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Update on TORCH Infections in the Newborn Infant

Sue G. Boyer, MN, RN, Kenneth M. Boyer, MD
NAINR. 2004;4(1)

TORCH infections are unique in their pathogenesis and have potentially devastating clinical manifestations. Congenital
toxoplasmosis remains an important cause of blindness, although avoiding exposure to cats and uncooked meat can prevent it. Congenital syphilis has
declined in incidence due to mandatory prenatal testing and effective therapy. The incidence of congenital and neonatal varicella and of congenital rubella
has been lowered due to vaccination. Perinatally acquired HIV infection continues to increase at a frightening pace in the developing world. The use of
antiretroviral therapy in mothers and the newborn, however, has resulted in a decrease in incidence in the United States. While cytomegalovirus remains the
most common cause of congenital infection in the United States, the possibility of effective treatment with Ganciclovir (Hoffman-LaRoche, Basel,
Switzerland) has emerged from recent studies. In neonatal herpes, selective use of cesarean delivery and antiviral therapy can decrease incidence and
improve outcomes.
When a TORCH test or screening is ordered on a newborn, it is suspected that that child has been exposed in utero to one of several organisms that can
cause mild or subclinical disease in the mother but devastating damage to the infant. Over the recent past, the organisms involved in this testing have
changed in their incidence and outcomes based on new understanding of their pathogenesis, detection, treatment, and prevention. The following article is a
review of those pathogens. We will discuss their most common effects and the impact of public health measures, vaccination, molecular biologic
techniques, and new therapies.
TORCH, as an acronym, stands for Toxoplasmosis, Other [T. pallidum, Varicella-zoster virus (VZV), Parvovirus B19], Rubellavirus, Cytomegalovirus (CMV),
and Herpes Simplex Virus (HSV). Klein and Remington[1] have suggested that this classification is too limiting and that several additional infectious agents
should be considered in the Other category, such as enteroviruses, Borrelia burgdorferi (the cause of Lyme Disease), and, of course, human
immunodeficiency virus (HIV). This review, however, will only cover the traditional TORCH infections as well as HIV.
The usual way in which the fetus is infected is by transplacental spread after maternal infection in which the organism circulates in the mother's blood.
These infections, acquired in utero, can be severe enough to cause fetal loss or can result in intrauterine growth restriction, prematurity, or chronic postnatal
infection. In most cases the maternal illness is mild but the impact on the developing fetus is more severe. The degree of severity is dependent on the
gestational age of the fetus when infected, the virulence of the organism, the damage to the placenta, and the severity of maternal disease. For example, a
primary maternal infection such as herpes simplex is more likely to be vertically transmitted and cause a more severe disease than recurrence of same
infection in the mother.[1]
It is difficult to determine the percentage of fetal loss due to infection during early pregnancy. Although fetal loss during the first few weeks of pregnancy has
been estimated to be 31% after implantation, this percentage may be misleading. Often women are unaware they are even pregnant when the embryonic
death occurs and thus these losses are unaccountable.[2] The earliest recognizable effects of infection are usually seen after six to eight weeks of
pregnancy. At this stage it is still difficult to determine whether intrauterine death is due to interference with organogenesis or the systemic effects of
infection.

The pathogenetic mechanisms of these infections are unique. Because of their relatively low virulence, the organisms involved seldom lead to fetal death
beyond the earliest stages of embryogenesis. Since the fetus is essentially a graft of foreign tissue in the uterus, the placenta constitutes a protective
immunologic barrier that shields the fetus from the mother's humoral and cell-mediated immune responses. This makes the fetus especially susceptible to
infection during the first trimester and the perinatal period. Early in pregnancy the most complex events in embryogenesis take place, making sensory
organs such as the eyes and ears vulnerable. The immature fetus lacks the immunologic mechanisms necessary to completely eliminate an infecting
organism. Therefore, a state of immunologic tolerance is often established, which results in persistence of organisms that ordinarily would be eliminated by a
normal child or adult.[1,3]
Clinical evidence of infection may be seen at birth, soon afterward, or not until years later. The infected newborn infant may display growth retardation,
developmental anomalies, or multiple clinical and laboratory abnormalities. The pathogens vary in whether they cause damage as a congenital agent or
during the prenatal period ( ). The infection can also lead to the late onset of the disease in what appears to be a "normal" newborn, eg, the development of
vision-threatening chorioretinitis in an adolescent with congenital toxoplasmosis. Progressive tissue destruction is seen in rubella, HSV, CMV,
toxoplasmosis, and syphilis as the infective agents continue to survive and replicate in the tissues for months or years after initial infection. This is
particularly unfortunate when treatment is possible. The sequelae of these diseases can also progress over time, eg, the hearing loss that is secondary to
rubella infection can progress or develop even after years of normal hearing. Figure 1, adapted from Klein and Remington,[1] gives a very concise description
of the possible outcomes of maternal infection on the developing fetus.
Table 1. Vertical Transmission of Infection: Relative Frequency of Congenital and Perinatal Infections According to Pathogen

Pathogen

Congenital Perinatal

Toxoplasma gondii

+++

Treponema pallidum

+++

Varicella-zoster virus

++

++

++++

+++

+++

+++

Cytomegalovirus

+++

Herpes Simplex Virus

+++

Parvovirus B19
Human immunodeficiency Virus
Type 1
Rubella virus

Note: ++++ = most frequent, + = least frequent, 0 = organism not transmitted this way.

