Congenital Rubella - UpToDate

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Congenital rubella
Author: Antonio C Arrieta, MD, FIDSA
Section Editors: Morven S Edwards, MD, Leonard E Weisman, MD
Deputy Editor: Carrie Armsby, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2022. | This topic last updated: Jun 16, 2021.
INTRODUCTION
Congenital rubella infection (CRI) will be reviewed here. The epidemiology of rubella
infection and issues related to rubella in pregnancy, including risk of rubella-associated
congenital defects, are discussed separately. (See "Rubella" and "Rubella in pregnancy".)
TERMINOLOGY
The terms congenital rubella infection and congenital rubella syndrome are used
throughout this topic:
● Congenital rubella infection (CRI) –CRI is the broader term, encompassing the full
spectrum of outcomes from intrauterine rubella infection, ranging from miscarriage or
stillbirth, to combinations of birth defects (ie, congenital rubella syndrome), to
asymptomatic infection [1].
● Congenital rubella syndrome (CRS) –CRS is a subcategory of CRI that refers to

variable constellations of birth defects (eg, sensorineural hearing loss [SNHL],
congenital heart disease, cataracts, congenital glaucoma) ( table 1) [1].
EPIDEMIOLOGY
The epidemiology of congenital rubella infection (CRI) and congenital rubella syndrome
(CRS) is generally similar to the epidemiology of rubella infection in pregnancy, which is
discussed separately. (See "Rubella in pregnancy", section on 'Epidemiology'.)
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CRS is rare in developed countries with established rubella immunization programs [2-4]. In
the United States, rubella is no longer endemic and there have been fewer than 10 people
reported as having rubella each year since 2012; all cases had evidence that they were
infected when they were living or traveling outside of the United States [5]. Following a 15-
year initiative involving widespread immunization, rubella was declared to have been
eliminated from the whole of the Americas region in 2015 [6].
In other parts of the developing world, rubella control is accelerating through widespread
implementation of vaccine programs. (See "Rubella", section on 'Burden of disease'.)
PATHOGENESIS
Maternal-fetal transmission of rubella virus occurs via hematogenous spread during

maternal viremia, which usually occurs five to seven days after maternal inoculation. After
infecting the placenta, the virus spreads through the vascular system of the developing
fetus. The resulting congenital defects stem from cytopathic damage to blood vessels and
ischemia in affected organs [7-10]. Fetal infection is chronic, persisting throughout gestation
and after birth.
The risk of maternal-fetal transmission varies depending upon the time of maternal
infection, with the highest risk in the first 10 weeks of gestation. The clinical manifestations
also vary depending upon the time of maternal infection. Structural cardiac and eye defects
typically result when maternal infection occurs before eight weeks, whereas hearing loss
may be observed in maternal infections until 18 weeks gestation [11,12]. Congenital defects
are unlikely if maternal infection occurs after 18 to 20 weeks gestation. (See "Rubella in
pregnancy", section on 'Congenital rubella syndrome'.)
There are two proposed mechanisms for rubella cytopathology:
● Virus-induced inhibition of cell division – Support for virus-induced inhibition of cell

division is provided by observations that organs of congenitally infected infants are
smaller and contain fewer cells than those of uninfected infants [13], mitotic activity is
depressed in congenitally infected embryonic primary cell cultures [9], cell division is
slowed in human fetal cells and BHK-21 cells that have been infected with rubella virus
in vitro [14-16], and a protein extracted from rubella virus-infected human fetal cells
inhibits mitosis in uninfected cells [17].
● Direct cytopathic effects – Support for direct cytopathic effects is provided by an in

vitro study demonstrating variable degrees of rubella virus-induced programmed cell
death (apoptosis) in different cell lines [18]. These findings suggest that programmed
cell death depends upon unique cellular properties and may provide an explanation for

selective organ damage in congenital rubella syndrome (CRS). Subsequent studies

demonstrating cell-specific rubella virus-induced apoptosis (in chorionic villi explants,
monolayers of cytotrophoblasts, and adult lung fibroblasts but not in primary human
fetal fibroblasts) may help to explain the persistence of virus in CRS [19,20].
Other possible explanations for the persistence of rubella virus in CRS include defects in cell-
mediated immunity and selective immune tolerance to the rubella virus E1 protein [21-23].
IMMUNOLOGIC RESPONSE
● Humoral response – During the first 16 to 20 weeks of gestation, only 5 to 10 percent

of maternal immunoglobulin G (IgG) rubella antibody is passively transferred to the
fetus. The fetus's own immunoglobulin M (IgM), IgG, and immunoglobulin A (IgA)
appear at 9 to 11 weeks of gestation, but circulating fetal antibody levels remain low.
Fetal antibody levels increase at mid-gestation, with predominance of IgM. At the time
of delivery, IgG predominates and is mainly of maternal origin; IgM levels are lower but
entirely of fetal origin [24].
After birth, the infant's IgM increases while maternally derived IgG decreases. In
infants with congenital rubella infection (CRI), rubella-specific IgM generally persists for
at least six months, often persisting for up to one year, and occasionally persisting for
up to two years [25]. High levels of infant rubella-specific IgG antibody usually are
sustained for several years after detectable rubella virus excretion ends. Over time,
rubella-specific antibody levels decrease [25]; in 10 to 20 percent of patients, they may
become undetectable [26-29].
Some patients with CRI have a relative hypergammaglobulinemia (particularly of IgM

and IgG) during the first few years of life, which results from the increased antigenic
stimulus accompanying the chronic infection [30]. There are a few case reports of
hypogammaglobulinemia following intrauterine rubella infection, which usually affects
only IgA but may involve IgG, IgM, and IgA [30,31]. Alternatively, IgG may be decreased
and IgM increased (two to three times normal adult levels) with or without
abnormalities in IgA [30].
● Lack of booster response – Children with CRI whose rubella-specific antibody titers
have decreased to an undetectable level do not develop a boost in antibody titer after
rubella vaccination [27,32]. This may reflect immunologic tolerance following
intrauterine exposure to rubella virus. The mechanism of immune tolerance is not
known but may be related to selective tolerance to the rubella virus E1 protein or the
immaturity of the fetal immune system during the first trimester of gestation [23,33].

