Neuroimmunology
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Congenital rubella …
- Updated 01.30.2024
- Released 08.10.1993
- Expires For CME 01.30.2027
Congenital rubella
Introduction
Overview
Congenital rubella infection classically causes a severe syndrome with multi-organ manifestations encompassing visual, hearing, and neurologic disabilities; it may, however, also present with more subtle findings that can lead to significant diagnostic delays if the treating physician is not familiar with the consequences of maternal rubella infection. Although widespread vaccination programs have significantly reduced the global burden of rubella, rubella persists as an important pathogen that remains endemic in many regions of the world, and its varied presentation requires vigilance on behalf of health providers.
Key points
• Rubella infection rates and risk of congenital rubella syndrome are highest during the first trimester of pregnancy and during primary infection of the pregnant mother. | |
• Because the virus may persist for up to 1 year of age, pregnant women should not handle or expose themselves to congenitally infected infants. | |
• Despite high vaccine coverage, rubella infection persists in unimmunized groups, those with low seroconversion status, or as a result of reinfection. |
Historical note and terminology
In the mid-18th century, rubella (German measles) was termed "Rötheln" and was considered to be a lesser form of measles or scarlet fever, as symptoms and the associated exanthematous rash were less severe (33). By the 19th century, Rötheln was formally recognized as a distinct infection and renamed "rubella," derived from Latin meaning “little red.” An Australian ophthalmologist was the first to note cataracts and heart disease in newborn children of mothers infected during pregnancy (10). Subsequent studies confirmed rubella's teratogenic potential. The viral etiology of rubella was established in 1962 (24; 32). Diagnostic serologic tests soon followed, and by 1969 live attenuated vaccines were licensed for use.
Clinical manifestations
Presentation and course
Postnatal (acquired) rubella infection. Rubella infection in adults and children is usually a mild febrile illness associated with variable degrees of malaise, pharyngitis, upper respiratory symptoms, and regional lymphadenopathy (with postauricular, suboccipital, and posterior cervical lymph nodes typically involved). Rubella is transmitted by respiratory droplets, and local replication in regional lymphoid tissues occurs prior to viremia. Prodromal symptoms typically last a few days prior to development of the rash, and fever generally abates once the rash has appeared. The rash is classically a macular erythematous exanthem, which typically starts over the face and is most prominent over the neck and trunk. Although individuals with rubella are most infectious when the rash is appearing, virus can be shed from 7 days before to 5 to 7 days after the onset of the rash; thus, the overall period of infectivity lasts approximately 2 weeks.
With primary infection, older age is typically associated with more severe symptomatology in the acute phase of the illness. Many infections in younger children, however, may be entirely asymptomatic: an estimated 20% to 50% of infections are asymptomatic. Although acquired postnatal rubella is typically self-limited and without sequelae, the most common complication of acquired rubella infection is arthralgia, which can occasionally present as overt arthritis. Post-rubella arthralgia is described more commonly in women and is typically self-limited, occurring from the time of rash and lasting up to 3 weeks. Encephalitis is a rare but serious complication of rubella infection and is estimated to occur in 1 per 5000 to 6000 rubella cases (27). Encephalitis generally presents within a week of the rash, though confirmed cases exist wherein no rash was reported. Presenting symptoms of rubella encephalitis are nonspecific, including fever, headache, vomiting, altered mental state, and seizures. Focal neurologic signs are uncommon. Cerebrospinal fluid (CSF) shows a mild to moderate lymphocytic pleocytosis with normal glucose and moderately elevated total protein. EEG typically shows nonspecific generalized slowing. Brain MRI shows focal cortical or diffuse T2 hyperintensity, the latter finding typically seen with diffuse cerebral edema. The clinical course is generally brief, lasting days, and in the current era, outcomes are favorable in spite of a reported fatality rate of 0% to 20%.
Congenital rubella syndrome. The most serious consequence of rubella infection is congenital rubella syndrome affecting the fetus as a result of the acute infection of a pregnant woman. Congenital rubella syndrome is a complex entity as the timing of maternal infection is paramount in considering risk to the fetus (see prognosis and complications). Congenital rubella syndrome may variably involve multiple organ systems and may present with both transient and permanent deficits. Further complicating the protean manifestations of congenital rubella syndrome is that some conditions associated with it may not be recognized until later in life, even in adulthood.
