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Rubella Virus 

Rubella Virus
Chapter:
Rubella Virus
Author(s):

Emmaculate Lebo

and Susan Reef

DOI:
10.1093/med/9780190604813.003.0013
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Rubella is an RNA virus, genus Rubivirus, in the family Togaviridae. The virus usually causes mild illness in children and adults. Rubella infection in pregnant women, especially during the first trimester, can result in miscarriages, fetal deaths, stillbirths, or a constellation of congenital anomalies known as congenital rubella syndrome (CRS). In 1941, Dr. Norman Gregg, an Australian ophthalmologist, was the first to associate rubella infection in pregnancy with cataracts and heart defects in infants1. Following maternal infection, the rubella virus infects the placenta and, subsequently, the fetus2.

The risk of developing a congenital defect is highest when the rubella infection occurs during the first 12 weeks of gestation; the risk for any defect decreases after the 12th week of gestation. Defects are rare when infection occurs after the 16th gestational week. Fetal infection without clinical signs of CRS can occur during any stage of pregnancy3. The risks associated with fetal infection are primarily in pregnant women who are not immune to the rubella virus; immunity is acquired through vaccination with a rubella-containing vaccine or develops naturally following infection with the virus. Asymptomatic maternal reinfection during pregnancy presents only a very minimal risk to the fetus, but several isolated reports have been made of fetal infection and CRS among infants born to mothers who had documented serological evidence of rubella immunity4,5,6. The highest risk for CRS is found in countries with a high proportion of rubella-susceptible women of childbearing age, primarily in countries without rubella-containing vaccination in their routine childhood immunization program.

Epidemiology and Pathogenesis

Rubella virus transmission occurs primarily through direct or droplet contact from nasopharyngeal secretions; humans are the only known source of infection. In the pre-vaccine era and in countries that have not introduced rubella vaccination, rubella outbreaks occur seasonally, with epidemics occurring every 6–9 years. In endemic countries, rubella is mainly a childhood illness. A review of prevaccine epidemiology of rubella in Africa during 2000–2009 showed that 75% of the cases occurred in children 1–9 and 91% in children 1–14 years of age. However, 5% of cases occurred among women of childbearing age, showing susceptibility among this group and representing a risk for CRS7. During the 1964–1965 rubella epidemic in the (U.S.), an estimated 12.5 million rubella cases occurred, resulting in approximately 11,250 fetal deaths attributable to spontaneous or therapeutic abortions, 2,100 stillbirths or neonatal deaths, and 20,000 infants born with CRS8.

Rubella is vaccine-preventable, and the primary goal of a rubella vaccination program is the prevention of congenital rubella infection including CRS. In 2000, the World Health Organization (WHO) published the first rubella vaccine position paper recommending that all countries that have not introduced rubella-containing vaccine consider introducing it into the childhood immunization program9. In 2011, the WHO rubella vaccine position paper was updated to recommend conducting a national rubella vaccination campaign (with measles in a combination vaccine) targeting children from 9 months to 14 years of age, followed by introduction of rubella vaccine into the childhood immunization program, as the preferred strategy. In addition, it recommended that countries take the opportunity to use measles elimination activities as a platform to introduce rubella-containing vaccine and advance rubella and CRS elimination10.

In line with the 2011 WHO rubella position paper, the Global Alliance for Vaccines and Immunization (now the GAVI Alliance) started providing financial support to eligible countries for large-scale catch-up campaigns targeting children aged 9 months to 14 years, with the measles-rubella vaccine. In 2012, the Global Vaccine Action Plan, endorsed by the World Health Assembly, established the goal to eliminate rubella and CRS in two WHO regions by 2015 and to eliminate rubella in five WHO regions by 202011. During 2000–2014, the reported number of rubella cases declined by 95%, from 670,894 cases in 102 countries in 2000 to 33,068 cases in 162 countries in 2014; 141 CRS cases were reported from 114 countries in 201412. In 2016, three WHO regions (the Americas, Europe, and the Western-Pacific) had established a rubella elimination goal and 152 (78%) of 194 countries globally had introduced rubella-containing vaccine into their routine immunization programs (Table 13.1).

