Abnormal Development - Rubella Virus

Embryology - 2 Dec 2023        Expand to Translate
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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

ICD-11

KA62.8 Congenital rubella syndrome - A disease caused by an infection with the rubella virus in utero. This disease presents with symptoms depending on the timing of infection of the fetus and may present with birth defects (such as hearing loss), or intrauterine growth retardation. Transmission is by vertical transmission. Confirmation is by identification of rubella virus or detection of anti-rubella virus IgM antibodies in the neonate or infant. KA00.3 Foetus or newborn affected by maternal infectious diseases - A condition affecting fetuses or newborns, that is (or suspected to be) caused by a maternal infection with a bacterial, viral, fungal, or parasitic source. JA85.3 Maternal care for known or suspected damage to foetus from viral disease in mother

Introduction

Child with Measles back rash day 3 (CDC)

Rubella Virus, transmission electron micrograph (Image: CDC USA)

Rubella virus (Latin, rubella = little red), also known as "German Measles" (due to early citation in German medical literature), infection during pregnancy can cause congenital rubella syndrome (CRS) with serious malformations of the developing fetus. The type and degree of abnormality relates to the time of maternal infection.

Rubella peaked in 1964 and 1965, when 12.5 million cases were reported (USA). As a result, 20,000 babies were born with birth defects, 6,200 babies were stillborn, and an estimated 5,000 births were aborted, both naturally and assisted. At that time no treatment by vaccination existed and this only became available in 1969. The disease was dangerous because in children it was almost unnoticable and pregnant women often did not know that they had been exposed. Initial vaccination strategies varied between countries, in the United States infants were first to be vaccinated, while in the United Kingdom adolescent girls were first to be vaccinated.

Pregnancy effects of measles results in a higher risk of premature labor, spontaneous abortion, low-birth-weight, and possibly rare cases of birth defects with no definable pattern of malformation.

Children infected with rubella before birth (a condition known as congenital rubella) are at risk for the following: growth retardation; malformations of the heart, eyes, or brain; deafness; and liver, spleen, and bone marrow problems.

The complete genomic sequence of Rubella is now known. Rubella is a 9755 bp single stranded RNA positive-strand virus with no DNA stage (Togaviridae; Rubivirus) encoding nonstructural protein, capsid protein, glycoproteins E1 and E2. (More? Rubella Genome)

 ICD-11 KA72.8 Congenital rubella syndrome.

Tinycc Rubella Virus page - http://tiny.cc/Rubella_Virus

Category:Rubella

Rubella control map (2000-2016)

USA Measles cases and outbreaks graph

Some Recent Findings

Progress in Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2016 "Abstract Although rubella virus infection usually causes a mild fever and rash illness in children and adults, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or infants with a constellation of congenital malformations known as congenital rubella syndrome (CRS) (1). Rubella is a leading vaccine-preventable cause of birth defects. Preventing these adverse pregnancy outcomes is the focus of rubella vaccination programs. In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national immunization schedules and recommended an initial vaccination campaign, usually targeting children aged 9 months-14 years (1). The Global Vaccine Action Plan 2011-2020 (GVAP), endorsed by the World Health Assembly in 2012, includes goals to eliminate rubella in at least five of the six WHO regions by 2020 (2). This report updates a previous report (3) and summarizes global progress toward rubella and CRS control and elimination from 2000 to 2016. As of December 2016, 152 (78%) of 194 countries had introduced RCV into the national immunization schedule, representing an increase of 53 countries since 2000, including 20 countries that introduced RCV after 2012." Rubella Seropositivity in Pregnant Women After Vaccination Campaign in Brazil's Federal District "Rubella is an acute viral disease that usually does not generate sequels; however, in pregnant women the infection can cause serious abnormalities to fetuses, which are collectively called congenital rubella syndrome. In Brazil, population immunization was started in 1992, but few epidemiological studies have been conducted to assess vaccination coverage and seroconversion since then. The aim of this work is to evaluate the seropositivity of pregnant women to rubella virus after vaccination campaign was carried out in 2008. Serological tests for rubella diagnosis were performed in 87 pregnant women who attended the University of Brasilia Hospital, Federal District, Brazil. Antirubella IgG antibodies were detected in 83 out of 87 pregnant women (95.4%), with an age-independent seroprevalence. Only one woman was positive in IgM serological tests." Americas region is declared the world’s first to eliminate rubella 29 April 2015 (PAHO/WHO) "The Americas region has become the first in the world to be declared free of endemic transmission of rubella, a contagious viral disease that can cause multiple birth defects as well as fetal death when contracted by women during pregnancy. Before mass-scale rubella vaccination, an estimated 16,000 to more than 20,000 children were born with CRS each year in Latin America and the Caribbean, while more than 158,000 rubella cases were reported in 1997 alone. In the United States, 20,000 infants were born with CRS during the last major rubella outbreak (1964-65)." PAHO Rubella "Rubella remains an important pathogen worldwide, with roughly 100 000 cases of congenital rubella syndrome estimated to occur every year. Rubella-containing vaccine is highly effective and safe and, as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by recent large outbreaks in Japan and elsewhere. In this Seminar, we provide present results regarding rubella control, elimination, and eradication policies, and a brief review of new laboratory diagnostics. Additionally, we provide novel information about rubella-containing vaccine immunogenetics and review the emerging evidence of interindividual variability in humoral and cell-mediated innate and adaptive immune responses to rubella-containing vaccine and their association with haplotypes and single-nucleotide polymorphisms across the human genome."