The most common neonatal manifestations of congenital rubella syndrome include sensorineural hearing loss, dermal erythropoiesis ("blueberry muffin syndrome"), hepatosplenomegaly, thrombocytopenia, and low birth weight (30). The most common complication overall is sensorineural hearing loss, which is typically bilateral. Other common complications include cardiovascular anomalies and ophthalmological problems. In the cardiovascular system, patent ductus arteriosus and pulmonary artery stenosis are most common. Other cardiac complications include atrial and ventricular septal defect, as well as myocarditis. Ocular manifestations include microphthalmia, nuclear cataracts (often unilateral), and pigmentary retinopathy (often asymptomatic) (04). The most common ocular finding is pigmentary retinopathy. The cataracts and pigmentary retinopathy may progress after birth; however, cataracts may not progress and resolve spontaneously.
Cataracts and heart disease typically result from maternal infection in the first 8 weeks of pregnancy when the fetal eyes and heart are being formed. Deafness, retinopathy, and neurologic damage generally occur with infection in the first 17 weeks. Multiple defects are common when infection occurs in the first 8 weeks, but unusual after that.
Nervous system abnormalities outside of sensorineural hearing loss include intellectual disability, behavioral and language disturbances, microcephaly, and meningoencephalitis. It is important to recognize that congenital rubella has been associated with childhood autism and affective disorders (01; 29). Cerebral calcifications are rare, though when present, they tend to be periventricular. Generally, children with intellectual disability from congenital rubella have concomitant hearing and visual abnormalities.
Other manifestations of congenital rubella syndrome include short stature, transient hemolytic anemia or thrombocytopenia with or without purpura, metaphyseal "celery stalking" changes in long bones, jaundice or hepatitis, transient pneumonitis, transient generalized lymphadenopathy, cryptorchidism, inguinal hernia, and dermatoglyphic abnormalities.
More than half of infected children with congenital rubella syndrome may be asymptomatic at birth but develop sequelae over the following years. Late-onset hearing loss has been reported up to 10 years of age. Active intraocular infection has been described in the third decade of life, emphasizing the virus may persist for decades (34). About 20% of congenital rubella patients develop type I diabetes mellitus as late as 33 years of age. These patients show an increased frequency of certain HLA haplotypes and autoantibodies, similar to other insulin-dependent diabetics. Thyroid problems, early menopause, osteoporosis, and precocious puberty have been reported, but their relationship to rubella has been questioned (03).
Rare cases of progressive rubella panencephalitis resulting from the persistent rubella infection have been described, following both congenital rubella as well as childhood postnatal rubella (35). Presenting symptoms typically begin in the second decade of life and include progressive cognitive impairment with seizures and cerebellar dysfunction, evolving over years to include upper motor neuron findings, progressive dementia, and ophthalmoplegia. The absence of myoclonus and the presence of cerebellar signs help distinguish this syndrome clinically from subacute sclerosing panencephalitis from measles.
Prognosis and complications
Fetal risk associated with maternal rubella infection is predicted by the immune status of the mother and the timing of maternal infection. Maternal infection just before conception carries negligible risk (05). Maternal reinfection or asymptomatic infections pose a lesser threat to the fetus than does a first symptomatic infection (21). Fetal infection rates in asymptomatic maternal infection are 0% to 19%, with fetal defects in only 0% to 4%. For comparison, maternal reinfection during the first trimester results in fetal infection in only 5% to 8% of cases, most of which are subclinical (04).
Highest risk to the fetus is associated with a primary symptomatic maternal infection, and prognosis for the neonate depends not only on the timing of the infection but also the extent of fetal infection and injury. Congenital rubella infection in the first trimester of pregnancy may result in miscarriage (spontaneous abortion rate of 4% to 5%), fetal death (stillborn rate of 1% to 2%), premature delivery, or congenital anomalies. Up to 90% of infants born to mothers who are infected during the first 11 weeks of gestation will develop congenital rubella syndrome (18). Rates of anomalies are 60% for maternal infection at 11 to 16 weeks, 6% with maternal infection at 17 to 30 weeks, and 0% with maternal infection after 30 weeks. Thus, infections later in pregnancy are rarely associated with congenital rubella syndrome after the 16th week, though deafness may occur with infection up to week 20 (11). Serious permanent sequelae of congenital rubella syndrome occur in about 50% of children infected during the first month of pregnancy but is much lower in later infections. The mortality rate in the first year of life is 10% to 20% and typically impacts only the most severely affected infants. With later onset of infection, growth retardation during preschool years, small head circumference, hearing loss, and cataracts can be the only findings. Congenital rubella is probably underdiagnosed, especially among affected children who have sensorineural hearing loss as the only deficit.