Table 13.1 Number of countries with rubella-containing vaccine in schedule, median CRS incidence per 100,000 live births and number of estimated CRS cases—World Health Organization regions

Region (Number of Countries)

Regional Target for Rubella

Number of Countries with Rubella-Containing Vaccine in Schedule by 2016 (%)

CRS Incidence per 100,000 Live Births, 2010 (95% CI)

Number of Estimated CRS Cases, 2010 (95% CI)

Africa (47)

None

13 (28%)

116 (56,235)

38,712 (18,063, 79,852)

Americas (35)

Elimination

35 (100)

< 0.01 (0,1)

< 1 (0, 136)

Eastern Mediterranean (21)

None

16 (76)

25 (4,61)

5,294 (827, 12,358)

Europe (53)

Elimination

53 (100)

1 (0,5)

98 (1,507)

South-East Asia(11)

Control

8 (73)

121(31,238)

49,229 (11,204, 96,976)

Western Pacific (27)

Elimination

27 (100)

23(12,50)

8,889 (4010, 21,118)

Global (194)

None

152 (78%)

105,391 (53,605, 158,041)

Rubella and CRS surveillance is essential in monitoring the disease burden, identifying and following up cases of pregnant women infected with rubella, and detecting CRS cases. Although efforts have been made to improve surveillance and reporting systems, rubella and CRS cases remain underreported in both developed and developing countries. Globally, the estimated number of CRS cases, based on seroprevalence data and modeling studies, decreased from 119,000 cases in 1996 to 105,000 cases in 201013 (Figure 13.1). The decrease was mostly seen in WHO regions that had rubella elimination goals, as well as countries that had introduced rubella-containing vaccines into routine immunization programs. In 2010, approximately 49,229 and 38,712 children with CRS were born in the South-East Asia and African WHO regions, respectively (Table 13.1). Countries are encouraged to introduce or strengthen their existing CRS surveillance systems to increase the number of CRS cases being detected and reported.

Figure 13.1 Estimated median incidence of CRS per 100,000 live births by country in 2010.

Figure 13.1 Estimated median incidence of CRS per 100,000 live births by country in 2010.

Source: Vynnycky E, Adams E, Cutts FT, Reef SNA, Simons E, Yoshida L, D. et al. Using seroprevalence and immunisation coverage data to estimate the global burden of congenital rubella syndrome, 1996–2010: A systematic review. PLoS One 2016;11:3. doi:10.1371/journal.pone.0149160

Rubella remains endemic in many parts of the world, especially in the African, Eastern Mediterranean, and South-East Asia regions, with periodic rubella outbreaks and subsequent clusters of CRS cases. In 2011, Vietnam experienced a large national rubella outbreak, with 279 CRS cases reported from January 2011 to December 2012, which led policymakers to introduce rubella-containing vaccine in 201514. Romania experienced large rubella outbreaks both in 2002–2003 and 2011–2012 because of immunity gaps in adolescents and young adults15,16. Japan and Poland, despite having introduced rubella-containing vaccine into their routine immunization programs, each country experienced a rubella outbreak in 2012—2013, primarily in susceptible adult males; this development reflected their history of selective vaccination of adolescent girls and women of childbearing age17,18. A total of 45 CRS cases were reported following the outbreak in Japan18.

In 2004, the U.S. declared that endemic rubella virus transmission had been interrupted in 2001. However, imported rubella cases continue to occur. Between 2004 and 2011, 77 rubella cases were reported, of which 42 (54%) were imported. Four CRS cases were reported during the same period, of which 3 (75%) had a history of maternal exposure outside the U.S.19 The last endemic rubella and CRS cases were reported in the U.S. Americas in 2009, and the region was declared free of endemic transmission in 201520.

Clinical Manifestations in the Infant

Rubella infection maybe asymptomatic in up to 50% of cases, making it difficult to retrospectively document maternal history of febrile rash during pregnancy, after an infant is diagnosed with CRS. Symptomatic pregnant women may present with a maculopapular rash (lasting 1–3 days), fever, malaise, and lymphadenopathy; polyarthritis and polyarthralgia are also common in women. Rare complications include post infection encephalitis, thrombocytopenia, hemorrhagic manifestations, and Guillain-Barré syndrome21,22. The incubation period is usually 12–23 days, with viremia occurring 5–7 days after exposure. The virus usually infects the placenta during the viremia phase. Placental infection leads to subsequent infection of fetal organs, which interferes with organogenesis during the first trimester of pregnancy and results in congenital defects2.

Infants born with CRS often present with a myriad of classical symptoms, including hearing impairment (60%), congenital heart defects (45%), cataracts (25%), and mental impairment (13%)22. Defects can present singly or in combination: hearing impairment alone is the most common single sequelae, with hearing impairment and congenital heart defects being the most common combination23. Gestational age at onset of rubella infection is important, because it is associated with congenital anomalies in the fetus; infection during the first 8 weeks of gestation is usually associated with ocular and cardiac defects, whereas infection in later pregnancy is associated with isolated hearing impairment23.