Pathogenesis of hematogenous transplacental infections. (From Klein J, Remington J: Current concepts of infections in the fetus and newborn infant, in
Remington J, Klein J (eds): Infectious Disease of the Fetus and Newborn Infant. Philadelphia, PA, Saunders, 2001, p 4).
Caused by the protozoan, Toxoplasma gondii, toxoplasmosis is most frequently acquired orally by eating raw meat or exposure to cat feces. The infant is
infected transplacentally after the parasites invade the placenta. Once acquired, the latent encysted organism will persist for life in the host. Like congenital
syphilis and perinatally acquired HIV infection, congenital toxoplasmosis is usually not apparent at birth. However, unlike syphilis and HIV, mothers in the
United States are not routinely screened prenatally for this disease. Unfortunately 70 to 90% of these infants who appear normal at birth will develop
significant clinical illness by young adulthood.[4] These infants develop chorioretinitis that can lead to blindness, obstructive hydrocephalus, and intracranial

calcifications that are associated with mental retardation, seizure activity, and motor and developmental delays. In Europe, pregnant women are screened
monthly for acquisition of the disease as part of standard prenatal care. Maternal servoconversion is thus more quickly identified. Testing for the infection in
the fetus whose mother has evidence of acute infection can now be more precisely accomplished, as early as 18 weeks' gestation, by using polymerase
chain reaction (PCR) amplification of the B1 gene of T. gondii in a sample of amniotic fluid. Whether the fetus has actual organ damage is determined by
serial ultrasound exams. This early detection is important because the mother can now be treated with spiramycin (1.5 grams every 12 hours) to prevent
fetal infection. If the fetus is found to be infected the treatment is changed to the synergistic combination of pyrimethamine and sulfadiazine. This must be
given in conjunction with folinic acid (Leukovorin), which blocks the marrow suppressing effects of pyrimethamine and sulfadiazine.[4]
Early diagnosis is also important because the disease is most severe in the fetus when the mother is acutely infected in the first trimester. However, the
disease is transmitted more frequently during the third trimester or at birth and causes less severe involvement during this time frame. Occasionally the
infant is identified as being at risk because the mother has a documented infection. However, the disease in the mother may be easily overlooked, as it is
often asymptomatic. It may also be overlooked because the maternal physical findings, eg, fever, lymphadenopathy, headache, myalgia, stiff neck, and
anorexia, can easily be attributed to other more common infections.
When serologic screening does not identify maternal infection, the disease may be suspected when the fetal ultrasound shows intrauterine growth
restriction, fetal hydrocephalus, intracranial calcifications, or ascities. The increased use of ultrasound during pregnancy is another more recent
advancement that supports earlier case finding.
Prevention can be provided by increased education of the public. Most pregnant women in the United States now recognize the mysterious dangers inherent
in the "cat litter box." Avoiding ingestion of raw or undercooked meat is equally important but less widely appreciated. A greater emphasis needs to be
placed on early maternal screening to detect seroconversion during pregnancy. Currently only a few states, ie, New Hampshire and Massachusetts,
routinely screen newborn infants, enabling more timely and effective postnatal treatment[5] (see Fig 2).

The life cycle of Toxoplasma gondii. (From Remington J, McLeod R, et al: Toxoplasmosis, in Remington J, Klein J (eds): Infectious Disease of the Fetus and
Newborn Infant. Philadelphia, PA, Saunders, 2001, p 209).
Congenital syphilis is caused by the transplacental transmission of the spirochete, Treponema pallidum, which has a 100% vertical transmission rate.
Syphilis in the mother is characterized by three different stages: the primary stage, which is characterized by the appearance of the syphilitic chancre and
lymphadenitis; the secondary stage, which is the result of hematogenous dissemination, is accompanied by a rash on the hands and feet 2 to 10 weeks
after the chancre heals. The newborn infant with congenital syphilis is considered to be in the secondary stage. This secondary stage is followed by the
early latent period and finally late syphilis appears, which is either asymptomatic (late latent) or symptomatic (tertiary stage). During the tertiary stage
neurological, cardiovascular, and gummatous lesions (granulomas of the skin and musculoskeletal system) are seen.[6]
Syphilis was at its peak in the 1940s, had a resurgence in the 1980s, and is currently at its lowest incidence since reporting first began in 1941. The decline
in incidence of congenital syphilis is attributable mainly to mandatory serologic screening during pregnancy. Rates for primary and secondary syphilis