● Cellular response – Defects in cell-mediated immunity and persistent T cell

abnormalities have been reported in patients with CRI, particularly when infection
occurs early in gestation [22,34-37]. Delayed-type hypersensitivity reactions,
lymphocyte-mediated cytotoxicity, phytohemagglutinin-induced lymphocyte
transformation, and interferon production are decreased compared with responses in
individuals with postnatal rubella infection. T cell abnormalities may predispose
patients with CRI to develop organ-specific autoimmunity.
● Possible role in autoimmunity – CRI is associated with increased risk for diabetes and
thyroid disease (see 'Late manifestations' below). Patients with CRI have a high
prevalence of pancreatic islet cell surface antibodies and antithyroid antibodies,
suggesting that immune-mediated mechanisms may play a role in the development of
diabetes and thyroid disease. However, there is no clear evidence that congenital
rubella predisposes to subsequent autoimmunity. Approximately 20 percent of patients
with congenital rubella syndrome (CRS) have pancreatic islet cell surface antibodies,
but pancreatic islet cell antibodies (which are more closely related to immune-mediated
diabetes) have not been detected [38-40]. This suggests that other factors, such as
human leukocyte antigen type, are also important in the development of type 1
diabetes in patients with CRI [38,39,41-44]. (See "Pathogenesis of type 1 diabetes
mellitus".)
CLINICAL FEATURES
Overview — Congenital rubella infection (CRI) may lead to fetal death in utero, preterm
delivery, or congenital defects [1]. CRI is a chronic infection and has a broad spectrum of
clinical manifestations that may manifest throughout life ( table 2) [1,45].
Deafness, cataracts ( picture 1), and cardiac disease are the classic manifestations of
congenital rubella syndrome (CRS) [46,47]. However, rubella virus may infect virtually every
fetal organ [30]. Once CRI is established, it can persist for long periods.
The manifestations of CRI vary depending upon the timing of maternal infection. The
incidence of defects may be as high as 80 to 85 percent if maternal rubella is acquired
during the first trimester [11,26,48]. Little, if any, risk of congenital defects is associated with
infection after 18 to 20 weeks gestation [11,49]; fetal growth restriction may be the only
sequela of third-trimester infection [26,50-52]. (See "Rubella in pregnancy", section on
'Congenital rubella syndrome'.)
The case definition for CRS is summarized in the table and discussed below ( table 1). (See
'Case definition' below.)

Early manifestations — The majority of infants with CRI are asymptomatic at birth but
develop manifestations over time ( table 2) [53-56]. However, severe symptomatic
neonatal infection can occur.
Early manifestations may include ( table 2) [12,21,48,57]:
● Fetal growth restriction – (See "Infants with fetal (intrauterine) growth restriction".)
● Sensorineural hearing loss (SNHL) – Nearly two-thirds of children with CRI have SNHL,
which is usually bilateral [1]. (See "Hearing loss in children: Screening and evaluation".)
● Central nervous system (CNS) involvement – CNS abnormalities may include

meningoencephalitis, large anterior fontanelle, microcephaly, developmental delay,
motor delay, and behavioral disorders [12,30].
● Congenital heart disease – Approximately one-half of children infected in early

gestation have congenital heart disease [1]. Patent ductus arteriosus and branch
pulmonary artery stenosis are the most common lesions [58]. Other reported lesions
include pulmonary valvular stenosis, aortic stenosis, ventricular septal defect, tetralogy
of Fallot, and coarctation of the aorta [45,58]. Stenosis of other vessels may be related
to coronary, cerebral, renal, and peripheral vascular disease during adulthood [59,60].
(See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants,
children, and adults" and "Valvar aortic stenosis in children" and "Pathophysiology,
clinical features, and diagnosis of tetralogy of Fallot".)
● Eye disease – Findings may include cloudy cornea, cataract ( picture 1), infantile
glaucoma, and/or retinopathy ( picture 2). Cataracts occur in approximately one-
quarter of infants with CRS; infantile glaucoma is less common [1]. Cataracts and
infantile glaucoma usually become apparent during the early weeks of life. "Salt and
pepper" retinopathy ( picture 2) is caused by disturbed growth of the pigmentary
layer of the retina [12,30]. (See "Cataract in children" and "Overview of glaucoma in
infants and children", section on 'Secondary glaucoma'.)
● Other – Other findings that can be seen in the newborn include:
• Petechiae and purpura ("blueberry muffin lesions") ( picture 3)

• Thrombocytopenia
• Hemolytic anemia
• Hepatosplenomegaly, jaundice, hepatitis
• Diarrhea
• Interstitial pneumonia
• Myocarditis
• Radiolucent bone lesions (in the long bones)
• Lymphadenopathy
Many of these neonatal manifestations are transient and not necessarily specific for
CRI [30]. They typically clear spontaneously over days or weeks.
The early manifestations have important prognostic implications. The risk of mortality
is increased in neonates with severe defects (eg, very low birth weight, extreme
prematurity, extensive meningoencephalitis, gross cardiac lesions or myocarditis with
early heart failure, fulminant interstitial pneumonitis, and rapidly progressive hepatitis)
[12].
In prospective surveillance of 4005 infants born after the 1964 rubella epidemic in the United
States, 68 percent of infected newborns had subclinical infection during the neonatal period
[53]. However, 71 percent of those who were followed developed clinical manifestations in
the first five years of life. The lack of clinical manifestations during the newborn period and
the risk for progression highlight the importance of timely diagnosis and appropriate short-
and long-term management [30].
Late manifestations — Delayed manifestations occur in at least 20 percent of children with

CRS [59]. Some of the late manifestations may relate to subtle damage that is present but
not detected in early life. Late manifestations include [59]:
● Hearing loss – Permanent hearing loss is the most common late manifestation of CRI,
ultimately occurring in up to 80 percent of patients [30]. SNHL is usually bilateral. It
ranges in severity from mild to profound and may progress over time. Rarely, sudden
onset of hearing loss may occur after years of normal hearing [61,62].
● Endocrine disorders – Late manifestations of intrauterine rubella infection may

include diabetes, thyroid disease, and growth hormone deficiency [59].
In the available case series, approximately 1 percent of individuals with CRS developed
diabetes in childhood and adolescence [40,63-65]. The risk increases in adulthood. In
long-term follow-up of patients with CRS following the 1941 rubella epidemic in
Australia, 22 percent developed diabetes by age 60 years (compared with a background
prevalence of approximately 10 to 15 percent) [54]. (See "Pathogenesis of type 1
diabetes mellitus", section on 'Role of viruses'.)
Thyroid dysfunction affects approximately 5 percent of patients with CRS. It manifests

as hyperthyroidism, hypothyroidism, and thyroiditis [66-70]. A high prevalence of
thyroid microsomal or thyroglobulin antibodies has been observed in patients with
CRS, suggesting that immune-mediated mechanisms may play a role, but there is no
clear evidence that congenital rubella predisposes to autoimmunity. (See "Clinical
manifestations and diagnosis of Graves disease in children and adolescents" and
"Acquired hypothyroidism in childhood and adolescence" and 'Immunologic response'

above.)
CRS may occasionally be associated with growth hormone deficiency and short stature
[71]. (See "Diagnosis of growth hormone deficiency in children".)
● Eye problems – Late-onset ophthalmologic manifestations of CRS may include

pigmentary retinopathy (in approximately 40 to 60 percent of cases) ( picture 2),
cataracts, glaucoma (in 2 to 15 percent of cases), keratic precipitates, keratoconus,
corneal hydrops, microphthalmos (estimated to occur in 10 to 20 percent of cases),
strabismus, and absorption of the cataractous lens [59,72,73]. This damage can appear
years or even decades after birth [45].
● Vascular disease – Vascular sequelae of CRS may include fibromuscular proliferation of

the intima, sclerosis of arteries, systemic hypertension secondary to renal disease, and
subretinal neovascularization [59,60]. These lesions are potential causes of coronary,
cerebral, and peripheral vascular disease in adulthood.
● Panencephalitis – Progressive rubella panencephalitis most commonly occurs in the

second decade of life [74,75]. It is slowly progressive and fatal. The initial findings are
usually learning problems and ataxia.
● Immune defects – Defects in specific antibody production, repeated infections, and

defective T cell response with associated autoimmune phenomena have been observed
in patients with CRS [76,77].
● Prolonged viral shedding – After fetal infection, rubella virus persists throughout
gestation and for months postnatally. It can be recovered from multiple sites.
Pharyngeal shedding of rubella virus is common, prolonged, and intense during the
months after delivery. At one year of age, as many as 20 percent of infants with CRS
continue to shed rubella virus in the pharynx, but by two years of age, pharyngeal
shedding is rare [48,78-82].
In patients with ocular and CNS involvement (eg, cataracts, late subacute
panencephalitis), rubella virus has been cultured from the crystalline lens and
cerebrospinal fluid in children older than one year of age [75,78,83,84].
EVALUATION
Clinical suspicion — The possibility of congenital rubella infection (CRI) should be

considered in [1,85]:

