Current Concepts of Infections of the Fetus and Newborn Infant

Placental Infection Without Infection of the Fetus

After reaching the intervillous spaces on the maternal side of the placenta, organisms can remain localized in the placenta without affecting the fetus. Evidence that placentitis can occur independently of fetal involvement has been shown for maternal tuberculosis, syphilis, malaria, coccidioidomycosis, CMV, rubella virus, and mumps vaccine virus infection. The reasons for the lack of spread to the fetus after placental infection are unknown. Defenses of the fetus that may operate after placental infection include the villous trophoblast, placental macrophages, and locally produced immune factors, such as antibodies and cytokines.

Fetal Infection Without Overt Infection of the Placenta

Microorganisms may traverse the chorionic villi directly through pinocytosis, placental leaks, or diapedesis of infected maternal leukocytes and erythrocytes. Careful histologic studies usually reveal areas of placentitis sufficient to serve as a source of fetal infection, however.

Absence of Fetal and Placental Infection

Invasion of the bloodstream by microorganisms is common in pregnant women, yet in most cases, neither fetal nor placental infection results. Bacteremia may accompany abscesses, cellulitis, bacterial pneumonia, pyelonephritis, appendicitis, endocarditis, or other pyogenic infections; nevertheless, placental or fetal infection as a consequence is rare. In most cases, the fetus is likely protected through efficient clearance of microbes by maternal innate or preexisting adaptive immunity.

Many bacterial diseases of the pregnant woman, including typhoid fever, pneumonia, gram-negative bacterial sepsis, and urinary tract infections, may affect the developing fetus without direct microbial invasion of the placenta or fetal tissues. Similarly, protozoan infection in the mother, such as malaria, and systemic viral infections, including varicella, variola, and measles, also may affect the fetus indirectly. Fever, anoxia, circulating toxins, or metabolic and hematologic derangements in the mother concomitant with these infections can affect the pregnancy, possibly resulting in abortion, stillbirth, or premature delivery.

The effects of microbial toxins on the developing fetus are uncertain. The fetus may be adversely affected by toxic shock in the mother secondary to Staphylococcus aureus or Streptococcus pyogenes infection. Botulism in pregnant women has not been associated with disease in infants. A unique case of Guillain-Barré syndrome in mother and child shows that infection-induced, antibody-mediated autoimmune disease in the mother may be transmitted to her infant. In this case, the disease was diagnosed in the mother during week 29 of pregnancy. A healthy infant was delivered vaginally at 38 weeks of gestation, while the mother was quadriplegic and on respiratory support. On day 12 of life, the infant developed flaccid paralysis of all limbs with absence of deep tendon reflexes, and cerebrospinal fluid (CSF) examination revealed increased protein concentration without white blood cells. The delay in onset of paralysis in the infant seemed to reflect transplacentally transferred blocking antibodies specifically directed at epitopes of the mature, but not the fetal, neuromuscular junction. The infant improved after administration of intravenous immunoglobulin.

The association of maternal urinary tract infection with premature delivery and low birth weight is a well-studied example of a maternal infection that adversely affects growth and development of the fetus, despite no evidence of fetal or placental infection. Asymptomatic bacteriuria in pregnancy has been linked to increased low-birth-weight deliveries. A meta-analysis of interventional studies concluded that antibiotic treatment is effective in reducing the risk of pyelonephritis in pregnancy and the risk for preterm delivery, although the evidence supporting this latter conclusion is not as strong. The basis for the premature delivery and low birth weight of infants of mothers with bacteriuria remains obscure and may, in part, reflect an altered maternal genital tract microbiome and dysbiosis-associated preterm labor (see Chapter 3 ).

Infection of Placenta and Fetus

Microorganisms disseminate from the infected placenta to the fetal bloodstream through infected emboli of necrotic chorionic tissues or through direct extension of placental infection to the fetal membranes, with secondary amniotic fluid infection and aspiration by the fetus.

Embryonic Death and Resorption

Various organisms may infect the pregnant woman in the first few weeks of gestation and cause death and resorption of the embryo. Because loss of the embryo usually occurs before the woman realizes she is pregnant or seeks medical attention, it is difficult to estimate the incidence of this outcome for any single infectious agent. The incidence of early pregnancy loss after implantation from all causes has been estimated to be 31%. The proportion of cases of loss because of infection is unknown.

Abortion and Stillbirth

The earliest recognizable effects of fetal infection are seen after 6 to 8 weeks of pregnancy and include abortion and stillbirth. Intrauterine death may result from overwhelming fetal infection, or the microorganisms may interfere with organogenesis to such an extent that the development of functions necessary for continued viability is interrupted. The precise mechanisms responsible for early spontaneous termination of pregnancy are unknown; in many cases, it is difficult to ascertain whether fetal death caused or resulted from the expulsion of the fetus.