remain highest in the African-American population and in southeastern United States [7]
While transmission can occur at any stage of the pregnancy, congenital syphilis is more likely to be transmitted by women who are in the primary or
secondary stages of the disease rather than in the latent phase. Congenital syphilis is divided into two classifications: early disease (seen in children before
two years) and late disease (seen after two years). Without treatment fetal or perinatal deaths occur in 40% of those infected. The remaining 60% survive
with two-thirds being asymptomatic at birth. Routine prenatal screening easily identifies these. If not detected or/treated these live-born infants will display
symptoms within weeks or months of birth.[8]
Early manifestations of congenital infection involve multiple body systems. Infants may display hemorrhagic nasal discharge ("sniffles"),
hepatosplenomegaly, jaundice, increased liver enzymes, lymphadenopathy, hemolytic anemia, thrombocytopenia, osteochondritis and periostitis,
mucocutanous rash, central nervous system (CNS) abnormalities, failure to thrive, chorioretinitis, nephritis, and nephrotic syndrome. Late manifestations
result primarily from chronic inflammation of bone, teeth, and CNS.[6]
Diagnosis is certain when the T. pallidum is seen using dark-field microscopy or detected using direct immunofluorescence on specimens from the placenta,
umbilicus, or skin lesions. However, serologic tests are the main means of diagnosis. VDRL (Venereal Disease Research Laboratory) and RPR (rapid
plasma reagin) tests detect antibodies against cardiolipin. While not specific for syphilis, these "nontreponemal" tests are useful in its diagnosis because
the quantitative results of these tests correlate with disease activity. Thus, they are practical for screening purposes. Since they become nonreactive or
borderline within a few months, they indicate whether adequate treatment has been provided. Treponemal tests, which measure antibody specific for T.
pallidum, include the T. pallidum immobilization test (TPI), the fluorescent treponemal antibody absorption test (FTA-ABS), and microhemmagglutination
assays for T. pallidum (MHA-TP). Treponemal tests are used to confirm the positive results from nontreponemal antibody tests (VDRL, RPR). Tests for T.
pallidum using PCR are being developed but are not yet in general clinical laboratory use.[6]
Infants who are symptomatic are evaluated and treated. Asymptomatic infants are considered at risk if the mother's nontreponemal and treponemal
serologies are positive. These infants should be evaluated if maternal treatment is unknown, undocumented, or inadequate; if maternal treatment was less
than 30 days before delivery; if the mother was treated with a nonpenicillin antibiotic; or if the mother's nontreponemal titers did not decrease sufficiently to
demonstrate a cure. If the mother's treatment was adequate and it was completed greater than one month before delivery, an infant's positive nontreponemal
test reflects passively acquired antibody and the infant does not require treatment. The Centers for Disease Control and Prevention (CDC) have carefully
outlined the recommendations for treatment of infants based on the infected mother's history and laboratory results.[9]
In general, effective treatment for congenital syphilis requires a 10-day course of penicillin (aqueous penicillin G 100,000 to 150,000 units/kg/24 hours divided
q12 hours for the first week and q8 hours thereafter, or Procaine Penicillin G 50,000 units/kg IM daily for 10 days).[8] Adequate maternal treatment eliminates
the risk to the infant, but the infant should be followed up until the nontreponemal serology (VDRL or RPR) is negative. Treated infants should also be
followed up serologically to confirm reversion to negative nontreponemal antibody titers.
As all states require prenatal testing, prevention should be easily achieved if the mother receives prenatal care. However, the growing number of those who
do not seek prenatal care means that this screening may not occur until shortly before birth. Testing of the mother's serum rather than cord blood is
preferred because titers are usually lower in the infant and may even be nonreactive if the mother is infected late in pregnancy. It is obviously important that
newborns should never leave the hospital without the results of the maternal serological determination being known. Any woman who delivers a stillborn at
less than 20 weeks' gestation should be tested and, in communities where syphilis is endemic, it is recommended that pregnant women be tested three

times during their pregnancy: at first diagnosis, at 28 weeks (third trimester), and at delivery.[9]
Varicella-zoster virus is closely related to herpes simplex virus. Primary infection causes chickenpox but the virus also establishes itself in the dorsal root
ganglia and can reactivate to cause herpes zoster ("shingles"). Varicella infection in the pregnant woman can cause severe consequences for both the
mother and infant. Infection of the fetus early in pregnancy results in congenital varicella syndrome; transplacental infection at delivery results in neonatal
varicella. Interestingly, recurrent VZV infection ("shingles") does not cause congenital varicella syndrome or neonatal varicella.
In 1995, before the use of varicella vaccine, 4 million cases of chickenpox were seen each year in the United States. Ninety to 95% of all children acquired
varicella as a result of late winterspring epidemics with a secondary attack rate of 90% among uninfected household contacts.[10] Because most adults at
present are immune as a result of childhood illness, the incidence of maternal varicella is low (0.7% per 1,000 women in a study of 30,000 pregnancies).[11]
As with the rubella vaccine, the future of varicella disease will indeed be altered by the recent widespread use of varicella vaccine.[12] The clinical experience
in Japan, which is now being substantiated by long-term studies in the United States, indicates that the immunity persists for prolonged periods after
childhood immunization.[13]
Overall about 25% of fetuses become infected when the mother has varicella but not every infected fetus is clinically affected. About 2% of fetuses whose
mothers have varicella in the first 20 weeks of pregnancy will develop VZV embryopathy. The period of greatest risk to the fetus correlates with the interval
during which there is major development and innervation of limb buds and maturation of the eye. At 6 to 12 weeks' gestation, limb development can be
interrupted, at 16 to 20 weeks greater involvement of the eye and brain is seen.[14] Infants infected later in pregnancy have less frequent and less severe
involvement. Transplacental passage of antibodies that develop in the mother during recovery modify the course of the disease in the second and third
trimester fetus, but cannot reach the fetus during the first trimester or in the perinatal period.
The anomalies associated with congenital varicella syndrome involve many organ systems. There are unusual cutaneous defects, with cicatrical skin scars,
atrophy of extremities, and evidence of damage to the autonomic nervous system. Autonomic nervous system dysfunction is manifested as neurogenic
bladder, hydroureter, hydronephrosis, or severe gastroesophageal reflux with recurrent aspiration pneumonia. Central nervous system manifestations include
microcephaly, cortical atrophy, seizures, and mental retardation. Eye involvement results in chorioretinitis, microphthalmia, and cataracts.[10]
The diagnosis of VZV fetopathy is based on maternal history of gestational chickenpox and the stigmata seen in the fetus. The virus cannot be cultured from
the infant but viral DNA can be detected in tissue samples by PCR. Infected infants have VZV-specific IgM and IgG antibodies detectable in the cord blood.
IgM titers drop quickly after birth but IgG persists. Chorionic villi sampling and fetal blood sampling for the detection of the viral DNA, the virus itself, or
antibody have been used to diagnose fetal infection. The usefulness of these tests for management and counseling has not been established.
For those women exposed to varicella and at risk for infection, varicella-zoster immune globulin (VZIG) is sometimes given. Once maternal infection is
established, however, this antibody preparation does not protect the fetus. The antiviral agent acyclovir is given to pregnant women with severe varicella.
Although its safety and efficacy for the fetus is not rigorously proven, the benefits of the treatment outweigh the risks. Unlike rubella or CMV, the virus does
not actively replicate after birth so antiviral treatment for infants with the congenital syndrome is of no value.[15]
When women contract the virus during the last few days of gestation, the infant is at risk for contracting neonatal varicella with an attack rate of 20%. Those
born within the interval from two days before and up to four days after the onset of maternal varicella can develop progressive varicella with an untreated
mortality rate of 30%.[10] The administration of VZIG to these high-risk infants is one of the most valuable uses of this biological product. Infants born more

