Viral infections in pregnancy are major causes of maternal and fetal morbidity and mortality.

Infections
can develop in the neonate transplacentally, perinatally (from vaginal secretions or blood), or
postnatally (from breast milk or other sources). The clinical manifestations of neonatal infections vary
depending on the viral agent and gestational age at exposure. The risk of infection is usually inversely
related to gestational age at acquisition, some resulting in a congenital malformation syndrome.
Infections known to produce congenital defects have been described with the acronym TORCH
(Toxoplasma, others, rubella, cytomegalovirus [CMV], herpes). The "others" category has rapidly
expanded to include several viruses known to cause neonatal disease.
Traditionally, the only viral infections of concern during pregnancy were those caused by rubella virus,
CMV, and herpes simplex virus (HSV). Other viruses now known to cause congenital infections
include parvovirus B19 (B19V), varicella-zoster virus (VZV), West Nile virus, measles
virus, enteroviruses, adenovirus, and human immunodeficiency virus (HIV).
Also of importance is hepatitis E virus because of the high mortality rate associated with infection in
pregnant women. Recently, lymphocytic choriomeningitis virus (LCMV) has been implicated as a
teratogenic rodent-borne arenavirus.
Worldwide, congenital HIV infection is now a major cause of infant and childhood morbidity and
mortality, responsible for an estimated 4 million deaths since the start of the HIV pandemic. The
breadth and depth of this problem is beyond the scope of this article.
With emerging concerns for an influenza pandemic, attention has also now been directed to the
effects of influenza on pregnant women. One study found that influenza vaccination of high-risk
pregnant patients also provides some protective immunity for newborns and reduces subsequent
hospitalizations in the infants.
[1]
Influenza has historically been shown to produce significant morbidity
and mortality in this population (see Influenza and H1N1 Influenza [Swine Flu]).
Cytomegalovirus
CMV is a double-stranded DNA herpes virus and represents the most common congenital viral
infection. The CMV seropositivity rate increases with age. Geographic location, socioeconomic class,
and work exposure are other factors that influence the risk of infection. CMV infection requires
intimate contact through saliva, urine, and/or other body fluids. Possible routes of transmission
include sexual contact, organ transplantation, transplacental transmission, transmission via breast
milk, and blood transfusion (rare).
Primary, reactivation, or recurrent CMV infection can occur in pregnancy and can lead to congenital
CMV infection. Transplacental infection can result in intrauterine growth restriction, sensorineural
hearing loss, intracranial calcifications, microcephaly, hydrocephalus, hepatosplenomegaly, delayed
psychomotor development, and/or optic atrophy.
Vertical transmission of CMV can occur at any stage of pregnancy; however, severe sequelae are
more common with infection in the first trimester, while the overall risk of infection is greatest in the
third trimester. The risk of transmission to the fetus in primary infection is 30%-40%. Most (90%) CMV
infections cause no symptoms, but 10% result in signs and symptoms such as microcephaly,
thrombocytopenia, hepatosplenomegaly, intrauterine growth restriction, or a combination thereof.
Thirty percent of infants with severe CMV infection die; among survivors, more than half eventually
develop neurological sequelae, including microcephaly, mental retardation, and/or sensorineural
hearing loss. Seven percent of asymptomatic neonates develop sensorineural hearing loss or
developmental delays during the first 2 years of life.
[2, 3, 4, 5, 6]
Five percent eventually develop
microcephaly and neuromuscular defects, and 2% develop chorioretinitis. Congenital hearing loss is
the most common sequela of recurrent CMV infection.
Herpes simplex virus
Thirty to 60% of women receiving obstetric care have serologic evidence of past HSV infection.
Although both HSV-1 and HSV-2 may cause neonatal herpes, HSV-2 is responsible for 70% of cases.
Neonatal herpetic infection is defined as infection within 28 days of birth. Ninety percent of infections
are perinatally transmitted in the birth canal. HSV infection acquired in this manner carries a 70% risk
of dissemination and is associated with 3 distinct syndromes, each with its own typical outcome. The
first and most common (45%) is localized skin, eye, or mouth disease. Approximately 30% of cases
manifest as central nervous system (CNS) disease, including meningitis or encephalitis, with evidence
of HSV DNA in the cerebrospinal fluid (CSF). Finally, 25% of neonatal herpetic infections manifest as
disseminated disease that involves multiple organs. Initial symptoms of this disease usually present
during the first 4 weeks of life.
Approximately 10% of infections are congenital, usually a consequence of the mother acquiring
primary HSV infection during pregnancy and the fetus acquiring the infection transplacentally or via an
ascending infection from the cervix. Intrauterine infection is associated with intrauterine growth
restriction, preterm labor, and miscarriage.
[7, 8]
The risk of neonatal herpes and death is highest in
infants born to mothers who have not seroconverted by the time of delivery.
Viral infections and pregnancy. Transmission electron micrograph of herpes simplex virus. Some nucleocapsids
are empty, as shown by penetration of electron-dense stain. Image and caption from US Centers for Disease Control
and Prevention Public Health Image Library, available at: http://phil.cdc.gov/Phil/search.asp. Use Image ID 281.
Viral infections and pregnancy. Blisters on the vulva due to a recurring herpes II (HSV-2) virus infection. Image and
caption from US Centers for Disease Control and Prevention Public Health Image Library, available at:
http://phil.cdc.gov/Phil/search.asp. Use Image ID 2319.
Rubella
Rubella is one of the more teratogenic viruses. Congenital rubella syndrome (CRS) is characterized
by intrauterine growth restriction, intracranial calcifications, microcephaly, cataracts, cardiac defects
(most commonly patent ductus arteriosus or pulmonary arterial hypoplasia), neurologic disease (with
a broad range of presentations, from behavior disorders to meningoencephalitis), osteitis, and
hepatosplenomegaly.
Viral infections and pregnancy. Transmission electron micrograph of rubella virus. Image and caption from US
Centers for Disease Control and Prevention Public Health Image Library, available at:
http://phil.cdc.gov/Phil/search.asp. Use Image ID 269.
Neonates with rubella may have a "blueberry muffin" appearance caused by purpuric skin lesions that
result from extramedullary hematopoiesis. Heart defects in these infants include ventricular septal
defects, patent ductus arteriosus, pulmonary stenosis, and coarctation of the aorta. The presentation
of rubella at birth varies greatly. Most of these complications develop in infants born to mothers who
acquire rubella infection during the first 16 weeks of pregnancy. Ninety percent of infants present with
some finding of congenital rubella if infection occurs within the first 12 weeks, and 20% present with
congenital disease if the infection occurs between weeks 12 and 16.
[9]
Cataracts results when infection
occurs between the third and eighth week of gestation, deafness between the 3rd and 18th week, and
heart abnormalities between the 3rd and 10th week.
[10]