The presence of delayed manifestations of congenital rubella syndrome underscores the importance of careful follow-up of these patients; an altered immune system presumably allows complications to take place later in life. About 5% have some form of thyroid disease starting in their teenage years, 20% have diabetes by the age of 35 (susceptibility to this complication varies between populations, higher in Caucasians and in individuals with the HLA A1-B8 haplotype), and progressive rubella panencephalitis is a rare but ultimately fatal delayed manifestation of congenital rubella syndrome.
Clinical vignette
A 33-year-old female from South Asia in her third trimester of pregnancy presented to a United States hospital in labor. After a spontaneous vaginal delivery, the infant was found to have microcephaly with low birth weight, a systolic murmur, and no response to auditory stimuli. The liver and spleen were palpable, and laboratory evaluation was significant for elevated transaminases. Cerebrospinal fluid was normal. Echocardiography confirmed patent ductus arteriosus and pulmonary artery stenosis, and auditory testing revealed severe hearing impairment. His mother described a flu-like disorder with arthralgia of small joints early in the second trimester of pregnancy and had received limited prenatal care. Although she had documentation of vaccinations, review of WHO data indicated that her home country did not support a rubella vaccination program. Among serological tests, rubella IgM was highly positive, and reverse transcriptase polymerase chain reaction of nasopharyngeal secretions was also positive for rubella virus. The child was placed in contact isolation with droplet precautions. Avidity testing confirmed high IgG avidity, suggesting rubella infection had occurred during gestation. Upon discharge, caregivers and potential close contacts were educated about precautions to prevent transmission and close follow up was arranged with multiple specialties. Liver enzymes returned to normal over 4 months. Nasopharyngeal specimens were collected every 3 months until virus was no longer detected by PCR. The child engaged in physical and educational treatment programs and was being followed up for late manifestations of congenital rubella syndrome.
Biological basis
Etiology and pathogenesis
Rubella virus is an enveloped single-stranded RNA virus of the Rubivirus genus of the togavirus family. Humans are the only known host. The virion is small and spherical, measuring approximately 60 nm in diameter. The genome is less than 10 Kb and encodes 3 structural proteins as well as 2 nonstructural proteins involved with replication and transcription (06). The E1 structural protein is important for receptor binding and induction of membrane fusion. Rubella virus demonstrates wide cell tropism, enters cells through receptor-mediated endocytosis, and replicates in cell endosomes. The host receptor for the virus is not known.
The rubella virus invades cells of the upper respiratory tract though receptor-mediated endocytosis after transmission by infected aerosol droplets. The virus replicates locally in lymphoid tissues prior to hematogenous spread to other organ systems. When viremia occurs in a pregnant woman, the virus may seed the placenta and become disseminated in the fetus, where it produces a chronic infection. As previously discussed, rubella may be recovered for several months to years when a child is infected in utero.
Fetal infection can occur at any time during pregnancy; the virus infects the placenta, crosses into the fetus, and particularly in the first 12 weeks of fetal life, affects the development of fetal cells and organs. Infection rates and the risk of congenital rubella syndrome are highest during the first trimester. Maternal IgG does not transfer efficiently in the first trimester, during which time fetal blood levels of IgG are only 5% to 10% of maternal levels. Maternal IgG protects the fetus from anomalies in the second and third trimesters. The fetus produces its own antibodies in late pregnancy when levels may exceed those in maternal serum.