Numerous modifying factors probably determine the ultimate consequence of intrauterine infection, including virulence or tissue tropism of the microorganisms, stage of pregnancy, associated placental damage, and severity of the maternal illness. Primary infection is likely to have a more important effect on the fetus than recurrent infection. Recurrent maternal CMV infection is less severe than primary infection and is significantly less likely to result in congenital CMV infection of the fetus. Available studies do not distinguish between the direct effect of the microorganisms on the developing fetus and the possibility of an indirect effect attributable to illness or poor health of the mother.

Prematurity

Prematurity is defined as the birth of a viable infant before week 37 of gestation. Premature birth may result from almost any agent capable of establishing fetal infection during the last trimester of pregnancy. Many microorganisms commonly responsible for prematurity are also implicated as significant causes of stillbirth and abortion ( Table 1-5 ).

Previous studies have shown that women in premature labor with bacteria-positive amniotic fluid cultures have elevated amniotic fluid levels of multiple proinflammatory cytokines. In many patients with elevated levels of interleukin-6 (IL-6), results of amniotic fluid culture were negative. Premature births are invariably observed, however, in women in premature labor having positive amniotic fluid culture and elevated amniotic fluid levels of IL-6. To clarify further the role of elevated levels of IL-6 in amniotic fluid, Hitti and colleagues amplified bacterial DNA encoding 16S ribosomal RNA (rRNA) by using a polymerase chain reaction (PCR) assay to detect infection in amniotic fluid of women in premature labor whose membranes were intact. In patients who were culture-negative, PCR assay detected bacterial infection in a significant percentage of those with elevated IL-6 levels. These data suggest that 33% of women in premature labor with culture-negative amniotic fluid but with elevated IL-6 levels may have infected amniotic fluid. The investigators concluded that the association between infected amniotic fluid and premature labor may be underestimated on the basis of amniotic fluid cultures and that a broad-spectrum bacterial 16S rDNA PCR assay may be useful for detecting prenatal infection. The utility of amniotic fluid testing for IL-6 and other biomarkers in predicting risk for preterm birth is discussed further in Chapter 3 .

In recent years, many studies have explored how abnormal composition of the vaginal flora, maternal vaginal colonization with Ureaplasma or Mycoplasma spp., or development of bacterial vaginosis (BV) during pregnancy can influence the risk of preterm birth. Meta-analyses of recent interventional studies of antibiotic administration to correct such dysbiosis during the first trimester are, to date, inconclusive with respect to reducing preterm birth. Further advances in the detection of microbes and the assessment of microbial diversity through high-throughput, next-generation sequencing–based assessment offer the promise to better understand the role of microbes in preterm labor and its untoward consequences (see Chapter 3 ).

Intrauterine Growth Restriction and Low Birth Weight

Infection of the fetus may result in birth of an infant who is small for gestational age. Although many maternal infections are associated with low-birth-weight infants and infants who are small for gestational age, causal evidence is sufficient only for congenital rubella, VZV infection, toxoplasmosis, and CMV infection, although it is likely that congenital syphilis can, in some cases, also result in intrauterine growth restriction (see Chapter 16 ).

The organs of infants dying with congenital rubella syndrome or congenital CMV infection contain reduced numbers of morphologically normal cells. By contrast, in infants who are small for gestational age with growth deficit from noninfectious causes, such as maternal toxemia or placental abnormalities, the parenchymal cells are normal in number but have a reduced amount of cytoplasm, presumably because of fetal malnutrition.

Developmental Anomalies and Teratogenesis

CMV, rubella virus, and VZV cause developmental anomalies in the human fetus. Coxsackieviruses B3 and B4 have been associated with congenital heart disease. Although the pathogenetic mechanisms responsible for fetal abnormalities produced by most infectious agents remain obscure, histologic studies of abortuses and congenitally infected infants have suggested that some viruses render these effects through mediating cell death, alterations in cell growth, or chromosomal damage. Inflammation and tissue destruction, rather than teratogenic activity, seem to be responsible for the widespread structural abnormalities characteristic of congenital syphilis, transplacental HSV and VZV infection, and toxoplasmosis. Infants with congenital toxoplasmosis may have microcephaly, hydrocephalus, or microphthalmia, but these manifestations usually result from an intense necrotizing process involving numerous organisms and are more appropriately defined as lesions of congenital infection, rather than as effects of teratogenic activity of the organism.