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Abnormal Development Rubella Virus

Congenital Rubella Syndrome

Older papers

These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. Rubella and congenital rubella syndrome control and elimination - global progress, 2000-2012 "Rubella virus usually causes a mild fever and rash in children and adults. However, infection during pregnancy, especially during the first trimester, can result in miscarriage, stillbirth, or infants with congenital malformations, known as congenital rubella syndrome (CRS). In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national routine immunization schedules with an initial wide-age-range vaccination campaign that includes children aged 9 months-15 years. WHO also urged all member states to take the opportunity offered by accelerated measles control and elimination activities as a platform to introduce RCVs. The Global Measles and Rubella Strategic Plan (2012-2020) published by the Measles Rubella Initiative partners in 2012 and the Global Vaccine Action Plan endorsed by the World Health Assembly in 2012 include milestones to eliminate rubella and CRS in two WHO regions by 2015, and eliminate rubella in five WHO regions by 2020. This report summarizes the global progress of rubella and CRS control and elimination during 2000-2012. As of December 2012, a total of 132 (68%) WHO member states had introduced RCV, a 33% increase from 99 member states in 2000. A total of 94,030 rubella cases were reported to WHO in 2012 from 174 member states, an 86% decrease from the 670,894 cases reported in 2000 from 102 member states." Results of the rubella elimination program in Catalonia (Spain), 2002-2011 "Rubella is usually a mild disease with nonspecific symptoms, but can cause congenital rubella syndrome (CRS) when infection occurs during pregnancy. The objective of this study was to evaluate the sensitivity and positive predictive value of different data sources used for surveillance purposes in the Rubella Elimination Program of Catalonia between 2002 and 2011. The Urgent Notification to the Statutory Disease Reporting System, the Individualized Disease Reporting System, screening for other viruses included in the Measles Elimination Program, the Microbiological Reporting System and the Minimum Hospital Discharge Data were evaluated. 100 suspected cases of postnatal rubella and 6 suspected cases of CRS were detected. ... Most confirmed postnatal cases (25 cases, 48.1%) were in the 25-44 y age group followed by the 15-24 y age group (11 cases, 21.2%)." Controlling rubella and preventing congenital rubella syndrome – global progress, 2009 "In 2009, a total of 121,344 rubella cases were reported to WHO from 167 countries, a 82% decrease from 2000" An update on cardiovascular malformations in congenital rubella syndrome (CRS) "We searched the English literature from 1941 through 2008 to identify studies that used cardiac catheterization or echocardiography to evaluate the cardiovascular malformations in CRS. Although published studies of CVMs in CRS have in general reported patent ductus arteriosus (PDA) as the CVM phenotype most commonly associated with CRS, among CRS cases evaluated by catheterization, branch pulmonary artery stenosis was actually more common than PDA. Moreover, although the combination of branch pulmonary artery stenosis and PDA was more common than either branch pulmonary artery stenosis or PDA alone, isolated branch pulmonary artery stenosis was twice as common as isolated PDA. ...Among children with suspected CRS, clinical evaluations for the presence of cardiovascular malformations should include examinations for both branch pulmonary artery stenosis and PDA."

