin-allergic women at low risk for anaphylaxis. ⁵¹

The mother’s strain should be tested for sensitivity to clindamycin and inducible resistance (D-zone test) because 25% of GBS strains are resistant to clindamycin. If the test is not available, clindamycin should not be used. Erythromycin should also not be used for IAP. Vancomycin is the recommended drug for women with severe allergic reactions if the strain has not been tested for susceptibility to clindamycin. IAP with vancomycin is probably effective but is considered inadequate (in terms of neonatal management) because of the lack of efficacy data.

According to the American College of Obstetrics and Gynecology (ACOG) the following women should receive antibiotic prophylaxis:

Pros: IAP has resulted in a dramatic reduction in incidence of early-onset disease. Figure 13-4 illustrates the decline in incidence of early-onset GBS disease over the past decade as IAP programs were implemented. The graph is based on composite data from surveillance centers of the Centers for Disease Control and Prevention (CDC), a National Institute of Child Health and Development multicenter study reviewing disease rates from 1992 to 1997, and ongoing surveillance at the author’s center. The incidences of disease from 1990 to 1993 represent the pre-IAP era, whereas data from 1993 to 1996 followed the ACOG and American Academy of Pediatrics (AAP) recommendations published in 1993. The third data set reflects the impact of the CDC recommendations published in 1996.

Cons:

In 2010 the CDC published new guidelines for prevention of early-onset GBS sepsis ( http://www.cdc.gov/groupbstrep/guidelines/index.html). These are summarized in Figure 13-5.

A recent retrospective analysis revealed that women undergoing GBS screening at the time of labor were as likely to have false-negative cultures as those undergoing screening between 35 and 37 weeks’ gestation. This study claimed that the majority of false-negative screens result from inappropriate collection or processing of specimens. Another ongoing challenge is clinical adherence to current guidelines; missed opportunities for GBS prevention happen frequently, particularly among women delivering preterm infants.

Most infants who contract late-onset disease acquire the organism outside the hospital. Mothers of these infants may have no history of genital colonization with GBS during pregnancy. ⁵⁵

Staphylococcus Epidermidis

CoNS are commensal skin and mucosal flora. Nearly 99% of healthy neonates will have positive nose or umbilicus swabs for CoNS by day 4 of life. However, these organisms also account for up to one half of reported bloodstream infections in VLBW (<1500 g) infants. ⁵⁶

Improved survival rates of VLBW infants have resulted in an increased risk for sepsis because of the many invasive therapies required for management, such as central venous catheters. Central lines are associated with an increased risk of CoNS bacteremia. Colonization precedes infection with this species. Therefore CoNS infections present a particular dilemma because their isolation from a single blood culture in a neonate can either reflect contamination or true bacteremia. A suggested algorithm for interpreting blood cultures caused by CoNS is shown in Figure 13-6. ⁵⁷

Umbilical vessels and intravascular catheters are essential in the NICU, and results of blood cultures can yield ambiguous interpretations (e.g., contamination versus catheter colonization versus systemic infection). Some microbiological features can be useful assisting this decision, such as time to growth (the longer the time elapsed between obtaining the blood culture and its growth, the more likely it is it represents a contaminant), number of positive cultures (especially if obtained from different sources; peripheral and central), the organisms’ isolates (contamination is more likely when multiple specimens grow), and clinical signs. ⁵⁸⁵⁹

The initial recommended therapy is vancomycin, which may be modified once the isolate susceptibility is known. In cases of persistent bacteremia, a combination of vancomycin and rifampin may increase efficacy.

When an indwelling catheter must be left in place, antibiotic therapy should be administered through the catheter. Removal of the catheter may be necessary if the culture remains positive. The same applies for other medical devices, such as meningitis resulting from an infected ventriculoperitoneal shunt.

Because of concerns regarding the emergence of vancomycin-resistant organisms, routine use of prophylactic vancomycin for all neonates at risk of CoNS bacteremia is not currently recommended. ⁶¹⁶²

Candida

Approximately 1.4% of early-onset neonatal infections result from Candida species (mainly Candida albicans but increasingly from other species, such as Candida parapsilosis and Candida glabrata). For late-onset sepsis the incidence varies from 2.6% to 16.7% among VLBW infants and up to 20% for extremely-low-birth-weight infants. There is a marked inverse correlation between mortality caused by Candida species and neonatal weight; a recent analysis reported an all-cause mortality rate of 26% in infants weighing less than 1000 g with candidiasis compared with 13% in infants without candidiasis. ⁶⁶⁶⁷

Early-onset candidal disease, or congenital candidiasis, arises from exposure of the infant to organisms colonizing the maternal genital tract. Cutaneous findings are the hallmark of the disease, but the association with pulmonary disease conveys a poor prognosis despite systemic antifungal therapy. On the other hand, catheter-associated fungemia generally arises from organisms on the skin or within the gastrointestinal tract.

Candida infections acquired after the first week of life might be limited to the bloodstream, urine, or CSF or may disseminate to involve one or many organ systems. Fungal abscesses may be found in the heart, bones, kidneys, bladder, eyes, or brain. The medical literature concerning end-organ evaluation after neonatal candidemia is heterogeneous; however, a retrospective study suggested potential damage from the following sources: endophthalmitis (median, 3%), meningitis (15%), brain abscess or ventriculitis (4%), endocarditis (5%), positive renal ultrasound (5%), and positive urine culture (61%). ⁶⁸⁶⁹

The highest risk period for ICIs in preterm neonates occurs during the first 4 to 8 weeks of life. Several studies have shown that fluconazole prophylaxis can reduce those infections among preterm infants, with highest efficacy among VLBW infants and those weighing 750 g or less. The pros and cons of antifungal prophylaxis are summarized in Table 13-7. ⁷⁰

Studies in more than 4000 neonates have demonstrated efficacy and safety with fluconazole prophylaxis in extremely preterm neonates, with an overall reduction of 83%. No significant increases in azole-resistant strains have been documented. Enteral fluconazole is 90% absorbed; therefore once neonates achieve enteral feeding, the dosing can be switched from intravenous to oral administration to complete 4 to 6 weeks of prophylaxis. ⁷¹

A randomized control trial of infants with birth weight below 1500 g compared oral fluconazole to oral nystatin prophylaxis started in the first 7 days of life and continued until enteral feeding was achieved. ICIs occurred in 5.3% of fluconazole-treated patients compared with 14.3% of nystatin-treated infants. The study also raised the question of safety of enteral nystatin in extremely premature infants when they were not receiving full enteral feedings. The oral nystatin suspension contains a high concentration of sucrose and is highly osmolar. This raises a theoretical concern of bacterial translocation and increased risk of necrotizing enterocolitis. Other advantages of fluconazole over nystatin are lower cost, administration twice-weekly compared with thrice daily, and ability to administer the drug intravenously when the infant is not receiving anything by mouth. ⁷²

Although empiric or prompt standardized treatment (including prompt removal of central venous catheters) may reduce Candida-related deaths, neurodevelopmental impairment may still occur in the survivors, particularly in those weighing less than 1000 g. Strategies to reduce morbidity and mortality in NICUs are summarized in Table 13-8. ⁷³⁷⁴⁷⁵

According to the Infectious Diseases Society of America Guidelines published in 2009, amphotericin B deoxycholate remains the mainstay of therapy (dose is 1 mg/kg/day). Although side effects include nephrotoxicity, hypokalemia, hepatotoxicity, and bone marrow suppression, the drug appears to be well tolerated in neonates. If urinary tract involvement is excluded, the lipid formulation of amphotericin B (3 to 5 mg/kg/day) can be used. Fluconazole at 12 mg/kg/day is a reasonable alternative. The recommended length of treatment is 3 weeks. Echinocandins (e.g., caspofungin) should be used with caution among neonates and are usually reserved for situations in which resistance or toxicity precludes the use of fluconazole or amphotericin. ⁷⁶⁷⁷

A lumbar puncture and dilated retinal examination are recommended in neonates with sterile body fluid or urine cultures positive for Candida species. Imaging of the kidney and heart should be performed if the results of sterile body fluid cultures are positive.

