Epidemiology and Transmission

Labial and oropharyngeal infections are predominantly caused by HSV-1 and may be transmitted by respiratory droplet spread or direct contact with infected secretions or vesicular fluid. Most HSV-1 infections occur in childhood and are usually asymptomatic, sometimes causing a gingivostomatitis or mononucleosis-like syndrome. Girls have a higher seroprevalence than boys. Black children have a 35% seroprevalence by age 5 compared with 18% in white children, and the seroprevalence remains twice as high through the teen years, but is equivalent by 60 years of age.⁹⁷

Because genital infections are usually transmitted by direct sexual contact with HSV-2, transmission most often occurs during or after adolescence. Symptomatic and asymptomatic individuals may transmit infection. Primary genital infection may cause localized pain and burning of the labia and vaginal mucosa 2 to 7 days after contact. After a period of paresthesia, vesicles full of seropurulent fluid develop. These vesicles break down easily, forming shallow ulcers and releasing numerous infectious virus particles. There is often copious watery vaginal discharge, edema, dysuria, and bilateral pelvic and inguinal lymphadenopathy, accompanied by systemic symptoms of fever, malaise, and headache. Healing may occur several weeks later. Many primary genital infections are asymptomatic, however.

Seroprevalence rates among pregnant women have indicated that at least 30% of women have serologic evidence of infection with HSV-2, but most of these women lack a history or symptoms of infection. Not only was this seroprevalence largely unsuspected among these pregnant women, but asymptomatic viral shedding also occurred among them at a rate (roughly 1% viral shedding at any time in pregnancy) similar to that in women with symptomatic recurrences. Seroprevalence increases dramatically as the number of sexual partners increases. Recurrence is higher among women with genital HSV-2 infection than among women with HSV-1, probably because HSV-2 is more likely than HSV-1 to establish latency in the inguinal dorsal root ganglia. When viral replication is not medically suppressed, there are a median of four HSV-2 recurrences in the first year after a primary infection. Herpes simplex virus-1 recurs about once a year. Finally, for 70% of all women whose infants develop HSV infection, there is no history of infection or symptoms or of intercourse with a partner who has had the infection.

About 10% of HSV-2 seronegative women have HSV-2 seropositive partners. These women may remain uninfected with HSV-2 over prolonged periods despite continued, unprotected contact with a partner who is HSV-2 seropositive. Because the seroconversion rate is 20% per year for these women and most genital HSV-2 infections are asymptomatic, these women are at high risk of an unsuspected, primary HSV-2 genital infection during pregnancy.⁹⁷ Seroconversion rates are similar among pregnant and nonpregnant women. It is estimated that about one third of women who asymptomatically shed HSV in labor have been recently infected and that their infants have a tenfold or more greater risk of being infected than the infants of mothers with recurrent disease.

Women who are seronegative for HSV-1 and HSV-2 and have HSV-1–seropositive partners may acquire HSV-1 genital infection with oral sex. Oral sex has become more popular among teens because they believe it is safer sex. Overall, a woman who is seronegative for HSV-1 and HSV-2 with a discordant partner has a 3.7% chance of acquiring infection with either virus during pregnancy, and a woman who is seropositive for HSV-1 and seronegative for HSV-2 with an HSV-2–seropositive partner acquires HSV-2 infection in 1.7% of pregnancies.⁹⁷

Transmission from mother to infant may occur via many different routes, including transplacental, intrapartum, and postnatal acquisition. Transplacental transmission (5%), which is responsible for in utero infection, is inferred by the documentation of HSV skin lesions and viremia at birth and by elevated specific cord IgM levels. Primary and recurrent maternal infections have been associated with congenital infection.