The exact pathogenesis of congenital rubella syndrome is not completely understood (07). Humans are the only known host and no animal models exist. As such, data describing pathogenesis have mostly come from human studies. Hypothesized mechanisms for disease include necrosis of capillary endothelium and obstructive vasculopathy or apoptosis of certain cell populations with inhibition of dividing precursor cells involved in organogenesis, with susceptibility varying amongst different embryonic cell types. Endothelial damage, thrombosis of small vessels, and spreading of virus-infected emboli may result in small, scattered focal infections within hypoplastic tissues. Autoimmune reaction, immune complex deposition, or cellular immune defects are other possible mechanisms of damage. Late-onset manifestations may result from viral persistence, autoimmune response, and immune-mediated tissue destruction.
Data from 3 near-term fatal cases of congenital rubella syndrome from the Romanian outbreak in 2011 to 2012 describe the finding of viral antigens in myocardial fibroblasts as well as adventitial fibroblasts of large blood vessels, without evidence of virus in cardiac myocytes or frank myocarditis (16). These data suggest that cardiac anomalies observed in congenital rubella syndrome may stem from infection of cardiac fibroblasts, which are essential to normal cardiac development. The authors additionally identified rubella antigen in the brain, specifically localized to progenitor cells of the granular layer, which are multipotent neural stem cells that serve as precursors to important glial and neuronal cell lines; abnormalities of these cells may result in microcephaly and cognitive impairment. Other data from aborted fetuses with cataracts in the first and second trimesters from the 2011 to 2012 Vietnam epidemic showed evidence for viral infection of epithelial cells in the ciliary body, suggesting a potentially important mechanism contributing to the common development of cataracts (20). This report described evidence of more diffuse viral spread to multiple organ systems through mononuclear cells, as well as significant hepatic inflammation and necrosis. Differences between these 2 studies likely represent different pathology at different stages of disease.
Epidemiology
Rubella virus remains a significant viral pathogen worldwide with an estimated global burden of 100,000 cases of congenital rubella syndrome annually (15). At the current time it is estimated that 9.4% of pregnant women are seronegative and, thus, remain susceptible to infection (23). In the pre-vaccine era, outbreaks in temperate climates typically occurred during late winter and spring, and infection was most common in young children between 5 to 9 years of age. Larger epidemics occurred every 6 to 9 years, with major pandemics at 10- to 30-year intervals.
The last major outbreak in the United States occurred during the 1962 to 1965 pandemic, at which time an estimated 12 million people were infected with an estimated 10,000 fetal and 2000 neonatal deaths, and 20,000 cases of congenital rubella syndrome (25). With the introduction of a live attenuated vaccine in 1969 and effective vaccination programs, the number of rubella infections has dramatically decreased. In the Americas, endemic transmission has not been detected since 2009; however, rubella remains endemic in multiple nations without vaccination programs, and as of 2018, 13% of countries were not providing rubella vaccine (09). Although the incidence of congenital rubella syndrome is estimated to be less than 0.01 per 100,000 live births in regions with comprehensive vaccination programs, the incidence in African and South Asian regions (which do not have vaccination programs) is as high as 18 to 309 per 100,000 live births (31).
Outbreaks have highlighted the importance of offering broad vaccine coverage to susceptible populations. In 2012 to 2013, an outbreak affecting Japan stressed the importance of complete vaccination coverage, as the majority of cases were identified in men aged 20 to 39 years who were not immunized in a program that focused on immunization of adolescent girls (28). Countries with high vaccine coverage may still witness rubella outbreaks originating from individuals who refuse to participate in vaccination programs as well as unvaccinated indigenous populations (12).
Prevention
Prevention of congenital rubella depends on achieving and maintaining high immunization levels, accurate surveillance of acquired and congenital rubella cases, and effective outbreak control (22). Congenital rubella syndrome is preventable by immunization; at least 95% of vaccinees develop detectable antibodies that persist at least 17 years, but seropositivity may decline thereafter. As rubella virus circulates in many parts of the world, it is necessary to maintain vaccine coverage levels over 95%. Supplementary catch-up programs are also needed because seropositivity and, thus, immunity may wane over time, resulting in the accumulation of a susceptible population of young adults. The World Health Organization emphasizes the value of rubella vaccination when opportunities arise (ie, supplementary immunization for all rubella-susceptible children, adolescents, and women of childbearing age).