The recurrence of Candida disease has been described in four immunocompetent infants after a prolonged period of latency (up to 1 year). All the infants presenting with Candida arthritis and osteomyelitis were born prematurely, had received parenteral nutrition through indwelling catheters, and had a history of systemic candidiasis during the newborn period. The pathogenesis of these latent infections remains unknown. ⁷⁸

Infection Control

Incidence rate is the number of new cases of a disease that occur during a specific period of time in a population at risk for developing the disease (i.e., number of cases of bacteremia per 1000 catheter-days). Prevalence is the number of affected persons present in the population at a specific time divided by the number of persons in the population at the time (i.e., proportion of pneumonia cases in a neonatal unit on a particular day).

Endemic infections represent the bulk of nosocomial infections and are the usual level of infection expected during a given period for a given population. Epidemic infections are marked by an unusual increase in the incidence of disease entity.

Neonates, especially if premature, require intensive medical care and are among the patients at highest risk for HAIs. Some series have reported that more than 20% of critically ill neonates who survive longer than 48 hours acquire a HAI, with a significant worsening of their prognosis and excessive direct health costs. ⁷⁹

Nonmaternal routes of transmission (generally accepted when symptoms start 3 days or longer after admission) can be categorized as follows:

Specific microorganisms can be spread by more than one route, but in most cases one mechanism predominates. Most of the HAIs are caused by the infant’s own flora. ⁸⁰

Patients suspected of having tuberculosis, varicella, or measles must be placed on airborne precautions in negative-pressure rooms to prevent aerosol spread of their infection. It is important to assess the family members of such patients because they might be potential sources of the infection as well. ⁸¹

Patients (or nonimmune staff or visitors) must be isolated from day 8 to day 21 after documented exposure to a person with active varicella zoster virus (VZV) infection. If a patient has received varicella-zoster immune globulin (VZIG), the incubation period is extended to 28 days. Varicella immunization is recommended for people without evidence of immunity, provided there are no contraindications for vaccine use.

Contact precautions involve the use of barriers to prevent transmission of organisms by direct or indirect contact with the patient or contaminated objects in the patient’s immediate environment. Ideally, patients should be placed in private rooms. Cohorting of patients infected with the same microorganisms can be a safe and effective alternative. Health care workers should wash hands when entering and leaving the room and wear clean nonsterile gloves and a cover gown when entering the room.

The following diseases require contact isolation:

Droplet precautions are intended to reduce the risk of transmission of infected agents by large-particle droplets from an infected person. Such transmission usually occurs when an infected person generates droplets while coughing, sneezing, or talking and during procedures such as suctioning.

Patients should be placed in private rooms, and staff should wear masks when working within 3 feet of the patient. Examples of conditions that necessitate droplet precautions include influenza virus, adenovirus, parvovirus, rubella, pertussis, and meningitis caused by Haemophilus influenzae or Neisseria meningitidis.

Standard precautions are designed to reduce the risk of transmission of microorganisms from recognized and unrecognized sources and are to be followed for the care of all patients, including neonates. They apply to blood; all body fluids, secretions, and excretions except sweat; nonintact mucous membranes; and skin.

Components of standard precautions include performing proper hand hygiene and wearing gloves, gowns, masks, and other forms of eye protection.

Hand hygiene plays a key role for caregivers in the reduction of HAIs for patients.

Soap and water should be used when hands are visibly soiled or contaminated with proteinaceous materials, blood, or body fluids and after using the restroom.

When hands are not visibly soiled, alcohol-based hand rubs, foams, or gels are important tools for hand hygiene. Compared with washing with soap and water, use of alcohol-based products is at least as effective against a variety of pathogens and requires less time. Furthermore, these agents are less damaging to skin.

Hand disinfection with an alcohol-based hand rub is the preferred method because of its rapid action and effectiveness. In addition, alcohol-based rubs contain emollients that serve as dermal protectors and decrease bacterial dispersal. In contrast, antiseptic skin washes can damage the skin barrier and offer no advantages. ⁸²

CDC guidelines recommend nonsterile, fluid-resistant gowns to be worn as protection when soiling of clothing is anticipated and in performing procedures likely to result in splashing or spraying of body substances.

Gloves should be worn whenever contact with blood, body fluids, secretions, excretions, and contaminated items are anticipated. Wearing gloves is not a substitute for hand hygiene. Hand hygiene should be performed immediately after glove removal.

The principles of family-centered care encourage liberal visitation policies in neonatal units (well-infant nurseries and NICUs). Parents and siblings should be allowed liberal visitation. Written policies should be in place to guide siblings’ visits, and parents should be encouraged to share the responsibility of protecting the newborn from contagious illness. ⁸³

Conjuntivitis

Ophthalmia neonatorum is a conjunctivitis that occurs within the first 4 weeks of life. It has been associated with a variety of organisms, which have changed in their relative importance and geographic distribution over a period of years. The introduction of neonatal ocular prophylaxis and routine screening and treatment of maternal gonorrhea and more recently Chlamydia trachomatis infection have altered the epidemiology of ophthalmia neonatorum. In the United States C. trachomatis is likely the most common cause of conjunctivitis in neonates.

In addition to C. trachomatis and Neisseria gonorrhoeae, S. aureus and various gram-negative bacteria such as E. coli, Klebsiella species, and rarely Pseudomonas species have also been associated with neonatal conjunctivitis.

Viral causes of conjunctivitis are rare during the first month; however, 70% of cases with viral etiology are due to HSV, which may also cause severe systemic disease.

The age at onset may suggest a specific etiology; however, there is substantial overlap among the various causes depending on obstetric factors such as prolonged rupture of membranes ( Table 13-9). ⁸⁴⁸⁵

The first step should be a Gram stain of the conjunctiva exudate. If it shows gram-negative intracellular bean-shaped diplococci, Neisseria gonorrhoeae (or other Neisseria species) should be assumed to be the cause of the eye discharge, and the infant should be admitted for urgent systemic treatment. If treatment is delayed, the infection could spread to the cornea leading to ulcerations and ultimately loss of vision. Note that the eye discharge seen in gonococcal ophthalmia is often thick, copious, and golden-yellow in color. Cultures of blood, eye discharge, and other potential sites of infection, such as CSF, should be performed to confirm the diagnosis and determine antimicrobial susceptibility. Testing for concomitant infection with C. trachomatis, Treponema pallidum, and human immunodeficiency virus (HIV) should also be done, as well as a review of hepatitis B status in the mother.

NAATs are highly sensitive and specific, but only a few are approved by the U.S. Food and Drug Administration (FDA) for conjunctival specimens; therefore the diagnosis still relies on culture. A combined DNA probe for the detection of both N. gonorrhoeae and C. trachomatis is also commercially available. Remember that C. trachomatis is an obligate intracellular organism, so the collection swab must be scraped across the conjunctiva or nasopharynx to ensure that there are adequate cells for detection. In the eye the pus should be wiped away before the conjunctiva scrapings are obtained. If herpes conjunctivitis is suspected, a PCR test for herpes simplex or culture should also be done. The identification of C. trachomatis or N. gonorrhoeae in a newborn infant indicates untreated infection in the parents. ⁸⁶

Nondisseminated gonococcal neonatal infections such as ophthalmia neonatorum should be treated with ceftriaxone, at a dose of 25 to 50 mg/kg administered intravenously or intramuscularly given once, not to exceed 125 mg. Additional topical therapy is not needed when ceftriaxone is used; however, the infant’s eyes should be irrigated with normal saline frequently until the discharge has resolved.