● Any infant born to a woman who had documented or suspected rubella infection at any
time during pregnancy; treatment of maternal rubella infection with immunoglobulin
does not guarantee protection from fetal infection (see "Rubella in pregnancy", section
on 'Treatment')
● Any infant with fetal growth restriction or other clinical manifestations suggestive of
congenital rubella syndrome (CRS) ( table 1 and table 2)
Testing — The evaluation of a newborn with suspected CRI or CRS includes [1,24]:
● Review of maternal history to confirm documentation of rubella immunity
● Complete physical examination assessing for stigmata consistent with the syndrome (
table 2) (see 'Clinical features' above)
● Complete blood count
● Liver enzymes and bilirubin (total and direct)
● Lumbar puncture
● Cardiac evaluation – Some experts suggest echocardiography for all infants in whom
CRS is suspected, whereas others suggest cardiology consultation and
echocardiography based upon clinical examination findings [1,58] (see "Identifying
newborns with critical congenital heart disease")
● Radiographs of long bones
● Ophthalmologic evaluation
● Audiologic evaluation
● Neuroimaging (eg, ultrasonography, computed tomography) [86]
● Rubella serology (see 'Serology' below)
DIAGNOSIS
Laboratory confirmation — Laboratory confirmation of congenital rubella infection (CRI)

can be established with any of the following ( table 1) [87]:
● Demonstration of rubella-specific IgM antibodies (see 'Serology' below)
● Demonstration of rubella-specific IgG antibodies that persist at a higher concentration

or longer duration than expected from passive transfer of maternal antibody (ie, titer

does not drop at the expected rate of a twofold dilution per month) (see 'Serology'
below)
● Isolation of rubella in viral culture from a nasopharyngeal swab, blood sample

(including cord blood), urine, or cerebrospinal fluid (see 'Viral culture' below)
● Detection of rubella virus RNA by polymerase chain reaction (PCR) (see 'Polymerase
chain reaction' below)
Laboratory evaluation should be performed before the child reaches one year of age, after
which it is difficult to establish a diagnosis of CRI [88]. (See 'Evaluation' above and
'Retrospective diagnosis' below.)
The cost, length of time required for definitive results, and expertise required for
performance of these tests vary. Demonstration of rubella-specific IgM antibodies with
commercially available enzyme immunoassay kits is the preferred initial test, particularly for
infants in the first two months of life [1,89]. Measurement of rubella-specific IgG is most
helpful in infants between 6 and 12 months of age [1,48]. Consultation with an expert in
pediatric infectious diseases is suggested if there are questions regarding the appropriate
diagnostic strategy.
Case definition — The case definition for congenital rubella syndrome (CRS)/CRI used by the
Centers for Disease Control and Prevention is based upon both clinical and laboratory
criteria. Depending on the findings, cases are classified as "suspected," "probable,"
"confirmed," or "infection only," as outlined in the table ( table 1) [87].
Retrospective diagnosis — It is difficult to establish a diagnosis of CRI in children older than

one year of age [24,88]. At this age, serologic testing usually is not diagnostic and isolation
of virus in culture is unlikely because viral shedding has typically waned by this age.
Retrospective diagnosis of CRI in children >1 year old can be established with PCR, which is
highly sensitive (see 'Polymerase chain reaction' below); however, PCR may not be available
in all settings and it can be negative when performed in older children with CRI. In such
cases, the following tests support the diagnosis of CRI:
● Measuring lymphocyte response to rubella in vitro [32,90,91]
● Measuring rubella IgG avidity (strength of antigen-antibody binding); children with

intrauterine rubella infection have low rubella-specific IgG avidity [21,24,92-95]
● Measuring antibody response to rubella vaccination (in children with compatible

manifestations but nondetectable antibody); children with CRS generally do not
respond to rubella vaccination [21,23,27,32,33] (see 'Immunologic response' above)

Laboratory tests for diagnosis
Serology — Serologic confirmation of CRI consists of demonstration of rubella-specific IgM

antibody or infant IgG rubella antibody level that persists at a higher level and for a longer
time than expected from passive transfer of maternal antibody [85,87]. Serologic testing is
more likely to be available in developing countries [1]. (See 'Immunologic response' above.)
● Rubella-specific IgM antibody – Detection of rubella-specific IgM antibody in the

neonatal serum or cord blood provides laboratory evidence of recent postnatal or CRI
in the newborn [21,30,85]. IgM testing is most helpful in infants younger than two
months, although IgM may be detectable for as long as 12 months in some infants [1].
Infants with symptoms consistent with CRS who test negative soon after birth should
be retested at age one month because approximately 20 percent of infected infants
tested for rubella IgM may not have detectable titers before age one month [85]. In
infants older than two months, positive IgM is helpful, but negative IgM does not
exclude infection. False-positive IgM results may be caused by rheumatoid factor,
parvovirus, and heterophile antibodies [88].
● Rubella-specific IgG antibody – Monitoring rubella-specific IgG over time (eg, at 3, 6,

and, if necessary, 12 months of age) also may confirm congenital or recent postnatal
rubella infection if rubella-specific IgG persists at a higher level and for a longer time
would be expected for maternal IgG [85,87]. Maternal rubella antibody has a half-life of
approximately 30 days; it should decrease by four- to eightfold by three months of age
and should disappear by 6 to 12 months of age [24,30,85]. (See 'Immunologic response'
above.)
Monitoring rubella-specific IgG is less desirable than the other methods of laboratory
diagnosis because it may delay diagnosis, does not necessarily distinguish congenital
from postnatal infection, and does not absolutely exclude intrauterine infection (if the
infant has low antibody levels because of agammaglobulinemia or
dysgammaglobulinemia) [24,85]. In questionable cases, assessment of IgG rubella
antibody avidity may be helpful [92,93]. (See 'Retrospective diagnosis' above.)
Viral culture — The diagnosis of CRI can be confirmed by the isolation of the rubella virus
in culture [1]. Rubella virus is most frequently isolated from nasopharyngeal secretions,
although it can also be cultured from blood (including cord blood), placenta, urine, and
cerebrospinal fluid [30,85]. Specialized testing is necessary for rubella virus, so laboratory
personnel should be notified that rubella virus is suspected [88].
Virus isolation should be attempted as soon as congenital rubella is suspected because viral
excretion wanes during infancy [30]. Isolation of rubella virus may be possible for several
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years from lens tissue in children with cataracts or cerebrospinal fluid in children with
encephalitis [75,83].
Polymerase chain reaction — Detection of rubella virus RNA by PCR also confirms CRI
[85,87,88] but may not be available in all settings [1]. PCR may be performed on pharyngeal
swabs, respiratory secretions, central nervous system (CNS) tissues and cerebrospinal fluid,
amniotic fluid, products of conception, urine samples, and lens tissue (in children with ocular
anomalies) [21,88,96-98].
DIFFERENTIAL DIAGNOSIS
Congenital rubella syndrome (CRS) must be differentiated from other congenital infections (
table 3) and other conditions that have similar manifestations in the newborn.
Appropriate viral testing and serologies will distinguish congenital rubella infection (CRI)
from these other causes:
● Congenital toxoplasmosis (see "Congenital toxoplasmosis: Clinical features and

diagnosis", section on 'Evaluation')
● Congenital cytomegalovirus (see "Congenital cytomegalovirus infection: Clinical

features and diagnosis", section on 'Clinical manifestations')
● Congenital syphilis (see "Congenital syphilis: Clinical features and diagnosis")
● Congenital Zika virus infection (see "Zika virus infection: Evaluation and management
of pregnant women", section on 'Congenital infection')
● Congenital lymphocytic choriomeningitis virus (see "Viral meningitis in children:

Epidemiology, pathogenesis, and etiology", section on 'Lymphocytic choriomeningitis
virus')
● Other conditions that cause sensorineural hearing loss (SNHL) ( table 4) (see
"Hearing loss in children: Etiology", section on 'Congenital')
● Other conditions that cause cataracts ( table 5) (see "Cataract in children", section on
'Etiology')
● Other conditions that are associated with congenital heart disease (eg, genetic
syndromes, gestational diabetes) (see "Identifying newborns with critical congenital
heart disease", section on 'Risk factors')
MANAGEMENT
Supportive care and surveillance are the cornerstones of management for congenital rubella
infection (CRI).
No role for antiviral therapy — The clinical course of intrauterine CRI or subsequent

congenital rubella syndrome (CRS) is not altered by treatment with antiviral or biologic
agents [30,31,99,100], nor are there any agents that have any long-term effect on the
duration of viral shedding.
Management of complications — Most infants with CRS have multiple medical problems

and require multidisciplinary management [30]. At the time of diagnosis, a comprehensive
evaluation should be performed to determine the extent of disease severity. (See 'Evaluation'
above.)
The medical problems that may occur in CRS are generally managed in the same manner as
in patients without CRI [101]:
● Hearing loss – Hearing loss may require hearing aids and referral to an early
intervention program. (See "Hearing loss in children: Treatment".)
● Eye disease – Cataracts, retinopathy, infantile glaucoma, and other eye complications
require specialized management by a pediatric eye care specialist. (See "Overview of
glaucoma in infants and children" and "Cataract in children", section on 'Management'.)
● Central nervous system (CNS) manifestations – In the early postnatal period, CNS
disease may manifest as meningoencephalitis (eg, abnormal neurologic findings,
seizures). Provision of empiric antimicrobial therapy until culture or polymerase chain
reaction (PCR) results for bacterial and viral pathogens of cerebrospinal fluid results are
available and supportive care are the cornerstones of therapy for meningoencephalitis
in neonates. Initial supportive care measures may include stabilization of
cardiorespiratory status and treatment of seizures. (See "Bacterial meningitis in the
neonate: Treatment and outcome" and "Treatment of neonatal seizures".)
After infancy, CNS manifestations may include intellectual disability, autism, and
cerebral palsy, which may require special education services and speech, language,
occupational, and/or physical therapy. (See "Intellectual disability (ID) in children:
Management, outcomes, and prevention" and "Cerebral palsy: Overview of
management and prognosis" and "Autism spectrum disorder in children and
adolescents: Behavioral and educational interventions".)
● Congenital heart disease – Cardiac evaluation and management is the same as for
infants without CRS. Patent ductus arteriosus and pulmonary stenosis are the most
common lesions [58]. (See "Identifying newborns with critical congenital heart disease"

and "Management of patent ductus arteriosus in term infants, children, and adults"
and "Pulmonic stenosis in infants and children: Management and outcome".)
● Endocrine abnormalities – The late-onset endocrine abnormalities (eg, diabetes,

thyroid dysfunction) should be managed by an endocrinologist. (See "Overview of the
management of type 1 diabetes mellitus in children and adolescents" and "Treatment
and prognosis of Graves disease in children and adolescents" and "Acquired
hypothyroidism in childhood and adolescence".)
● Neonatal thrombocytopenia – Thrombocytopenia is generally mild to moderate and

transient. Although purpura and petechiae may be severe, clinically significant bleeding
is uncommon. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation,
and management", section on 'Management'.)
● Neonatal respiratory distress – Neonates with respiratory distress should be managed

with oxygen or ventilatory (invasive or noninvasive) support as necessary. (See
"Management of respiratory distress syndrome in preterm infants", section on 'Clinical
approach'.)
● Neonatal hyperbilirubinemia – Hyperbilirubinemia in CRS is typically conjugated and

rarely severe; it generally does not require any specific therapy. Neonates with
unconjugated hyperbilirubinemia are managed in the same manner as are those
without suspected CRS [101]. (See "Unconjugated hyperbilirubinemia in term and late
preterm infants: Management".)
Surveillance and long-term follow-up — Patients with CRI require lifelong follow-up care
and surveillance. Clinical manifestations of CRS may develop over time ( table 2). Hearing
loss usually has onset during the first several years of life, but other manifestations may
manifest later in childhood, adolescence, or adulthood [26,49,54-56,102].
Infants with CRI require close monitoring during the first 6 to 12 months of life, particularly
for hearing impairment and developmental abnormalities [30,101]. These are among the
most frequent late CRS manifestations and often occur in infants who were asymptomatic at
birth. Repeat assessment over time is necessary to detect new or progressive
manifestations.
● Hearing assessments – Hearing loss is the most common manifestation of CRS, and
prompt diagnosis and institution of early intervention and educational programs are
among the most important aspects of management [1,101].
Infants exposed to rubella virus in utero should undergo objective hearing assessment
during the neonatal period, at least once between 24 and 30 months of age (preferably
more frequently) and then according to the American Academy of Pediatrics periodicity
schedule (whether or not the infant has other manifestations of congenital rubella
syndrome [CRS]) [101,103,104]. (See "Hearing loss in children: Screening and
evaluation", section on 'Screening for hearing loss in children'.)
If hearing loss is detected, the child should be referred for early intervention services
and fitted with an appropriate amplification device [101]. (See "Hearing loss in children:
Treatment".)
● Vision assessment and follow-up eye examination – All children with CRS should
have routine vision screening performed at each primary care visit and should have
regular follow-up with a pediatric eye care specialist. The frequency of follow-up will
depend on whether an eye problem is identified and, if so, what type and how severe it
is. Patients who develop new concerning findings (vision changes, leukocoria, excessive
tearing) should be referred for more urgent ophthalmologic evaluation. (See "Vision
screening and assessment in infants and children" and "Cataract in children", section
on 'Follow-up' and "Overview of glaucoma in infants and children".)
● Developmental-behavioral screening – Children with CRS are at increased risk for

developmental problems. Developmental surveillance and screening are essential
components of long-term care. (See "Developmental-behavioral surveillance and
screening in primary care".)
● Cardiac follow-up – Patients with congenital heart disease as a consequence of CRS