than five days after the onset of maternal varicella, although they may have lesions at birth or soon after, are not at high risk. They are protected by the
transplacental transference of maternal IgG antibodies to VZV.
Most commonly, parvovirus B19 causes the childhood viral exanthem erythema infectiosum (Fifth disease or "Slapped cheek disease") that was first
associated with the virus in 1983. By age 15 years, 50% of adolescents have detectable IgG antibodies to the virus.[16] Transmission is airborne or by
droplet spread. Most infections in adulthood are asymptomatic or mild causing a subtle rash and arthralgia. Maternal infection during pregnancy can result in
miscarriage or the development of nonimmune hydrops fetalis. Massive edema and effusions of the pericardial, pleural, and peritoneal spaces characterize
hydrops fetalis. The pathogenesis in the fetus is cardiac failure as a result of profound anemia caused by virus-induced arrest of red cell production. The risk
of transplacental infection is about 30% and the risk of fetal loss about 9%, primarily in the second trimester. Chronic congenital infection with perinatal
sequelae is rare.[17] The best way to diagnose B19 infection in the fetus is the demonstration of viral DNA in amniotic fluid, fetal blood, or tissues. The PCR
method has been used by many investigators and is now available in reference laboratories.[18]
The optimum management of pregnant women with exposure to/or infection with B19 parvovirus is not well developed. Management of susceptible women
(those with no detectable specific IgG or IgM antibodies) is problematic because the infected individual is most likely to transmit the virus during the
prodromal period, which is before the characteristic rash occurs. After the rash appears, management of the infected woman is controversial. Numerous
protocols have been suggested but none have been evaluated with controlled studies.[19] A baseline fetal ultrasound at time of maternal diagnosis is
suggested. Some practitioners do serial ultrasounds to detect the development of fetal hydrops, but the yield is too low to justify routine use for all women
who become IgM anti-B19-positive during pregnancy. Intrauterine transfusion has been successful for some fetuses with hydrops but there have been no
studies that indicate that survival is actually improved after this risky procedure.[19]
The pathogen most recently added to the "other" category is the human immunodeficiency virus (HIV) type 1, which was first identified as the cause of AIDS
in 1984.[20] Although the impact of this virus among newborns has decreased dramatically in the United States during the past decade, it remains a
relentless epidemic in Africa and is also spreading rapidly in southeast Asia, India, and South America.[21] Despite the advances in prenatal treatment of
infected mothers in the United States, new infant cases continue to occur when pregnant women fail to receive prenatal care, are not tested for HIV during
pregnancy, or are noncompliant with prescribed antiretroviral treatment.[22]
There are three routes of transmission to the fetus or newborn from the HIV-infected mother: (1) in utero via transplacental infection, (2) intrapartum by
exposure to blood during labor and delivery, and (3) postpartum via HIV-contaminated human milk. Intrapartum transmission is the most common mode of
acquisition in the United States.[23] In the absence of treatment, vertical transmission rates range from 15 to 40%, with the highest rates reported in
breastfeeding populations.[22] Risk factors that can influence transmission are classified as viral, maternal, and obstetric. Viral risk factors include the
maternal plasma viral load (during pregnancy or, more importantly, at delivery), the virus phenotype, and, with treatment, drug resistance. Maternal risk
factors include malnutrition, vitamin A deficiency, parenteral drug use, cigarette smoking, and breastfeeding of the infant. Obstetric risk factors include
prolonged rupture of the membranes (greater than 4 hours), chorioamnionitis, fetal scalp electrode use, and the presence of genital ulcers or lacerations.
Mutations of the CCR 5 gene, which codes for the HIV viral receptor on lymphocytes, can confer innate immunity to an exposed infant. The strongest
predictor of perinatal transmission is the maternal plasma HIV RNA viral load at delivery.[24,25] Elective (not emergency) cesarean section offers some
protection for those women who are not receiving antiretroviral treatment or who have high levels of HIV in their blood at the time of delivery.[26]
Due to transplacental passage of maternal antibodies, all exposed infants are seropositive at birth. If the baby does not become infected, these antibodies
disappear by age 18 months (seroreversion). If the infant has become infected in utero, the virus can be detected at birth by culture, antigen detection, or,