Infants with chlamydial conjunctivitis are treated with oral erythromycin (50 mg/kg/day divided into four equal doses) for 14 days. Additional topical therapy is not needed. Because the efficacy of erythromycin is only 80%, a second course may be required, and follow-up of infants is recommended. Limited data suggest that azithromycin at an oral dose of 20 mg/kg given once a day for 3 days may be effective. Herpes conjunctivitis is rare and is almost always accompanied by other systemic manifestations of neonatal herpes. The treatment for neonatal herpes conjunctivitis is parenteral acyclovir plus topical therapy with 1% trifluridine solution, 0.1% iododeoxyuridine, or 3% vidarabine applied to the eye every 2 hours for 7 days or until the cornea has re-epithelialized. ⁸⁷

The visual loss associated with trachoma is caused by irreversible corneal damage resulting from chronic folliculitis owing to repeated chronic infections. Because of their immature immune systems, newborns lack the requisite lymphoid tissue in their conjunctiva to mount such an inflammatory response. The length of infection also makes a difference. Even older children do not develop folliculitis until the infection has been present for at least 1 to 2 months; newborn conjunctivitis caused by C. trachomatis usually clears by 2 months even without antibiotic treatment, so it rarely results in long-term sequelae. Another important factor may be that the serotypes of C. trachomatis that cause endocervical infections in women and conjunctivitis in neonates (types D through K) differ from the serotypes that cause blinding trachoma (types A through C).

No. Topical silver nitrate, tetracycline, and erythromycin given at birth are equally effective in preventing gonococcal ophthalmia neonatorum, but none of these agents significantly decreases the incidence of chlamydial conjunctivitis. The only way to prevent Chlamydia infections in the newborn is by treating infected mothers before delivery.

Chlamydial Infections

C. trachomatis is the most common sexually transmitted pathogen in Western industrialized countries. Most of the infections in adults are asymptomatic but can cause severe reproductive complications in women; chronic salpingitis caused by C. trachomatis can lead to infertility and an increased risk for ectopic pregnancy. This is in contrast with gonococcal infections, in which most infected individuals are symptomatic and therefore present acutely for care. Although studies are conflicting, C. trachomatis infection in pregnancy is weakly linked to premature rupture of membranes and premature delivery. Between 10% and 30% of women with chlamydial infections who undergo induced abortions develop late endometritis. ⁸⁸⁸⁹

Chlamydia infection can be transmitted from an infected mother to her newborn during delivery, resulting in conjunctivitis, pneumonia, or both.

An infant born to a mother with chlamydial infection of the cervix is at 60% to 70% risk of acquiring the infection during passage through the birth canal. Of exposed infants, 20% to 50% develop conjunctivitis at 5 to 14 days of age and 10% to 20% develop pneumonia between 4 and 12 weeks of life (conjunctivitis is not a prerequisite to develop pneumonia). In utero transmission is not known to occur.

The remaining infants develop an apparently asymptomatic colonization of the nasopharynx, rectum, or vagina. These infants can remain colonized for up to 3 years, although most clear the infection even without treatment by 1 year of age. There is no evidence to suggest that infants with chlamydial infections should be isolated. Note that successful treatment of the mother during pregnancy with oral erythromycin or azithromycin prevents most cases of vertical transmission. ⁹⁰

C. pneumoniae is a common cause of atypical pneumonia in school-age children and young adults; along with Mycoplasma species. It is not known to cause pulmonary diseases in newborns.

Chlamydia culture of the conjunctiva (for conjunctivitis) or nasopharynx (for pneumonia) remains the gold standard for diagnosis. However, cultures have many disadvantages; specimens require special handling, which can make transport to the laboratory challenging and generally require 3 to 7 days for processing, which may delay treatment. NAATs have largely replaced tissue culture isolation and nonamplified direct detection methods (e.g., DNA probe, direct fluorescent antibody [DFA] test or enzyme immunoassays [EIA]) because of their better sensibility and specificity.

NAATs have FDA approval for cervical swabs from women, urethral swabs for men, and urine from women and men. Published evidence of NAATs on conjunctival specimens or nasopharyngeal samples is limited, but preliminary results show that their sensitivity and specificity is as high as with culture. Serologic diagnosis of chlamydial infections are difficult to interpret and only done in a few clinical laboratories

Mothers with positive endocervical cultures should be treated during pregnancy to prevent vertical transmission. The recommended treatment for pregnant women is azithromycin (1 g orally as single dose) or amoxicillin (1.5 g/day in 3 divided daily doses for 7 days). Repeated testing (preferably NAATs) is recommended in pregnant women 3 weeks after treatment to determine whether treatment has been successful; if not, a second course of treatment may be indicated. Sexual partners of positive women must be treated as well. Chlamydia infection in both male and female genital tracts can be asymptomatic, which is why routine screening in pregnancy is warranted. ⁹¹

Until recently, the AAP recommended that babies born to mothers with untreated chlamydial cervical infections receive oral erythromycin (50 mg/kg per day in four divided doses) for 14 days, starting on the first day of life. However, the efficacy of prophylactic treatment is unknown; moreover, reports of an association between the use of oral erythromycin for pertussis and infantile hypertrophic pyloric stenosis have appeared. The AAP now recommends that treatment be reserved for infants with actual infection and not for prophylaxis.

Neonates with chlamydial conjunctivitis or pneumonia should receive oral erythromycin base or ethylsuccinate, 50 mg/kg/day in four divided doses, for 14 days. The efficacy of erythromycin is approximately 80%; therefore a second course may be required, and follow-up of infants is recommended. Limited data on azithromycin for treatment of chlamydial infection in infants suggest that dosing of 20 mg/kg as a single dose for 3 days may be effective. Its shorter treatment course and less severe gastrointestinal side effects could improve treatment compliance. ⁹²

The onset of C. trachomatis pneumonia usually occurs between 4 and 12 weeks of age (a few cases present as early as 2 weeks, but none has been reported beyond 4 months). Most infants have a prodromal period of approximately 1 week’s duration that involves nasal obstruction or discharge without fever and a persistent paroxysmal staccato cough that can lead to respiratory distress. Expiratory wheezing occurs in fewer than 25% of infants with the disease; 60% have abnormal eardrum findings. Although a severe illness is relatively rare, affected infants appear irritable, eat poorly, and cough often.

The chest x-ray shows hyperinflation of the lungs with bilateral diffuse nonspecific infiltrates. Possible laboratory findings include a distinctive peripheral eosinophilia (>300 to 400/mm³), mild arterial hypoxemia, and elevated serum immunoglobulins.

Without treatment, symptoms last an average of 6 weeks. Treatment of any previous conjunctivitis with oral erythromycin seems to prevent pneumonia, although there are case reports of treatment failures. Approximately 50% of the infants with chlamydial pneumonia do not have a history of previous conjunctivitis. ⁹³⁹⁴

Osteomyelitis and Septic Arthritis

Because most cases of neonatal osteomyelitis arise as a consequence of bacteremia, the organisms responsible for causing osteomyelitis reflect the changing trends in the ethology of neonatal sepsis as well as the different likelihood of osteoarticular shedding within pathogens.

Although osteomyelitis was rare in the past, recent studies suggest that it might be increasing in neonates. The overall rate of nosocomial bone and joint infections is approximately 1 or 2 in 1000 admissions.

Hematogenous dissemination is responsible for most cases; however, skeletal infections can also result from the following:

Hematogenous infection of long bones is initiated in dilated capillary loops of the metaphysis, adjacent to the cartilaginous growth plate (physis), where blood flow slows, providing pathogenic bacteria with an ideal environment to multiply. In neonates there is an anatomic communication between the circulatory systems of the metaphysis and epiphysis (transphyseal vessels) that can lead to severe damage of the cartilage cells on the epiphyseal side of the growth plate when infection occurs. This damage is generally irreversible and results in abnormal growth of the bone. The vascular connection is obliterated at 8 to 18 months of age when the epiphyseal and metaphyseal become totally separated.

Decompression of the primary metaphyseal abscess through the adjacent cortex also permits entrance of pus into the articular space of the bones whose metaphyses lie within the articular capsule of the joint. Suppurative arthritis of hips, shoulders, elbows, and knees is frequently seen in osteomyelitis of the humerus or the femur ( Fig. 13-8).