require regular follow-up with a pediatric cardiologist. The frequency of follow-up
depends upon the specific defect and whether any intervention has been performed.
Clinicians should ask about any new or worsening cardiac symptoms at all routine
visits. In infants, this includes lethargy and tiring feeds, trouble coordinating feeding
and breathing, respiratory distress, and excessive sweating. Concerning symptoms in
older children include exercise intolerance, chest pain, and syncope. If these are
present, the patient should follow up with their cardiologist more urgently. (See
"Suspected heart disease in infants and children: Criteria for referral", section on
'Symptoms'.)
It is important to screen for cardiac symptoms even in patients whose initial evaluation
was negative for congenital heart disease since some lesions may be mild initially and
then progress over time (eg, pulmonic or aortic valve stenosis). (See "Pulmonic stenosis
in infants and children: Clinical manifestations and diagnosis" and "Valvar aortic
stenosis in children".)
● Screening for diabetes and thyroid disease – It is important to monitor children with
CRS for the development of diabetes and thyroid disease. Patients and caregivers
should be educated about the signs and symptoms of these conditions. Health care

providers should ask about symptoms and signs at health maintenance visits. Patients
with clinical manifestations should undergo appropriate testing. Antithyroid antibodies
may be measured as surrogate markers of disease. (See "Epidemiology, presentation,
and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Clinical
manifestations and diagnosis of Graves disease in children and adolescents" and
"Acquired hypothyroidism in childhood and adolescence".)
● Immune deficiency – A small number of patients with CRS have low levels of serum
IgG [101]. Serum immunoglobulins should be measured when clinically indicated (eg,
in children with recurrent infections). (See "Approach to the child with recurrent
infections".)
OUTCOME
● Perinatal mortality – Most newborns with congenital rubella infection (CRI) survive.
However, perinatal and early postnatal death can occur in extremely preterm neonates
and those with severe disease. Severe manifestations in these fatal cases can include
extensive meningoencephalitis, severe cardiac lesions or myocarditis with early heart
failure, fulminant interstitial pneumonitis, and rapidly progressive hepatitis [12].
● Long-term outcome – Information on the long-term outcome of congenital rubella

syndrome (CRS) is provided in a series of follow-up studies of a cohort of 50 patients
born during the 1939 to 1943 rubella epidemic in Australia [54-56]:
• At 25 years, 48 of 50 patients were deaf; 43 of the 48 had severe bilateral deafness;

and hearing impairment was detected in all patients by seven years of age, in most
patients by three years of age, but in only five patients by one year of age.
• At 25 years, 11 patients had congenital cardiovascular defects (patent ductus

arteriosus, pulmonary stenosis, elevated systemic blood pressure); only two of these
were detected in the first year of life. At 60 years, 21 of 32 patients had mild aortic
valve sclerosis on echocardiography and 12 were being treated for hypertension.
• At 25 years, 26 of 50 patients had typical rubella cataracts or chorioretinopathy; at

60 years, virtually all 32 patients had ocular conditions: rubella retinopathy (12),
glaucoma (8), cataracts with onset between the 50- and 60-year follow-up (3),
blindness (1), and other ocular conditions (8).
• At 25 years, 50 percent of patients were below the 10th percentile for weight and/or
height; at 50 years, 6 of 40 patients (15 percent) were below the 3rd percentile for
height.

• At 50 years, 5 of 40 patients (12.5 percent) were diabetic; at 60 years, the prevalence

of type 2 diabetes (22 percent), thyroid disorders (19 percent), early menopause (73
percent), and osteoporosis (12.5 percent) was increased compared with the
Australian population.
PREVENTION
Prevention is the most important aspect of management of congenital rubella infection

(CRI).
● Vaccine – All children should be vaccinated against rubella in early childhood. Measles,
mumps, and rubella immunization are discussed in detail separately. (See "Measles,
mumps, and rubella immunization in infants, children, and adolescents", section on
'Measles, mumps, and rubella disease'.)
● Testing in pregnancy – In pregnant women, immunity to rubella should be

documented as part of initial prenatal care. Rubella in pregnancy is discussed in detail
in a separate topic review. (See "Rubella in pregnancy".)
● Prevention of transmission – Rubella virus is spread from person to person via

airborne transmission or droplets shed from respiratory secretions [105]. It may be
transmitted by persons with subclinical or asymptomatic infection.
Newborns with congenital rubella syndrome (CRS)/CRI remain actively infected and
contagious at the time of birth [101]. Droplet precautions should be instituted for
hospitalized patients as soon as CRS/CRI is suspected [30]. Only individuals known to
be rubella immune should care for contagious or potentially contagious patients [106].
No special precautions are necessary in the household setting for infants with
congenital rubella syndrome (CRS) [101]. However, the family should be advised about
the potential risks to pregnant visitors.
Children with CRS/CRI are considered to be contagious until at least one year of age
unless two clinical specimens obtained one month apart are negative for rubella virus
by culture or by polymerase chain reaction (PCR) after three months of age [85,107]. In
childcare settings, children with CRS/CRI who remain contagious should be cared for
only by individuals who are immune to rubella (ie, have received at least one dose of
rubella-containing vaccine on or after the first birthday or have a positive serologic test
for rubella-specific IgG antibody) [85].
CASE REPORTING
Cases of congenital rubella infection (CRI) and congenital rubella syndrome (CRS), whether
suspected or confirmed, in the United States should be reported to the Centers for Disease
Control and Prevention through local and state health departments [85,87]. These cases
should be reported as soon as they are suspected, even if laboratory confirmation is
pending. Cases of CRI/CRS indicate the presence of rubella infections in the community that
may previously have been unrecognized and should trigger intensified surveillance for
rubella and CRS [85]. In the United States, CRS is exceedingly rare and typically presents in
newborns or infants born to immigrant mothers or susceptible women who travelled to
areas of the world where rubella is still frequent [108,109].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: TORCH infections".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or email these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword[s] of interest.)
● Basics topic (see "Patient education: Rubella (The Basics)")
SUMMARY AND RECOMMENDATIONS
● The clinical spectrum of congenital rubella infection (CRI) is broad, ranging from
miscarriage or stillbirth, to congenital rubella syndrome (CRS; which can include
various birth defects), to asymptomatic infection. (See 'Terminology' above.)
● CRI is rare in developed countries with established rubella immunization programs. The
risk of maternal-fetal transmission and clinical manifestations of CRI vary with the
timing of maternal infection. (See 'Epidemiology' above and 'Pathogenesis' above and
"Rubella in pregnancy", section on 'Congenital rubella syndrome'.)
● Sensorineural hearing loss (SNHL), cataracts ( picture 1), and congenital heart
disease are the classic manifestations of CRS ( table 1). However, rubella virus may
affect virtually every organ in the developing fetus ( table 2). (See 'Clinical features'
above.)
● The evaluation of an infant with suspected CRI or CRS includes (See 'Testing' above.):
• Review of maternal history for documentation of rubella immunity