Intrapartum transmission is responsible for 85% of neonatal infections. The actual transmission is influenced by the type of maternal infection. A high titer of viral particles (>10⁶/0.2 mL inoculum) is excreted for about 3 weeks with a primary maternal infection, which is more likely to involve cervical shedding than a recurrent maternal infection, in which 10² to 10³ viral particles per 0.2 mL inoculum are shed for only 2 to 5 days. Maternal neutralizing antibodies may also be partially protective for a newborn in recurrent infections and may not yet be present (and available to cross the placenta) in a primary maternal infection. In a 20-year trial, 0.3% of women were found to be shedding either HSV-1 or HSV-2 asymptomatically at delivery. Neonatal disease resulted in 57% of first episode primary maternal infections (defined as having HSV-1 or HSV-2 isolated from genital secretions without having concurrent HSV antibodies), 25% of first episode nonprimary maternal infections (defined as HSV-2 isolated from genital secretions of a woman with only HSV-1 antibodies, or HSV-1 isolated from a woman with only HSV-2 antibodies), and 2% of recurrent maternal infections (present when the virus isolated from genital secretions was the same type as antibodies present in the serum at the time of labor).²⁷

Because recurrent infections are so much more common, half of all neonatal HSV-2 infections occur secondary to recurrent maternal infection, even though transmission from mother to infant occurs in only 2% of the cases. The amount of neutralizing antibody also affects the severity of neonatal disease. Infants who do not receive much transplacental transfer of antibody are more likely to develop disseminated disease. Prolonged rupture of membranes (>4-6 hours) also increases the risk of viral transmission, presumably from ascending infection. Delivery via cesarean section, preferably before rupture of membranes, but at least before 4 to 6 hours of rupture, can reduce the risk sevenfold.²⁷

Neonatal infection does still occur, however, even with cesarean delivery. Fetal scalp electrodes may accelerate transcervical infection and breach the infant’s skin barrier, also increasing risk of infection. It was shown more recently that vacuum extraction may cause scalp lacerations resulting in HSV skin lesions at the site of application. The relative risk of vacuum extraction resulting in HSV infection was nearly 7.5 times that of spontaneous vaginal or cesarean delivery. Antenatal maternal viral culture screening for HSV shedding is of no predictive value in determining who will be shedding virus at delivery.

Finally, transmission may occur postnatally (10%). Restriction enzyme DNA analysis has been used to document postnatal acquisition of HSV and its spread within a nursery by identifying infection with the same herpes strain in infants born to different mothers. The father and the mother and maternal breast lesions have been implicated in neonatal infections. There is also concern regarding symptomatic and asymptomatic shedding among hospital personnel, one third of whom may have a history of HSV-1 lesions, and 1% of whom still have recurrent labial lesions. Individuals with a herpetic whitlow should be removed from the nursery. Removal of health care workers with other lesions would pose significant risk to neonates because it would cause significant disruption of care. Orolabial lesions should be covered with a mask, and skin lesions should be covered with clothing or a bandage. Workers should be counseled on good hand hygiene and not touch a lesion.

Congenital Herpes Simplex Virus Infection

Congenital infection was found in 5% of the infants in the National Institute of Allergy and Infectious Disease (NIAID) Collaborative Antiviral Study Cohort.²¹⁶ These infants with growth restriction characteristically have skin lesions, vesicles and scarring, neurologic damage (intracranial calcifications, microcephaly, hypertonicity, and seizures), and eye involvement (microphthalmia, cataracts, chorioretinitis, blindness, and retinal dysplasia). Congenital infections are described throughout pregnancy and after primary and recurrent infections, but are most likely with a primary infection, or if the mother has disseminated infection and is in the first 20 weeks of pregnancy. Most cases are caused by HSV-2. The manifestations probably result from destruction of normally formed organs rather than defects in organogenesis because the lesions are similar to lesions of neonatal herpes. A few children, usually in association with prolonged rupture of membranes, have isolated skin lesions that may be more amenable to antiviral therapy.

Neonatal Herpes Simplex Virus Infection

Although asymptomatic HSV infections are common in adults, they are exceedingly rare in neonates. Of all neonatal infections, 20% are caused by HSV-1 rather than HSV-2. Half of the infants are born prematurely, usually between 30 and 37 weeks of gestation, and many have complications of prematurity, particularly respiratory distress syndrome. Two thirds of the term newborns have a normal neonatal course and are discharged before the onset of disease. They may also have simultaneous bacterial infections. One fourth of the infants present on the first day of life, and two thirds present by the end of the first week.

Clinically, neonatal infections are classified as (1) disseminated, involving multiple organs, with or without central nervous system (CNS) involvement; (2) encephalitis, with or without skin, eye, or mouth involvement; and (3) localized to the skin, eyes, or mouth. Approximately 25% of cases are disseminated; 30% have CNS involvement; and 45% are localized to the skin, eyes, or mouth.

