Pathogenesis of Intrauterine Infection

Intrauterine infection is a result of clinical or subclinical maternal infection with a variety of agents (cytomegalovirus [CMV], Treponema pallidum, Toxoplasma gondii, rubella virus, varicella virus, parvovirus B19) and hematogenous transplacental transmission to the fetus. Transplacental infection may occur at any time during gestation, and signs and symptoms may be present at birth or may be delayed for months or years (Fig. 103-1). Infection may result in early spontaneous abortion, congenital malformation, intrauterine growth restriction, premature birth, stillbirth, acute or delayed disease in the neonatal period, or asymptomatic persistent infection with sequelae later in life. In some cases, no apparent effects are seen in the newborn infant.

Figure 103-1 Pathogenesis of hematogenous transplacental infections.

(From Klein JO, Remington JS: Current concepts of infections of the fetus and newborn infant. In Remington JS, Klein JO, editors: Infectious diseases of the fetus and newborn infant, ed 5, Philadelphia, 2002, WB Saunders.)

The timing of infection during gestation affects the outcome. First-trimester infection may alter embryogenesis, with resulting congenital malformations (congenital rubella) (Chapter 239). Third-trimester infection often results in active infection at the time of delivery (toxoplasmosis, syphilis) (Chapters 282 and 210). Infections that occur late in gestation may lead to a delay in clinical manifestations until some time after birth (syphilis).

Maternal infection is a necessary prerequisite for transplacental infection. For some etiologic agents (rubella), maternal immunity is effective and antibody is protective for the fetus. For other agents (CMV), maternal antibody may ameliorate the outcome of infection or may have no effect (Chapter 247). Even without maternal antibody, transplacental transmission of infection to a fetus is variable because the placenta may function as an effective barrier.

Pathogenesis of Ascending Bacterial Infection

In most cases, the fetus or neonate is not exposed to potentially pathogenic bacteria until the membranes rupture and the infant passes through the birth canal and/or enters the extrauterine environment. The human birth canal is colonized with aerobic and anaerobic organisms that may result in ascending amniotic infection and/or colonization of the neonate at birth. Vertical transmission of bacterial agents that infect the amniotic fluid and/or vaginal canal may occur in utero or, more commonly, during labor and/or delivery (Fig. 103-2). Chorioamnionitis results from microbial invasion of amniotic fluid, often as a result of prolonged rupture of the chorioamniotic membrane. Amniotic infection may also occur with apparently intact membranes or with a relatively brief duration of membrane rupture. The term chorioamnionitis refers to the clinical syndrome of intrauterine infection, which includes maternal fever, with or without local or systemic signs of chorioamnionitis (uterine tenderness, foul-smelling vaginal discharge/amniotic fluid, maternal leukocytosis, maternal and/or fetal tachycardia). Chorioamnionitis may also be asymptomatic, diagnosed only by amniotic fluid analysis or pathologic examination of the placenta. The rate of histologic chorioamnionitis is inversely related to gestational age at birth (Fig. 103-3) and directly related to duration of membrane rupture. Rupture of membranes for longer than 24 hr was once considered prolonged because microscopic evidence of inflammation of the membranes is uniformly present when the duration of rupture exceeds 24 hr. At 18 hr of membrane rupture, however, the incidence of early-onset disease with group B streptococcus (GBS) increases significantly; 18 hr is the appropriate cutoff for increased risk of neonatal infection.

Figure 103-2 Pathways of ascending or intrapartum infection.

Figure 103-3 Histologic chorioamnionitis in liveborn preterm babies by gestational age (n = 3,928 babies).

(From Lahra MM, Jeffery HE: A fetal response to chorioamnionitis is associated with early survival after preterm birth, Am J Obstet Gynecol 190:147–151, 2004.)

Bacterial colonization does not always result in disease. Factors influencing which colonized infant will experience disease are not well understood but include prematurity, underlying illness, invasive procedures, inoculum size, virulence of the infecting organism, genetic predisposition, the innate immune system, host response, and transplacental maternal antibodies (Fig. 103-4). Aspiration or ingestion of bacteria in amniotic fluid may lead to congenital pneumonia or systemic infection, with manifestations becoming apparent before delivery (fetal distress, tachycardia), at delivery (failure to breathe, respiratory distress, shock), or after a latent period of a few hours (respiratory distress, shock). Aspiration or ingestion of bacteria during the birth process may lead to infection after an interval of 1-2 days.

Figure 103-4 Factors influencing the balance between health and disease in neonates exposed to a potential pathogen. ROM, rupture of membranes.