• Complete physical examination
• Blood tests, including complete blood count, liver enzymes and bilirubin, and
rubella serologies
• Lumbar puncture
• Cardiac evaluation
• Radiographs of long bones
• Ophthalmologic evaluation
• Audiologic evaluation
• Neuroimaging (eg, ultrasonography, computed tomography)
● Laboratory confirmation of CRI can be established with any of the following ( table 1)
(see 'Diagnosis' above):
• Demonstration of rubella-specific immunoglobulin M (IgM) antibody (see 'Serology'

above)
• Demonstration of rubella-specific immunoglobulin G (IgG) antibody that persist at a

higher concentration or longer duration than expected from passive transfer of
maternal antibody (see 'Serology' above)
• Isolation of rubella virus in viral culture from a nasopharyngeal swab, blood sample
(including cord blood), urine, or cerebrospinal fluid (see 'Viral culture' above)
• Detection of rubella virus RNA by polymerase chain reaction (PCR) (see 'Polymerase
chain reaction' above)
● The case definition for CRS used by the Centers for Disease Control and Prevention is
based upon both clinical and laboratory criteria. Depending on the findings, cases are
classified as "suspected," "probable," "confirmed," or "infection only," as outlined in the
table ( table 1). (See 'Case definition' above.)
● The differential diagnosis for CRS includes other intrauterine infections ( table 3) and
other conditions that can cause SNHL ( table 4), cataracts ( table 5), and congenital
heart disease. (See 'Differential diagnosis' above.)
● Supportive care and surveillance are the cornerstones of management for CRI. Antiviral
therapy is not used, because it does not alter the course. (See 'Management' above.)
● Most infants with CRS have multiple medical problems ( table 2) and require
multidisciplinary management. The medical problems that occur in CRS are generally
managed in the same manner as in patients without CRI. (See 'Management of
complications' above.)
● Patients with CRI require lifelong follow-up care and surveillance. Clinical
manifestations of CRS may develop over time ( table 2). Hearing loss usually has
onset during the first several years of life, but other manifestations may manifest later
in childhood, adolescence, or adulthood. (See 'Surveillance and long-term follow-up'
above.)
● Prevention is the most important aspect of management of CRI. Preventive measures

include immunization in early childhood and documenting rubella immunity early in
pregnancy. (See "Measles, mumps, and rubella immunization in infants, children, and
adolescents" and "Rubella in pregnancy".)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Simon R Dobson, MD, FRCP(C), who contributed
to an earlier version of this topic review.
Use of UpToDate is subject to the Terms of Use.
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Topic 6047 Version 35.0

GRAPHICS
Case definition and classification criteria for congenital rubella syndrome
Clinical case definition
An illness, usually manifesting in infancy, resulting from rubella infection in utero

and characterized by clinical findings from the following categories:
Category A: Cataracts/congenital glaucoma, congenital heart disease (most commonly,

patent ductus arteriosus or peripheral pulmonary artery stenosis), hearing impairment,
pigmentary retinopathy
Category B: Purpura, hepatosplenomegaly, jaundice, microcephaly, developmental delay,

meningoencephalitis, radiolucent bone disease
Laboratory criteria (any 1 of the following)
Demonstration of rubella-specific IgM
Infant rubella antibody level (IgG) that persists at a higher level and for a longer time than
expected from passive transfer of maternal antibody (ie, rubella titer that does not drop at the
expected rate of a twofold dilution per month)*
Isolation of rubella
PCR positive for rubella virus
Classification Criteria
Suspected An infant that does not meet the criteria for a probable or confirmed case but
has 1 of more of the above clinical findings (category A or B)
Probable¶ An infant without an alternative etiology that does not have laboratory
confirmation of rubella infection but has either:
At least 2 clinical findings from category A above, or
1 finding from category A and 1 or more from category B above
Confirmed An infant with at least 1 of the above clinical findings that is clinically
consistent with congenital rubella syndrome (category A or B), and laboratory
evidence of congenital rubella infection, as demonstrated by any of the above
laboratory criteria
Infection onlyΔ An infant without any clinical symptoms or signs but with laboratory evidence
of infection, as demonstrated by any of the above laboratory criteria
IgM: immunoglobulin M; IgG: immunoglobulin G; PCR: polymerase chain reaction; CRS:

congenital rubella syndrome.
* Infants with symptoms consistent with CRS who test negative soon after birth should be
retested at age 1 month. Approximately 20% of infected infants tested for rubella IgM may not
have detectable titers before age 1 month.
¶ In probable cases, either or both of the eye-related findings (cataracts and congenital
glaucoma) count as a single complication.

Δ If any compatible signs or symptoms (eg, hearing impairment) are identified later, the case is
reclassified as confirmed.
Adapted from: Centers for Disease Control and Prevention. Rubella, Congenital Syndrome (CRS): 2010 Case Definition.
Available at: https://ndc.services.cdc.gov/case-definitions/rubella-congenital-syndrome-2010/ (Accessed on April 19,
2022).
Graphic 55913 Version 8.0

Frequency and clinical course of selected clinical findings following

intrauterine rubella infection
Manifestations in infancy
Typical time of
Clinical manifestation Frequency Course
onset
Hearing impairment 60% Early infancy Permanent
Heart defect 45%
Patent ductus arteriosus 20% Early infancy Permanent
Peripheral pulmonic stenosis* 12% Early infancy Permanent
Microcephaly 27% Neonatal Permanent
Cataracts 25% Early infancy Permanent
Low birth weight (<2500 g) 23% Neonatal Poor weight gain

may persist
Hepatosplenomegaly 19% Neonatal Transient
Purpura 17% Neonatal Transient
Intellectual disability (mental 13% Variable Permanent

retardation)
Meningoencephalitis 10% Neonatal Transient
Radiolucent bone lesions 7% Neonatal Transient
Retinopathy 5% Early infancy Permanent
Late-onset manifestations¶
Hearing loss Permanent
Intellectual disability Permanent
Diabetes mellitus Permanent
Thyroid dysfunctionΔ Permanent
Progressive panencephalitis Permanent
* Includes pulmonary arterial hypoplasia, supravalvular stenosis, valvular stenosis, and

peripheral branch stenosis.
¶ The frequency of these manifestations is not known, given the difficulty of establishing a
diagnosis of congenital rubella infection in individuals older than 1 year of age.
Δ Includes hyperthyroidism, hypothyroidism, and thyroiditis.
Adapted from:
1. Reef SE, Plotkin S, Cordero JF, et al. Preparing for elimination of congenital Rubella syndrome (CRS): summary of a
workshop on CRS elimination in the United States. Clin Infect Dis 2000; 31:85.
2. Banatvala JE, Brown DW. Rubella. Lancet 2004; 363:1127.


Congenital rubella cataract
This photograph shows cataracts due to congenital rubella

syndrome.
Courtesy of Centers for Disease Control and Prevention Public Health Image Library.

Congenital rubella retinopathy
"Salt and pepper" retinopathy of congenital rubella syndrome:
(A) Color fundus photograph
(B) Fluorescein angiogram
Reproduced with permission from: Gold, DH, Weingeist, TA. Color Atlas of the Eye in
Systemic Disease. Baltimore: Lippincott Williams & Wilkins, 2001. Copyright © 2001
Lippincott Williams & Wilkins.

Blueberry muffin lesions
This infant with congenital rubella syndrome presented with

"blueberry muffin" skin lesions. These lesions indicate cutaneous
hematopoiesis and may occur in other intrauterine infections and
hematologic disorders.
Courtesy of Centers for Disease Control and Prevention Public Health Image Library.