Virus Structure

Identical genotype B3 sequences from measles patients in 4 countries, 2005.

Lineage: Viruses; ssRNA viruses; ssRNA negative-strand viruses; Mononegavirales; Paramyxoviridae; Paramyxovirinae; Morbillivirus; Measles virus

• ssRNA; linear; Length: 15,894 nt Measles virus, complete genome
• virus replication involves a viral RNA-dependent RNA polymerase (vRdRp), using as a template a nucleocapsid (NC) made of a single strand of RNA in tight complex with the nucleoprotein (N).
• negative-strand genome contains six transcription units encoding the N, phospho (P), matrix (M), fusion (F), hemagglutinin (H), and large (L) or polymerase protein.
• each N protein binds to 6 nucleotides.
• the N polymer entirely covers the 15,894-nucleotide genome.
• 23 known measles genotypes.

This transmission electron micrograph (TEM) shows the presence of Rubella virus virions, as they were in the process of budding from the host cell surface to be freed into the host’s system. Inside the capsid lies the Rubella virus’ positive-sense single-stranded RNA ((+)ssRNA) genome. (Image: CDC)	The spherical virions' icosahedral capsid is enclosed in the host cell membrane, budding and producing an enveloped virus particle. (Image: CDC)

Model of cell virus RNA accumulation

The following 5 -step model has been described for cell virus accumulation following hours post-infection (hpi)

1. 0 to ~5 hpi - incoming viral RNA-dependent RNA polymerase (vRdRp) initiated primary transcription from every gene with no detectable lag phase.
2. ~5 to ~12 hpi - mRNA accumulates exponentially.
3. ~12 to ~24 hpi - mRNAs, genomes, and antigenomes accumulate exponentially because of the increase of both newly available template and vRdRp.
4. ~24 to ~30 hpi - genomes and antigenomes continue to accumulate exponentially at the same rate, whereas the accumulation of the transcripts slows down.
5. 30+ hpi - genome and antigenome accumulation slows down, and the cell content in viral transcripts tends to decrease.

Vaccination

Rubella and measles elimination in the Americas

Japan - first introduced to Japan in 1966 and adopted in the national regular immunization program from 1978.

WHO Rubella Information

PAHO Countries reporting measles and rubella (2013-2014)

• Causative agent - Virus
• Reservoir - Humans
• Spread - Close respiratory contact and aerosolized droplets
• Transmission period - A few days before to seven days after rash; up to one year of age in congenitally infected
• Subclinical infection - Common
• Duration of natural immunity - Lifelong
• Risk factors for infection (for unvaccinated individuals) - Highly transmissible; crowding; low socioeconomic status
• Case-fatality rate - Less than 0.1 percent (dependent on care)
• Vaccine (number of doses); route - Rubella (one or two); subcutaneous
• Vaccine efficacy - 95 percent (at 12 months and up)
• Duration of immunity after primary series - Lifelong in most; presumed rare cases of waning immunity after one dose, not two
• Schedule - First dose at 12 to 15 months; when given, a second dose with measles vaccine
• Status as of the end of 2001 - 110 countries in 2003
• Comments - Lower efficacy when maternal antibody present

The World Health Organization recommends that the combination measles-rubella or measles-mumps-rubella vaccines be introduced only after careful evaluation of public health priorities within each country and following the establishment of an adequate program for measles control as demonstrated by high coverage rates as part of a well-functioning childhood immunization program.

Sources: WHO 2002, 2004.

Rubella History

Norman Gregg (1892-1966)

1941

Norman Gregg (1892-1966) was a Sydney ophthalmologist who in 1941 identified the link between maternal rubella infection and developmental abnormalities (atypical congenital cataracts, congenital heart defects, infants small-for-gestational age) initially in his own practice. This had coincided with a rubella epidemic that occurred between 1940 to 1941.

An example of the types of congenital defects following first trimester infection was also described later by Swan (1944).

Links: Norman Gregg

1962

The rubella virus was initially isolated

1969

United States first licensed live, attenuated rubella vaccines introduced.