Viral infections and pregnancy. Infant with congenital rubella and blueberry muffin skin lesions. Lesions are sites
of extramedullary hematopoiesis and can be associated with several different congenital viral infections and
hematologic diseases. Image and caption from US Centers for Disease Control and Prevention Public Health Image
Library, available at: http://phil.cdc.gov/Phil/search.asp. Use Image ID 713.
Parvovirus B19
B19V causes erythema infectiosum (fifth disease). Although most adults with B19V infection are
asymptomatic, the effects of this virus on the fetus are much greater and include miscarriage, fetal
anemia, hydrops fetalis, myocarditis, and/or intrauterine fetal death. Infection occurs most frequently
in the winter and spring. B19V infection accounts for 15%-20% of cases of nonimmune hydrops
fetalis. Thirty to 40% of pregnant women are seronegative for B19V and are thus susceptible to
infection.
Various studies have estimated that 3%-14% of intrauterine fetal deaths occur in the setting of B19V
infection. Second-trimester infections have been studied most frequently because infection in this
trimester carries a 1%-3% risk of hydrops; however, infection in any trimester may result in
intrauterine fetal loss. The critical period for the development of fetal hydrops is when maternal B19V
infection is acquired between the 13th and 16th week of gestation, possibly because of the relative
immaturity of the fetal immune response, as well as the shortened life span of the red blood cells at
this gestational age.
Varicella-zoster virus
VZV is a common virus that carries risks for both the mother and fetus during pregnancy. Morbidity
and mortality rates associated with VZV infection are much higher in adults than in children. Primary
varicella infection during pregnancy is considered a medical emergency. Pneumonitis due to VZV
infection is 25 times more common in adults than in children; in the third trimester, the risk for life-
threatening ventilatory compromise is significant, with a mortality rate of 14%. Prior to the
development of antiretrovirals, pneumonitis in pregnant women carried a mortality rate of 45%. Other
risk factors for the development of pneumonitis include smoking and a large lesion burden (>100
lesions).
[11]

Congenital varicella syndrome (CVS) results in spontaneous abortion, chorioretinitis, cataracts, limb
atrophy, cerebral cortical atrophy, and/or neurological disability. Spontaneous abortion has been
reported in 3%-8% of first-trimester VZV infections, and CVS has been reported in 12%.
[12]
Acquisition
of infection by the mother in the perinatal period, specifically 5 days prior to delivery or 2 days
afterward, poses a risk of severe neonatal varicella, which carries a mortality rate of 30%. Infection at
this time prevents development of maternal antibodies that avert transplacental transfer of
immunoglobulin G (IgG) antibodies, which confer passive immunity to the fetus.
Enterovirus
Enterovirus infections are not believed to cross the placenta and cause fetal disease.
[13]
However,
some studies have linked coxsackievirus and echovirus to miscarriage, neurodevelopmental delay,
myocarditis, and cortical necrosis.
[14, 15]
One study linked the presence of coxsackievirus in the third
trimester with respiratory failure and global cognitive defects.
[16]