Among the 202 infants with HSV infections followed in the NIAID Collaborative Antiviral Study Group, mortality was significantly greater with disseminated infection (57%) than with encephalitis (15%), and did not occur with disease limited to the skin, eyes, or mouth.²¹⁶ The relative risk of death was 5.2 for infants in or near coma at onset of treatment, 3.8 for disseminated intravascular coagulopathy, and 3.7 for prematurity.²¹⁵ Among infants with disseminated disease, the infants with pneumonitis had a greater mortality. Sequelae among survivors were more common with encephalitis or disseminated infection, particularly with HSV-2 infection, or in the presence of seizures, but also were more likely in infants with skin, eye, or mouth infection who had three or more recurrences of vesicles within 6 months.²¹⁵ Sequelae were found in 75% of survivors with HSV-2, and only 27% of survivors with HSV-1 infection, which may be related to the in vitro susceptibility of HSV-1 to acyclovir.²¹⁷

Diagnosis

Isolation of virus is definitive diagnostically. Cultures of the newborn (scrapings of mucocutaneous lesions, CSF, stool, urine, nasopharynx, and conjunctivae) should be delayed to 24 to 48 hours after birth to differentiate viral replication in the newborn from transient colonization of the newborn at birth. The specimens for culture may be combined to save money because it is not important where the virus is located, but whether the virus is present, with the exception of CSF specimens, which are needed to determine CNS involvement.⁹⁷ If the culture shows cytopathic effects, typing should be done. Serologic testing is not useful in neonatal disease because transplacentally transferred maternal antibody confounds the interpretation. Polymerase chain reaction testing has become invaluable, especially for the CSF, which has a very low recovery rate for HSV cultures. Polymerase chain reaction can also be used to test blood, scrapings of lesions, the conjunctiva, or the nasopharynx. However, PCR has detected HSV DNA in the amniotic fluid of women with symptomatic infection, yet the infants were uninfected and healthy.⁴

Therapy

Vidarabine was the first antiviral agent used to treat HSV that was efficacious despite the toxicity. Acyclovir, a deoxyguanosine analog, is preferentially taken up by virus-infected cells and phosphorylated by thymidine kinase, which is encoded in the virus. Host cell enzymes then effect di- and tri-phosphorylation. Acyclovir triphosphate prevents DNA polymerase and is a chain terminator, preventing viral DNA synthesis. Acyclovir is the only drug recommended for use in neonates. When a low-dose acyclovir (30 mg/kg per day in three divided doses) was compared with vidarabine, the morbidity and mortality were equivalent, but the ease of acyclovir administration and decreased toxicity resulted in it readily supplanting vidarabine in use. High-dose intravenous acyclovir (60 mg/kg per day in three divided doses) was then compared with low-dose acyclovir for a longer treatment duration (21 days for disseminated or CNS disease and 14 days for disease localized to skin, eyes, or mouth). High-dose acyclovir resulted in a much improved survival rate: Infants with disseminated infection had an odds ratio of survival of 3.3, and infants with CNS disease had a similar survival. The likelihood of developmentally normal survival had an odds ratio of 6.6 compared with infants treated with the lower dose.99,100

Infants with an abnormal creatinine clearance need to have the acyclovir dose adjusted, and all infants need to be monitored for neutropenia. Infants with CNS disease need to have a repeat lumbar puncture at the end of the course of treatment. Treatment should be continued until the CSF is PCR negative. Infants who continue to have detectable HSV DNA in the CSF by PCR at the end of therapy are more likely to die or have moderate to severe impairment. Poor prognostic indicators are lethargy and severe hepatitis in disseminated disease, and prematurity and seizures in CNS disease.99,100