most reliably, PCR. If intrapartum transmission has occurred, the virus can be detected as early as two weeks postnatally or, with greater sensitivity, at one
or four months of age. Thus, exposed infants are generally tested by PCR at birth, one month, and four months of age. If all PCRs are negative, a final
serologic test is performed at 18 months of age to confirm seroreversion.[21]
Infected children are usually asymptomatic at birth regardless of whether the virus was acquired prenatally or perinatally. Early clinical manifestations are
nonspecific and include lymphadenopathy, hepatosplenomegaly, oral candidiasis, invasive bacterial infections, failure-to-thrive, pneumonia, and
developmental delays. Candidiasis and pneumonia that are nonresponsive to treatment should lead to consideration of serologic testing for HIV.
Paradoxically, hyperimmunoglobulinemia G, A, M, or E, is present in 90% of infected infants by six months of age, a reflection of immune dysregulation.[27]
Prevention of vertical transmission requires knowledge of the maternal infection status as early in the pregnancy as possible. The US Public Health Service
revised its guidelines in 2001, emphasizing HIV testing as part of routine prenatal testing and strongly encouraging the testing of all pregnant women.[28] The
Pediatric AIDS Clinical Trials Group (PACTG) study 076 demonstrated that the risk of mother-to-child transmission could be reduced from 25.5 to 8.3% by
treating the pregnant woman and the neonate with zidovudine (ZDV).[29] Based on this study, infected pregnant women in the United States typically are
treated during gestation with ZDV perinatally and with intravenous ZDV during delivery. The infant is also prescribed six weeks of ZVD therapy starting
immediately after birth. The only side effect documented in prophylaxed infants to date has been clinically insignificant anemia. More aggressive multidrug
treatment of mothers, with a goal of reduction in viral load to undetectable levels at delivery, has been associated with even more dramatic reductions in
vertical transmission.[29] In many centers in the United States, vertical transmission has virtually been eliminated by this management strategy. Even in the
absence of maternal treatment during pregnancy, the use of ZDV during labor and immediately after delivery, often with the additional use of the drug
nevirapine (Boehringer Ingelheim, GmbH, Germany), can significantly reduce transmission.[30]
There are concerns about the long-term effects of the use of antiretrovirals in neonates and pregnant women, but at present the benefits appear to far
outweigh the possible risks. Long-term follow-up of this population will be essential. The only antiretroviral drug absolutely contraindicated during pregnancy
is Efavirens, which causes CNS malformations in primates. The fact that mothers who receive no prenatal care continue to be a high-risk group for vertical
transmission has led to the Mother- to -Infant Rapid Identification at Delivery (MIRIAD) study funded through the CDC.[31] Focusing on disadvantaged
mothers in five major metropolitan areas, novel approaches that include rapid bedside testing, counseling, and referral to care for HIV-positive women and
their infants are being piloted at the involved institutions.
The progress in controlling this disease in resource-poor countries of the developing world is far less satisfactory. The US recommendation to use formula
and to avoid breastfeeding is extremely problematic in environments where there is a lack of sanitation and refrigeration. Delivery by elective cesarean
delivery is also problematic due to inadequate facilities and surgical asepsis. The aim of current studies is to develop strategies for antiretroviral prophylaxis
that achieve the greatest preventive efficacy with the targeted use of the least expensive drugs.[21]
A benign, self-limited viral illness, rubella is characterized by an exanthem and posterior cervical lymphadenopathy. Much of its significant morbidity is
secondary to the effects of the illness when contracted by the fetus in utero. The congenital rubella syndrome that was so common before 1969 included
growth retardation, deafness, congenital heart disease, and mental retardation. Since the availability of mass immunization, the reported incidence of rubella
has dropped from 57,686 cases in 1969 to 200 to 400 cases (30 to 60 cases/year) from 1992 to 1998 (see Fig 3). [32] Although protection of women of
childbearing age is the goal of all immunization strategies, serological surveys in the United States continue to document 10 to 20% susceptibility in this
population. Once a disease of school-aged children, adolescents and young adults now account for the majority of cases seen. Currently outbreaks occur
primarily among unvaccinated foreign-born adults. Since the early 1990s, rubella has disproportionately affected non-US-born Hispanic persons in the United

States.[33,34] A further reduction of rubella has probably occurred as a by-product of the requirement in most states that children receive two measles
mumpsrubella vaccinations before the start of school. This policy resulted from the nationwide outbreak of measles (not rubella) that occurred in 1989 to
1990.

Rubella and Congenital Rubella Syndrome cases reported to the Center for Disease Control, United States, 19661999.
The gestational age at the time of infection determines the intensity of fetal involvement. Up to 20% of maternal infections occurring in the first eight weeks'
of gestation result in miscarriage, spontaneous abortion, or stillbirth. Those fetuses infected before 11 weeks have multiple organ damage while those after
11 to 12 weeks are more likely to have only deafness and/or retinopathy. Fetal damage rarely occurs after 16 weeks' of gestation.[35] Clinical manifestations
can be evident at birth but more commonly result in a "normal" newborn with late-onset sequelae. Early clinical manifestations can be transient or
progressive. Transient early clinical manifestations of congenital rubella include generalized lymphadenopathy, hepatosplenomegaly, intrauterine growth
restriction, hepatitis, jaundice, thrombocytopenic purpura, with petechiae and "blueberry muffin" lesions. These transient manifestations resolve in days or
weeks usually without long-term sequelae. The most common permanent problems seen are sensorineural deafness, cataracts, peripheral pulmonary
stenosis, mental retardation, central language defects, diabetes mellitus type 1, and hypogammaglobulinemia.[36]
In contrast to acquired rubella infection, congenital infection results in persistent progressive infection. Contact isolation is required for neonates suspected
to have congenital rubella. With confirmed cases, infants should be considered infectious until they are one year of age unless results from multiple urine
and nasopharyngeal cultures performed for three months are negative.[37] No specific treatment is available. Those infants with presumed and progressive
infection should undergo complete evaluation for their associated defects.
The infant should be evaluated for congenital rubella if there is a maternal history of rubella during the pregnancy or neonatal manifestations suggestive of a