(Adapted from Baker CJ: Group B streptococcal infections, Clin Perinatol 24:59–70, 1997.)

Resuscitation at birth, particularly if it involves endotracheal intubation, insertion of an umbilical vessel catheter, or both, is associated with an increased risk of bacterial infection. Explanations include the presence of infection at the time of birth or acquisition of infection during the invasive procedures associated with resuscitation.

Pathogenesis of Late-Onset Postnatal Infections

After birth, neonates are exposed to infectious agents in the nursery or in the community. Postnatal infections may be transmitted by direct contact with hospital personnel, the mother, or other family members; from breast milk (HIV, CMV); or from inanimate sources such as contaminated equipment. The most common source of postnatal infections in hospitalized newborns is hand contamination of health care personnel.

Most cases of meningitis result from hematogenous dissemination. Less often, meningitis results from contiguous spread as a result of contamination of open neural tube defects, congenital sinus tracts, or penetrating wounds from fetal scalp sampling or internal fetal electrocardiographic monitors. Abscess formation, ventriculitis, septic infarcts, hydrocephalus, and subdural effusions are complications of meningitis that occur more often in newborn infants than in older children.

Immunoglobulins

Immunoglobulin (Ig) G is actively transported across the placenta, with concentrations in a full-term infant comparable to or higher than those in the mother. The specificity of IgG antibody in cord blood depends on the mother’s previous antigenic exposure and immunologic response. In premature infants, cord IgG levels are directly proportional to gestational age. Studies of type-specific IgG antibodies to GBS have shown that the ratio of cord to maternal serum concentrations is 1.0 at term, 0.5 at 32 wk of gestation, and 0.3 at 28 wk. Levels of maternally derived IgG fall rapidly after birth. Infants with birthweights <1,500 g become significantly hypogammaglobulinemic, with mean plasma IgG concentrations in the range of 200-300 mg/dL in the 1st wk of life. Other classes of immunoglobulins are not transferred across the placenta, although a fetus can synthesize IgA and IgM in response to intrauterine infection.

The presence of passively transferred specific IgG antibody in adequate concentration provides neonates protection against infections to which protection is mediated by that antibody (tetanus, encapsulated bacteria such as GBS). Specific bactericidal and opsonic antibodies against enteric gram-negative bacteria are predominantly in the IgM class. Newborn infants usually lack antibody-mediated protection against Escherichia coli and other Enterobacteriaceae.

Complement

The complement system mediates bactericidal activity against certain organisms such as E. coli and functions as an opsonin with antibody in the phagocytosis of bacteria such as GBS. No transplacental passage of complement from the maternal circulation takes place. A fetus begins to synthesize complement components as early as the 1st trimester. Full-term newborn infants have slightly diminished classical pathway complement activity and moderately diminished alternative pathway activity. Considerable variability, however, is seen in both the concentration and activity of complement components. Premature infants have lower levels of complement components and less complement activity than full-term newborns do. These deficiencies contribute to diminished complement-derived chemotactic activity and to a lesser ability to opsonize certain organisms in the absence of antibody. Opsonization of Staphylococcus aureus is normal in neonatal sera, but various degrees of impairment have been noted with GBS and E. coli.

Neutrophils

Quantitative and qualitative deficiencies of the phagocyte system contribute to the newborn’s susceptibility to infection. Neutrophil migration (chemotaxis) is abnormal at birth in both term and preterm infants. Neonatal neutrophils have decreases in adhesion, aggregation, and deformability, all of which may delay the response to infection. Abnormal expression of cell membrane adhesion molecules (the β₂ integrins and selectins) and abnormalities in the neonatal neutrophil cytoskeleton contribute to abnormal chemotaxis. With adequate opsonization, phagocytosis and killing by neutrophils are comparable in newborn infants and adults. In the presence of infectious or noninfectious stress (respiratory distress syndrome), however, the ability of neonatal neutrophils to phagocytose gram-negative (but not gram-positive) bacteria is decreased. Impairment of the oxidative respiratory burst of neonatal neutrophils is a factor in the increased risk of sepsis, especially in preterm infants.

The number of circulating neutrophils is elevated after birth in both term and preterm infants, with a peak at 12 hr that returns to normal by 22 hr. Band neutrophils constitute less than 15% in normal newborns and may increase in newborns with infection and other stress responses, such as asphyxia.