Clinical manifestations that are suggestive of specific congenital

infections in the neonate
Congenital toxoplasmosis
Intracranial calcifications (diffuse)
Hydrocephalus
Chorioretinitis
Otherwise unexplained mononuclear CSF pleocytosis or elevated CSF protein
Congenital syphilis
Skeletal abnormalities (osteochondritis and periostitis)
Pseudoparalysis
Persistent rhinitis
Maculopapular rash (particularly on palms and soles or in diaper area)
Congenital rubella
Cataracts, congenital glaucoma, pigmentary retinopathy
Congenital heart disease (most commonly patent ductus arteriosus or peripheral

pulmonary artery stenosis)
Radiolucent bone disease
Sensorineural hearing loss
Congenital cytomegalovirus
Thrombocytopenia
Periventricular intracranial calcifications
Microcephaly
Hepatosplenomegaly
Herpes simplex virus
Perinatally acquired HSV infection
Mucocutaneous vesicles
CSF pleocytosis
Thrombocytopenia

Elevated liver transaminases
Conjunctivitis or keratoconjunctivitis
Congenital (in utero) HSV infection (rare)
Skin vesicles, ulcerations, or scarring
Eye abnormalities (eg, micro-ophthalmia)
Brain abnormalities (eg, hydranencephaly, microcephaly)
Congenital varicella
Cicatricial or vesicular skin lesions
Microcephaly
Congenital Zika syndrome
Microcephaly
Intracranial calcifications
Arthrogryposis
Hypertonia/spasticity
Ocular abnormalities
CSF: cerebrospinal fluid; HSV: herpes simplex virus.

Causes of hearing loss in infants and children
Features
Conductive hearing loss
Conditions affecting the outer ear
Obstruction (eg, by Cerumen is the most common cause of outer ear obstruction.
cerumen or by bony Exostoses are benign broad-based osseous lesions that usually
growths) present in adolescence or early adulthood. There is often a
history of chronic cold water exposure. The lesions are often
multiple and bilateral.
Osteomas are benign solitary smooth-round osseous lesions
occurring inside the bony ear canal. These lesions usually
present in middle age, but can occur in childhood.
Otitis externa Typically develops after local trauma to the ear canal or when
impacted cerumen becomes contaminated by bacteria after
swimming or showering.
Hearing loss occurs if there is considerable accumulation of
debris, edema, or inflammation in the ear canal.
Symptoms include ear pain, pruritus, and discharge.
Congenital May occur in isolation or may be part of a broader clinical

malformations (eg, syndrome (eg, CHARGE syndrome or hemifacial microsomia).*
microtia, stenosis or
atresia of the
external auditory
canal)
Conditions affecting middle ear
Infection (eg, acute Most common causes of conductive hearing loss in childhood.
otitis media and Hearing loss is usually mild to moderate (approximately 25 dB
otitis media with on average).
effusion)
Tympanic membrane Can be caused by barotrauma, ear infections, foreign body

perforation injury (eg, cotton-tipped applicator), temporal bone fractures,
ear infections, or blast injury.
The degree of conductive hearing loss depends upon the size
and location of the perforation.
Trauma (eg, Middle ear injury occurs in more than one-half of patients with
temporal bone temporal bone basilar skull fractures; injuries can also occur
fracture) after direct blunt trauma to the external auditory canal (eg, hand
blow to ear).
Findings may include hemotympanum and otorrhea (bloody or
clear).
Hearing loss is often mixed (both conductive and SNHL).
Tumors (eg, A cholesteatoma is an abnormal growth of squamous

cholesteatoma, epithelium in the middle ear and mastoid. It may progressively
otosclerosis) enlarge to surround and destroy the ossicles. Suggestive
findings include a white mass behind an intact tympanic
membrane, a deep retraction pocket, or focal granulation on the
surface of the tympanic membrane.
Otosclerosis is an abnormality of bone remodeling that
produces overgrowth of sclerotic bone, particularly on the
footplate of the stapes. It is uncommon in childhood.
Malignant tumors (eg, squamous cell carcinoma) and
proliferative disorders (eg, Langerhans cell histiocytosis) are rare
causes of conductive hearing loss in childhood.
Congenital Usually occur as part of a syndrome (eg, Treacher-Collins

malformations of the syndrome, branchio-oto-renal syndrome, Stickler syndrome,
ossicles (eg, ossicular velocardiofacial (DiGeorge) syndrome, Beckwith-Wiedemann
chain fixation) syndrome)*; occasionally occur as isolated events.
Congenital
Hereditary hearing Numerous hereditary syndromes are associated with SNHL.

loss Examples include Waardenburg syndrome, Usher syndrome,
Pendred syndrome, Alport syndrome, and Jervell and Lange-
Nielsen syndrome (long QT syndrome with deafness), and GJB2
mutations.*
Nonhereditary
Congenital Congenital CMV is a major cause of pediatric SNHL. Hearing loss

infection (eg, can occur in infants with overtly symptomatic infection and in
CMV) those who lack apparent symptoms. SNHL can be progressive or
delayed in onset, and it can be either unilateral or bilateral.
Other TORCH infections that can cause SNHL include congenital
toxoplasmosis, rubella, syphilis, and Zika virus.
Inner ear Hearing loss can range from mild to progressive to complete
dysplasias or deafness.
malformations May be associated with vestibular problems (eg, poor balance or
(eg, enlarged late walking).
vestibular Diagnosis is made with high-resolution CT or MRI.
aqueduct)
Perilymph fistula Leak of inner ear fluid through a defect in the otic capsule
permitting communication between the middle ear and the
inner ear.
Uncommon cause of SNHL.
Typical symptoms include fluctuating severe SNHL,
dysequilibrium, and aural fullness.
Acquired

Prematurity Prematurity is an important risk factor for SNHL, though it is not

a cause per se.
Factors that contribute to increased risk of SNHL in preterm
infants include perinatal complications, hyperbilirubinemia,
ambient noise, and use of ototoxic drugs.
Hyperbilirubinemia The risk of hearing loss is greatest in neonates with

hyperbilirubinemia above the threshold for exchange
transfusion.
Infection (eg, SNHL occurs early in the course of bacterial meningitis, with
bacterial meningitis) possible recovery or worsening during the first two weeks of
illness.
Follow-up hearing assessment is important.
Ototoxic drugs Examples of ototoxic drugs include aminoglycosides, high-dose

loop diuretics, certain chemotherapeutic agents (eg, cisplatin),
salicylates, and antimalarial drugs (eg, quinine and chloroquine).
SNHL associated with many of these drugs is permanent.
Noise exposure Can occur over time with constant or repeated exposure to loud
noise (eg, using a personal listening device at high volume for
an extended period of the day) or following a short blast of very
loud noise (eg, >150 dB).
Initially presents as high-frequency hearing loss but can
progress to involve more frequencies.
Trauma (eg, Trauma to the temporal bone can cause SNHL or mixed hearing
temporal bone loss.
fracture)
Tumor (eg, vestibular Vestibular schwannoma (also called acoustic neuroma) occurs
schwannoma) most commonly in children with neurofibromatosis type 2.
Symptoms and signs include tinnitus, disequilibrium, dizziness,
headaches, facial hyperesthesia, facial muscular twitching, and
facial paresis/paralysis.
Heavy metals Lead poisoning can cause high frequency SNHL.

Cadmium, mercury, and arsenic also may have toxic effects on
cochlear cells.
Central auditory disorders
Cortical deafness Associated with brain injury or disease. The abnormality may be
due to global brain injury or lesions in areas involved in auditory
neural processing, from the cochlear nucleus of the brainstem
to the primary auditory complex in the temporal lobe of the
brain.
Central auditory Refers to inefficient and/or ineffective processing and utilization

processing disorder of auditory information by the central nervous system.