Mortality has been tremendously decreased with high-dose acyclovir and is now 29% for disseminated disease; 4% for CNS disease; and 0% for skin, eye, or mouth disease.99,100 Although the percentage of survivors with normal development (31%) has not changed for CNS disease, normal development among survivors of disseminated disease is now 83%, and for skin, eye, or mouth disease is greater than 98% (Figures 57-1 and 57-2).^99,100 Neonates with skin, eye, or mouth disease with neurodevelopmental abnormalities on follow-up may represent undetected CNS disease, adverse effects of inflammation secondary to disease, or seeding from recurrent skin lesions. In a study of 77 neonates with culture-proven HSV disease, CSF PCR detected HSV DNA in 7 of 29 infants who had been classified as SEM disease, 13 of 14 classified as disseminated disease, and 26 of 34 who had been classified as CNS disease. Herpes simplex virus DNA remains in the CSF for an average of 10 days after the onset of CNS disease.¹⁰³ It has also been shown that infants with fewer than 100 copies of HSV DNA per microliter of CSF after 4 days of treatment had improved survival and neurological outcome.⁴⁸ To improve outcome, earlier recognition and treatment of infection are needed. Initiation of therapy in the high-dose acyclovir trial usually began 4 to 5 days after onset of symptoms, which is no better than occurred in the low-dose trial.⁹⁹ Topical ophthalmic antiviral drugs should be given to infants with ocular involvement in addition to parenteral therapy. This may include 1% trifluridine, 0.1% iododeoxyuridine, or 3% vidarabine. All other therapy is supportive. Early data indicate that quantitative PCR for HSV DNA in the blood may be useful in determining outcome and treatment, but there are not enough data to recommend this currently. Infants with disseminated disease have higher viral loads than infants with CNS disease and infants with SEM disease.¹⁰⁵ The viral load is also higher in those infants who die than in those who survive with neurologic disease or those who survive without neurologic disease.

Oral suppressive acyclovir therapy for 6 months after completion of treatment has been used to decrease recurrences in infants.⁹⁶ There is a significant reduction in the recurrence of skin lesions in infants with any of the three disease classifications and improved neurodevelopmental outcomes with CNS HSV disease.^22,104,175 Infants are treated with three doses per day at 300 mg/m²/dose and the neutrophil counts need to be checked at 2 and 4 weeks, then monthly during therapy.

Resistance to acyclovir is a concern and has been seen in mothers who have had multiple recurrences treated with suppressive acyclovir, mothers who have taken oral acyclovir for suppression in the later part of pregnancy, and even in a few infants on suppressive therapy for the 6 months after the end of treatment.

Prevention

In 1999, the American College of Obstetrics and Gynecology recommended that cesarean delivery be performed if a mother had HSV genital lesions or prodromal symptoms at the time of delivery. Seventy percent of mothers of infants with neonatal disease do not have a history or symptoms of HSV infection, however, and their partners do not have a history of HSV infection, and neonatal infection may still occur even if a cesarean delivery is performed. Repetitive cervical cultures do not predict whether a mother will be shedding virus at delivery. Mothers should be counseled regarding the signs and symptoms of disease, and some may then recognize infection. If rupture of membranes has been present longer than 6 hours, some experts still recommend cesarean delivery in the face of genital lesions, but data are lacking, and controversy exists. Scalp electrodes should be avoided. There is also no consensus for treatment with ruptured membranes in a mother with lesions except for a very immature fetus.

If an infant is delivered vaginally to a mother with recurrent genital lesions (5% risk of infection), most experts do not recommend treating the infant. Cultures and PCR of the neonate should be obtained at 24 hours of life, and the infant should be observed carefully. Circumcision should be delayed until cultures are known to be negative. Hand washing should be emphasized. Breastfeeding may be allowed if there are no lesions on the breast. The mother needs to be taught the signs and symptoms of neonatal disease because the cultures do not always detect neonatal disease.

Whenever a mother has active genital lesions at the time of the birth of the baby, and she has no history of prior herpetic infection, both a herpes culture and PCR need to be sent, regardless of whether the birth is via cesarean section or vaginal (Figures 57-3 and 57-4).¹⁰² Type-specific serology can be used to determine if this is a recurrent infection or is a first episode infection (Table 57-1). Because the risk of infection to the newborn is greater than 50% in a primary, first-episode infection and 25% in a nonprimary, first-episode infection in the mother, these infants should have surface cultures and blood and surface PCR for HSV, serum ALT and CSF cell count, chemistries, and PCR for HSV sent at 24 hours of life, and earlier if the baby is ill or premature or had prolonged rupture of membranes. Acyclovir should be started after the evaluation. If it is a recurrent infection, the acyclovir may be discontinued after a negative evaluation. Empiric acyclovir treatment should be considered for 10 days for any first-episode infection, whether primary or nonprimary, even if the baby’s evaluation is negative. If a CSF infection is suspected, treatment should be continued for 21 days, after which a repeat CSF PCR needs to be sent. Another 7 days of acyclovir should be given whenever the PCR is positive for HSV.