United States Elimination of rubella and congenital rubella syndrome, 1969-2004

1. 1969 - First official recommendations are published for the use of rubella vaccine. Vaccination is recommended for children aged 1 year to puberty.
2. 1978 - Recommendations for vaccination are expanded to include adolescents and certain adults, particularly females.
3. 1981 - Recommendations place increased emphasis on vaccination of susceptible persons in training and educational settings.
4. 1984 - Recommendations are published for vaccination of workers in daycare centres, schools, colleges, companies, government offices, and industrial sites. Providers encouraged to conduct prenatal testing and postpartum vaccination of susceptible women. Recommendations for vaccination are expanded to include susceptible persons who travel abroad.
5. 1990 - Recommendations include implementation of a new 2-dose schedule for measles-mumps-rubella vaccine.

Rubella and measles elimination in the Americas

2014

In 2014 a Philippines measles outbreak of over 50,000 cases occurred. Travellers to and from the Philippines during this period led to an increase in cases occurring in other countries. For example, the USA experienced the highest number of measles cases CDC had reported in 20 years, over 600, many of the people who got measles last year were linked to travelers who had gotten measles from the Philippines.

Links: CDC 2014 travel advisory | NSW Health

2015

From January 1 to January 28, 2015, 84 people from 14 states were reported to have measles. Most of these cases are part of a large, ongoing outbreak linked to an amusement park in California. On January 23, 2015, CDC issued a Health Advisory to notify public health departments and healthcare facilities about this multi-state outbreak and to provide guidance for healthcare providers nationwide. For more information see CDC Press Briefing Transcript: Measles in the United States, 2015, January 29, 2015.

Congenital Rubella Syndrome

The following are some examples of developmental abnormalities associated with Congenital Rubella Syndrome (CRS).

ICD-11 Beta - KA72.8 Congenital rubella syndrome
Description A disease caused by an infection with the rubella virus in utero. This disease presents with symptoms depending on the timing of infection of the fetus and may present with birth defects (such as hearing loss), or intrauterine growth retardation. Transmission is by vertical transmission. Confirmation is by identification of rubella virus or detection of anti-rubella virus IgM antibodies in the neonate or infant.
Additional Information Congenital rubella syndrome (CRS) is a group of anomalies that an infant may present as a result of maternal infection and subsequent foetal infection with rubella virus. In France, the prevalence at birth of CRS has decreased markedly to less than 1 case per 100,000 live births in 2002. The main defects caused by congenital rubella infection are sensorineural deafness (alteration of brainstem auditory evoked potentials) that may progress after birth, eye defects (such as cataract), cardiovascular defects, brain damage (occurring only after infection between the 3rd and 16th week of gestation) that may cause mild to severe intellectual deficit, microcephaly and spastic diplegia, and prematurity and low birth weight. Major structural malformations are rare. The prenatal diagnosis of foetal infection must be done in case of contact of the pregnant woman with an infected patient, with or without eruptive disease. If the woman was not vaccinated recently, a primary rubella infection is certain in case of: increased blood levels of IgG or seroconversion with IgM above the positivity threshold; low avidity of IgG; identification of IgM in foetal blood (foetal blood sampling can only be performed after 22 weeks of gestation); identification by gene amplification of the viral genome in the amniotic fluid; presence of specific IgM in the blood of the newborn or in any other sample from the foetus/newborn. In case of positive prenatal diagnosis of primary infection, the full congenital rubella syndrome is common when maternal infection occurs during the first two months of pregnancy. Up to 12 weeks gestation, about 80% of exposed foetuses are affected, and between 12 and 16 weeks, about half of exposed foetuses are affected. During this latter period of gestation, deafness is the most common abnormality encountered; the other defects and growth impairments appear to occur only after exposure during the first trimester. Congenital anomalies and growth impairment are rare with infection after 16 weeks gestation.
ICD-10 : P35.0 ICD-10
Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

Vision

Congenital rubella syndrome retinopathy

• retinopathy
• cataracts
• micropthalmia
• glaucoma
• retinitis

Links: Vision Abnormalities | Vision Development

Hearing

• sensorineural deafness

Links: Hearing Abnormalities | Hearing Development

Neural

• mental retardation
• meningoencephalitis
• (rare) progressive rubella panencephalitis
• microcephaly

Cardiovascular

• patent ductus arteriosis
• atrial septal defect
• ventricular septal defect
• peripheral pulmonic stenosis

Endocrine

• insulin dependent diabetes mellitus
• thyroiditis

Other Systems

• general growth retardation
• radiolucent bone disease
• heptosplenomegaly
• heamatologic abnormalities (thrombocytopenia, purpura)
• pneumonitis