congenital infection, such as thrombocytopenic purpura or cataracts. Diagnosis of congenital rubella requires virologic or serologic confirmation. The virus
can be isolated for up to one year or more from the nasopharynx, cerebrospinal fluid (CSF), urine, and buffy coat of the blood. Serologic confirmation is
difficult. Although rubella-specific IgM can be measured in cord blood or neonatal serum, it is often associated with false positive and false negative results. It
is recommended that serial measurements of IgG specific antibodies be done at three and six months to document persisting high antibody levels.
Presence of rubella-specific hemagglutination inhibition (HAI) or enzyme immunoassay antibodies after nine months of age is diagnostic of congenital
infection.[36]
The prevention of congenital rubella obviously is dependent upon adequate early immunization, resulting in a high prevalence of immunity in women of
childbearing age. If there is any doubt that they are immune, women should be screened for rubella immunity at the beginning of pregnancy. Immunization of
seronegative women is recommended immediately after delivery.[33] Although inadvertent immunization of pregnant women has not resulted in fetal
abnormality, postpartum immunization is considered safe.
Currently CMV is the most common cause of congenital infection in the United States. Ten to 20% of infected infants may suffer sensorineural hearing loss,
ocular damage, or impairment of cognitive and motor function. CMV is common in all socioeconomic groups but congenital infection with significant
impairment is seen at highest rates in populations in which pregnant women have the highest risk of acquiring primary infection. At this time, the
subpopulation with the highest rates of congenital disease is young, single, nonwhite mothers.[38] In addition to the transplacental route, CMV can be
transmitted at delivery via the maternal genital tract, during the postpartum period in breast milk, and in transfused blood products. CMV is easily spread in
daycare centers and in families with young children. The organism can cause significant illness by endogenous reactivation among immunosuppressed
individuals, including transplant recipients.
Approximately 40% of maternal primary infections are transmitted to the fetus. The likelihood of transmission is similar early as well as late in gestation.
However, first trimester primary maternal infection is more likely to cause neonatal infection that is evident at birth and more likely to result in severe
sequelae such as deafness and mental retardation. Transmission of CMV from the mother to fetus can occur even if the mom was infected long before
conception. However, maternal infections that result from reactivation of the virus usually cause only asymptomatic viral shedding in the infant.[39]
Congenitally infected infants are often divided into two groups: those with findings that are apparent in the neonatal period and those with signs of CNS
damage that become apparent later in childhood. Those symptomatic at birth are most compromised. In addition to intrauterine growth restriction, over 70%
have evidence of CNS involvement: microcephaly, lethargy, hypotonia, optic atrophy, decreased hearing, and intracranial calcifications. Such infants have a
mortality rate of 12% by six months of age. Of infants who are asymptomatic at birth, 10 to 20% eventually will have CNS involvement. Congenital CMV is
said to be the second leading cause of mental retardation in the United States. and is currently the leading cause of sensorineural deafness. Hearing loss
secondary to congenital CMV is progressive in childhood; even those with normal hearing at birth can develop hearing loss later.[40]
Congenital disease is diagnosed by culturing the virus in body fluid (oral secretions or urine) in the first three weeks of life. Modifications of conventional
cultures such as virus detection with antibodies or DNA detection by PCR can yield results in 24 hours. After three weeks of age, finding the virus in the
infant does not always indicate congenital disease because the child may well have acquired the organism at the time of delivery or postnatally via breast
milk.[39]
Most recently, severe congenital CMV is being treated under experimental protocols with intravenous ganciclovir. Controlled studies show treated infants are
less likely to manifest hearing loss at 6 and >12 month follow-ups. As the research has only been done with infants who have severe disease and there are

potentially severe side effects to the drug, the use of this treatment is currently restricted to severely involved patients.[39] A new oral form of ganciclovir,
valganciclovir, offers promise as a more easily administered treatment, which could be used for a wider range of clinical manifestations.
Transmission of the virus requires direct contact with bodily fluids. Thorough hand washing and other preventive hygienic measures can decrease spread in
daycare centers and at home. Prepregnancy titers can also identify at-risk women. In the future, a CMV vaccine currently being evaluated in young adults
may be of use.[41]
While herpes simplex infections were recognized by the ancient Greeks, the association between herpes simplex type 2 as a cause of neonatal disease
and genital herpes was not made until the 1960s.[42] The recent development of antiviral therapy enables the reduction of mortality and morbidity. As herpes
simplex is most often acquired during delivery rather than during gestation, it is more preventable and treatable compared with CMV or rubella. Like the
varicella-zoster virus, the herpes simplex virus can persist in the latent state, resurfacing at any time during the individual's life span.
While there have been fluctuations in incidence of the disease, it is estimated that there are approximately 30 cases/100,000 live births in the United States.
It is interesting that neonatal infection occurs far less frequently than might be expected given the high prevalence (one in five) of seropositivity to HSV-2 in
childbearing women.[43] The infant attack rate among women with primary infection is 33 to 50%, while those with recurrent disease only show an attack
rate of 1 to 3%.[44] Unfortunately, however, only 15 to 20% of women whose infants develop neonatal herpes infection have a history of symptomatic disease
and only 25% have relevant symptoms at delivery.[43]
Perinatal infection manifests itself during the first month of life with 9% of infections occurring on day one and 40% by the end of the first week of life. There
are three major categories seen: (1) localized skin, eye and mouth infection; (2) encephalitis with or without skin, eye, and mouth disease; and (3)
disseminated infection. CNS infections tend to be evident at days 8 to 12 postpartum, while the other categories surface earlier at days five to six
postpartum.[45] Infants with disseminated disease have the worst prognosis. Many are born to mothers with a new herpes infection who have not developed
or passively transferred antibodies against the virus to the infant. Multiple organs are involved and initial signs and symptoms include irritability, seizures,
respiratory distress, jaundice, bleeding diathesis, and shock.
Diagnosis of disseminated disease is difficult because symptoms are vague, nonspecific, and similar to those of bacterial sepsis or enteroviral infections.
Nearly one-third of all infants with neonatal herpes have only encephalitis as the initial manifestation. Clinical manifestations of encephalitis include seizures,
lethargy, irritability, poor feeding, temperature instability, and a bulging fontanel. As with disseminated disease, not all of these infants display the
characteristic vesicular exanthem. Infection localized to the skin, eye, and/or mouth may seem benign but, in the absence of treatment, this onset is often
associated with the subsequent development of the more serious disease manifestations. Skin vesicles are noted in 90% and keratoconjunctivitis may be
evident with eye involvement. Long-term neurological impairment is frequent in children who have recovered from encephalitis.[43]
Herpes simplex disease needs to be diagnosed quickly and accurately to prevent needless morbidity and mortality. Skin, eye, and mouth infection is
usually detectable in 24 to 36 hours by viral cultures. Encephalitis may be diagnosed by culture of CSF or, more sensitively, by DNA detection by PCR.
Abnormal liver enzymes and culture of the virus from surface sites suggest disseminated disease. Serology is not a reliable tool for rapid diagnosis because
of the presence of transplacental maternal antibodies. A positive genital tract culture from the mother greatly increases the probability that a newborn's
illness is herpes.
Treatment should include acyclovir IV (20 mg/kg/dose) q8 hours for 14 to 21 days. This high dose may be associated with neutropenia, thus requiring

