Abnormal Development - Rubella Virus

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Child with Measles back rash day 3
Child with Measles back rash day 3 (CDC)
Rubella Virus EM
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.[1]

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.[2] 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)

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

Viral Links: TORCH Infections | Cytomegalovirus | Hepatitis Virus | HIV | Parvovirus | Polio Virus | Rubella Virus | Chickenpox | Lymphocytic Choriomeningitis Virus | Zika Virus | Rotavirus | Vaccination | Environmental
Historic Embryology - Viral 
1941 Rubella Cataracts | 1944 Rubella Defects
File:USA Measles cases and outbreaks graph
USA Measles cases and outbreaks graph

Some Recent Findings

  • Rubella Seropositivity in Pregnant Women After Vaccination Campaign in Brazil's Federal District[3] "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[4] "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."
  • Rubella and congenital rubella syndrome control and elimination - global progress, 2000-2012[5] "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[6] "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 [7] "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)[8] "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."
More recent papers
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in 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.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches

Search term: Abnormal Development Rubella Virus

Thalia Velho Barreto de Araújo, Ricardo Arraes de Alencar Ximenes, Demócrito de Barros Miranda-Filho, Wayner Vieira Souza, Ulisses Ramos Montarroyos, Ana Paula Lopes de Melo, Sandra Valongueiro, Maria de Fátima Pessoa Militão de Albuquerque, Cynthia Braga, Sinval Pinto Brandão Filho, Marli Tenório Cordeiro, Enrique Vazquez, Danielle di Cavalcanti Souza Cruz, Claudio Maierovitch Pessanha Henriques, Luciana Caroline Albuquerque Bezerra, Priscila Mayrelle da Silva Castanha, Rafael Dhalia, Ernesto Torres Azevedo Marques-Júnior, Celina Maria Turchi Martelli, Laura Cunha Rodrigues, investigators from the Microcephaly Epidemic Research Group, Brazilian Ministry of Health, Pan American Health Organization, Instituto de Medicina Integral Professor Fernando Figueira, State Health Department of Pernambuco Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infect Dis: 2017; PubMed 29242091

Cora Alexandra Voekt, Therese Rinderknecht, Hans Hellmuth Hirsch, Annette Blaich, Irene Mathilde Hösli Ultrasound indications for maternal STORCH testing in pregnancy. Swiss Med Wkly: 2017, 147;w14534 PubMed 29185251

Gavin B Grant, Susan E Reef, Minal Patel, Jennifer K Knapp, Alya Dabbagh Progress in Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2016. MMWR Morb. Mortal. Wkly. Rep.: 2017, 66(45);1256-1260 PubMed 29145358

L D Frenkel, F Gomez, F Sabahi The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small? Eur. J. Clin. Microbiol. Infect. Dis.: 2017; PubMed 28980148

Yanna K M Nóbrega, Bruna C de Carvalho, Nadjar Nitz, Tamires E Vital, Franco B Leite, Inês J Sequeira, Elsa E Moreira, Juliana K B de Andrade, Lenora Gandolfi, Riccardo Pratesi, Mariana M Hecht Rubella Seropositivity in Pregnant Women After Vaccination Campaign in Brazil's Federal District. Viral Immunol.: 2017; PubMed 28972455

Search term: Congenital Rubella Syndrome

Qinghong Meng, Jie Luo, Lijun Li, Wei Shi, Jinqian Yu, Yingjie Shen, Li Li, Yajuan Wang, Kaihu Yao Rubella seroprevalence among pregnant women in Beijing, China. BMC Infect. Dis.: 2018, 18(1);130 PubMed 29544450

Ashlesha Kaushik, Sanjay Verma, Praveen Kumar Congenital rubella syndrome: A brief review of public health perspectives. Indian J Public Health: 2018, 62(1);52-54 PubMed 29512566

Robert S Baltimore, Katherine Nimkin, Katherine A Sparger, Virginia M Pierce, Stanley A Plotkin Case 4-2018: A Newborn with Thrombocytopenia, Cataracts, and Hepatosplenomegaly. N. Engl. J. Med.: 2018, 378(6);564-572 PubMed 29414276

Walter A Orenstein, Lisa Cairns, Alan Hinman, Benjamin Nkowane, Jean-Marc Olivé, Arthur L Reingold Measles and Rubella Global Strategic Plan 2012-2020 midterm review report: Background and summary. Vaccine: 2018, 36 Suppl 1;A35-A42 PubMed 29307368

Quang Duy Trinh, Ngan Thi Kim Pham, Kazuhide Takada, Shihoko Komine-Aizawa, Satoshi Hayakawa Myelin Oligodendrocyte Glycoprotein-Independent Rubella Infection of Keratinocytes and Resistance of First-Trimester Trophoblast Cells to Rubella Virus In Vitro. Viruses: 2018, 10(1); PubMed 29300335

Virus Structure

Identical genotype B3 sequences from measles patients in 4 countries
Identical genotype B3 sequences from measles patients in 4 countries, 2005.[9]

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).[10]
  • 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.
Rubella virus 01.jpg Rubella virus 03.jpg
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)[10]

  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.