On account of a relatively thin cortex, the abscess usually spreads into the subperiosteal space and rapidly involves the entire circumference and length of the bone. This free communication between the original site of osteomyelitis and the subperiosteal space prevents the necrosis and cortical sequestra that happens in older children and adults. The efficient vasculature and fertility of the inner layer of the periosteum encourage early development of new bone formation (involucrum), permitting remodeling of bone within a very short time after the infectious process has been controlled.

In most studies the ESR is significantly elevated on days 2 through 5. ESR values slowly return to normal within 3 weeks of therapy. In contrast, CRP rises within 6 to 12 hours of a triggering stimulus and returns to normal within 1 week of therapy. A secondary rise in either ESR or CRP could be a sign of recrudescence. Neither CRP nor ESR can be used to rule out osteomyelitis when normal. ⁹⁸

Candida species have become a more frequent cause of bone and joint infection. Some studies report that approximately 17% of septic arthritis in premature infants is caused by Candida species.

Joint aspiration with incision and drainage is appropriate whenever there is a significant collection of pus in the soft tissues. Often, surgical drainage is indicated for relief of intraarticular pressure when the hip or shoulder is affected.

See Table 13-10.

Neonatal osteomyelitis of the maxilla is a distinct clinical entity usually caused by S. aureus. The clinical course of this condition begins with acute onset of fever and nonspecific systemic symptoms that shortly after are accompanied by the following:

This entity can be confused with orbital cellulitis or dacryocystitis.

Once cultures are obtained, the initial choice of antimicrobial agents must be based on the presumptive bacteriologic diagnosis. Penicillinase-resistant penicillins (i.e., oxacillin) are effective against methicillin-sensitive S. aureus, group A streptococci, and GBS. Vancomycin should be used if MRSA or CoNS infection is suspected. Osteomyelitis caused by enteric organisms is sufficiently common in neonates to justify adding an aminoglycoside to the initial regimen.

If the organism is identified and antibiotic sensitivities have been determined, treatment should be changed to the safest and most effective drug. Therapy should be continued for a minimum of 4 to 6 weeks. In the neonatal age group, orally administered antibiotics are not used because there are insufficient data regarding their absorption and efficacy. ⁹⁹

Pyelonephritis and Urinary Tract Infection

The signs and symptoms suggest an acute infectious process. The urinalysis is consistent with a diagnosis of acute pyelonephritis (assuming that the specimen has been properly obtained). The incidence of UTI in infants during the first month of life varies between 0.1% to 1% depending on the population studied. Unlike the distinction of cystitis and pyelonephritis in older infants and children, infection of the urinary tract in the neonate often involves the kidney.

Asymptomatic bacteriuria occurs in 2% of healthy term neonates and up to 10% of premature infants. Males are affected more often than females in the neonatal period, and uncircumcised males are even more susceptible, with a threefold to sevenfold increased risk.

Unlike in older infants, hematogenous spread of infection is more common in neonates than ascending infection. Anatomic or physiologic abnormalities of the urinary tract, such as obstructive uropathy, are also common underlying factors. Urinary tract anomalies have been detected in 30% to 55% of infants with UTI younger than 2 months of age.

The symptoms of UTI are varied and nonspecific. UTI can present as an insidious illness with failure to thrive and low-grade fever or simply as a fever without apparent source or septicemia. Jaundice is an important feature of UTI; it usually occurs suddenly and clears rapidly after adequate treatment has been started. Many infants with UTIs and jaundice have positive blood cultures.

The definitive diagnosis is made by positive culture of urine that is obtained by percutaneus aspiration or urethral catheterization of the bladder. Urine from bags and other nonsterile materials should not be used because false-positive results are very common. The yield of urine culture in neonates younger than 3 days of age is poor.

Urinalysis is not very helpful insofar as neither the presence nor absence of pyuria is completely reliable evidence for or against UTI. However, an enhanced urinalysis (leukocytes measured in unspun urine by a hemocytometer) has been shown to be a sensitive marker of UTI when more than 10 WBC/mm³ are found. A dipstick test for leukocyte sterase and nitrite is inadequate to exclude UTIs in neonates.

The most common organism causing UTI in neonates is E. coli, which accounts for 91% of community-acquired infection in children younger than 8 weeks of age. Other organisms include Proteus, Pseudomonas, Klebsiella, and Enterococcus species or S. aureus, which may be associated with localized suppurative lesions in the urinary tract. With prolonged hospitalization, CoNS and Candida species can also cause UTIs in patients with or without urinary catheters. Candidiasis can be associated with fungal balls in the kidney and renal pelvis, which can lead to obstruction. ¹⁰⁰

Parenteral antibiotics are used to treat pyelonephritis, usually a combination of a penicillin and an aminoglycoside. The clinician should try to obtain a urine culture before initiating antibiotic treatment and then modify the treatment once culture results and sensitivities are known. For suspected staphylococcal infection, a penicillinase-resistant penicillin or vancomycin should be considered. Amphotericin is used for Candida species infection. For an uncomplicated UTI the duration of therapy is usually 10 to 14 days. The transition to an oral regimen depends on the clinical and microbiological response and the presence of bacteremia or anatomic abnormalities. A second urine sample is often obtained after 48 hours to ensure clearance of the organisms from the urinary tract.

In the past, prophylactic antibiotics were often used for structural anomalies of the urinary tract or vesicoureteral reflux. However, a systematic review of randomized controlled trials revealed limited evidence for its efficacy. Moreover, antibiotic prophylaxis may increase the risk of a subsequent UTI by a resistant microrganism. ¹⁰¹¹⁰²

A UTI is generally a bloodborne disease; however, some neonates may have associated meningitis and septicemia. Therefore, in addition to urinalysis and urine culture, neonates should have blood and CSF culture specimens drawn before the initiation of antibiotics.

In addition to diagnosing UTI, it is also important to evaluate the urinary tract for underlying structural or functional abnormalities that may predispose the infant to recurrent UTIs. Abdominal ultrasound is a safe and noninvasive method of evaluating structural abnormalities of the urinary tract and is the initial imaging test of choice. Intravenous pyelography can be useful in assessing the function of the kidneys. Radionuclide scans such as dimercaptosuccinic acid scans can also be used to evaluate function and structural abnormalities, specifically renal scars following UTI. Vesicoureterography to evaluate the presence or absence of vesicoureteric reflux should be performed after completion of treatment of the UTI, because transient vesicoureteral reflux commonly occurs with the acute infection. ¹⁰³

Omphalitis

In hospitalized infants the incidence is approximately 2%. In infants delivered at home the incidence may be as high as 21%.

Serosanguinous drainage may be seen with a patent urachus or omphalomesenteric duct.

First-line treatment includes a penicillinase-resistant penicillin and an aminoglycoside antibiotic. If MRSA is suspected, vancomycin should be considered.

Leukocyte adhesion deficiency is a life-threatening, autosomal-recessive inherited deficiency of cell adhesion molecules associated with chronic omphalitis or delayed separation of the umbilical cord. The hallmark of leukocyte adhesion deficiency is the absence of granulocytes at the site of infection.

Funisitis is a mild inflammation of the umbilical stump with minimal drainage and erythema in the surrounding tissue. It is a local noninvasive infection that may become invasive and lead to a severe abdominal wall inflammation associated with necrotizing fasciitis. ¹⁰⁶

Listeriosis

Listeriosis causes an estimated 2500 serious illness and 500 deaths annually in the United States. The incidence is highest among newborns: 2 to 13 cases per 100,000 live births, representing 30% to 40% of the total cases in humans. Pregnant women along with elderly adults and those with immunodeficiencies are also at-risk groups. Pregnant women account for about 27% of cases, with the highest incidence in the third trimester. Fecal carriage in pregnant women may lead to vaginal colonization and can be responsible for late-onset infections in infants born of healthy mothers. The frequent presence of chorioamnionitis in the absence of ruptured membranes supports the hypothesis that Listeria infection can occur through a transplacental route.

