Congenital rubella syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

In 1941, congenital rubella syndrome was recognized as a complication of rubella infection among pregnant women who became infected with the virus early in their pregnancy. An Australian ophthalmologist made the connection and reported 78 cases of congenital cataract among infants born to mothers who had a rubella infection early in their pregnancy. The pathogenesis of congenital rubella syndrome is multifactorial. However, pregnant women who are not vaccinated against rubella are at high risk of contracting the infection. If they get infected during pregnancy, the virus can infect the placenta and spread to the fetus, leading to disruption of the normal process of organogenesis. Rubella virus has largely been eradicated in many parts of the developed world. However, in the developing world where MMR vaccine is not available or accessible, infection with rubella and consequently, congenital rubella syndrome is an important health issue. Many of the congenital infections have overlapping features and hence, congenital rubella must be differentiated from the other TORCH infections. Congenital rubella syndrome affects multiple organ systems. The classic triad consists of cataracts, sensorineural hearing loss and patent ductus arteriosus (PDA).

Originally, rubella was referred to as the third disease, because it was thought to branch from measles or Scarlet fever. However, in 1814, it was recognized as a separate entity of disease and became known as German measles.^[1][2] In 1941, congenital rubella syndrome was recognized as a complication of rubella infection among pregnant women who became infected with the virus early in their pregnancy.^[1][2] An Australian ophthalmologist made the connection and reported 78 cases of congenital cataract among infants born to mothers who had a rubella infection early in their pregnancy.^[1][2]

There is no classification scheme for congenital rubella syndrome. However, in 2009, the CDC published the case classification of congenital rubella syndrome and divided into suspected cases, probable cases, confirmed cases and infection only, based on symptoms and/or laboratory findings.^[3]

The pathogenesis of congenital rubella syndrome is multifactorial. However, pregnant women who are not vaccinated against rubella are at high risk of contracting the infection. If they get infected during pregnancy, the virus can infect the placenta and spread to the fetus, leading to disruption of the normal process of organogenesis. The degree of severity of malformations depends on the gestational age of the onset of infection. The highest risk of fetal anomalies or poor pregnancy outcomes such as spontaneous abortion and stillbirth is highest if a woman becomes infected prior to conception or in the in the first 8-10 weeks of gestation.^{[1][4][5][6][7]}

The cause of congenital rubella syndrome is rubella virus. Rubella virus is a single-stranded, positive-sense RNA virus (ssRNA). It is the only member of the genus Rubivirus and belongs to the family of Togaviridae.

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from CRS.^[8][9]

The exact incidence of congenital rubella syndrome is hard to estimate, because in many parts of the developing world rubella has been eliminated. However, very few cases are still reported in the U.S and they are believed to be imported cases. In addition, rubella infection and congenital rubella syndrome are still a challenge in the developing world, with most cases occurring in Africa and Southeast Asia.^[5][10]In countries without rubella immunization, the incidence is estimated to range between 60-220 per 100,000 cases.^[11]

There is no screening test for congenital rubella syndrome.^[12]

Congenital rubella syndrome can cause serious birth defects and the prognosis depends on the severity of the problem. Heart defects can be corrected but neurological damage is permanent.^{[1][4][13][8][9][5]}

The symptoms of rubella in the pregnant woman are similar to those seen in any child or adult with rubella infection. Of note, young women are more likely to suffer from sequelae of polyarthritis and polyarthralgia. In the infant, symptoms such as irritability, low birth weight, skin lesions, white appearance to the cornea may be seen and be suggestive of congenital rubella syndrome.^{[14][15][16][2][17][1][4][9][18][19]}

Congenital rubella syndrome affects multiple organ systems. The classic triad of congenital rubella syndrome consists of cataracts, sensorineural hearing loss and patent ductus arteriosus (PDA). However, many other findings are evident on physical examination, including low birth weight, skin lesions and hepatosplenomegaly.^{[1][4][9][18][19]}

Prenatal testing consists of direct isolation of the virus, viral nucleic acid quantification or detection of antibodies against rubella in fetal blood via various invasive techniques, such as amniocentesis, fetal blood sampling and chorionic villi sampling.^{[1][20][21][22][23]} Postnatal testing consists of isolation of the virus from throat or urine cultures^[3] and detection of serology (IgG or IgM antibodies against rubella).^{[1][24][25][26][27][28]} Other laboratory findings in infants with congenital rubella syndrome include thrombocytopenia and elevated levels of PT, PTT and bilirubin.^[9]

Electrocardiogram findings in a child of congenital rubella syndrome depends on the type of heart defect (mostly PDA) and its severity.