Measles virus
Measles virus infection (rubeola) during pregnancy, as with VZV infection, tends to be severe, with
pneumonitis predominating. Although it is not known to be teratogenic, rubeola has been associated
with spontaneous abortion, premature labor, and low birth weight. Neonates born to mothers with
active measles virus infection are at risk of developing neonatal measles, but no congenital syndrome
has been described.
[17]

Lymphocytic choriomeningitis virus
LCMV has been associated with sporadic cases of congenital infection worldwide. Affected infants
demonstrate chorioretinitis, hydrocephalus, mental retardation, and/or visual impairment; in addition,
intrauterine death is possible. Unlike congenital CMV and rubella infections, hearing deficits and
hepatosplenomegaly are rarely seen in congenital LCMV.
Other viruses
Other viruses postulated to cause congenital infections include echovirus, hepatitis B virus, hepatitis
C virus, and adenovirus.
[18]
In 2002, an article in Morbidity and Mortality Weekly Report discussed a
single case of West Nile virus infection in a mother and associated chorioretinitis in her newborn.
[19]
A
causal link has not been determined. Since then, the Centers for Disease Control and Prevention
(CDC) has maintained a registry of West Nile virus infections during pregnancy. Other congenital
malformations have been described in this registry, but a direct cause-effect relationship has not yet
been established. Infants born to mothers who develop symptomatic West Nile virus infection within 3
weeks prior to delivery may develop symptomatic West Nile virus disease shortly after birth.
Influenza poses a significant threat to the health of the mother and infant. Historic reports of the 1918
Spanish flu pandemic and the 1957 Asian flu pandemic reported a mortality rate of approximately
50% among infected pregnant women.
[20]

Pathophysiology
Human CMV is the largest of the beta herpes viruses and can cause lytic and productive infection.
Like other herpes viruses, it can be latent and reactivate. CMV infection in pregnancy can be primary
(initial acquisition in pregnancy) or recurrent. Vertical transmission can occur transplacentally; in
addition, the virus can be transmitted via cervicovaginal secretions at the time of delivery or by
ingestion of breast milk postpartum. Transplacental transmission is associated with congenital CMV
infection. Maternal shedding at time of delivery is associated with a 50% risk of infection.
[21]
CMV
infection acquired through exposure to infected cervical secretions or breast milk is usually
asymptomatic and is not associated with neonatal sequelae.
Herpes may be transmitted to the fetus in the peripartum period (as the neonate passes through the
birth canal [85%]), via intrauterine transmission (either from ascending infection through the cervical
canal or transplacentally [5%]), or via postnatal transmission (10%). Both HSV and VZV have
tropisms for neural tissue. Peripartum transmission leads to disseminated disease in 70% of infants
and is characterized by skin lesions, encephalitis, and neurological disability. The risk of neonatal
herpetic infection is much higher in women with primary infection (ACOG Practice Bulletin). Primary
infection carries a transmission rate of 25%-50%, while recurrent maternal herpes infection carries a
transmission rate of less than 1%.
[22]
The difference in transmission rates may be due to the presence
of antibodies and lower viral loads with recurrent infection.
In addition to miscarriage, B19V can cause fetal anemia due to effects on fetal red blood cell
precursors, which can lead to hydrops. B19V has a tropism for the fetal bone marrow and liver,
causing apoptosis of erythroid precursors and thus inhibiting erythropoiesis. Fetal liver erythroblasts
exhibit viral DNA and pathognomonic changes of B19V infection. The myocardium has also been
affected, causing myocarditis and resultant heart failure.
VZV is a DNA herpes virus. Following primary VZV infection, it can remain latent in the dorsal root
ganglia. Primary varicella usually confers lifelong immunity. VZV is most often transmitted to the fetus
transplacentally; however, ascending infection from lesions in the birth canal has been
reported.
[23]
The mechanism of in utero VZV infection is unknown. Infection of developing nerve
bundles may explain limb atrophy and chorioretinitis in CVS.
Rubella is an RNA virus found to infect only humans. It is spread by airborne respiratory secretions
and is most common in late winter and early spring. The virus travels from the upper respiratory tract
to the cervical lymph nodes and is then disseminated throughout the body. The incubation period is 2-
3 weeks. Antibodies against rubella do not appear in the serum until after the rash has developed.
Fetal infection results from transplacental vertical transmission.
Frequency
CMV is the most common virus known to be transmitted in utero, affecting approximately 0.5%-1.5%
of births.
[6]
Approximately 40% of maternal CMV infections during pregnancy result in congenital
infection.
[24]