Listeria species organisms are ubiquitous in nature. Although direct transmission to humans from infected animals has been reported, most human infections are acquired through ingestion of contaminated food. The relative resistance of Listeria organisms to high temperatures and their ability to multiply at low temperatures provide opportunities for heavy colonization of dairy products if pasteurization has been improperly carried out. Outbreaks are commonly associated with prepared meat products and seafood products. Although L. monocytogenes is probably ingested frequently, the incidence of clinical diseases in humans is relatively low, suggesting that the organism has a relatively low virulence. This is supported by the large inoculum required to cause infection in normal hosts. Nevertheless, listeriosis represents the leading cause of death from foodborne diseases in the United States. ¹⁰⁷¹⁰⁸

After ingestion of the microorganism, the incubation period for L. monocytogenes is less than 24 hours, but it can range from 6 hours up to 3 weeks. Invasion of the intestinal mucosal barrier leads to bacteremia, resulting in a flulike illness with fever, chills, myalgia, arthralgia, headache, and backache. Premature labor in pregnant women with listeriosis is common in approximately 70% of cases. The neonatal mortality rate, including stillbirth and abortion, is 40% to 50%. Often the placenta becomes a reservoir for bacterial proliferation, resulting in amnionitis with persistence of maternal symptoms until abortion or delivery occurs. Symptoms in the mother usually subside with or without antibiotic treatment soon after delivery. If the infection is recognized promptly, the mother may be treated effectively, preserving the pregnancy. ¹⁰⁹¹¹⁰

Similar to GBS, neonatal listeriosis is divided into two clinical forms defined by age: early onset (≤1 week) and late onset (>1 week). Evidence of preceding maternal illness is often described in infants with early-onset disease, and most cases are clinically apparent at delivery with meconium-stained fluid, septicemia, and pneumonia. In severe infections a granulomatous rash—called granulomatosis infantiseptica—has been described with microabscesses throughout the body but particularly on the the liver and spleen. Blood cultures are positive in 75% of cases, and death might occur within a few hours in up to 25% of infected newborns, particularly if premature.

Late-onset neonatal listeriosis commonly presents as meningitis. Affected infants may not appear particularly ill and might elude diagnosis for several days. A striking predominance of boys has been noticed in most series. Other clinical forms of diseases at this age include colitis with associated diarrhea and sepsis without meningitis. Gram stain of the CSF does not always yield the correct diagnosis because variable decoloration results in organisms that appear as either gram-negative rods or gram-positive cocci. The mortality risk of late-onset disease is generally low if treatment is started promptly. ^111112113

L. monocytogenes is an intracellular, facultative anaerobic, non–spore-forming, motile gram-positive bacillus that multiplies intracellularly. Once phagocytized, invasive L. monocytogenes replicates rapidly within the cytosol, thanks to its major virulence factor, listeriolysin O. Using the cell’s own cytoskeletal actin polymerization mechanism, L. monocytogenes pushes outward on the host cell’s membrane, forming filopods, which are then injected into neighboring cells. Cell-to-cell transmission spreads rapidly without exposure to extracellular host defenses such as antibodies or neutrophils. T-lymphocytes therefore provide the only natural recognition and immunity toward L. monocytogenes, although macrophage killing (probably using nitric oxide) may also occur. Because cellular immunity is suppressed during pregnancy and is naturally deficient during early neonatal life, L. monocytogenes enjoys an advantage during these host-vulnerable periods. In hosts with adequate cellular responses, symptomatic infection is rare and self-limited. ¹¹⁴

L. monocytogenes remains sensitive to ampicillin. Adding an aminoglycoside, usually gentamicin, is recommended for severe infections because of synergism with ampicillin. Because of the organism’s tendency to hide in tissue reservoirs, higher doses of ampicillin are usually recommended for extended durations (10 to 14 days for invasive infections and 14 to 21 days for meningitis). Longer courses might be necessary for patients who are severely ill or have endocarditis or rhombencephalitis (brainstem encephalitis).

Trimethoprim-sulfamethoxazole (TMP-SMX) can be considered for mothers who are sensitive to penicillin. Cephalosporins are not active against listeriosis. Iron therapy for anemia should be withheld during treatment of listeriosis because iron enhances the organism’s growth in vitro and is therefore a virulence factor, contributing to the host’s susceptibility to infection. Listeriosis is a notifiable disease in the United States. ¹¹⁵

Syphilis

The changing incidence of congenital syphilis over the years follows the trend of acquired syphilis in women. After a major public success in early 1990, with the lowest rates since reporting began in 1941 (10.5 cases/100,000 live births), the incidence of primary and secondary syphilis has increased since 2005, particularly in large urban areas and in the southern United States. Insufficient public health resources, use of illegal drugs (particularly crack cocaine), and coinfection with HIV are factors implicated in this increase. The World Health Organization (WHO) estimates that 1 million pregnancies are affected by syphilis worldwide. ¹¹⁶

Congenital syphilis starts with T. pallidum crossing the placenta from mother to fetus. Fetal infection can occur as early as at 9 to 10 weeks’ gestation, but infection can occur any time after that, including at birth because of contact with maternal lesions. Transmission in utero causes the wide dissemination of the spirochetes in the fetus, analogous to secondary-acquired syphilis. Untreated congenital syphilis can progress through the same stages as postnatally acquired syphilis (except for the absence of a primary stage or chancre).The likelihood of vertical transmission is directly related to the maternal stage of syphilis: 60% to 100% during primary and secondary syphilis, 40% in early latent infection, and 8% with late latent infection.

Syphilis has commonly been described as the “great imitator” because of the variety of clinical manifestations; approximately two thirds of infected newborns are asymptomatic at birth, but later (even decades later) manifestations are not uncommon. Clinical manifestations appearing within the first 2 years of life are considered early congenital syphilis, and manifestations occurring after this time are considered late congenital syphilis ( Table 13-11). ¹¹⁷

Pneumonia alba, a fibrosing pneumonitis, is characterized by yellow-white, heavy, grossly enlarged lungs. There is a marked increase in the amount of connective tissue in the interalveolar septa and interstitium histologically, with loss of alveolar spaces and obliterative fibrosis. The classic radiographic appearance is one of complete opacification of both lung fields. This may lead to a chronic pulmonary disease in 10% of cases.

The findings of Hutchinson teeth, interstitial keratitis, and eighth nerve deafness constitute Hutchinson triad and are virtually pathognomonic for late congenital syphilis. ¹¹⁸

All women should be screened for syphilis during pregnancy with a nontreponemal test, and no neonate should leave the hospital without determination of the mother’s status at least once during pregnancy and close to delivery in high-risk populations.

Nontreponemal tests for syphilis include the Venereal Diseases Research Laboratory (VDRL) test and the rapid plasma regain (RPR) test. These tests are inexpensive and rapid, so they are used mainly for screening. Quantitative results can assist in monitoring disease activity or response to treatment (preferably if performed in the same laboratory). They can be falsely negative in early primary syphilis and late congenital syphilis. Any reactive nontreponemal test needs to be confirmed with a specific treponemal test to exclude a false-positive reading, but treatment should not be delayed if the patient is symptomatic or at high risk for infection. A positive VDRL in CSF is highly specific for neurosyphilis but is insensitive. Treponemal tests include fluorescent treponemal antibody absorption (FTA-ABS) and T. pallidum particle agglutination (TP-PA). These tests will remain reactive for life even after successful treatment, and they correlate poorly with disease activity. ¹¹⁹

Occasionally, a nontreponemal test performed on serum samples containing high concentrations of antibodies against T. pallidum can be weakly positive or falsely negative. Diluting the serum results in a positive test.

Even if the evaluation is normal, all infants born to mothers who are untreated or who have been treated less than 4 weeks before delivery, or have received a nonpenicillin drug, or who have evidence of relapse or re-infection should be evaluated at delivery.

Infants should be treated if they have the following:

Aqueous crystalline penicillin G intravenous for 10 days is the regimen of choice for congenital syphilis. ¹²⁰

All infants with reactive serologic tests for syphilis or born from mothers who were seroreactive at delivery should receive careful follow-up with repeated nontreponemal testing every 2 or 3 months until they become nonreactive or the titer has decreased at least fourfold. Nontreponemal tests should decrease by 3 months and should be nonreactive by 6 months if the infant was adequately treated or the elevated titers resulted from transplacentally acquired maternal antibodies. The serologic response might be slower for infants treated after the neonatal period.