Rubella is available as either a monovalent vaccine or in combination with other vaccines, including measles, mumps, or varicella. It is important to recognize that the risk of autism from the measles mumps rubella vaccine has not been substantiated. In the United States, a first dose is recommended at 12 to 15 months of age, with a second dose at 4 to 6 years of age (before kindergarten or first grade). Viremia is a potential complication of vaccination, and women are cautioned to avoid pregnancy for at least 28 days after receiving the rubella vaccine.
Despite high vaccine coverage, rubella infection and congenital rubella syndrome exist in the United States due to communities that remain unvaccinated, immigrant groups, individuals who do not seroconvert after immunization, and reinfection. Rubella virus antibody screening should be included in prenatal care; detectable antibodies provide evidence of immunity. Vaccinated women should be instructed not to become pregnant for 1 month after vaccination, though the actual risk of congenital rubella syndrome is recognized to be very low for the offspring of women who inadvertently received rubella vaccine while pregnant (17). Although rubella vaccine is contraindicated during pregnancy, an inadvertent vaccination of a pregnant woman does not warrant termination or prenatal diagnosis because miscarriages are rare, and no data suggest that vaccination can cause congenital rubella syndrome (19).
Contact with women of childbearing age with infected infants should be avoided because of excreted virus in urine, saliva, and tears for many months.
Differential diagnosis
The differential diagnosis of congenital rubella includes other causes of congenital infection (cytomegalovirus, toxoplasmosis, herpes simplex, varicella zoster, syphilis, parvovirus, human immunodeficiency virus, enteroviruses, zika), as well as noninfectious processes (neonatal hyperthyroidism, tuberous sclerosis, incontinentia pigmenti, Aicardi syndrome, hereditary congenital cataract with hypertrophic cardiomyopathy).
The differential diagnosis of postpartum rubella includes other infections that can produce exanthems (scarlet fever, measles, infectious mononucleosis, toxoplasmosis, roseola, parvovirus, and certain enteroviral infections) as well as allergic exanthems.
Diagnostic workup
Maternal rubella is frequently asymptomatic. When symptoms are present, a history of recent exposure or a typical clinical syndrome is important in the diagnosis; however, it must be recognized that symptoms and signs are nonspecific, and many infections can be minimally symptomatic or asymptomatic. Laboratory confirmation plays an important role in diagnosis. Laboratory testing involves serologic tests showing a significant rise in anti-rubella IgG antibodies using acute and convalescent sera drawn 2 to 3 weeks apart. Antibodies may be measured by enzyme linked immunosorbent assays, latex agglutination, or hemagglutination inhibition assays. Another way to confirm recent maternal infection is to demonstrate maternal anti-rubella IgM antibodies. Antirubella IgM enzyme linked immunosorbent assays are relatively sensitive, but cross reactivity with other viruses, such as parvovirus B19 and Epstein-Barr virus, as well as rheumatoid factor may occur. Capture assays are sensitive tests that measure IgM, which appears within 1 week of infection and lasts 2 months. A single specimen can be obtained 1 to 2 weeks after onset of the rash. Antibody avidity determination or immunoblot techniques have been suggested for differentiation between primary infection and reinfection during pregnancy.
Diagnostic difficulty arises in women tested more than 4 to 6 weeks after contracting rubella infection in early gestation, as IgM disappears and only IgG antibody is detected in serum. In such cases it is recommended to check for IgG avidity in order to confirm recent seroconversion. Avidity reflects the strength of binding between antigen and antibody and increases over time to reflect maturation of the immune response. Low avidity IgG is present for up to 3 months after infection, whereas high avidity IgG is consistent with a more remote infection.
For prenatal diagnosis, a number of potential diagnostic approaches exist: viral culture or reverse transcriptase polymerase chain reaction (RT-PCR) from the amniotic fluid, examination of chorionic villus biopsy for rubella antigen and RNA, and ultrasound-guided cord blood sampling to show specific IgM at 20 to 26 weeks’ gestation. RT-PCR of amniotic fluid has a specificity of 100% and sensitivity between 83% and 95% in diagnosing primary infection during pregnancy (13). PCR results correlate well with anti-rubella IgM/IgG in infants.