Neutropenia, which is frequently observed in preterm infants and infants with intrauterine growth restriction, increases the risk for sepsis. The neutrophil storage pool in newborn infants is 20-30% of that in adults and is more likely to be depleted in the face of infection. Mortality is increased when sepsis is associated with severe sepsis-induced neutropenia and bone marrow depletion. Granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are cytokines that play important roles in the proliferation, differentiation, functional activation, and survival of phagocytes. These cytokines stimulate myeloid progenitor cells, increase the bone marrow neutrophil storage pool, induce peripheral blood neutrophilia, and influence neutrophil function, including enhancement of bactericidal activity. Although these myeloid colony-stimulating factors influence neutrophil number and function, their clinical utility in the treatment and/or prevention of neonatal sepsis remains undetermined.

Monocyte-Macrophage System

The monocyte-macrophage system consists of circulating monocytes and tissue macrophages, particularly in the liver, spleen, and lung. Activated macrophages are involved in antigen presentation, phagocytosis, and immune modulation. The number of circulating monocytes in neonatal blood is normal, but the mass or function of macrophages in the reticuloendothelial system is diminished, particularly in preterm infants. In both term and preterm infants, chemotaxis of monocytes is impaired; this impairment affects the inflammatory response in tissues and the results of delayed hypersensitivity skin tests. Monocytes from neonates ingest and kill microorganisms as well as monocytes from adults.

Natural Killer Cells

Natural killer (NK) cells are a subgroup of lymphocytes that are cytolytic against cells infected with viruses. NK cells also lyse cells coated with antibody in a process called antibody-dependent cell-mediated cytotoxicity (ADCC). NK cells appear early in gestation and are present in cord blood in numbers equivalent to those in adults; neonatal NK cells have decreased cytotoxic activity and ADCC in comparison with adult cells. The diminished cytotoxicity against herpes simplex virus (HSV)–infected cells may predispose to disseminated HSV infection in newborns (Chapter 249).

Cytokines/Inflammatory Mediators

The patient’s response to infection and clinical outcome involves a balance between pro-inflammatory and anti-inflammatory cytokines. Several adverse neonatal outcomes, including brain injury, necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia, may be mediated by the cytokine response to infection in the mother, fetus, or newborn. The mediators that have been studied in newborns include tumor necrosis factor-α (TNFα), interleukin 1 (IL-1), IL-4, IL-6, IL-8, IL-10, IL-12, platelet-activating factor, and the leukotrienes. The release of various inflammatory mediators in response to infection offers the potential opportunity to facilitate an early laboratory diagnosis of infection. Potential surrogate markers for bacterial sepsis, pneumonia, and NEC include TNFα, IL-6, and IL-8.

Innate immunity involves nonspecific cellular and humoral responses to an infectious agent without previous exposure. Recognition of pathogens is initiated by soluble components in plasma (including mannose-binding lectin) and by recognition of receptors on monocytes and other cells. Toll-like receptors play an important role in pathogen recognition. Genetic polymorphisms (mutations) of various proteins involved in the immune response may increase the risk and severity of neonatal infections. The neutrophil is another important cellular component of innate immunity. Neutrophil granules contain many enzymes; one protein, bactericidal/permeability-increasing protein (BPI), binds to the endotoxin in the cell wall of gram-negative bacteria. This protein facilitates opsonization and prevents the inflammatory response to endotoxin. BPI activity may be decreased in neonates.

Prematurity

The most important neonatal factor predisposing to infection is prematurity or LBW. Preterm LBW infants have a 3- to 10-fold higher incidence of infection than full-term normal birthweight infants. Possible explanations are as follows: (1) maternal genital tract infection is considered to be an important cause of preterm labor, with an increased risk of vertical transmission to the newborn (Figs. 103-5 and 103-6); (2) the frequency of intra-amniotic infection is inversely related to gestational age (see Fig. 103-3); (3) premature infants have documented immune dysfunction; and (4) premature infants often require prolonged intravenous access, endotracheal intubation, or other invasive procedures that provide a portal of entry or impair barrier and clearance mechanisms.

Figure 103-5 Potential pathways from choriodecidual bacterial colonization to preterm delivery.

(From Goldenberg RL, Hauth JA, Andrews WW: Intrauterine infection and preterm delivery, N Engl J Med 342:1500–1507, 2000. Copyright 2000, Massachusetts Medical Society.)

Figure 103-6 Potential sites of bacterial infection within the uterus.

(From Goldenberg RL, Hauth JA, Andrews WW: Intrauterine infection and preterm delivery, N Engl J Med 342:1500–1507, 2000. Copyright 2000, Massachusetts Medical Society.)