There is also considerable controversy concerning the prevention of a primary HSV genital infection in a seronegative pregnant woman. Although some authorities advocate for type-specific serologic screening for HSV in all pregnant women, arguing that many mothers want the information, that they may be counseled against oral or unprotected sex, and that strategies may be devised from the data that are collected, others argue against testing, stating that it is not cost effective, there is no recommended intervention, and the unexpected positive test can cause significant psychological and social distress. Targeting women for testing who are at high risk for infection misses too many seronegative women. Some treatment strategies do exist, however. It has been shown that the use of condoms in at least 70% of sexual intercourse between a woman seronegative for HSV and a man seropositive for HSV reduced transmission by more than 60%.⁹⁷ Antiviral suppression with valacyclovir for 8 months in seropositive male partners reduced the transmission of HSV-2 infection to pregnant women by 48% and symptomatic infection by 75%.⁴⁰

Many obstetricians now routinely recommend antiviral prophylaxis (valacyclovir or acyclovir usually) in the last trimester of pregnancy to suppress viral recurrences. Although no major malformations have been associated to date with the use of acyclovir in pregnancy, the safety to the fetus has not been determined. In a Cochrane Database meta-analysis of third-trimester antiviral prophylaxis, women were less likely to have a recurrence at delivery (relative risk 0.28), a cesarean delivery for genital lesions (relative risk 0.30), and HSV detected at delivery (relative risk 0.14).⁸⁰ Although there were no cases of neonatal disease among the infants, there were too few patients to draw a conclusion about neonatal risk. Neonatal infection may occur because viral shedding does still occur. There has been some success in vaccine development for women who are seronegative for HSV-1 and HSV-2, but the trials still need to be performed.

Epidemiology and Transmission

Cytomegalovirus is currently the most common intrauterine infection. Cytomegalovirus is responsible for congenital infection in 0.15% to 2% of newborns, and it is a leading cause of deafness and learning disability. Infection is more prevalent in underdeveloped countries and among lower socioeconomic groups in developed countries, where crowding and poor hygiene are more common. Each year, 2% of middle to high socioeconomic class women of childbearing age seroconvert compared with 6% of women from lower socioeconomic groups. Seropositivity also increases with age, breastfeeding for more than 6 months, nonwhite race, number of sexual contacts, and parity. A study of US national death certificate and census data from 1990 to 2006 documented that African Americans and Mexican Americans were at increased risk for congenital CMV infection and that African Americans and Native Americans had a much greater mortality under 1 year of age because of congenital CMV.²³

Transmission of CMV requires close contact with contaminated secretions because the virus is not very contagious. The virus can be cultured from urine, cervical secretions, saliva, semen, breast milk, blood, and transplanted organs, and all these sites intermittently excrete virus. Viral excretion is particularly prolonged after primary infection, but also occurs with reactivation of infection. Congenitally infected infants may shed virus for years and serve as a large reservoir for spreading infection to others. Toddlers also may shed the virus for prolonged periods compared with adults, in whom the humoral and cellular defense mechanisms lead to a latent state within a few months.

Transplacental transmission is responsible for congenital infection in 1% of newborns, and intrauterine fetal death may be more likely. Congenital infection may occur after either a primary or a reactivated infection in the mother. Overall, only 5% to 10% of congenital infections are symptomatic, and these are more likely after a primary maternal infection, although symptomatic infections have been reported in women with reactivation infections. Reinfection is also implicated as the cause of some of these symptomatic infections. Symptomatic infants have a mortality of 20% to 30%, and two thirds of survivors may have sequelae. The 90% of infants with asymptomatic infection at birth also have a 5% to 15% risk of later sequelae, however.