Hearing impairment in CRS cases can range from mild unilateral hearing impairment to profound bilateral sensorineural deafness. However, hearing defects are usually detected after 2 years of age and might not be attributed to congenital rubella infection, especially when presenting as a singular defect. Introduction of newborn hearing screening in many developed countries has increased the likelihood of detecting congenital hearing impairment and screening for CRS within the first year of life22.

Primary heart defects occurring in CRS cases include patent ductus arteriosus (PDA) and atrial septal defects, with PDAs occurring alone in 30% of CRS cases with heart defects. Other defects include ventricular septal defects and pulmonary arterial lesions such as valvular stenosis and stenosis of peripheral branches, which can occur alone or in combination with other defects24. Infants born with CRS who have congenital heart defects usually have a high mortality rate (11–31%), especially in the first year of life. The mortality rate associated with congenital heart defects might also be higher in developing countries depending on access to treatment23.

Pigmentary retinopathy, characterized by a salt-and-pepper appearance of the retina, is the most common eye defect in CRS cases, but it is asymptomatic. CRS cases also present with unilateral or bilateral cataracts, accompanied by micropthalmos in one-third of cases. Secondary glaucoma also may occur in cases with a cataract or following cataract surgery1,25.

Mental impairment occurs frequently in combination with hearing and eye defects; it is a challenge to assess the severity of mental impairment, especially in those cases with comorbid hearing, visual impairment, or both. In addition, infants with CRS frequently exhibit both intrauterine and postnatal growth retardation. CRS cases can present with transient defects in newborns, including thrombocytopenic purpura, hepatosplenomegaly, meningoencephalitis, and discrete bluish red lesions of dermal erythropoiesis characteristically known as blueberry muffin syndrome. Although most transient defects are self-limiting, a 35% mortality rate was observed in a group of infants presenting with neonatal thrombocytopenia26. CRS is also associated with long-term sequelae and autoimmune diseases; several studies have reported an increased risk for diabetes and thyroid disease among CRS cases27,28.

Infants born with congenital rubella infection might be asymptomatic at birth and might not become symptomatic until late infancy or childhood. Early identification of these cases is important because they can shed virus up to 1 year of age; however, in several cases, virus can persist for several years29,30. Early detection may also provide an opportunity for intervention and reduce the disability associated with congenital defects.

In 2015, the WHO published CRS case definitions to guide with case identification and classification (Table 13.2 and Box 13.1)31. These case definitions are currently being adopted by the WHO regions to implement and conduct CRS surveillance and report confirmed cases.

Table 13.2 WHO Standardized Congenital Rubella Syndrome Case Definitions

Case Category

Definition

Suspected CRS case

Any infant in whom a healthcare worker suspects CRS when the infant aged 0–11 months presents with heart disease and/or suspicion of hearing impairment and/or one or more of the following eye signs: cataract, congenital glaucoma, and pigmentary retinopathy. A healthcare worker should also suspect CRS when an infant’s mother has a history of suspected or confirmed rubella during pregnancy, even when the infant shows no signs of CRS.

Clinical-confirmed CRS case

An infant in whom a qualified physician detects at least two of the complications listed in group (a) below, or one in group (a) and one in group (b):

  1. (a) Cataract(s), congenital glaucoma, congenital heart disease, hearing impairment, and pigmentary retinopathy;

  2. (b) Purpura, splenomegaly, microcephaly, developmental delay, meningoencephalitis, radiolucent bone disease, and jaundice that begins within 24 hours of birth.

Laboratory-confirmed CRS case

An infant who is a suspected case [with one condition from the following: cataract(s), congenital glaucoma, congenital heart disease, hearing impairment, pigmentary retinopathy] and meets the laboratory criteria for CRS laboratory confirmation

Congenital rubella infection

An infant who does not have group (a) clinical signs of CRS, but who meets the laboratory criteria for CRS

Diagnosis

Laboratory testing is required to confirm suspected CRS cases since birth defects are common (around 6% of worldwide births) and may be caused by diverse factors (e.g., genetic disorders, environmental factors, and various teratogenic pathogens)32. Detection of rubella-specific immunoglobulin M (IgM) antibodies in cord blood, serum, or oral fluid is the most commonly used diagnostic method for CRS confirmation in newborns and infants. Most infants with CRS are IgM-positive from birth until 3–6 months of age33. The absence of rubella IgM in a specimen collected 1 month after birth unequivocally rules out CRS. If CRS is suspected after 6 months of age when rubella IgM typically declines to an undetectable level, testing for the presence of rubella IgG may be of value. Since maternal IgG antibodies begin to disappear from the infant’s circulation after about 6 months of age, rubella-specific IgG detected at age 7–11 months, from paired sera, may be suggestive of CRS34.