Depending on the demographic population, neonatal herpes infection affects 1 per 1700 to 1 per
12,500 live births.
[22]
The rate of HSV-2 seroconversion during pregnancy is estimated to be 0.2%-4%.
The estimated incidence of primary B19V infection in pregnancy ranges from 1%-5%.
Varicella occurs in approximately 1-7 per 10,000 pregnancies.
[12]

In 1999, the incidence of rubella was 0.1 per 100,000. The incidence of congenital rubella syndrome
has decreased dramatically in the United States because of rubella vaccination; currently, fewer than
50 cases occur each year.
[25]

LCMV infection occurs in the Americas and Europe in areas where people are exposed to the host
species of hamsters, Mus domesticus and Mus musculus.Infections tend to occur in focal geographic
areas in autumn.
Morbidity and mortality
The risk of primary maternal CMV infection leading to congenital CMV infection is approximately 40%.
Of neonates with congenital CMV infection, 85%-90% are asymptomatic at birth, yet 10%-15%
eventually present with developmental, visual, hearing, or dental abnormalities in the first years of life.
Of those who are symptomatic at birth, about half will present with some isolated findings, while the
other half will present with cytomegalic inclusion disease. CMV disease in this group carries a
mortality rate of around 30%; up to 80% of affected infants develop late complications, including
developmental, visual, or hearing delay.
Morbidity and mortality rates are higher in patients infected with HSV-2 than in those with HSV-1.
Neonatal disseminated HSV infection acquired perinatally carries a 65% mortality rate if untreated
and a 25% mortality rate if treated.
Congenital varicella syndrome (CVS) carries a 30% mortality rate.
[12]
Acquisition of varicella infection
by the mother in the immediate perinatal period, specifically 5 days prior to or 2 days following
delivery, poses the greatest risk for severe neonatal varicella infection, as maternal antibodies have
not yet developed to confer passive immunity to the fetus. Reactivation of the virus results in zoster
infection, commonly known as shingles. No evidence has shown that herpes zoster infection causes a
more severe infection in pregnancy or results in congenital malformations.
Fifty to 80% of infants exposed to rubella virus within 12 weeks of conception show signs of
congenital infection.
[25]
The rate of congenital infection drops dramatically with advancing gestational
age, such that the risk of congenital infection is very small if infection occurs after 18 weeks of
gestation.
LCMV infection is rarely fatal in the adult host, but fetal acquisition may lead to intrauterine death.
Up to 20% of pregnant women who acquire hepatitis E develop fulminant hepatic failure.
Historic data from previous pandemics suggest a mortality rate of up to 50% among pregnant women.
During the 2009 H1N1 pandemic, pregnant women were more likely to be hospitalized and accounted
for 5% of all influenza mortality.
[26]