Human Immunodeficiency Virus

Pediatric acquired immunodeficiency syndrome (AIDS) cases account for less than 1% of all reported cases of AIDS in the United States, and the CDC estimates that each year 215 to 370 infants acquire HIV in the United States, mainly as a consequence of missed prevention opportunities. The rate of vertical transmission has decreased to below 2% in the United States and Europe.

This scenario is drastically different in resource-limited countries where the prevention of mother-to-child transmission is a major public health challenge. Despite knowing the routes of transmission of the virus, approximately 500,000 children worldwide acquire the infection each year, primarily through mother-to-child transmission. Children still represent 14% of new HIV infections worldwide and almost one fifth of annual HIV-related deaths. ¹²¹

The risk of infection for an infant born to an HIV-infected mother without an intervention to prevent transmission is estimated to range between 12% and 40%. Dramatic declines in the number of HIV-infected children, to less than 2%, have been observed after the introduction of universal antenatal HIV testing, combination antiretroviral treatment during pregnancy, elective cesarean section, and avoidance of breastfeeding.

HIV infection may be transmitted in utero, intrapartum, or after birth through breastfeeding. In the absence of breastfeeding, it is believed that approximately 20% to 30% of perinatal infections occur in utero, with the remaining 70% to 80% occurring during the intrapartum period. If an infant escapes infection in utero and during delivery but is then breastfed, the risk for HIV transmission is approximately 15% when breastfeeding is continued for at least 6 months. ¹²²

Every woman worldwide should be tested at least once for HIV during pregnancy. Because risk factor assessments fail to detect more than 40% of HIV-infected pregnant women, the AAP and ACOG both recommend routine HIV counseling to all pregnant women, with universal voluntary HIV testing.

The ELISA measures IgG anti-HIV antibodies, which readily cross the placenta in the third trimester; therefore antibody assays are not informative for diagnosis of infection in children younger than 18 months of age unless assay results are negative.

The preferred test for diagnosis of HIV infection in infants is the HIV DNA PCR assay, which can detect 1 to 10 copies of proviral DNA in peripheral mononuclear cells. Plasma HIV RNA assays also have been used to diagnose HIV infection, but false-positive results might occur in infants receiving antiretroviral prophylaxis.

All HIV-exposed infants should have an HIV PCR-DNA assay performed at 14 to 21 days of age; if results are negative, it should be repeated at 1 to 2 months of age and again at 4 to 6 months of age. An infant is considered infected if two separate samples test positive for DNA or RNA PCR. ¹²³

The CD4+ T-lymphocyte percentage and the absolute CD4+ T-lymphocyte count are used to monitor immunogenic function in HIV-infected individuals. Remember that normal CD4+ counts for infants and children are much higher than those found in adults (a normal infant CD4 count is 2500 to 3500/mL³, and normal adult values are 700 to 1000/mL³). The risk of opportunistic infections correlates with the CD4+ T-lymphocyte count.

Close prenatal monitoring, attention to nutritional status, antiretroviral therapy, and elective cesarean sections are all recommended for infected pregnant women. Current guidelines recommend cesarean delivery for HIV-infected women if the viral load is above 1000 copies/mL or unknown at the time of delivery.

Starting antiretroviral treatment in an infant depends on virologic, clinical, and immunologic parameters. Recommendations change with time, and consultation with a pediatric HIV expert is advised. Current guidelines are available online at http://www.aidsinfo.nih.gov.

Pneumocystis jiroveci pneumonia (PCP) is the most common serious HIV-related infection in infancy. The peak age of onset is 3 to 9 months, and it carries a 50% mortality rate. Fortunately, PCP can be prevented by TMP-SMX prophylaxis. All exposed infants should start PCP prophylaxis at 6 weeks of age and continue until HIV infection is definitively excluded. Growth failure (i.e., failure to thrive) and a progressive encephalopathy are other common serious complications of HIV infection in the first year of life.

Cytomegalovirus (CMV)

Congenital CMV infection occurs in 1% to 2% of all live births. It is transmitted transplacentally and is 40% more common after primary infections in the mother during the first half of the pregnancy than in those who have serologic evidence of previous CMV infection. Approximately 90% of infants with congenital CMV infection are asymptomatic at birth. The major concern in these babies is the 5% to 10% risk of developing hearing loss during the preschool years. ¹²⁴

Vertical transmission can occur in utero by transplacental passage of the virus, at birth by passage through an infected birth canal, or postnatally by infected breast milk.

Approximately 10% of infected babies have symptoms at birth. Manifestations include the following:

The diagnosis of congenital CMV is challenging because of the ubiquity of the virus. Isolation of CMV from urine during the first 2 to 4 weeks of life is the most reliable method for diagnosing congenital infection. Detection of strongly positive IgM antibodies to CMV in serum obtained within the first few days after birth is highly suggestive of congenital infection, but different assays vary in accuracy for identification of primary infection. ¹²⁵

Transmission of CMV to neonates by blood transfusion can be prevented by using blood that is obtained from seronegative donors, frozen in glycerol, or depleted of WBCs.

Sensorineural hearing loss (SNHL) can be unilateral or bilateral. It varies in severity and can be progressive up to 7 years of age. Half of babies with SNHL and CMV infection identified at birth will have no other finding of CMV. SNHL is delayed in onset in approximately 20% of infants and progressive in 50% of cases. By 5 years of age, SNHL can be observed in about one third of those babies with abnormal physical findings at birth and about 10% of those with no manifestations at birth.

Long-term neurologic disability (excluding SNHL) has been reported in approximately 50% of those with manifestations and less than 5% of those without manifestations at birth. ¹²⁶

Data in infants with symptomatic congenital CMV involving the CNS suggest that the prognosis at 1 to 2 years of age may be improved if infected infants are treated with parenteral ganciclovir for 6 weeks. Valganciclovir given orally provides the same systemic levels of intravenous ganciclovir. ¹²⁷¹²⁸

Patients treated with ganciclovir need to have their absolute neutrophil count monitored closely because as many as 60% of patients will develop significant neutropenia. If neutropenia is evident, the dose should be reduced by 50%; if neutropenia persists, the therapy should be discontinued. ¹²⁹

Herpes Simplex Virus

Newborns with skin vesicles should be rapidly evaluated for the possibility of neonatal HSV infection. HSV PCR is the diagnostic method of choice, especially with CNS involvement (a reported sensitivity of 75% to 100% with CSF). HSV PCR can also be used to test serum; however, the test is not as reliable when serum is used. HSV grows readily in cultures. Babies in whom the diagnosis is established or who are strongly suspected of having neonatal HSV should be further evaluated for the possibility of disseminated infection and involvement of the CNS. Usually this means obtaining liver function tests, an ophthalmologic examination, lumbar puncture, and magnetic resonance imaging (MRI) or computed tomography (CT) scan. ¹³⁰¹³¹

Until fairly recently, it was thought that women with frequent reactivation episodes of genital HSV were at greatest risk to deliver an infected infant. Prospective studies, however, indicate that the infant at greatest risk of developing neonatal HSV is born to a woman with a primary asymptomatic genital HSV infection. The risk of infection is only about 2% in infants born to mothers with recurrent HSV but 25% to 60% in infants born to women with a primary HSV at term. All women need to be examined for the presence of active lesions; however, even this will miss asymptomatic infections. The best screening test for prevention of severe neonatal HSV is a high index of suspicion when an infant develops vesicular skin lesions because more than three quarters of vertically infected infants are born from mothers with no history or clinical findings suggestive of HSV. ACOG recommends that women with active recurrent genital herpes be offered suppressive viral therapy at or beyond 36 weeks’ gestation to delivery. Universal screening is not recommended. ¹³²

Clinically, HSV infection in newborns can manifest in the following ways: (1) disease localized to the skin, eye, or mouth in 45% of cases; (2) disseminated infection involving multiple organs, especially the liver and lungs in 25% of cases; and (3) CNS involvement with or without skin involvement in 30% of cases.