The chest radiograph may show increased pulmonary vascularity and cardiomegaly due to ventricular enlargement. The heart size might be normal if the shunt is small. However, CXR findings depend on the size and type of associated heart defect.

Congenital rubella syndrome is associated with craniofacial abnormalities, most commonly microcephaly or hydrocephaly. Hence, CT scan is able to assess the underlying brain and the forebrain is usually most affected.^[29] In addition, a multi-detector CT scan (MDCT) is used to detect the various cardiac anomalies associated with congenital rubella syndrome. Findings such as patent ductus arteriosus, its degree of severity as well as other associated cardiac anomalies may be seen.^[30]

Congenital rubella syndrome is associated with craniofacial abnormalities, most commonly microcephaly or hydrocephaly. Hence, MRI is able to assess the underlying brain and the forebrain is usually most affected.^[29]

On echocardiography, the several cardiac anomalies associated with congenital rubella syndrome may be seen. These include patent ductus arteriosus, pulmonary artery stenosis, coarctation of the aorta, as well as septal defects (VSD or ASD).^[18][31] Prenatal ultrasound, although not sensitive, is highly specific in detecting the various anomalies associated with congenital rubella syndrome. Findings such as IUGR, fetal hydrops, microcephaly, cardiac and ophthalmic defects may be seen on ultrasound.^[1][5][32]

There are no other imaging findings associated with congenital rubella syndrome.

There are no other diagnostic studies associated with congenital rubella syndrome.

There is no specific medical treatment for congenital rubella syndrome.^[33]

The role of surgery in patients with congenital rubella syndrome consists of treating the several cardiac^[34], ophthalmic^[35][36] and hearing complications that arise as a result.^{[1][4][9][18][19]}

MMR vaccination prior to pregnancy can prevent congenital rubella syndrome.^[4]

Infants with congenital rubella syndrome should be placed in isolation during their hospital stay. In addition, appropriate measures should be taken to ensure that all healthcare workers and caregivers of the infected child are immune to rubella.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Originally, rubella was referred to as the third disease, because it was thought to branch from measles or Scarlet fever. However, in 1814, it was recognized as a separate entity of disease and became known as German measles.^[1][2] In 1941, congenital rubella syndrome was recognized as a complication of rubella infection among pregnant women who became infected with the virus early in their pregnancy.^[1][2] An Australian ophthalmologist made the connection and reported 78 cases of congenital cataract among infants born to mothers who had a rubella infection early in their pregnancy.^[1][2]

• Originally, rubella was referred to as the third disease, because it was thought to branch from measles or Scarlet fever. However, in 1814, it was recognized as a separate entity of disease and became known as German measles.^[1][2]
• It was not until 1941 that congenital rubella syndrome became recognized as a complication of rubella infection among pregnant women who became infected with the virus early in their pregnancy.^[1][2]
• This connection was made by the Australian ophthalmologist, Norman Gregg, who reported 78 cases of congenital cataract among pregnant women who were infected with rubella virus during the early phases of their pregnancy.^[1][2]
• Rubella virus was first isolated from tissue in 1962.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

There is no classification scheme for congenital rubella syndrome. However, in 2009, the CDC published the case classification of congenital rubella syndrome and divided into suspected cases, probable cases, confirmed cases and infection only, based on symptoms and/or laboratory findings.^[1]

There is no classification scheme for congenital rubella syndrome. However, in 2009, the CDC published the case classification of congenital rubella syndrome and divided into suspected cases, probable cases, confirmed cases and infection only, based on symptoms and/or laboratory findings. For more information on the CDC case classification, click here.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

The pathogenesis of congenital rubella syndrome is multifactorial. However, pregnant women who are not vaccinated against rubella are at high risk of contracting the infection. If they get infected during pregnancy, the virus can infect the placenta and spread to the fetus, leading to disruption of the normal process of organogenesis. The degree of severity of malformations depends on the gestational age of the onset of infection. The highest risk of fetal anomalies or poor pregnancy outcomes such as spontaneous abortion and stillbirth is highest if a woman becomes infected prior to conception or in the in the first 8-10 weeks of gestation.^{[1][2][3][4][5]}

The pathogenesis of congenital rubella syndrome (CRS) is believed to be multifactorial. In an attempt to explain the pathogenesis, the following must be noted:^{[1][2][3][4][5]}