Clinical Presentation
The hallmark of diagnosis of congenital disease is maternal history and history of any recent
exposures to ill individuals, physical findings in the newborn, and appropriate laboratory testing. The
maternal immunization history is also extremely important.
History
CMV
Maternal CMV infection is most likely due to reactivation of latent virus and thus causes no symptoms
or manifests as low-grade fever, malaise, and myalgias. Primary CMV infection is usually
asymptomatic but may manifest as a mononucleosislike picture, with fever, fatigue, and
lymphadenopathy. Women who are in close contact with toddlers or preschool-aged children, daycare
workers, or health care workers are at a higher risk for CMV infection.
HSV
Asking about previous HSV lesions is important; however, approximately 70% of women who have
been exposed to HSV do not know they are infected. The 3 stages of HSV infection include primary,
nonprimary first episode, and recurrent infection, categorized based on clinical presentation and
serological findings. Primary infection demonstrates a more severe symptomatic picture. One third of
patients with primary infection report multiple painful vesicular eruptions on the vulva and perineum. In
rare cases, a systemic flulike illness develops. Rare forms of disseminated disease are associated
with hepatitis, pneumonia, or encephalitis.
[27]
Nonprimary infections and recurrent infections due to
reactivation of latent virus are associated with fewer systemic manifestations, fewer lesions, less pain,
and a shorter duration of viral shedding than primary infection.
B19V
Adults with parvovirus infection may present with fever, arthralgias, and flulike symptoms; however,
20%-30% are asymptomatic. A faint macular rash associated with arthralgias may be a clue to B19V
infection in the mother. The clinician should ask about exposure to an infected child with the classic
facial rash that manifests as erythema of the cheeks (slapped-cheek appearance).
Varicella
The incubation period of chickenpox is 10-21 days. Primary infection is associated with a
maculopapular and vesicular rash accompanied by constitutional symptoms that last 3-5 days.
Varicella pneumonia manifests as nonproductive cough, dyspnea, fever, and pleuritic chest pain.
Rubella
A history of typical rubella rash starting on the face or neck, along with suboccipital lymphadenopathy,
arthralgias, fever, and cough, suggests rubella. Obtaining an immunization history and rubella titers
(usually obtained at the outset of pregnancy) are important. Immigrants from developing countries are
often inadequately immunized; thus, the alert clinician inquires about rash acquired during early
pregnancy in this population. Of note, 20%-50% of infected patients are asymptomatic.
Measles
Measles virus infection is also associated with inadequate immunization and is characterized by
cough, coryza, and conjunctivitis. Koplik spots are pathognomonic for measles and appear as bluish-
gray spots on a red base in the buccal mucosa.
[17]
The rash begins several days prior to fever and
spreads from the head downward to cover most of the body.
LCMV
This infection may also present as nonspecific flulike symptoms, including fever, malaise, myalgias,
and headache. It may progress to aseptic meningitis in adults but is usually self-limited in
nonpregnant adults, with resolution within 2-3 weeks.
Physical
CMV
Most infants with congenital CMV infection are asymptomatic at birth but may develop sequelae later
in life. Symptomatic infants may have splenomegaly, petechiae, or jaundice. Congenital CMV
infection, occurring in 5%-10% of infants, is characterized by jaundice, hepatosplenomegaly, petechial
rash, respiratory distress, and neurological involvement, which may include microcephaly, motor
delay, cerebral calcifications, lethargy, and seizures.
HSV
Most infants exposed to HSV during gestation appear healthy at birth. Findings in those who develop
clinical disease may include fever or temperature instability, respiratory distress, lethargy, and poor
feeding. HSV infection can also rapidly lead to sepsis and septic shock. The classic skin findings of
vesicular lesions may be absent or may appear late.
B19V
The mother may present with a photosensitive erythematous rash on the face that spares the
periorbital and nasal area. She may develop painful, swollen, stiff joints, especially of the wrist, hand,
knees and ankle that may persist up to 1-3 weeks.
[28]
This infection may lead to hydrops fetalis, which
is characterized by 2 or more fluid filled-cavities in the fetus (pleural effusion, ascites, skin edema,
hydropic placenta, pericardial effusion, cardiomegaly, or heart failure). These findings are usually
identified with ultrasonography. In some cases, the infection resolves spontaneously, leaving the fetus
or infant unaffected. Although a congenital parvovirus infection syndrome has been described in
premature infants, most intrauterine parvovirus infections do not have a teratogenic effect.
[29]

Varicella
Mothers with VZV infection may experience fever, malaise, and myalgia prior to the onset of rash,
which is vesicular and may affect the face, trunk, oropharynx, and scalp. Adults are more prone to
complications, including bacterial superinfection of the vesicles, pneumonitis, and CNS abnormalities
such as Guillain-Barr syndrome. Manifestations of CVS in infants may include multiple reddish
pigmented areas or dermatoma scarring, hypoplastic limbs or other limb abnormalities, chorioretinitis,
optic nerve atrophy, and failure to thrive. Most of these cases occur if the mother was infected
between 8 and 20 weeks gestation.
[30]
Neonatal VZV infection that occurs when the mother has been
infected within two weeks of delivery may manifest as fever and a vesicular eruption. Some cases of
herpes zoster have also been described in infants born to mothers who had varicella in pregnancy.
[31]