With regards to postnatal diagnosis, congenital rubella syndrome should be considered in any neonate with cardiac, ocular, hearing, or CNS deficits. The U.S. Centers for Disease Control has classified congenital rubella syndrome as either confirmed (clinically compatible case with laboratory proof), compatible (cases with 2 major, or 1 major and 1 minor clinical feature), or possible (cases with some clinical features) (02). For surveillance purposes, major clinical features include hearing loss, congenital heart disease, cataracts, congenital glaucoma, and pigmentary retinopathy. Minor clinical features are purpura, splenomegaly, jaundice, microcephaly, mental retardation, meningoencephalitis, and radiolucent bone disease. Laboratory-confirmed diagnosis involves virus isolation, demonstration of rubella-specific IgM antibody, or documentation of stable or increasing antibody levels in an infant.
Postnatally, congenital infection is confirmed by virus culture, serological tests, or RT-PCR. Rubella virus is best isolated from the neonate's pharynx but can also be cultured from conjunctiva, CSF (positive in one third of all patients), urine, feces, leukocytes, nasopharynx, or amniotic fluid. The lens (92%) and oral fluid (60%) specimens are particularly useful for the quantification of viral load (26). The virus may persist for up to 1 year of age and, rarely, until older ages in severely affected infants. Despite improvements in virus isolation and nucleic acid amplification techniques, serology remains the mainstay of diagnosis. Congenital rubella is usually diagnosed by detection of rubella-specific IgM. Although anti-rubella IgM synthesis may not start before 22 weeks’ gestation, it is present at birth and lasts 6 to 12 months. It may be difficult to serologically confirm a diagnosis of congenital rubella in children over 3 months of age. A positive IgM in the infant’s serum or CSF, or in cord blood, is diagnostic; however, false negatives and positives may occur. An alternative approach is to monitor anti-rubella IgG in the infant over time and document rising titers, noting that maternally derived IgG steadily falls and disappears by 12 to 15 months of age. Persistence of IgG at or after 6 months of age is, therefore, supportive of a rubella diagnosis. Specific antibody responses to rubella antigen epitopes may be helpful to determine the timing and outcome of intrauterine rubella infections (08).
Management
There are no specific antiviral therapies for rubella, and prevention of infection through vaccination remains the cornerstone of management. Hyperimmune globulin with high rubella-specific titer has been given to exposed susceptible pregnant women, particularly with symptomatic infection, without proven efficacy. Intravenous immunoglobulin may correct the associated dysgammaglobulinemia (14).
Counseling of pregnant women with confirmed or suspected rubella infection may be difficult because not every infection leads to fetal damage. As previously discussed, risk of fetal damage is most closely associated with the timing of maternal infection, and confirmation of fetal infection does not define the extent of fetal injury. Therapeutic abortion may be performed based on the calculated fetal risk and informed parental choice.
It is important to recognize that newborns with possible congenital rubella are considered contagious and, as such, should be isolated. The diagnosis of congenital infection should be confirmed by virus isolation and serologic studies. Susceptible women should not handle these infants. Because 2% to 20% of infected infants will shed virus for a year or more, it is important to educate caregivers about secondary transmission risks and periodic laboratory surveillance, which is carried out to determine when infants are no longer contagious. Multispecialty care is important to support development and improve clinical outcomes.
Special considerations
Pregnancy
Congenital rubella involves maternal infection during pregnancy. First trimester symptomatic maternal infection carries the greatest risk of fetal damage.
Anesthesia
No complications due to anesthesia have been reported in the literature.
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
William R Tyor MD FAAN
Dr. Tyor of Emory University School of Medicine has no relevant financial relationships to disclose.
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Taylor B Harrison MD
Dr. Harrison of Emory University School of Medicine and Grady Memorial Hospital has no relevant financial relationships to disclose.
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Editor
-
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
See Profile
Former Authors
- Patricia Coyle MD (original author), Banu Anlar MD, Raymond P Roos MD, and Meena Kannan MD
Patient Profile
- Age range of presentation
-
- 0 to 1 month
- Sex preponderance
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- male=female
- Heredity
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- none
- Population groups selectively affected
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- none selectively affected
- Occupation groups selectively affected
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- none selectively affected
ICD & OMIM codes
- ICD-9
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- Congenital rubella: 771.0
- ICD-10
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- Congenital rubella syndrome: P35.0
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