Congenital rubella

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 — Rubella virus is an important cause of vaccine-preventable birth defects and can cause epidemics. 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'.)

CRS is rare in countries with established rubella immunization programs [2-5]. A single dose of rubella-containing vaccine (RCV) can provide lifelong protection against rubella. (See "Measles, mumps, and rubella immunization in infants, children, and adolescents".)

As of 2015, rubella has been eliminated from the entire Americas region [5,6]. In the United States, 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 [7].

In other parts of the world, rubella control is accelerating through widespread implementation of vaccine programs. Among the 194 World Health Organization member states, the number with RCV in their routine immunization schedules increased from 132 (68 percent) in 2012 to 173 (89 percent) in 2020. In 2020, 70 percent of the world's infants were vaccinated against rubella [5]. (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 [8-11]. 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 [12,13]. 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 [14], mitotic activity is depressed in congenitally infected embryonic primary cell cultures [10], cell division is slowed in human fetal cells and BHK-21 cells that have been infected with rubella virus in vitro [15-17], and a protein extracted from rubella virus-infected human fetal cells inhibits mitosis in uninfected cells [18].

●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 [19]. 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 [20,21].

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 [22-24].

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 [25].

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 [26]. 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 [26]; in 10 to 20 percent of patients, they may become undetectable [27-30].

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 chronic infection [31]. There are few case reports of hypogammaglobulinemia following intrauterine rubella infection, which usually affects only IgA but may involve IgG, IgM, and IgA [31,32]. Alternatively, IgG may be decreased and IgM increased (two to three times normal adult levels) with or without abnormalities in IgA [31].

●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 [28,33]. 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 [24,34].

●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 [23,35-38]. 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 type 1 diabetes mellitus 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 [39-41]. 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 [39,40,42-45]. (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) [1,46].

Deafness, cataracts (picture 1), and cardiac disease are the classic manifestations of congenital rubella syndrome (CRS) [47,48]. However, rubella virus may infect virtually every fetal organ [31]. 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 [12,27,49]. Little, if any, risk of congenital defects is associated with infection after 18 to 20 weeks gestation [12,50]; fetal growth restriction may be the only sequela of third-trimester infection [27,51-53]. (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) [54-57]. However, severe symptomatic neonatal infection can occur.

Early manifestations may include (table 2) [13,22,49,58,59]:

●Fetal growth restriction – (See "Fetal growth restriction (FGR) and small for gestational age (SGA) newborns".)

●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 [13,31].

●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 [60]. Other reported lesions include pulmonary valvular stenosis, aortic stenosis, ventricular septal defect, tetralogy of Fallot, and coarctation of the aorta [46,60]. Stenosis of other vessels may be related to coronary, cerebral, renal, and peripheral vascular disease during adulthood [61,62]. (See "Patent ductus arteriosus (PDA) in term infants, children, and adults: Clinical manifestations and diagnosis" and "Valvar aortic stenosis in children" and "Tetralogy of Fallot (TOF): Pathophysiology, clinical features, and diagnosis".)

●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 [13,31]. (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 [31]. 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) [13].

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 [54]. 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 [31].

Late manifestations — Delayed manifestations occur in at least 20 percent of children with CRS [61]. Some of the late manifestations may relate to subtle damage that is present but not detected in early life. Late manifestations include [61]:

●Hearing loss – Permanent hearing loss is the most common late manifestation of CRI, ultimately occurring in up to 80 percent of patients [31,58]. 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 [63,64].

●Endocrine disorders – Late manifestations of intrauterine rubella infection may include diabetes, thyroid disease, and growth hormone deficiency [61].

In the available case series, approximately 1 percent of individuals with CRS developed diabetes in childhood and adolescence [41,65-67]. 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) [55]. (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 [68-72]. 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 [73]. (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 [58,61,74,75]. This damage can appear years or even decades after birth [46].

●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 [61,62]. 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 [76,77]. 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 [78,79].

●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 [49,80-84].

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 [77,80,85,86].

EVALUATION

Clinical suspicion — The possibility of congenital rubella infection (CRI) should be considered in [1,87]:

●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 born in a region where rubella is endemic who has fetal growth restriction or other clinical manifestations suggestive of congenital rubella syndrome (CRS) (table 2)

Components of the evaluation — The evaluation of a newborn with suspected CRI or CRS includes [1,25]:

●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

●Echocardiography

●Radiographs of long bones

●Ophthalmologic evaluation

●Audiologic evaluation

●Neuroimaging (eg, ultrasonography, computed tomography) [88]

●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) [89]:

●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 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 [90]. This is because the patient will have received rubella vaccine by this age and would be expected to have detectable IgG. Other viral detection tests generally have very low yield after 12 months. (See '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 after birth [1,91]. Infants with clinical findings of CRS who test negative soon after birth should be retested later in infancy. Approximately 20 percent of infected infants tested for rubella IgM may not have detectable titers before age one month.

Measurement of rubella-specific IgG is most helpful in infants between 6 and 12 months of age [1,49].

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 (CDC) 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) [89,92].