Even with appropriate antiviral therapy, the prognosis for infants with disseminated HSV and CNS disease is much poorer than that for infants who have infection confined to the skin, eye, and mouth. It is believed that administering early therapy with acyclovir to infants with disease localized to the skin, eye, or mouth can decrease the incidence of disseminated and CNS disease. Therefore it is recommended that all infants with skin lesions caused by HSV, even if they are otherwise well, should be treated with acyclovir.

Initial signs can occur at any time between birth and 6 weeks of age, although most infected infants exhibit symptoms within the first month of life. Infants with disseminated disease and involvement of the skin, eye, and mouth present earlier, usually between the first and second week of life; infants with CNS involvement usually present later, between the second and third week of life.

Most often, the virus multiplies on the mucosa of the maternal genital tract, and the baby is infected during vaginal delivery. In only about 5% of infections the virus crosses the placenta to cause congenital, rather than neonatal, infection. If the diagnosis of maternal primary HSV is known at delivery and the membranes are not ruptured, infection of the newborn infant can be prevented by performing

a cesarean section. The risk that the infant will be infected is increased if the skin is broken for any reason (e.g., from a scalp monitor). Infants also can be infected with HSV type 1 if a mother has primary active HSV-1 infection, usually in the throat and mouth, at delivery. Furthermore, infants can become infected by nursing on an infected breast. Transmission from care providers, fathers, and grandparents has also been demonstrated. ¹³³

The treatment is administration of intravenous acyclovir to all infants in whom the diagnosis of neonatal HSV is either established or suspected pending diagnostic studies. Acyclovir is an antiviral drug that interferes with the replication of HSV DNA by acting as a chain terminator and interfering with the action of DNA polymerase. Because its action occurs mainly in infected cells, it is very well tolerated. Early therapy with acyclovir has decreased mortality and morbidity resulting from serious HSV infections by 30% to 50%. Acyclovir is usually administered at a dosage of 60 mg/kg/day intravenously for 14 to 21 days, depending on the condition of the infant. ¹³⁴

Approximately 50% of infants who survive neonatal HSV experience cutaneous recurrences. Use of oral acyclovir suppressive therapy for 6 months after treatment of acute neonatal HSV diseases has been shown to improve neurodevelopmental outcomes in infants with HSV CNS involvement and to prevent skin recurrences in all infants infected with HSV regardless of their neonatal manifestations. Neutrophil counts should be monitored at 2 and 4 weeks after initiation of therapy and then monthly during the acyclovir treatment. The rate of severe neutropenia (<500 cells/mL) ranges from 20% to 25% while on acyclovir suppressive therapy; in every instance, the neutropenia was reversible and no infants had associated complications. ¹³⁵

Cesarean section is recommended for mothers who have active genital lesions and a suspected primary infection. Infants born to mothers with active genital HSV disease should be isolated from other infants and evaluated with “surface cultures” at 24 to 48 hours of life. Those infants born to mothers with primary disease might benefit from empiric parenteral acyclovir treatment after obtaining “surface cultures.” However, virtually no experts recommend treatment for infants born from mothers with active recurrent disease. If “surfaces cultures” are positive, the infant should be evaluated for HSV disease and should be treated to prevent progression to HSV disease. The duration of treatment is controversial. ¹³⁶

Antibody titers are of little use in the diagnosis of HSV because it takes at least several days after infection for antibodies to rise. Therefore it is preferable to demonstrate the presence of virus, viral antigens, or DNA in tissues for diagnosis. Antibody titers may be useful to differentiate between maternal first infections versus recurrence because many primary infections are asymptomatic. ¹³⁷

Varicella Zoster Virus

Congenital varicella syndrome is usually associated with maternal varicella during the first or early second trimester of pregnancy. Transmission of VZV from mother to infant occurs in 25% to 50% of cases of infected mothers. However, congenital varicella syndrome occurs in fewer than 2% of cases of maternal chickenpox before week 20 of gestation. Common manifestations of the syndrome include skin scarring (either generalized or localized in a dermatomal distribution), limb deformities (e.g., hypoplasia, missing digits), eye abnormalities (e.g., chorioretinitis, cataract, nystagmus, hypoplasia), low birth weight, and mental retardation.

Reactivation of VZV acquired in utero is common. Thus zoster develops in approximately 15% of infants with the congenital syndrome, usually in the first few years of life. ¹³⁸

Infants whose mothers have the onset of the rash of varicella within 5 days before delivery to 2 days postpartum are at high risk of developing varicella because of insufficient transfer of maternal antibodies and the immature cellular immunity of the neonate. In as many as 30% of infants who are untreated, the varicella may be disseminated and even fatal. This form of varicella resembles that seen in other immunocompromised patients, such as children with leukemia receiving chemotherapy.

It is possible to prevent this severe form of infant varicella by administering VZIG to the baby as soon as possible after birth. Rarely, VZIG may be ineffective in infants, so babies given this prophylaxis warrant close follow-up. Many will develop a mild form of clinical varicella with fewer than 100 skin vesicles despite VZIG. Indications for adding antiviral therapy (acyclovir) are extensive skin lesions and development of pneumonia, which suggests severe varicella. Hospitalized preterm infants exposed to VZV should receive VZIG if they are older than 28 weeks’ gestation and have mothers who lack immunity against VZV or if they are younger than 28 weeks’ gestation regardless of maternal immunity status. ¹³⁹

Infants whose mothers develop varicella more than 48 hours postpartum are at significantly less risk from varicella and do not require VZIG, although some physicians may elect to administer it in infants exposed to VZV during the first 2 weeks of life whose mothers lack immunity. In this case, infection of the infant would not result from exposure to VZV in utero but rather from postpartum exposure.

Infants whose mothers had the onset of varicella more than 5 days before delivery do not need to receive VZIG because they will have developed sufficient transplacental VZV antibodies by that time.

With regard to isolation of infants perinatally exposed to VZV, there are two points to consider:

The Red Book recommends airborne and contact precautions for neonates born to women with varicella, and if the neonate is still hospitalized, the isolation should be continued until 21 or 28 days of age after exposure for those who received VZIG or intravenous Ig. ¹⁴⁰¹⁴¹

Women with zoster have high antibody titers to VZV, and their infants are well protected from the virus by transplacental antibodies. Therefore no special management is required. VZIG is not indicated for neonates whose mothers have zoster.

Varicella in adults tends to be more severe than in children. Although the data are not conclusive, most experts believe that varicella in pregnant women is likely to be more severe than in nonpregnant women, especially in the third trimester of pregnancy. Therefore pregnant women with varicella should be closely observed, particularly for development of primary pneumonia. Pneumonia usually presents with fever, cough, dyspnea, and bilateral fluffy interstitial infiltrates on chest x-ray. Pregnant women with varicella pneumonia or even suspected varicella pneumonia should be treated with intravenous acyclovir for 7 days. Maternal acyclovir therapy has not been associated with fetal malformations, so most physicians will treat women who developed varicella or zoster within 1 day of the onset of varicella and 3 days of the onset of zoster. ¹⁴²

Varicella vaccine should not be administered to pregnant women because it contains a live virus. However, no cases of congenital varicella syndrome have been reported in women who inadvertently received the vaccine. Pregnancy is not a contraindication to immunizing children in the household. If a woman lacks VZV immunity after delivery, the varicella vaccine should be administered; there is no evidence of transmission of vaccine strain through breast milk. ¹⁴³

Toxoplasmosis

Toxoplasma gondii is a protozoan and obligate intracellular parasite that exists in three developmental stages: tachyzoite (in acute infections), tissue cyst containing bradyzoites in chronic latent infection, and oocyst containing sporozoites in the intestines of cats. Once infected with the tachyzoite, the organism may encyst, commonly in the skeletal muscles. Infection occurs in multiple animal species, but the cat appears to be the definitive host, and the parasite replicates sexually in the feline small intestine. Cats excrete millions of oocysts in their stool after primary infection. Oocysts must mature or sporulate in the soil (which takes at least 24 hours) before they are infectious. Sporulated oocysts can survive for a long time.