Rubella
In adults, rubella may manifest as fever and maculopapular rash on the face that spreads cephalad to
the feet. While infected patients may present with suboccipital lymphadenopathy, arthralgias,
conjunctivitis, and cough, 20%-50% are asymptomatic. Congenital rubella syndrome (CRS) is
associated with 4 common anomalies: deafness (60%-70% of fetuses), central nervous system
abnormalities (10%-25%), eye defects such as cataracts (10%-30%), and cardiac malformations
(10%-20%). At birth, many infants with congenital rubella show evidence of growth restriction and
bone disease. Hepatosplenomegaly may also be present. Extramedullary hematopoiesis results in a
"blueberry muffin" appearance in many infected infants. Physical examination may also reveal
findings of cataracts or evidence of congenital heart disease. Other associated abnormalities include
mental retardation, microcephaly, and blood abnormalities such as anemia and thrombocytopenia.
Influenza
Like the general population, pregnant women with influenza may exhibit fever, runny nose, cough,
sore throat, and myalgias. It remains unclear whether influenza has any effect on the fetus and
whether there is a risk of congenital abnormalities.
Workup
Laboratory studies
Careful interpretation of serologic markers for most of these infections is important. Immunoglobulin M
(IgM) can persist for up to a year, leading to difficulty in determining fetal exposure during pregnancy.
Furthermore, the specificity and positive predictive value of some of these tests may vary depending
on the method used, requiring that positive findings be confirmed by a specialized laboratory.
Serology for CMV can be difficult to interpret. Although 50-80% of women may have serological
findings of a past infection, this is not completely protective against reinfection. A 4-fold or greater rise
in the CMV-IgG titer within 2 weeks is consistent with a recent infection. Assessing for avidity of the
IgG antibody has also been useful to differentiate primary and recurrent CMV infection. Low-to-
moderate avidity IgG antibody is more likely to represent an acute infection. CMV infection is best
diagnosed with urine culture or polymerase chain reaction (PCR) using urine or serum.
Amniocentesis for CMV PCR can be performed after 21 weeks gestation; before this point, the fetus
does not mount an immunological response. Testing fetal serum for IgM antibodies is highly sensitive
for congenital infection; however, it must be performed after 21 weeks gestation, it carries a
significant risk to the pregnancy (fetal loss related to cordocentesis), and it is technically very
difficult.
[6, 32, 33]
As such, identification of CMV in the amniotic fluid by culture or CMV is the most
sensitive and specific test for congenital CMV, with a procedure loss rate of less than 1 in 200.
Type-specific antibodies to HSV-1 and HSV-2 are used to confirm past exposure and current infection
in the mother; however, because of the high prevalence of HSV infection, results may be difficult to
interpret in terms of diagnosing neonatal disease. The most sensitive test for detecting HSV is cell
culture, which is used to isolate the virus in tissue. PCR can be used to diagnose lesions found during
pregnancy. Papanicolaou tests and Tzanck tests are poor HSV-screening tests. When a neonate has
been exposed to HSV lesions, some groups advocate swabbing the skin and mucous membranes at
5- to 10-day intervals to screen for development of infection. HSV PCR of amniotic fluid is sensitive
but may not correlate with neonatal HSV infection.
[34]
In newborns with suspected disease, cultures of
the skin lesions, mouth, eyes, urine, blood, stool, rectum, and CSF should be obtained. PCR can be
used to detect HSV in the spinal fluid.
Traditionally, B19V infection has been confirmed with serological testing with IgM and IgG reactivity
against virus capsid proteins. IgM may be present 10-12 days after exposure and can persist for up to
6 months, while IgG antibodies are formed by 3 weeks and may persist for years, potentially
conferring lifelong immunity. In women with negative serology, repeat IgM and IgG 2-3 weeks later is
recommended. Other laboratory abnormalities in women with parvovirus infection may include
anemia, leukopenia, transaminitis, and elevated lactate dehydrogenase (LDH) levels. To test the
fetus, PCR has been shown to be a more sensitive diagnostic study and can be used with amniotic
fluid, cord blood, maternal serum, or placental tissue.
[35]
Cordocentesis, which is recommended in
fetuses with signs of anemia, may also reveal fetal thrombocytopenia.
Serology can be used to confirm VZV infection or previous exposure in the mother. A known lack of
exposure should prompt further testing of the antibody response.
[12]
Primary varicella confers lifelong
immunity. However, the diagnosis is usually made clinically. IgM can appear as soon as 3 days after
the onset of symptoms. Viral culture can be performed using skin lesions, or PCR for VZV DNA can
be performed using specimens obtained from unroofed skin lesions.
[36]
Prenatal diagnosis is possible
by detecting VZV antibodies via percutaneous blood sampling or DNA in fetal blood or amniotic fluid.
Unfortunately, although serological identification is possible, there is poor correlation with fetal
sequelae from VZV infection.
Diagnosis of VZV infection in the infant is difficult because only 27% have an IgM response. Serology
for VZV IgG can be performed after the sixth month of life. Viral culture in infants has not been found
to be helpful. PCR of skin tissue may be useful.
[12]

Rubella virus infection in the mother is confirmed with IgM and IgG serology.
[9]
Serum IgM levels peak
7-10 days after the onset of clinical illness and can persist for 6 weeks before declining. IgG can be
detected within 2-3 weeks of infection. IgG antibodies persist throughout life. PCR and viral culture of
amniotic fluid has been used for prenatal diagnosis in difficult cases. Chorionic villi sampling and
cordocentesis can also be used to test for rubella antigen with PCR. However, cordocentesis is
difficult before 20 weeks gestation, and fetal immunoglobulins usually go undetected before 22
weeks gestation. Although these tests can reveal rubella virus in the fetus, they do not indicate the
degree of fetal injury. Infection in infants can be diagnosed with acute and convalescent serology,
especially using rubella IgM or viral cultures of the throat, nasal secretions, urine, or CSF.
Coxsackievirus infection can be confirmed by serology in the mother. In situ hybridization or reverse-
transcriptase PCR of tissue can be performed on the newborn.
[16]