Even with primary maternal CMV infection during pregnancy, transplacental infection occurs in only 30% to 40% of the fetuses, and only 10% to 15% of these infected fetuses develop symptomatic disease. With recurrent maternal CMV infection during gestation, only 1% to 3% of fetuses are infected. Although transmission seems to be increased in the third trimester, the risk of malformations (which occur during the period of organogenesis) and developmental disabilities lessens. The fetus may be infected throughout gestation. Maternal IgG crosses the placenta and provides passive immunity for the fetus, but may also facilitate transport of CMV across the placenta, as IgG-virion complexes use the fetal F_C receptor on the syncytiotrophoblast for transcytosis. Villus core macrophages can neutralize complexes formed with high-avidity antibodies, but low-avidity antibody allows the virus to escape,³⁶ and seems to be more significant in the first half of pregnancy when the virus has considerable teratogenic potential. Neurons migrate from the periventricular germinal matrix to the cortex between 12 and 24 weeks of gestation. This process may be interrupted by infection, resulting in CNS malformations. In the second half of pregnancy, during the period of myelination, white matter lesions may develop, as seen on MRI.¹²²

Perinatal infection is responsible currently for an additional 3% to 5% of infections among newborns, resulting from exposure to cervical secretions and blood during delivery or via breast milk.¹³⁹ Transmission in early childhood may occur from child to child and from child to other family members. There is also an implication that infection may occur via fomites because virus may survive in urine for hours on plastic surfaces and has been cultured from toys in day-care centers. Nearly half of mothers of premature infants infected in the nursery seroconvert within 1 year, and the same proportion of susceptible family members seroconvert when a single family member is infected.

Day care compounds the problem. There is a 15% rate of infection among parents of children in day care, particularly if the child is younger than 18 months. Mothers of children in day care, particularly if they are of middle socioeconomic status and previously seronegative, are at significant risk of developing a primary CMV infection in a subsequent pregnancy; this may account for 25% of symptomatic congenital infections. Seronegative women who work at day-care centers have an 11% seroconversion rate per year, well above any predictable rate, and are at considerable occupational risk. Among children attending day care, 30% to 70% excrete virus.

Similar concern has been expressed about women health care workers and their occupational risk. Although these women are exposed to virus, the data do not support an increased risk of transmission of the virus.

After early childhood, viral transmission seems to be minimal until puberty, when sexual activity begins. Infection rates are highest among adults with multiple sexual partners. An additional risk of infection occurs with blood transfusions and organ transplantation, as the virus is present within the leukocytes and tissues. Transmission may be prevented by requiring all blood products to come from seronegative donors. Alternatively, the white blood cells carrying the virus may be removed by using frozen, deglycerolized red blood cell transfusions or by using filters to remove the leukocytes. Neither the transfusion method nor using filters completely protects against transmission of virus, however.

Cytomegalovirus transmission via human breast milk feeding has been reported to result in infection in premature infants (<32 weeks’ gestation), resulting in a sepsis-like infection. The virus is found in the whey portion of the milk, and mothers may excrete virus in their milk when they are not excreting virus elsewhere, such as in urine or saliva. Long-term outcome has not yet been determined, but in a report of 40 preterm infants who developed viruria in the nursery, most likely from breast milk feedings, neonatal outcome was not different from that of control infants. The infants exhibited cholestasis, elevation of C-reactive protein, mild neutropenia, and thrombocytopenia, but these symptoms resolved.¹⁴¹ There is still debate as to whether the virus contributes to bronchopulmonary dysplasia or if the most immature infants will develop hearing, neurologic, or developmental abnormalities.

Maternal Clinical Manifestations

Most women are asymptomatic during either primary or recurrent infection, and pregnancy does not alter the clinical picture. A mononucleosis-like illness, which is heterophil negative, may develop in 5% to 10% of women. Other manifestations are rare.

Asymptomatic Congenital Infection

Although 85% to 90% of all infants with congenital CMV are asymptomatic at birth, 15% may be at risk for later sequelae. The results of follow-up of 330 infants with asymptomatic infection who were mostly of low socioeconomic status are shown in Table 57-2. The most important sequela seems to be sensorineural hearing loss, which is often bilateral and may be moderate to profound. The presence of periventricular radiolucencies or calcifications on CT is highly correlated with hearing loss. The hearing loss may be present at birth or may appear only after the first year of life, and is frequently progressive, owing to continued growth of the virus in the inner ear. There is a very low risk of chorioretinitis; it may not be present at birth, but may develop later secondary to continued growth of the virus. A further finding may be a defect of tooth enamel in the primary dentition, leading to increased caries. Neurologic handicap may occur, but is uncommon. Premature infants are most at risk.