monitoring of blood counts.[45] Adequate hydration is important to minimize nephrotoxicity. Placement in an intensive care setting is essential to monitor for
signs of disseminated disease, to manage seizure activity, and to provide mechanical ventilation if necessary.
Newborns with this diagnosis should be isolated to prevent the potential for nosocomial transmission.[37] In pregnant women a reliable history of genital
herpes simplex disease should be determined for all patients. The American Academy of Pediatrics and the American College of Obstetrics and Gynecology
recommend cesarean section if primary, first episode, or recurrent HSV lesions are present in labor. The low attack rate of neonatal disease in women with
recurrent infection has made some practitioners question the use of cesarean sections. However, a recent prospective study has confirmed its value. Infants
should have cultures of nose, mouth, urine, and stool at 24 to 48 hours of age if any maternal cultures are positive or if disease is apparent.[46]
During the past 20 years, a number of scientific and sociological changes have altered the scope of TORCH infections. Incidence of these diseases has
changed significantly because there are better preventive measures in place. For example, in 1969, mass immunization for rubella reduced this illness from
one that caused 12.5 million cases of rubella in the pandemic of 1962 to 1964 with 20,000 infants developing congenital defects to an illness that is close to
eradication in the United States [47] The incidence of congenital varicella syndrome will also be affected by the recent widespread use of varicella vaccine.
The use of new therapeutic drugs has altered the picture of CMV and toxoplasmosis. Ganciclovir, (Hoffman LaRoche, Basil, Switzerland) is showing promise
as a drug to prevent those with severe CMV infection from developing the progressive deafness and other sequelae that characterize the disorder. Blood
products are now routinely tested for the virus and the use of seronegative blood permits the infection to be avoided in premature infants. Treatment for
toxoplasmosis in utero and during the first year of life has been shown to significantly improve outcomes.
From the negative perspective, shorter, rushed hospital stays make it more difficult to follow up on maternal serologies and to identify the infant who,
although "normal appearing," may have late-onset effects of the disease. The growing number of uninsured in our country leads to poorer prenatal care and
difficulties in promoting preventive interventions such as screening for toxoplasmosis. As several of these illnesses result in sensorineural hearing loss, the
growing number of mandated newborn hearing screening programs may be able to identify those with CMV or rubella who might otherwise be left untreated
until a later date. At present, the American Academy of Pediatrics endorses this initiative and 32 states currently have mandated programs.[48]
Advances in molecular diagnostics have enabled the development of faster, more precise methods to detect the presence of pathogens. DNA probes and
PCR are able to identify pathogens when cultures and serologic tests are slow, difficult, or inconclusive.[49] Toxoplasmosis, for example, can be quickly
detected in the amniotic fluid, allowing for earlier treatment of the fetus. Finally, the growing use of the Internet to access information has changed how
health professionals educate themselves and the public. Websites that make available authoritative information and practical advice exist for a number of
congenital infections and can be invaluable to parents.
The nature of TORCH infections has changed dramatically as a result of new vaccines, new pathogens, more sophisticated diagnostic testing, and greater
public awareness of the need for early prenatal care. In the future, nurses will find new organisms to consider, new vaccines to prevent these diseases, and
more effective treatments. The impact of the "new genetics" may enable the identification of those at risk for these infections even before conception.
References

1. Klein J, Remington J. Current concepts in infections of the fetus and newborn. In Infectious Diseases of the Fetus and Newborn Infant, eds Remington
J and Klein J. Saunders, Philadelphia, PA 2001, 1-24.

2. Wilcox AJ, Weinberg CR, O'Connor JF, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189-194.
3. Mims C, Nash A, Stephen J. Mims' Pathogenesis of Infectious Diseases, Academic Press, San Diego, CA 2001.
4. Boyer KM. Toxoplasmosis: Current status of diagnosis, treatment and prevention. Semin Pediatr Infect Dis 2000;11:165-171.
5. Guerina NG, Hsu HW, Meissner HC, et al. Neonatal serologic screening and early treatment for congenital Toxoplasma gondii infection. N Engl J
Med 1994;330:1858-1863.
6. Rawston S. Treponema pallidum (Syphilis). In Principles and Practice of Pediatric Infectious Diseases, eds Long S, Pickering L and Prober C.
Churchill-Livingston, New York, NY 2003, 954-965.
7. Centers for Disease Control and Prevention. Primary and secondary syphilisUnited States, 1998. MMWR 1999;48:1299-1302.
8. Azimi P. Syphilis (Treponema pallidum). In Nelson Textbook of Pediatrics, eds Behrman R, Kliegman R and Jenson H. Saunders, Philadelphia, PA
2004, 978-982.
9. Centers for Disease Control and Prevention. Sexually transmitted disease treatment guidelines 2002. MMWR 2002;51:1-80.
10. Arvin A. Varicella-zoster virus. In Principles and Practice of Pediatric Infectious Diseases, eds Long SS, Pickering LK and Prober CG. ChurchillLivingston, New York, NY 2003, 1041-1049.
11. Brunell PA. Varicella in pregnancy, the fetus and the newborn: Problems in management. J Infect Dis 1992;166:S42-S47.
12. Seward J, Watson B, Peterson C, et al. Varicella disease after introduction of varicella vaccine in the United States: 19952000. JAMA 2002;287:606611.
13. Johnson CE, Stancin T, Fattlar D, et al. A long-term prospective study of varicella vaccine in children. Pediatrics 1997;100:761-766.
14. Pastuszak AL, Levy M, Schick B, et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N Engl J Med 1994;330:901905.
15. Meyers M. Varicella zoster virus. In Nelson Textbook of Pediatrics, eds Behrman R, Kliegman R and Jenson H. 2004, 973-977. Philadelphia, PA.
16. Centers for Disease Control. Risks associated with human parvovirus B19 infection. MMWR 1989;38:81-97.
17. Miller E, Fairley CK, Cohen BJ, et al. Immediate and long term outcome of human parvovirus (B19) infection in pregnancy. Br J Obstet Gynaecol
1998;105:174-178.
18. Schwarz TF, Jager G, Holzgreve W, et al. Diagnosis of human parvovirus B19 by polymerase chain reaction. Scand J Infect Dis 1992;24:691.