• Pregnant women who are not vaccinated against rubella virus are at risk of contracting the infection. It must be noted however, that not every pregnant woman’s infection results in vertical transmission to her fetus. In addition, not every fetus infected with rubella virus has fetal abnormalities or CRS.
• The typical clinical course of CRS usually begins with a pregnant woman being exposed to the virus via the respiratory route. The virus then infects the placenta and spreads to the fetus. This results in systemic inflammation in the fetus and multiple fetal anomalies, due to disruption of organogenesis.
• Infected cells of the placenta enter the fetal circulation and spread to to various organs, such as the heart, brain, eyes and ears, resulting in thrombosis or ischemic lesions in these organs.
• In rubella-infected human fetal cells, interferons and cytokines are up-regulated. Hence, the immune system is thought to play a role in disrupting the normal differentiation of cells and result in the various congenital defects observed in congenital rubella syndrome.
• The timing of the maternal infection has important implications on the fetus. If the woman is infected just before conception or during the first 8-10 weeks of gestation, severe fetal anomalies are most likely to occur, including stillbirth. However, beyond 16 weeks of gestation, rarely any fetal defects are associated with maternal rubella infection.

• Noninflammatory necrosis is observed in the epithelium of the chorion, as well as in the endothelial cells.^[3]
• Cell mitosis is inhibited as a result of inhibition of actin assembly.^[3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Rubella virus is a single stranded, positive sense RNA virus (ssRNA). It is the only member of the genus Rubivirus and belongs to the family of Togaviridae. Rubella virus is only known to infect humans, and it is responsible for causing the common childhood Rubella infection. Rubella infection is also known as German Measles or Three Day Measles. The most devastating consequence is when Rubella virus infects pregnant women during their first trimester, as it may result in congenital rubella syndrome in the newborn. Rubella infection has largely been eradicated in the developed world since the introduction of the MMR vaccine. However, it is still a challenge in many parts of the developing world due to cost and availability of the MMR vaccine.

The Rubella virus genome is composed of 9762 nucleotides and encodes 2 nonstructural polypeptides (p150 and p90) within its 5′-terminal two-thirds and 3 structural polypeptides (C, E2, and E1) within its 3′-terminal one-third. Both envelope proteins E1 and E2 are glycosylated. The Rubella virus has the highest concentration of G/C nucleotides of any RNA virus, with 69.5% of the genome consisting of those nucleotides. Rubella has been sequenced completely for three strains showing >95% homology between the three strains.

There are three sites that are highly conserved in Togaviruses:

• A stem-and-loop structure at the 5′ end of the genome
• A 51-nucleotide conserved sequence near the 5′ end of the genome and
• A 20-nucleotide conserved sequence at the subgenomic RNA start site. Homologous sequences are present in the rubella genome.
  

The genome encodes several non-coding RNA structures. Among those is the rubella virus 3′ cis-acting element, which contains multiple stem-loops and one of the stem-loop structures has been found to be essential for viral replication.

Rubella virus is an enveloped virus, circular or oval in shape and 60nm in diameter. The virion is composed of a capsid core containing a single copy of genomic RNA. The outer membrane is a lipid bilayer containing specialized glycoproteins (E1 and E2) believed to be responsible for attachment to host cells. It is also believed that a pH of 6.0 or less induces conformational changes in the glycoproteins making attachment of the viral envelope to host cells more likely. Rubella virus likely enters cells via endocytosis. Once in the cell a conformational change occurs in the capsid shell releasing the genetic information into the cell. Replication is slow with a latency period of 8-12 hours, with structural proteins appearing at 12-16 hours and peak viral 36-48 hours after infection. In volunteer subjects infected via aerosol, the characteristic rash typically appears 16-20 days from the time of exposure.

On the basis of differences in the sequence of the E1 protein, two genotypes have been described which differ by 8-10%. These have been subdivided into 13 recognised genotypes: 1a, 1B, 1C, 1D, 1E, 1F, 1G, 1h, 1i, 1j, 2A, 2B and 2C.

For typing, the WHO recommends a minimum window that includes nucleotides 8731 to 9469.

• Genotypes 1a, 1E, 1F, 2A and 2B have been isolated in China.
• Genotype 1j has only been isolated from Japan and the Philippines.
• Genotype 1E is found in Africa, the Americas, Asia and Europe.
• Genotype 1G has been isolated in Belarus, Cote d’Ivoire and Uganda.
• Genotype 1C is endemic only in Central and South America.
• Genotype 2B has been isolated in South Africa.
• Genotype 2C has been isolated in Russia.