Measles virus infection can be confirmed by IgM serology.
[17]

LCMV infection can be diagnosed based on an IgM enzyme-linked immunosorbent assay (ELISA) of
CSF or serum. CSF pressure is generally increased, with protein levels of 50-300 mg/dL and
lymphocytes. Patients may also exhibit leukopenia or thrombocytopenia.
Diagnosis of influenza in pregnancy should be based on clinical symptoms without waiting for
diagnostic tests due to the high morbidity and mortality during pregnancy. Rapid influenza diagnostic
tests may not be sensitive enough to rule out infection, but more sensitive tests are more time
consuming.
Imaging
Fetal ultrasonography can be used to diagnose growth restriction and may reveal specific findings
associated with perinatal viral infections.
If a mother tests positive for B19V IgM and negative for IgG, suggesting a new infection, she should
undergo serial ultrasonography to monitor for development of fetal anemia for 10-12 weeks after
exposure. Fetal demise is most likely if infection occurs before 20 weeks' gestation, approaching
10%.
[28]
Doppler flow of the fetal middle cerebral artery is the most sensitive noninvasive test for fetal
anemia. The anemic fetus tries to preserve oxygen delivery to the brain by increasing flow of low-
viscosity blood. As such, Doppler assessment shows elevated middle cerebral artery peak systolic
velocity (MCA-PSV) in cases of fetal anemia.
[37]
Elevated MCA-PSV values warrant fetal blood
sampling to assess the degree of anemia and intrauterine transfusion, if necessary.
Chest radiography should be performed in any pregnant patient with a recent VZV infection and
respiratory symptoms to rule out pneumonia. Pneumonia demonstrates classic viral signs, with diffuse
peribronchial nodular infiltrates and interstitial pneumonitis.
Prenatal diagnosis of varicella infection is possible with examination at 5 or more weeks following the
initial time of suspected VZV infection in the first trimester. Ultrasonographic findings include limb
abnormalities such as hypoplasia, stippling of the epiphyseal plates, and club-foot deformities.
Ventriculomegaly may also be present. Fetal echocardiography should be performed to assess for
fetal cardiac abnormalities, with a follow-up postnatally in infants with CRS to evaluate for cardiac
defects, including patent ductus arteriosus.
Detailed fetal ultrasonography may also be used to identify fetal injury associated with congenital
rubella syndrome and include intracranial calcifications, hydrocephalus, microcephaly and cardiac
defects. Fetal growth evaluations may also show intrauterine growth restriction (IUGR). Fetal
echocardiogram is recommended to diagnose cardiac abnormalities, followed by postnatal
echocardiogram evaluation. The most common cardiac abnormality is patent ductus arteriosus.
Diagnostic procedures
Amniocentesis or chorionic villous sampling can assist in confirming infections with rubella virus,
CMV, B19V, and, possibly, HSV.
Treatment & Management
Medical care
The treatment of these infections had been limited in the past. However, many studies of antivirals
have shown that treatment may yield benefit in some selected cases. Among these newly described
treatments, the most studied include ganciclovir in congenital CMV infection and acyclovir in maternal
varicella infections (see Medication).
Other treatment options that have shown to be lifesaving in small case reports include intrauterine
blood transfusions to treat hydrops fetalis due to B19V infection. The procedure is performed with
continuous ultrasound guidance, and the umbilical vein is preferred. Cordocentesis has been
associated with a 1.2-4.9% fetal loss rate. Nonetheless, most studies have shown that this procedure
may confer survival and outcome advantages in patients with hydrops fetalis.
[38]

Surgical care
If primary or recurrent HSV genital infection occurs late in pregnancy, elective caesarian delivery is
performed to prevent neonatal infection, although neonatal infection is still possible via transplacental
passage of HSV prior to birth.
Consultations
The treatment of all of these infections should involve a team of well-experienced high-risk
obstetricians, as well as infectious disease specialists and neonatologists.
Follow-up
Further inpatient care
Some pregnant patients with varicella may require admission for treatment if pneumonitis is
suspected.
Further outpatient care
Infants with confirmed congenital CMV infection, even if asymptomatic at birth, should undergo
frequent audiometric evaluations through at least age 6 years.
[6]

Infants who survive intrauterine B19V infection generally have an excellent long-term prognosis.
Isolated reports have described neurological deficits in children who have received several
intrauterine transfusions; as such, these children should undergo follow-up to monitor psychomotor
development.
[25]