Some mycoplasmas and viruses produce chromosomal damage in circulating human lymphocytes or in human cells in tissue culture. The relationship of these genetic aberrations to the production of congenital abnormalities in the fetus is unknown.

Congenital Disease

Clinical evidence of intrauterine infections, resulting from tissue damage or secondary physiologic changes caused by the invading organisms, may be present at birth or may manifest soon thereafter or years later. The clinical manifestations of infection acquired in utero or at delivery in the newborn infant are summarized in Table 1-6 . Signs of widely disseminated infection may be evident during the neonatal period in infants with congenital rubella; toxoplasmosis; syphilis; or congenital CMV, HSV, or enterovirus infection. These signs include jaundice, hepatosplenomegaly, and pneumonia, each of which reflects lesions caused by microbial invasion and proliferation, rather than by defects in organogenesis. Although these signs of congenital infection are not detected until the neonatal period, the pathologic processes responsible for their occurrence have been progressing for weeks or months before delivery. In some infants, the constellation of signs is sufficient to suggest the likely congenital infection ( Table 1-7 ). In other infants, the signs are transient and self-limited and resolve as neonatal defense mechanisms control the spread of the microbial agent and tissue destruction. If damage is severe and widespread at the time of delivery, survival of the infant is unlikely.

It is frequently difficult to determine whether an infection in the newborn infant was acquired in utero, intrapartum, or postpartum. If the onset of clinical signs after birth occurs within the minimal incubation period for the disease (e.g., 3 days for enteroviruses, 10 days for VZV and rubella viruses), it is likely that the infection was acquired before delivery. The interval between malaria exposure in the mother and congenital malaria in the infant can be prolonged; one case of congenital malaria resulting from Plasmodium malariae occurred in an infant born in the United States 25 years after the mother had emigrated from China. Children with perinatal HIV infection can be diagnosed by 6 months of age using a DNA (or RNA) PCR method, which has largely replaced other approaches for viral detection. A variable fraction (less than half) of children with perinatal HIV contract the infection in utero, depending on the setting and maternal treatment. Virus-negative infants who later become virus-positive may have been infected in the intrapartum or early postpartum period, including via breastfeeding, especially when neither the infant nor the mother is receiving antiretroviral prophylaxis while breastfeeding. In this situation, up to a 54% increase in postpartum HIV transmission associated with breastfeeding has been documented.

Healthy Infants

Most newborn infants infected in utero by rubella virus, T. gondii, CMV, HIV, or Treponema pallidum have no signs of congenital disease. Fetal infection by a limited inoculum of organisms or with a strain of low virulence or pathologic potential may underlie this low incidence of clinical disease in infected infants. Alternatively, gestational age may be the most important factor in determining the ultimate consequences of prenatal infection. When congenital rubella and toxoplasmosis are acquired during the last trimester of pregnancy, the incidence of clinical disease in the infected infants is lower than when microbial invasion occurs during the first or second trimester. Congenital syphilis most commonly results from exposure during the second or third trimesters but can be transmitted to the fetus in the first trimester.

Absence of clinically apparent disease in the newborn may be misleading. Careful observation of infected but healthy-appearing children over months or years often reveals defects that were not apparent at birth. The failure to recognize such defects early in life may be due to the inability to test young infants for the sensory and developmental functions involved. Hearing defects identified years after birth may be the only manifestation of congenital rubella. Significant sensorineural deafness and other central nervous system deficiencies have affected children with congenital CMV infection who were considered to be normal during the neonatal period. In utero infection with Toxoplasma, rubella, and CMV may have manifestations that are difficult to recognize, including failure to thrive, visual defects, and minimal-to-severe brain dysfunction, including motor, learning, language, and behavioral disorders. Infants infected with HIV are usually asymptomatic at birth and for the first few months of life. The median age of onset for signs of congenital HIV infection is approximately 3 years, but many children remain asymptomatic for more than 5 years. Signs of perinatal infection related to HIV include failure to thrive, persistent diarrhea, recurrent suppurative infections, and diseases associated with opportunistic infections that occur weeks to months or years after birth. Of particular concern is a report by Wilson and colleagues showing stigmata of congenital T. gondii infection, including chorioretinitis and blindness, in almost all of 24 children at follow-up evaluations; the children had serologic evidence of infection but were without apparent signs of disease at birth and either did not receive treatment or received inadequate treatment.

Because abnormalities may become obvious only as the child develops and fails to reach appropriate physiologic or developmental milestones, it is crucial to perform careful and thorough follow-up examinations in infants born to women with known or suspected infections during pregnancy.