Therefore Toxoplasma infection is acquired through the ingestion of undercooked or raw meat (containing tissue cysts) or water or other foods contaminated by oocysts that have been excreted in the feces of infected domestic animals. It is possible to become infected through exposure to soil contaminated with cat feces. ¹⁴⁴¹⁴⁵

The incidence of congenital toxoplasmosis in the United States is estimated to be between 1 in 1000 and 1 in 10,000 live births. Congenital infection is associated with maternal primary infection in pregnancy. Transmission rates to the fetus depend on the stage of the pregnancy and treatment during pregnancy, but approximately one third of infected women will have an infected fetus. Transmission during the first trimester tends to produce a more severe disease. Maternal treatment with spiramycin may decrease the severity of sequelae in the fetus once congenital toxoplasmosis has occurred. ¹⁴⁶

Most infected newborns are asymptomatic at birth (70% to 90%), although a large proportion of them will have visual or hearing impairment, learning difficulties, seizure disorders, or mental retardation later in life. The classic triad of chorioretinitis, hydrocephalus resulting from aqueduct stenosis, and intracranial calcifications is very suggestive of congenital toxoplasmosis. Other features include maculopapular rash, petechial purpura, lymphadenopathies, hepatosplenomegaly, CSF pleocytosis, thrombocytopenia, eosinophilia, and metaphyseal bone lucencies.

When there is clear evidence of congenital infection in the newborn, pyrimethamine combined with sulfadiazine and supplemented with folinic acid is recommended as initial therapy. The treatment is continued for approximately 12 to 14 months (consult an expert on infectious diseases for confirmation regarding a specific case). For mild congenital toxoplasmosis many experts will alternate the previous combination with spiramycin during months 7 through 12 of treatment, but severe cases should receive combined pyrimethamine-sulfadiazine for the entire 12 months.

The dosage should be adjusted weekly. In addition, a CBC with differential should be performed by finger stick twice weekly to measure the absolute neutrophil count. Remember that pyrimethamine is a folic acid antagonist and therefore may cause thrombocytopenia, granulocytopenia, and anemia resulting from bone marrow suppression. The use of folinic acid can counteract this side effect. ¹⁴⁷¹⁴⁸

In this case, transfer of maternal antibodies may be suspected as the reason for the presence of IgG antibodies. A continuous decrease in transplacental IgG antibody should be observed, with the antibody becoming undetectable by 6 to 12 months of age. The diagnosis of congenital toxoplasmosis is complex, and consultation with an infectious disease specialist is recommended.

Ureaplasma Urealitycum

Ureaplasma can be isolated from the genital tract of 40% to 80% of sexually active asymptomatic women. Colonization has been linked to younger age, lower socioeconomic status, multiple sexual partners, oral contraceptive use, recent antibiotic treatment, and African-American ethnicity. ¹⁴⁹

The vertical transmission rate ranges from 25% to 60%. Transmission occurs in utero by ascending infection or during delivery through an infected birth canal. Preterm and VLBW infants are more likely to acquire U. urealyticum in the lower respiratory tract. The mode of delivery does not influence the rate of transmission, but it increases in the presence of chorioamnionitis or prolonged rupture of membranes. Neonatal colonization can last for several months, so a positive culture does not confirm causality in infections. ¹⁵⁰

Although usually limited to research settings, PCR techniques are available and have greater sensitivity than culture. The organism is fastidious, so specimens should be transported to the laboratory in special transport media and refrigerated if transport is not immediately possible. Serologic tests are not useful.

Causation has not been fully established for chronic lung disease and Ureaplasma. Furthermore, organisms are often present in healthy infants and can spontaneously disappear without treatment. Small randomized, controlled trials have not shown any benefit of treatment of U. urealyticum to prevent chronic lung disease.

Infectious Hepatitis

Several infectious agents can cause hepatitis in neonates and infants, including the TORCH pathogens: T. gondii, Other infectious etiologies (i.e., syphilis; hepatitis B, C, and D; and, rarely, hepatitis A virus), Rubella, CMV, and Herpes simplex. Additional etiologies in this age group include adenovirus, coxsackievirus, enterovirus, Epstein–Barr virus, HIV, and VZV. ¹⁵³

HBV is transmitted by infected blood or body fluids. Perinatal transmission occurs from exposure to blood during labor and delivery. Only a small proportion of infections occur in utero. With no postexposure prophylaxis the risk that an infant will acquire HBV from an infected mother is 70% to 90% if the mother is positive for hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg). The risk is lower (5% to 20%) for infants born from mothers who are HBsAg positive but HBeAg negative.

Age at infection is the main determinant of risk for progression to chronic disease. As many as 90% of infected newborns or infants younger than 1 year of age will develop chronic infection; 25% to 50% will develop chronic infection if the infection occurs between 1 and 5 years of age; and 5% to 10% will develop chronic infection when infection happens in older children or adults. In the absence of treatment, up to 25% of infants and children who have chronic hepatitis B will die as a result of hepatocellular carcinoma or cirrhosis. ¹⁵⁵

Hepatitis C is transmitted mainly by parenteral exposure to blood and blood products from a HCV-infected person. Approximately 5% of infected women transmit HCV to their neonates; however, transmission occurs only if the mother is HCV RNA positive at the time of delivery. Maternal coinfection with HIV has been associated with increased risk for perinatal transmission of HCV. Breastfeeding has not been shown to be a risk factor for transmission.

Signs and symptoms of HCV are similar to those of hepatitis A virus and HBV, although acute disease tends to be milder, with fewer occurrences of jaundice or elevated liver transaminases. However, 80% of infected children with HCV develop persistent infection, as many as 70% develop chronic hepatitis, and 20% develop cirrhosis that may progress to hepatocellular carcinoma.

Maternal HCV IgG antibody can persist in a neonate for up to 18 months. Therefore diagnosis in a neonate can be made only by using reverse transcriptase PCR assays for HCV RNA, which can be detected within 1 to 2 weeks of exposure. However, because false-negative and false-positive results can occur with PCR tests, a single result is not conclusive. It is therefore recommended that infants born to infected mothers be tested at or after the first well-baby visit at 1 or 2 months of age and then undergo repeat testing. Children with persistence of HCV RNA beyond 6 months’ duration are assumed to have chronic infection. ¹⁵⁶

Parvovirus

Parvovirus B19 is highly contagious, and almost 60% of adults are seropositive. Transmission occurs from person to person by droplets from oral secretions. Women who are not immune have a fivefold increased risk for parvovirus B19 if they have occupational daily contact with school-age children. In epidemic periods 1% to 4% of susceptible women become infected during pregnancy.

The risk of fetal death is between 2% and 6% when infection occurs during pregnancy. The greatest risk appears to occur during the first half of pregnancy. ¹⁵⁷

She need not worry. Canine parvovirus is not a human pathogen.

Classic EI with “slapped cheeks” appearance followed by a characteristic lacy or reticular rash on the trunk and limbs is fairly easy to diagnose clinically. Unfortunately, most adults infected with parvovirus B19 do not develop classic signs. In adults, especially women, joint symptoms occur in 60% to 80% of cases; knees are frequently involved in children, whereas fingers are commonly involved in women. The joint symptoms of parvovirus B19 infection usually manifest as the sudden onset of a symmetric peripheral polyarthropathy and might persist long enough to satisfy clinical diagnosis criteria for rheumatoid arthritis.

Parvoviruses require actively dividing cells to replicate. Therefore it preferentially infects red blood cell (RBC) precursors. In patients with hemolytic anemia and a high RBC turnover, the viral cytopathic effect destroys bone marrow RBC precursors, resulting in reticulocytopenia. The transient arrest of erythrocyte production results in profound anemia in persons with a shortened RBC survival, such as patients with hemolytic anemia. In fetuses shortened RBC survival (60 to 80 days versus 110 to 120 days in adults) also contributes to the severity of anemia. ¹⁵⁸