Rubella virus only infects humans and is spread from person to person through contact or from a cough or sneeze, as the virus lives in the mucus of an infected person. The virus can be transmitted up to a week before the rash appears and one to two weeks after. Rubella is also transmitted from an infected mother to her unborn child causing congenital rubella syndrome.

The rubella vaccine is included as a part of the common childhood vaccination known as MMR (Measles, Mumps, Rubella) vaccination. The Meruvax II or Rubella vaccination effectively prevents the disease after a single injection in humans 12 moths or older. While antibodies are usually developed after a single infection of the virus the vaccine is vital to prevent infection of expecting mothers who could pass on the virus to their unborn fetus. The vaccine is a freeze dried sample of the Wistar RA 27/3 strain of Rubella virus which when injected induces an immunity by causing a modified rubella infection. Rubella hemagglutinin antibodies are produced to prevent infection of wild rubella virus. Vaccination with MMR is a requirement in most states for children wishing to enter school. It is not yet clearly known if the immunity is permanent, however, it is known to last for at least 10 years.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from CRS.^[1][2]

The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from CRS:^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

The exact incidence of congenital rubella syndrome is hard to estimate because in many parts of the developing world, rubella has been eliminated. However, very few cases are still reported in the U.S and they are believed to be imported cases. In addition, rubella infection and congenital rubella syndrome are still a challenge in the developing world, with most cases occurring in Africa and Southeast Asia.^[1][2] In countries without rubella immunization, the incidence is estimated to range between 60-220 per 100,000 cases.^[3]

The exact incidence of congenital rubella syndrome is hard to estimate because in many parts of the developing world, rubella has been eliminated. However, very few cases are still reported in the U.S and they are believed to be imported cases. In addition, rubella infection and congenital rubella syndrome are still a challenge in the developing world, with most cases occurring in Africa and Southeast Asia.^[1][2]

• The introduction of rubella vaccines in 1969 led to the elimination of the rubella infection and congenital rubella syndrome in many parts of the world.
• In the U.S, rubella has been eliminated. Between the years 2004 and 2012, there have been 6 reported cases of congenital rubella syndrome in the U.S. However, these cases are thought to be imported or of unknown origin.
• In France, the incidence of congenital rubella syndrome in 2011 was estimated at 1.01 per 100,000 live births.

• The WHO is implementing strategies to eradicate rubella worldwide by the year 2020. This is still a challenge in many parts of the world, most notably Southeast Asia and Africa, due to the relative high cost and availability of the vaccine.
• Worldwide in 2008, the number of cases of congenital rubella syndrome exceeded 110,000, with 75% of cases occurring in Southeast Asia and Africa.
• In countries without rubella immunization, the incidence is estimated to range between 60-220 per 100,000 cases.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

An unimmunized woman who becomes infected with rubella just prior to conception or in the first 8-10 weeks of gestation is at a great risk of giving birth to a child with congenital rubella syndrome.^[1][2]

An unimmunized woman who becomes infected with rubella just prior to conception or in the first 8-10 weeks of gestation is at a great risk of giving birth to a child with congenital rubella syndrome.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

There is no screening test for congenital rubella syndrome.

There is no screening test for congenital rubella syndrome.^[1] However, if there is a high clinical suspicion of rubella infection during pregnancy, serum IgG and IgM antibodies against rubella may be ordered. Also, if a pregnant woman proves to be unimmune to rubella, vaccination with MMR should be deferred till after delivery due to the theoretical teratogenic effects of the rubella vaccine.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Congenital rubella syndrome can cause serious birth defects and the prognosis depends on the severity of the problem. Heart defects can be corrected but neurological damage is permanent.^{[1][2][3][4][5][6]}

If malformations associated with congenital rubella syndrome are not addressed, infants may end-up blind, deaf, and with severe mental deficits.

Maternal infection with rubella early in pregnancy can result in severe consequences on the fetus, which include spontaneous abortion, stillbirth, IUGR, and congenital rubella syndrome.^[7] Complications of congenital rubella syndrome itself include several birth defects, which can result in early and late complications.^{[1][2][3][4][5][6]}

The prognosis of congenital rubella syndrome depends on the severity of cardiac and neurological malformations. It is estimated that congenital rubella syndrome has a mortality rate of 20%.^[8] In addition, congenital rubella syndrome is associated with various long-term complications^{[1][2][3][4][5][6]}, which affect the quality of life of individuals.

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