CRS also can be confirmed by isolation of rubella virus in cell culture or rapid detection of rubella RNA by reverse transcription polymerase chain reaction (RT-PCR). Throat and nasopharyngeal swabs, cerebrospinal fluid (CSF), urine, blood, lens aspirate, or postmortem tissues may be tested for rubella virus. Although many cell lines are susceptible to rubella, Vero cells are typically used for virus isolation. Since rubella virus does not produce a distinct cell cytopathic effect, detection of rubella proteins or RNA is necessary to confirm the presence of virus in the culture. CRS infants excrete virus for months after birth, and duration of virus secretion varies for different body sites—for instance, up to 6 months in urine and blood and up to 18 months in nasopharyngeal secretions24,35. Continuous virus shedding in CRS cases poses a risk to persons in contact. Virus transmission (such as in day care centers) should be prevented by imposing contact restrictions. The infant is considered to be noninfectious after two consecutive negative RT-PCR tests are obtained.

Treatment

There is no specific treatment recommended for rubella infection during pregnancy. Immunoglobulin does not treat or prevent rubella infection in susceptible pregnant women and is not recommended for routine postexposure prophylaxis of rubella in pregnant women. Infants with CRS have been born to women who have received immunoglobulin after exposure36.

CRS can lead to significant long-term disability that varies depending on the presenting defect or combination of defects in the infant. Hearing impairment is usually associated with significant disability, especially if combined with visual defects, mental impairment, or both. Data for outcomes of CRS cases is mainly available from high-income countries, where early intervention for cardiac and ocular defects can reduce mortality and disability. It is estimated that 19–29 disability-adjusted life years (DALYs) are lost per CRS case, depending on income level23.

Prevention

For prevention of rubella in the U.S., vaccination with rubella-containing vaccine is recommended for persons 12 months of age or older. Live attenuated rubella vaccines were licensed for use in the U.S. in 1969. The vaccine that is most widely used is based on the RA 27/3 strain, although China uses the BRD-2 strain and Japan uses three strains of vaccine: Takahashi, Matsuura, and TO-33621. Rubella vaccine is given in combination with measles and other pathogen vaccines as measles-rubella (MR), measles-mumps-rubella (MMR), or measles-mumps-rubella varicella (MMRV) vaccine. Two doses are routinely recommended for prevention of measles. Rubella vaccine, containing the RA 27/3 strain, is 97% effectiveness in preventing clinical disease after a single dose and provides long-lasting immunity10,37.

All women of childbearing age should have documented evidence of immunity, either through documented vaccination, serological evidence of immunity, or laboratory confirmation of rubella disease. A prenatal serologic screen is recommended for all pregnant women who lack evidence of rubella immunity. Rubella vaccine is currently not recommended for pregnant women. However, vaccination of unknowingly pregnant women is not an indication for abortion37. After completion or termination of pregnancy, women with no documented evidence of immunity should be vaccinated before discharge from a healthcare facility. Nonpregnant susceptible women who are recommended to receive rubella vaccination should be counseled to avoid becoming pregnant for 28 days after administration of a rubella-containing vaccine. However, no evidence of teratogenicity has been observed after the vaccination of approximately 3,000 unknowingly pregnant women, including those vaccinated during mass campaigns conducted in Brazil and Costa Rica38,39,21.

Future Directions

The current gaps in research for rubella and CRS can be divided into three categories: surveillance, diagnostics, and economics. As countries and regions move forward toward elimination and eradication of rubella, additional gaps in research will be identified and studied.

Ascertainment of CRS cases is challenging, infants with CRS might present with a spectrum of clinical problems and cases are managed by multiple specialties. In resource-limited settings, infants with CRS may not be diagnosed because of the lack of specific diagnostic tools. To ensure the feasibility and sensitivity of CRS surveillance, research is needed to determine the optimal approach for conducting surveillance (e.g., using a single defect or a combination of defects), especially in systems with limited health infrastructure. CRS surveillance is often conducted using various approaches in different countries. To standardize CRS surveillance, global CRS surveillance indicators are currently being developed based on indicators used in the WHO Region of the Americas. However, additional research is needed to adapt these surveillance indicators for use in other WHO regions.