Patients have normal hearing sensitivity, yet have difficulty

interpreting sounds in complex situations (eg, speech or with
background noise).
The diagnosis cannot be made with audiologic testing alone and
usually requires a battery of behavioral tests.
CHARGE: coloboma, heart defects, choanal atresia, growth and/or developmental retardation,
urogenital abnormalities, ear abnormalities and deafness; dB: decibel; SNHL: sensorineural
hearing loss; CMV: cytomegalovirus; TORCH: toxoplasmosis, other, rubella, cytomegalovirus,
herpes simplex virus; CT: computed tomography; MRI: magnetic resonance imaging.
* The lists of hereditary hearing loss syndromes and syndromes associated with ear
malformations provided in this table are incomplete. Some of the more common examples are
listed here. For more details, refer to separate UpToDate content on the etiology of hearing loss
in children and congenital anomalies of the ear.

Pediatric disorders associated with cataracts
Ocular conditions and syndromes Dermatologic syndromes
Aniridia Ectodermal dysplasia

Persistent fetal vasculature Incontinentia pigmenti
Retinopathy of prematurity Rothmund-Thomson syndrome
Uveitis Werner syndrome
Congenital ichthyosis
Craniofacial syndromes Renal syndromes
Apert syndrome Alport syndrome

Crouzon syndrome Lowe syndrome
Hallermann-Streiff syndrome
Smith-Lemli-Opitz syndrome
Metabolic disease Central nervous system and neuromuscular

syndromes
Cerebrotendinous xanthomatosis Marinesco-Sjogren syndrome

Fabry disease Myotonic dystrophy
Galactosemia Neurofibromatosis type 2
Mannosidosis Walker-Warburg syndrome
Refsum disease
Zellweger syndrome
Endocrine disease Multisystem genetic syndromes
Diabetes mellitus Bardet-Biedl syndrome

Hypoparathyroidism Cockayne syndrome
Infantile hypoglycemia (ie, maternal Marshall syndrome
diabetes) Meckel-Gruber syndrome
Nail-patella syndrome
Norrie disease
Oculodentodigital dysplasia
Progeria
Rubinstein-Taybi syndrome
Skeletal syndromes Chromosomal anomalies
Chondrodysplasia punctata (Conradi- Down syndrome (trisomy 21)

Hünermann syndrome) Edward syndrome (trisomy 18)
Stickler syndrome Patau syndrome (trisomy 13)
Wolf-Hirschhorn syndrome (4p-syndrome)
Turner syndrome
Cri du chat syndrome (5p-syndrome)
Intrauterine infection

Cytomegalovirus
Herpes simplex and varicella
Rubella
Syphilis
Toxoplasmosis
Numerous diseases and genetic syndromes are associated with cataracts. This table represents a
partial list of the conditions most commonly associated with cataracts in childhood.

Contributor Disclosures
Antonio C Arrieta, MD, FIDSA No relevant financial relationship(s) with ineligible companies to
disclose. Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer [Group B
Streptococcus].
Other Financial Interest: Texas State University personal services agreement [Chagas
disease].
All of the relevant financial relationships listed have been mitigated. Leonard E Weisman,
MD Equity Ownership/Stock Options: Vax-Immune [Ureaplasma diagnosis, vaccines, antibodies, other
medical diagnostics and pre-analytical devices].
Patent Holder: Baylor College of Medicine [Ureaplasma
diagnosis, vaccines, antibodies, process for preparing biological samples].
All of the relevant financial
relationships listed have been mitigated. Carrie Armsby, MD, MPH No relevant financial
relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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7/28/22, 12:36 PM Congenital rubella - UpToDate

Official reprint from UpToDate®

● Congenital rubella syndrome (CRS) –CRS is a subcategory of CRI that refers to

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 1/42

Maternal-fetal transmission of rubella virus occurs via hematogenous spread during

There are two proposed mechanisms for rubella cytopathology:

● Virus-induced inhibition of cell division – Support for virus-induced inhibition of cell

● Direct cytopathic effects – Support for direct cytopathic effects is provided by an in

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 2/42

selective organ damage in congenital rubella syndrome (CRS). Subsequent studies

● Humoral response – During the first 16 to 20 weeks of gestation, only 5 to 10 percent

Some patients with CRI have a relative hypergammaglobulinemia (particularly of IgM

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 3/42

● Cellular response – Defects in cell-mediated immunity and persistent T cell

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Early manifestations may include ( table 2) [12,21,48,57]:

● Central nervous system (CNS) involvement – CNS abnormalities may include

● Congenital heart disease – Approximately one-half of children infected in early

● Other – Other findings that can be seen in the newborn include:

• Petechiae and purpura ("blueberry muffin lesions") ( picture 3)

Late manifestations — Delayed manifestations occur in at least 20 percent of children with

● Endocrine disorders – Late manifestations of intrauterine rubella infection may

Thyroid dysfunction affects approximately 5 percent of patients with CRS. It manifests

"Acquired hypothyroidism in childhood and adolescence" and 'Immunologic response'

● Eye problems – Late-onset ophthalmologic manifestations of CRS may include

● Vascular disease – Vascular sequelae of CRS may include fibromuscular proliferation of

● Panencephalitis – Progressive rubella panencephalitis most commonly occurs in the

● Immune defects – Defects in specific antibody production, repeated infections, and

Clinical suspicion — The possibility of congenital rubella infection (CRI) should be

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 7/42

Testing — The evaluation of a newborn with suspected CRI or CRS includes [1,24]:

● Review of maternal history to confirm documentation of rubella immunity

● Complete blood count

● Liver enzymes and bilirubin (total and direct)

● Radiographs of long bones

● Neuroimaging (eg, ultrasonography, computed tomography) [86]

● Rubella serology (see 'Serology' below)

Laboratory confirmation — Laboratory confirmation of congenital rubella infection (CRI)

● Demonstration of rubella-specific IgM antibodies (see 'Serology' below)

● Demonstration of rubella-specific IgG antibodies that persist at a higher concentration

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 8/42

● Isolation of rubella in viral culture from a nasopharyngeal swab, blood sample

Retrospective diagnosis — It is difficult to establish a diagnosis of CRI in children older than

● Measuring lymphocyte response to rubella in vitro [32,90,91]

● Measuring rubella IgG avidity (strength of antigen-antibody binding); children with

● Measuring antibody response to rubella vaccination (in children with compatible

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&us… 9/42

Laboratory tests for diagnosis

Serology — Serologic confirmation of CRI consists of demonstration of rubella-specific IgM

● Rubella-specific IgM antibody – Detection of rubella-specific IgM antibody in the

● Rubella-specific IgG antibody – Monitoring rubella-specific IgG over time (eg, at 3, 6,

https://www.uptodate.com/contents/congenital-rubella/print?search=congenital rubella syndrome&source=search_result&selectedTitle=1~46&u… 10/42

● Congenital toxoplasmosis (see "Congenital toxoplasmosis: Clinical features and

● Congenital cytomegalovirus (see "Congenital cytomegalovirus infection: Clinical

● Congenital syphilis (see "Congenital syphilis: Clinical features and diagnosis")

● Congenital lymphocytic choriomeningitis virus (see "Viral meningitis in children:

No role for antiviral therapy — The clinical course of intrauterine CRI or subsequent

Management of complications — Most infants with CRS have multiple medical problems