19. Torok T. Human parvovirus B19. In Infectious Diseases of the Fetus and Newborn Infant, eds Remington J and Klein J. Saunders, Philadelphia, PA
2001, 779-811.
20. Gallo RC, Salahuddin SZ, Popovfic M, et al. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk
for AIDS. Science 1984;224:500-503.
21. Mueller B, Pizzo P. Acquired immunodeficiency syndrome in the infant. In Infectious Diseases of the Fetus and Newborn Infant, eds Remington J and
Klein J. Saunders, Philadelphia, PA 2001, 447-475.
22. Bulterys M, Nolan M, Jamieson D, et al. Advances in prevention of mother-to-child HIV-1 transmission: Current issues, future challenges. AIDScience
2002;2:4.
23. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report 2000;12:1-45.
24. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with
zidovudine. N Engl J Med 1999;341:385-393.
25. Garcia P, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. N Engl
J Med 1999;341:394-402.
26. The European Mode of Delivery Collaboration. Elective cesarean section versus vaginal delivery in prevention of vertical HIV-1 transmission, a
randomized clinical trial. Lancet 1999;353:1035-1039.
27. Hilmers D, Kline M. Clinical manifestations of human immunodeficiency virus infection. In Principles and Practice of Pediatric Infectious Diseases,
eds Long S, Pickering L and Prober C. Churchill-Livingston, New York, NY 2003, 664-669.
28. Centers for Disease Control and Prevention. Revised recommendations for HIV screening of pregnant women. MMWR 2001;50:59.
29. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine
treatment. N Engl J Med 1994;331:1173-1180.
30. Wade N, Birkhead G, Warren B, et al. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency
virus. N Engl J Med 1998;339:1409-1414.
31. Bultreys M. Preventing vertical HIV transmission in the year 2000: Progress and prospects-a review. Placenta 2001;22:S5-S12.
32. Centers for Disease Control and Prevention. Rubella and congenital rubella syndromeUnited States 19911997. MMWR 1997;46:350-354.
33. Danovaro-Holliday MC, Gordon E, Woernle C, et al. Identifying risk factors for rubella susceptibility in a population at risk in the United States. Am J
Public Health 2003;93:289-291.

34. Reef SE, Frey TK, Theall K, et al. The changing epidemiology of rubella in the 1990s: On the verge of elimination and new challenges for control and
prevention. JAMA 2002;287:464-472.
35. Best JM, O'Shea S. Rubella virus. In Diagnostic Procedures for Viral, Rickettsial and Chamydial Infections, eds Lennette EH and Schmidt NJ.
American Public Health Association, Washington DC 1989, 731-795.
36. Maldonado Y. Rubella. In Nelson Textbook of Pediatrics, eds Behrman R, Kliegman R and Jenson H. 2004, 1032-1034. Philadelphia, PA.
37. In 2003 Red Book: Report of the Committee on Infectious Diseases, ed Pickering LK. American Academy of Pediatrics, Elk Grove Village, IL 2003.
38. Fowler KB, Stagno S, Pass RF. Maternal age and congenital cytomegalovirus infection: Screening of two diverse newborn populations: 19801990. J
Infect Dis 1993;168:552.
39. Pass R. Cytomegalovirus. In Principles and Practice of Pediatric Infectious Diseases, eds Long S, Pickering L and Prober C. Churchill-Livingston,
New York, NY 2003, 1050-1059.
40. Hicks T, Fowler K, Richardson M, et al. Congenital cytomegalovirus infection and neonatal auditory screening. J Pediatr 1993;123:779.
41. Pass RF, Duliere AM, Boppana S, et al. A subunit cytomegalovirus vaccine based on recombinant envelope glycoprotein B and a new adjuvant. J
Infect Dis 1999;180:970.
42. Nahmias A, Dowdle WR. Antigenic and biological differences in herpesvirus hominis. Prog Med Virol 1968;10:110-159.
43. Arvin A, Whitley R. Herpes simplex virus infections. In Infectious Diseases of the Fetus and Newborn Infant, eds Remington J and Klein J. Saunders,
Philadelphia, PA 2001, 425-446.
44. Prober CG, Yasukawa L, Aud S, et al. Low risk of herpes simplex virus infection in neonates exposed to virus at the time of vaginal delivery with
recurrent herpes virus infection. N Engl J Med 1987;316:240-245.
45. Kohl S. Herpes simplex virus. In Nelson Textbook of Pediatrics, eds Behrman R, Kliegman R and Jenson H. Saunders, Philadelphia PA 2004, 10511057.
46. Brown Z, Wald A, Morrow RA, et al. Effect of serologic status and cesarean delivery on transmission rates of herpes simplex from mother to infant.
JAMA 2003;289:203-209.
47. Cooper LZ, Alford CA. Rubella. In Infectious Diseases of the Fetus and Newborn Infant, eds Remington J and Klein J. Saunders, Philadelphia, PA
2001, 347-388.
48. American Academy of Pediatrics. Task Force on Newborn and Infant Hearing, Newborn and infant hearing loss, detection and intervention. Pediatrics
1999;103:527-530.

49. Pfaller MA. Molecular approaches to diagnosing and managing infectious diseases: Practicality and costs. Emerg Infect Dis 2002;7:312-319.
Reprint Address
Address correspondence to Sue G. Boyer, RN, MN, University of Illinois at Chicago, College of Nursing, Department of MaternalChild Health, Chicago, IL
60612, USA
NAINR. 2004;4(1) 2004 W.B. Saunders