Infants with congenital rubella syndrome have a guarded prognosis and require close follow-up for
psychomotor development and audiometric evaluation. Half of these children eventually need to
attend schools for the hearing impaired.
[45]

Deterrence and prevention
Animal studies of CMV immunization have shown promising results in the prevention of congenital
CMV infection and its complications.
[46, 47]
CMV vaccines currently in various stages of preclinical and
clinical testing include protein subunit vaccines, DNA vaccines, vectored vaccines using viral vectors,
peptide vaccines, and live attenuated vaccines.
[48]

Congenital CMV infection is an important cause of hearing, cognitive, and motor impairments in
newborns. A phase II, placebo-controlled, randomized, double blind trial by Pass et al evaluated a
recombinant CMV vaccine (enveloped glycoprotein B with MF59 adjuvant). Three doses of the CMV
vaccine or placebo were administered at 0, 1, and 6 months to 464 CMV-seronegative women within
1 year after they had given birth. After a minimum of 1-year follow-up, 49 confirmed infections were
noted, 18 in the vaccine group and 31 in the placebo group. One congenital infection among infants of
the study subjects occurred in the vaccine group, and 3 infections occurred in the placebo group.
Ongoing research continues to evaluate the potential for a CMV vaccine to decrease maternal and
congenital CMV infection.
[49]

Pregnant women who are seronegative for HSV can prevent infection by abstaining from sex. An
alternative would be the use of condoms and abstinence from oral-genital sex. As mentioned above,
the results of several trials suggest that the use of acyclovir or famciclovir near term decreases the
expression of genital herpes and, thus, the need for a cesarean delivery.
VZV immunization in unexposed women or teenage girls helps prevent CVS, but varicella vaccine
(live attenuated virus) is not administered during pregnancy. Inadvertent vaccination of a pregnant
woman is not an indication for pregnancy termination. The Varicella Vaccination in Pregnancy
Registry, a prospective outcome monitoring system, has not shown any adverse risk related to the
varicella vaccine in pregnancy.
Varicella-zoster immunoglobulin (VZIG) therapy after known exposure to varicella has been the
mainstay of disease prevention in pregnant women. However, the production of VZIG has been
ceased, and it is no longer available. VariZIG, a similar product, is available under expanded access
for use in pregnant women at a high risk of developing varicella. If this is not an option, IVIG can also
be administered.
VZIG administration may decrease the severity of neonatal disease in infants born to mothers with
active varicella at delivery. Again, the use of this medication may be limited by availability, and
VariZIG can be used under expanded access protocol.
The measles-mumps-rubella (MMR) vaccine was introduced in 1988, and worldwide universal
vaccination has become a priority. MMR vaccination is administered to all children in a series of 3
vaccinations and is offered to all women of child-bearing age who immigrate to the United States.
Patients should undergo testing for rubella immunity at their first prenatal visit. If they are susceptible
to infection, they should be counseled to avoid exposure to patients with viral exanthems and to report
any exposure to their provider. Additionally, seronegative women should be immunized immediately
after delivery prior to discharge from the hospital.
As it is a live attenuated strain, MMR vaccination is contraindicated within one month of pregnancy or
during pregnancy; however, no cases of CRS have been reported after inadvertent immunization
during pregnancy. Counseling the patient about the very low risk of CRS is warranted, and
termination of pregnancy, although optional, is not recommended. Adverse effects of the vaccine are
minimal, and 95% of vaccinated patients seroconvert.
Avoidance of rodents, including mice and hamsters, may help prevent LCMV infection.
The CDC and American College of Obstetrics and Gynecology (ACOG) recommend vaccination of all
pregnant women through the influenza season (October through May). Vaccination early in the
season and at any gestational age is recommended. Pregnant women receive the inactivated
influenza vaccine, and the nasal mist is not recommended in pregnancy, as it is a live-attenuated
vaccine. Although thimerosal, a mercury-containing preservative, has not been shown to be
associated with short- or long-term adverse effects (other than possibly site irritation), due to growing
concerns, a thimerosal-free, trivalent vaccine is available. As infants younger than 6 months are
unable to be vaccinated for influenza, vaccination of pregnant women allows for passive immunization
of the fetus.
[50]

Prognosis
Prognosis depends on the viral syndrome and the severity of the initial infection.
Patient education
It is important to educate women of child-bearing age about the importance of vaccination against
some of these diseases, as many of these congenital infections are preventable. Most of this
education should be targeted toward teenaged girls, as many young women will not seek medical
care outside their pediatrician until they are already pregnant.
Educating the pregnant patient to avoid contact with persons with viral infections and frequent hand
washing when handling children can prevent infection. If exposure does occur, the patient should
seek immediate assistance for postexposure prophylaxis with varicella immunoglobulin.