Retrospective diagnosis — It is difficult to establish a diagnosis of CRI in children older than one year of age [25,90]. At this age, serologic testing is not diagnostic after rubella immunization 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 [33,93,94]

●Measuring rubella IgG avidity (strength of antigen-antibody binding); children with intrauterine rubella infection have low rubella-specific IgG avidity [22,25,95-98]

●Measuring antibody response to rubella vaccination (in children with compatible manifestations but nondetectable antibody); children with CRS generally do not respond to rubella vaccination [22,24,28,33,34] (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 intrauterine transfer of maternal antibody [87,89]. 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 [22,31,87]. 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 [87]. 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 [90].

●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 than would be expected for maternal IgG [87,89]. 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 [25,31,87]. (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) [25,87]. In questionable cases, assessment of IgG rubella antibody avidity (available at specialized laboratories or at the CDC) may be helpful [95,96]. (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 [31,87]. Specialized testing is necessary for rubella virus, so laboratory personnel should be notified that rubella virus is suspected [90].

Virus isolation should be attempted as soon as congenital rubella is suspected because viral excretion wanes during infancy [31]. Isolation of rubella virus may be possible for several years from lens tissue in children with cataracts or cerebrospinal fluid in children with encephalitis [77,85].

Polymerase chain reaction — Detection of rubella virus RNA by PCR also confirms CRI [87,89,90] but may not be available in all settings [1]. PCR may be performed on pharyngeal swabs, respiratory secretions, cerebrospinal fluid, amniotic fluid, products of conception, urine, and lens tissue (in children with ocular anomalies), and other tissue specimens [22,90,99-101].

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 manifestations, evaluation, and diagnosis", section on 'Evaluation and diagnosis')

●Congenital Zika virus infection (see "Zika virus infection: Evaluation and management of pregnant patients", 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 [31,32,102,103], 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 [31]. 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 [104]:

●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 [60]. (See "Identifying newborns with critical congenital heart disease" and "Patent ductus arteriosus (PDA) in term infants, children, and adults: Management" and "Pulmonic stenosis in infants and children: Management and outcome".)

●Endocrine abnormalities – The late-onset endocrine abnormalities (eg, diabetes mellitus [DM], thyroid dysfunction) should be managed by an endocrinologist. Parents/caregivers should be counselled about the risk of type 1 DM, including signs to watch for (eg, polyuria, polydipsia, weight loss) to promote early detection of this complication and avoid development of diabetic ketoacidosis. (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 "Respiratory distress syndrome (RDS) in preterm infants: Management", section on 'Clinical approach'.)

●Neonatal hyperbilirubinemia – CRS is associated with direct (conjugated) hyperbilirubinemia that is rarely severe and generally does not require any specific therapy [104]. If the infant has concomitant unconjugated hyperbilirubinemia that requires treatment with phototherapy, there is a risk of developing bronze baby syndrome from the conjugated component. Phototherapy should generally be avoided if the infant has predominantly conjugated bilirubin (ie, if the direct [conjugated] component makes up >50 percent of the total bilirubin level). This is discussed in detail separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management", section on 'Adverse effects'.)

Surveillance and long-term follow-up — Patients with CRI require lifelong follow-up care and surveillance. Clinical manifestations of CRS typically develop or worsen 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 [27,50,55-57,105].

Infants with CRI require close monitoring during the first 6 to 12 months of life, particularly for hearing impairment and developmental abnormalities [31,104]. 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 [1,104].

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]) [104,106,107]. (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 [104]. (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 CRS-related congenital heart disease 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 parents/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 [104]. 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 [13].

●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 [55-57]:

•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 10^th percentile for weight and/or height; at 50 years, 6 of 40 patients (15 percent) were below the 3^rd 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 individuals, 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 [108]. 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 [104]. Droplet precautions should be instituted for hospitalized patients as soon as CRS/CRI is suspected [31]. Only individuals known to be rubella immune should care for contagious or potentially contagious patients [109].

No special precautions are necessary for vaccinated household contacts of infants with congenital rubella syndrome (CRS/CRI) [104]. 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 [87,110]. 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) [87].

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 (CDC) through local and state health departments [87,89]. These cases should be reported as soon as they are suspected, even if laboratory confirmation is pending. Cases of CRI/CRS may indicate the presence of rubella infections in the community that may previously have been unrecognized and should trigger intensified surveillance for rubella and CRS [87]. 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 endemic [111,112].

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 5^th to 6^th 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 10^th to 12^th 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

●Spectrum of congenital rubella infection – 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.)

●Epidemiology – CRI is rare in 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'.)

●Clinical features of CRS – 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.)

●Evaluation – The evaluation of an infant with suspected CRI or CRS includes (see 'Components of the evaluation' 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 – 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)

●Case definition – The case definitions for CRI and CRS used by the Centers for Disease Control and Prevention are 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.)

●Differential diagnosis – 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.)

●Management – 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.)

●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 early in infancy but may worsen during the first several years of life. Other manifestations may present later in childhood, adolescence, or adulthood. (See 'Surveillance and long-term follow-up' above.)

●Prevention – 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.