Symptomatic Congenital Infection

Cytomegalic inclusion disease occurs in only 10% to 15% of infected infants and results in multiorgan involvement, particularly of the reticuloendothelial system and CNS. Death may occur at birth or months later, resulting in an overall mortality of 20% to 30%, usually from disseminated intravascular coagulation, bleeding, hepatic failure, or bacterial infection.

Central nervous system involvement may be diffuse. Infants may be microcephalic, have poor feeding and lethargy, and have hypertonia or hypotonia. They may also exhibit intracranial calcifications of the basal ganglia and cortical and subcortical regions, ventricular enlargement, cortical atrophy, or periventricular leukomalacia. Most commonly, an infant who is small for gestational age or premature has hepatosplenomegaly and abnormal liver function tests. Hyperbilirubinemia, which occurs in more than half of infants, may be transient, but is more likely to be persistent, with a gradual increase in the direct component. Petechiae, purpura, and thrombocytopenia (direct suppression of megakaryocytes in the bone marrow) usually develop after birth and may persist for weeks. Approximately one third of infants with congenital infection are thrombocytopenic, and one third of those have severe thrombocytopenia, with platelet counts less than 10,000/dL. There may also be a Coombs-negative hemolytic anemia. Diffuse interstitial or peribronchial pneumonitis is possible, but less common than with perinatally acquired disease. Table 57-3 lists the clinical findings in 24 newborns with symptomatic CMV infection.

Prognosis.

Fowler and colleagues⁵⁸ showed that although maternal antibody may not prevent congenital CMV infection, it lessens the severity (Table 57-4). Sequelae were found in 25% of infants after primary infection, but in only 8% after recurrent infection. Likewise, mental impairment (IQ <70), sensorineural hearing loss, and bilateral hearing loss were found in 13%, 15%, and 8% of infants, respectively, after primary maternal infection, but only 5% of infants born after recurrent maternal infection had sensorineural hearing loss, and none had mental impairment or bilateral hearing loss. These infants also showed the progressive nature of sequelae after primary and recurrent infection (Figure 57-5).

TABLE 57-4

Sequelae in Children with Congenital Cytomegalovirus Infection According to Type of Maternal Infection

Sequelae	Primary Infection*	Recurrent Infection*	P Value
Sensorineural hearing loss	15 (18/120)	5 (3/56)	.05
Bilateral hearing loss	8 (10/120)	0 (0/56)	.02
Speech threshold ≥60 dB	8 (9/120)	0 (0/56)	.03
IQ ≤70	13 (9/68)	0 (0/32)	.03
Chorioretinitis	6 (7/112)	2 (1/54)	.20
Other neurologic sequelae	6 (8/125)	2 (1/64)	.13
Microcephaly	5 (6/125)	2 (1/64)	.25
Seizures	5 (6/125)	0 (0/64)	.08
Paresis or paralysis	1 (1/125)	0 (0/64)	.66
Death	2 (3/125)	0 (0/64)	.29
Any sequelae	25 (31/125)	8 (5/64)	.003

^*Percentage (number with sequelae/total number evaluated).

Data from Fowler K, et al. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med. 1992;326:663. Copyright 1992 Massachusetts Medical Society. All rights reserved.

Ramsay and colleagues¹⁶⁶ looked at the 4-year outcome of 65 neonates with symptomatic congenital CMV in the United Kingdom and found a better prognosis than previously reported from the United States (Table 57-5). Overall, the rate of neurologic abnormalities was 45%. Infants who presented with abnormal neurologic findings other than microcephaly had the worst prognosis, with a 73% rate of gross motor and psychomotor abnormalities compared with a 30% rate among children who did not present with neurologic findings. A Japanese study of 33 congenitally infected infants found that abnormal fetal ultrasound abdominal findings (ascites or hepatosplenomegaly) were associated with liver dysfunction and a 53-fold increase in mortality; infants who had no abdominal findings survived.¹²⁵ Data are also accumulating that neonatal viral blood load (>1000 copies per 10⁵ polymorphonuclear leukocytes [PMNLs] via quantitative PCR) may also predict infants who will develop sequelae, regardless of whether the infants were symptomatic or asymptomatic after birth.¹¹⁰ Chorioretinitis, periventricular calcifications, and microcephaly remain standard predictors of poor cognitive outcome. In contrast, children who have normal development and no hearing loss at 1 year of age are unlikely to develop neurodevelopmental handicaps.