Rubella and measles elimination in the Americas
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)


Norman Gregg (1892-1966) was a Sydney ophthalmologist who in 1941[11] 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).[12]

Links: Norman Gregg


The rubella virus was initially isolated [13][14]


United States first licensed live, attenuated rubella vaccines introduced.

USA rubella and congenital rubella syndrome cases.jpg

United States Elimination of rubella and congenital rubella syndrome, 1969-2004[15]

  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.jpg

Rubella and measles elimination in the Americas[16]


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


USA Measles cases and outbreaks graph 01.jpg

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 Abnormalities

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


Congenital rubella syndrome retinopathy
Congenital rubella syndrome retinopathy[17]
  • retinopathy
  • cataracts
  • micropthalmia
  • glaucoma
  • retinitis
Links: Vision Abnormalities | Vision Development


  • sensorineural deafness
Links: Hearing Abnormalities | Hearing Development


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


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


  • insulin dependent diabetes mellitus
  • thyroiditis

Other Systems

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


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  2. Dominguez G, Wang CY & Frey TK. (1990). Sequence of the genome RNA of rubella virus: evidence for genetic rearrangement during togavirus evolution. Virology , 177, 225-38. PMID: 2353453
  3. Nóbrega YKM, de Carvalho BC, Nitz N, Vital TE, Leite FB, Sequeira IJ, Moreira EE, de Andrade JKB, Gandolfi L, Pratesi R & Hecht MM. (2017). Rubella Seropositivity in Pregnant Women After Vaccination Campaign in Brazil's Federal District. Viral Immunol. , 30, 675-677. PMID: 28972455 DOI.
  4. Lambert N, Strebel P, Orenstein W, Icenogle J & Poland GA. (2015). Rubella. Lancet , 385, 2297-307. PMID: 25576992 DOI.
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  6. Barrabeig I, Torner N, Martínez A, Carmona G, Ciruela P, Batalla J, Costa J, Hernández S, Salleras L & Domínguez A. (2013). Results of the rubella elimination program in Catalonia (Spain), 2002-2011. Hum Vaccin Immunother , 9, 642-8. PMID: 23299566
  7. No authors listed Controlling rubella and preventing congenital rubella syndrome – global progress, 2009 Wkly Epidemiol Rec. 2010 Oct 15;85(42):413-8. PMID20949700 | PDF
  8. Oster ME, Riehle-Colarusso T & Correa A. (2010). An update on cardiovascular malformations in congenital rubella syndrome. Birth Defects Res. Part A Clin. Mol. Teratol. , 88, 1-8. PMID: 19697432 DOI.
  9. Rota J, Lowe L, Rota P, Bellini W, Redd S, Dayan G, van Binnendijk R, Hahné S, Tipples G, Macey J, Espinoza R, Posey D, Plummer A, Bateman J, Gudiño J, Cruz-Ramirez E, Lopez-Martinez I, Anaya-Lopez L, Holy Akwar T, Giffin S, Carrión V, de Filippis AM, Vicari A, Tan C, Wolf B, Wytovich K, Borus P, Mbugua F, Chege P, Kombich J, Akoua-Koffi C, Smit S, Bukenya H, Bwogi J, Baliraine FN, Kremer J, Muller C & Santibanez S. (2006). Identical genotype B3 sequences from measles patients in 4 countries, 2005. Emerging Infect. Dis. , 12, 1779-81. PMID: 17283637 DOI.
  10. 10.0 10.1 Plumet S, Duprex WP & Gerlier D. (2005). Dynamics of viral RNA synthesis during measles virus infection. J. Virol. , 79, 6900-8. PMID: 15890929 DOI.
  11. Gregg NM. Congenital cataract following German measles in the mother. (1941) Trans Ophthalmol Soc Aust. 3: 35–46. PubMed 1879476
  12. Swan C. A study of three infants dying from congenital defects following maternal rubella in the early stages of pregnancy. (1944) J. Pathol. Bact. 41(3): 289-295.
  13. PARKMAN PD, BUESCHER EL & ARTENSTEIN MS. (1962). Recovery of rubella virus from army recruits. Proc. Soc. Exp. Biol. Med. , 111, 225-30. PMID: 13941530
  15. Centers for Disease Control and Prevention (CDC). (2005). Elimination of rubella and congenital rubella syndrome--United States, 1969-2004. MMWR Morb. Mortal. Wkly. Rep. , 54, 279-82. PMID: 15788995
  16. Progress Report: Elimination of Rubella and CRS in the Americas, 2007 Powerpoint slide on Elimination of Rubella and Congenital Rubella Syndrome in the Americas: Progress Report. Pan American Health Organization World Health Organization.
  17. Jivraj I, Rudnisky CJ, Tambe E, Tipple G & Tennant MT. (2014). Identification of ocular and auditory manifestations of congenital rubella syndrome in mbingo. Int J Telemed Appl , 2014, 981312. PMID: 25525427 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


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.

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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.

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