Nosocomial Infections

Nosocomial (hospital-acquired) infections are responsible for significant morbidity and late mortality in hospitalized newborns. Many experts define nosocomial infections in newborns as infections occurring after 3 days of life that are not directly acquired from the mother’s genital tract. For the purposes of surveillance in the acute care setting, the CDC National Healthcare Safety Network (NHSN) defines health care–associated infections in newborns as those that result from passage through the birth canal as well as infections that occur from exogenous sources such as health care personnel, visitors, and equipment/devices in the health care environment. This surveillance definition includes any infection occurring after admission to the neonatal intensive care unit (NICU) that was not transplacentally acquired. Rates of nosocomial infection in healthy term infants who are either rooming-in with their mothers or staying in the well baby nursery are low (<1%). The majority of nosocomial infections occur in preterm or term infants who require intensive care. Risk factors for nosocomial infection in these infants include prematurity, LBW, invasive procedures, indwelling vascular catheters, parenteral nutrition with lipid emulsions, endotracheal tubes, ventricular shunts, alterations in the skin and/or mucous membrane barriers, frequent use of broad-spectrum antibiotics, and prolonged hospital stay. The most frequent nosocomial infections are bloodstream infections associated with an intravascular catheter and pneumonia, especially ventilator-associated pneumonia. Nonetheless, nosocomial sepsis may occur in the absence of a catheter or ventilator. In addition, infants receiving intensive care in the NICU are at risk to acquire community or hospital associated infections during seasonal epidemics (rotavirus, RSV, influenza).

Almost one quarter of VLBW infants (<1,500 g BW) experience nosocomial infections. Rates of infections increase with decreasing gestational age and birthweight. The NICHD Neonatal Research Network has reported rates of 43% for infants 401-750 g; 28% for those 751-1,000 g; 15% for those 1,001-1,250 g; and 7% for those 1,251-1,500 g. The CDC NHSN monitors device-associated nosocomial infection rates. Rates are inversely related to birthweight, and in level III NICUs, they range from 3.7 infections per 1,000 central line days for infants < 750 g to 2.0 infections per 1,000 central line days for those weighing > 2,500 g. The widespread differences in practice regarding the inclusion of lumbar puncture (LP) in the diagnostic evaluation of an infant with suspected sepsis make it more difficult to determine rates of late-onset meningitis.

Various bacterial and fungal agents colonize hospitalized infants, health care workers, and visitors. Pathogenic agents can be transmitted by direct contact or indirectly via contaminated equipment, intravenous fluids, medications, blood products, or enteral feedings. Colonization of the infant’s skin, umbilicus, and respiratory or gastrointestinal tract with pathogenic agents often precedes the development of infection. Antibiotic use interferes with colonization by normal flora, thereby facilitating colonization with more virulent pathogens.

Coagulase-negative staphylococci are the most frequent neonatal nosocomial pathogens. In a cohort of 6,215 VLBW infants in the NICHD Neonatal Research Network, gram-positive agents were associated with 70%, gram-negative with 18%, and fungi with 12% of cases of late-onset sepsis (Table 103-6). Coagulase-negative staphylococcus, the single most common organism, was isolated in 48% of these infections. The emergence of nosocomial bacterial pathogens resistant to multiple antibiotics is a growing concern. Among NICU patients, methicillin-resistant S. aureus, vancomycin-resistant enterococci, and multidrug-resistant gram-negative pathogens are particularly alarming. Organisms responsible for all categories of neonatal sepsis and meningitis may change with time (Table 103-7).

Table 103-6 DISTRIBUTION OF PATHOGENS ASSOCIATED WITH THE 1ST EPISODE OF LATE-ONSET SEPSIS IN VERY LOW BIRTHWEIGHT INFANTS*

* National Institute of Child Health and Human Development Neonatal Research Network, September 1, 1998, through August 31, 2000.

^† Patients with dual infections and patients with presumed coagulase-negative staphylococci (CONS) contaminants excluded. According to the definitions in text, 276 (44%) CONS were definite infections and 353 (56%) were possible infections.

Table 103-7 NEONATAL INBORN SEPSIS, 1928-2003

Viral organisms may also cause nosocomial infection in the NICU; they include RSV, varicella, influenza, rotavirus, and enteroviruses. For viral as well as bacterial infections, nursery outbreaks may occur in addition to individual cases. Hospital infection control policies are essential to prevent and/or contain nursery infection outbreaks.

The mean age at onset of the 1st episode of late-onset nosocomial sepsis is 2-3 wk, independent of the infecting pathogen. Nosocomial infections increase the risk of adverse outcomes, including prolonged hospitalization and mortality.

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