References

Textbooks

• Medical Microbiology. 4th edition. Baron S, editor. Galveston (TX): University of Texas Medical Branch at Galveston; 1996. Chapter 55 Togaviruses: Rubella Virus | Chapter 54Alphaviruses (Togaviridae) and Flaviviruses (Flaviviridae) | Table 55-1 Abnormalities Associated with Congenital Rubella Syndrome | Figure 55-3 Incidence rates of rubella USA 1966-1993
• Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002. Viruses Exploit Host Cell Machinery for All Aspects of Their Multiplication
• Disease Control Priorities in Developing Countries. 2nd edition. Jamison DT, Breman JG, Measham AR, et al., editors. Washington (DC): World Bank; 2006. Chapter 20Vaccine-preventable Diseases
• Antenatal Care: Routine care for the healthy pregnant woman. NICE Clinical Guidelines, No. 62. National Collaborating Centre for Women's and Children's Health (UK). London: RCOG Press; 2008 Mar. 10.8. Rubella

Reviews

George S, Viswanathan R & Sapkal GN. (2019). Molecular aspects of the teratogenesis of rubella virus. Biol. Res. , 52, 47. PMID: 31455418 DOI.

De Santis M, Cavaliere AF, Straface G & Caruso A. (2006). Rubella infection in pregnancy. Reprod. Toxicol. , 21, 390-8. PMID: 16580940 DOI.

Terada K. (2003). Rubella and congenital rubella syndrome in Japan: epidemiological problems. Jpn. J. Infect. Dis. , 56, 81-7. PMID: 12944671

Articles

Ye Z, Wang L, Yang T, Chen L, Wang T, Chen L, Zhao L, Zhang S, Zheng Z, Luo L & Qin J. (2019). Maternal Viral Infection and Risk of Fetal Congenital Heart Diseases: A Meta-Analysis of Observational Studies. J Am Heart Assoc , 8, e011264. PMID: 30995883 DOI.

Feng Y, Santibanez S, Appleton H, Lu Y & Jin L. (2011). Application of new assays for rapid confirmation and genotyping of isolates of rubella virus. J. Med. Virol. , 83, 170-7. PMID: 21108356 DOI.

Tipples G & Hiebert J. (2011). Detection of measles, mumps, and rubella viruses. Methods Mol. Biol. , 665, 183-93. PMID: 21116802 DOI.

Binnicker MJ, Jespersen DJ & Harring JA. (2010). Multiplex detection of IgM and IgG class antibodies to Toxoplasma gondii, rubella virus, and cytomegalovirus using a novel multiplex flow immunoassay. Clin. Vaccine Immunol. , 17, 1734-8. PMID: 20861325 DOI.

Fontana J, López-Iglesias C, Tzeng WP, Frey TK, Fernández JJ & Risco C. (2010). Three-dimensional structure of Rubella virus factories. Virology , 405, 579-91. PMID: 20655079 DOI.

Plotkin SA. (2006). The history of rubella and rubella vaccination leading to elimination. Clin. Infect. Dis. , 43 Suppl 3, S164-8. PMID: 16998777 DOI.

CORDES FC & BARBER A. (1946). Changes in lens of embryo after rubella; microscopic examination of eight week old embryo. Arch Ophthal , 36, 135-40. PMID: 20997667 DOI.

Search Pubmed

Search Pubmed: Rubella Virus | Congenital Rubella Syndrome | Congenital Rubella Infection

Historic

Pirrie GD. Rubella in pregnancy and congenital defects. (1947) Br Med J. 17;1(4506): 694. PMID 20343527

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• The Australian Immunisation Handbook 10th edition (updated June 2015) – Rubella http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook10-home~handbook10part4~handbook10-4-18
• World Health Organization (WHO)
  • WHO position paper on rubella vaccines (2011). Weekly Epidemiological Record, No. 29, 2011, 86, 301–316 http://www.who.int/wer/2011/wer8629.pdf Webpage
  • WHO-recommended surveillance standard of rubella and congenital rubella syndrome | PDF
  • [http://www.euro.who.int/en/what-we-do/health-topics/communicable-diseases/me

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Cite this page: Hill, M.A. (2023, December 2) Embryology Abnormal Development - Rubella Virus. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Rubella_Virus

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