TABLE 57-5

Outcome of Symptomatic Congenital Cytomegalovirus Infection

			Disability
Neonatal Presentation	No. Infants	Normal N (%)	Motor or Psychomotor N (%)	Sensorineural Deafness N (%)
Group 1	22	6 (27)	14 (64)	2 (9)
Group 2	35	22 (63)	8 (23)	5 (14)
Group 3	8	8 (100)	0	0
All groups	65	36 (55)	22 (34)	7 (11)

Group 1: Abnormal neurologic findings at presentation.

Group 2: Hepatomegaly, splenomegaly, or purpura at presentation without neurologic abnormality.

Group 3: Microcephaly or respiratory problems at presentation without neurologic abnormality.

Data from Ramsay MEB, et al. Outcome of confirmed symptomatic congenital cytomegalovirus infection. Arch Dis Child. 1991;66:1068.

Perinatal Infection

Mothers with recurrent CMV infection usually transfer significant antibody to the infant in utero. Even if this antibody transfer does not occur, a term infant who acquires infection after birth, denoted a perinatal infection, is usually asymptomatic. Transmission may occur in passage through the birth canal, via breast milk, or secondary to blood transfusion. Breastfeeding infants largely seroconvert. The incubation period is 4 to 12 weeks. Term infants may develop pneumonitis secondary to CMV, and present with cough, tachypnea, congestion, wheezing, and apnea. Few infants require hospitalization, and there is spontaneous resolution in most term infants. In contrast, premature infants, often infected through blood transfusion, have a high rate of serious or fatal illness. They also may develop pneumonitis, but with a picture of overwhelming sepsis, hepatosplenomegaly, thrombocytopenia, and neutropenia. There may be an increased risk in these infants of neuromuscular handicaps, although there does not seem to be a higher rate of sensorineural hearing loss, microcephaly, or chorioretinitis.

Neurologic Impairment

Not all infants with symptomatic disease at birth have neurologic impairment. One third of these infants may have a normal neurologic outcome; however, 5% to 15% of asymptomatic infants may have sequelae. Increasing data are correlating abnormal findings on cerebral ultrasound, CT, or MRI with long-term neurodevelopmental or neurosensory sequelae. The numbers of infants per report are small, but collectively all show this correlation. Of symptomatic infants with abnormal CT findings, 90% had neurodevelopmental or neurosensory sequelae,¹⁸ whereas all infants with abnormal ultrasound findings had either one or more sequelae or death; however, none of 45 infants with normal ultrasound results had long-term sequelae (Table 57-6).⁷ Magnetic resonance imaging may be particularly useful in detecting white matter or gyral abnormalities.^{7,16,18,70,145,200} However, white matter involvement can be variable. The MRI is predictive of a poor outcome when cortical malformations, such as polymicrogyria, ventriculomegaly, and hippocampal or cerebellar dysplasia, are found. Finally, a β₂-microglobulin concentration in the CSF also seems to indicate the severity of brain involvement in congenital disease.

TABLE 57-6

Value of Cranial Ultrasound Scanning in Predicting Outcome in 57 Patients with Congenital Cytomegalovirus Infection

	No. (%) Newborns with Poor Outcome
	Normal US Results	Pathologic US Results*	Odds Ratio (95% CI)	p Value	PPV (%)	NPV (%)
DQ ≤85	0/45	8/11 (72.7%)	NE	<.001	72.7	100
Motor delay	0/45	6/11 (54.5%)	NE	<.001	54.5	100
SNHL	3/45 (6.7%)	6/11 (54.5%)	16.8 (3.2-89)	<.001	54.5	93.3
Death or any sequel	3/45 (6.7%)	11/12 (91.7%)	154 (17.3-1219.6)	<.001	91.7	93.3

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