Laboratory methods for diagnosis and confirmation of rubella infection are critical for the elimination of rubella. Most developing countries have limited resources and capacity for rubella virus detection, and most rubella and CRS surveillance systems rely on serology (specifically IgM assays) to detect rubella infection. Currently, serological testing can be used reliably only during the first year of life, prior to vaccination with rubella-containing vaccine. Serological biomarkers are being evaluated for the ability to confirm CRS in children older than 1 year of age. These biomarkers can be used as a way to estimate the burden of CRS in persons with CRS-associated defects (e.g., hearing impairment, cataracts).

There is also a need to better understand the global distribution of endemic rubella virus genotypes and to verify the elimination of genotypes. This information will be useful in understanding the transmission of rubella virus, especially in identifying the importation of cases into countries that have eliminated or nearly eliminated endemic rubella virus. As more of the global population is vaccinated against rubella and rubella incidence declines, it will be important to better understand the immunological and serological responses to rubella over time since the immunological response following vaccination is not as robust as that following the natural disease. Understanding the duration of rubella immunity over time in a vaccinated population will be important when rubella is eradicated and there is no opportunity for additional boosting.

Research on the economics of rubella and CRS is needed, with a focus on understanding the cost of global control versus eradication. One major gap in understanding the economics of CRS is the cost of CRS cases. In high- and middle-income countries, caring for CRS cases is costly. The annual cost of each CRS case from a health system perspective (i.e., cost of hospitalization and management) ranged from $4,261 in Brazil to $58,023 in Panama40,41. In Oman, the societal cost of a CRS case over a lifetime was estimated to be $139,91042.

In both industrialized and less industrialized countries in Latin America and the Caribbean, where rubella-containing vaccine coverage is more than 80%, cost-benefit studies of rubella vaccination have demonstrated that the benefits of vaccination outweigh the costs of clinical management and long-term disabilities associated with CRS, and that rubella vaccination is economically justified, particularly when combined with measles vaccination43. However, the cost of CRS in low-income countries is currently unknown. There are several studies ongoing to better understand the cost of CRS in terms of both indirect and direct costs. This information will provide data to support the case for investing in measles and rubella eradication, looking at the expected costs and benefits of eradication of both diseases over the next 30–40 years.

Conclusion

Significant progress has been made toward reducing the burden of rubella and CRS cases globally through the introduction of rubella-containing vaccines in many countries. The majority of countries that have yet to introduce rubella-containing vaccine into their childhood immunization systems are in the WHO Eastern Mediterranean and African Regions. Of the 40 countries in these two regions that have not yet introduced rubella vaccine, 32 (82%) have financial support from GAVI for introduction and are scheduled to introduce the vaccine before 2022. Success from the Region of the Americas has shown that the current vaccine is highly effective and rubella elimination is feasible using the present strategies. However, there are significant remaining challenges to achieve elimination in other regions, including civil unrest in the Eastern Mediterranean Region, low routine coverage in the African and South-East Asia Regions, and vaccination hesitancy in the European Region.

Further progress to reduce the burden of rubella and CRS is contingent on the following key strategies: introducing rubella-containing vaccine in the remaining countries, attaining high rubella vaccine coverage, and conducting high-quality rubella and CRS surveillance. Political will, partner commitment, and program coordination are critical at the global, regional, and national levels to meet the WHO regional rubella elimination goals.

Acknowledgments

We would like to thank Ludmila Perlygina, Joseph Icengole, and James Alexander for their contributions to the chapter.

Disclaimer

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Bibliography

1. Gregg NM. Congenital cataract following German measles in mother. Opthalmol Soc Aust 1941;3:35.Find this resource:

    2. Cooper L, Alford C Jr. Rubella. In Infectious Diseases of the Fetus and Newborn Infant. 6th ed. Philadelphia: W.B Saunders, 2006, 893–926.Find this resource:

    3. Miller E, Cradock-Watson JE, Pollock TM Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet 1982;2, 781–784.Find this resource:

    4. Bullens D, Smets K, Vanhaesebrouck P. Congenital rubella syndrome after maternal reinfection. Clin Pediatr (Phila) 2000;39, 113–116.Find this resource:

    5. Banerji A, Ford-Jones EL, Kelly E, Robinson JL. Congenital rubella syndrome despite maternal antibodies. CMAJ 2005;171(13):1678–1679.Find this resource:

    6. Robinson J, Lemay M, Vaudry WL. Congenital rubella after anticipated maternal immunity: two cases and a review of the literature. Pediatr Infect Dis J 1994;9, 812–815.Find this resource:

    7. Goodson J, Masresha B, Dosseh A, Byabamazima C, Nshimirimana D, Cochi S, Reef S. Rubella epidemiology in Africa in the prevaccine era, 2002–2009. J Infect Dis 2011;Suppl 1, S215–225.Find this resource:

    8. National Communicable Disease Center. Rubella surveillance.Bethesda, MD: U.S. Department of Health, Education, and Welfare, 1969.Find this resource:

      9. World Health Organization (WHO). Rubella Vaccines. Geneva, Switzerland: World Health Organization, 2000.Find this resource:

        10. World Health Organization (WHO). Rubella vaccines: WHO position paper, Weekly Epidem Rec 2011;86(29):301–316.Find this resource:

          11. World Health Organization (WHO). Global Vaccine Action Plan. Geneva, Switzerland: World Health Organization, 2012.Find this resource:

            12. Grant G, Reef S, Dabbagh A, Gacic-Dobo M, Strebel PM. Global progress toward rubella and congenital rubella syndrome control and elimination—2000–2014, MMWR Morb Mortal Wkly Rep 2015 Sep 25;64(37):1052–1055.Find this resource:

            13. Vynnycky E, Adams E, Cutts FT, Reef SNA, Simons E, Yoshida L, D. et al. Using seroprevalence and immunisation coverage data to estimate the global burden of congenital rubella syndrome, 1996–2010: A systematic review. PLoS One 2016;11:3.Find this resource:

            14. Toda K, Reef S, Tsuruoka M, Iijima M, Dang TH, Duong TH, Nguyen VCNguyen TH. Congenital rubella syndrome (CRS) in Vietnam 2011–2012—CRS epidemic after rubella epidemic in 2010–2011. Vaccine 2015;33(31):3673–3677.Find this resource:

            15. Janta D, Stanescu A, Lupulescu E, Molnar G, Pistol A. Ongoing rubella outbreak among adolescents in Salaj, Romania, September 2011–January 2012, Euro Surveill 2012;17:7.Find this resource:

              16. Rafila A, Marin M, Pistol A, Nicolaiciuc D, Lupulescu E, Uzicanin A, Reef S. A large rubella outbreak, Romania—2003. Euro Surveill 2004;9:4, 7–9.Find this resource:

              17. Korczyńska MR, Paradowska-Stankiewicz I. Rubella in Poland in 2013. Przegl Epidemiol 2015;69:2, 341–343.Find this resource:

                18. Sugishita Y, Shimatani N, Katow S, Takahashi T, Hori N. Epidemiological characteristics of rubella and congenital rubella syndrome in the 2012–2013 epidemics in Tokyo, Japan. Jpn J Infect Dis 2015;68(2):159–165.Find this resource:

                19. Papania MJ, Wallace GS, Rota PA, Icenogle JP, Fiebelkorn AP, Armstrong GL, et al. Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience. JAMA Pediatr 2014;168(2):148–155.Find this resource:

                20. Pan American Health Organization. Elimination of rubella and congenital rubella syndrome in the Americas. www.paho.org, April 29, 2015. Accessed May 8, 2017, from http://www.paho.org/hq/index.php?option=com_content&view=article&id=10798%3A2015-americas-free-of-rubella&Itemid=1926&lang=en.

                21. Plotkin S, Reef S. Rubella vaccine. In Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines, Philadelphia: Saunders, 2013;688–717.Find this resource:

                  22. Reef SE, Plotkin S, Cordero JF, Katz M, Cooper L, Schwartz B, et al. Preparing for elimination of congenital rubella syndrome (CRS): summary of a workshop on CRS elimination in the United States. Clin Infect Dis 2000;31:1, 85–95.Find this resource:

                  23. Simons EA, Reef SE, Cooper LZ, Zimmerman L, Thompson KM. Systematic review of the manifestations of congenital rubella syndrome in infants and characterization of disability-adjusted life years (DALYs). Risk Anal 2014;36(7): 1332–1356.Find this resource:

                  24. Cooper LZ, Krugman S. Clinical manifestations of postnatal and congenital rubella. Arch Ophthalmol 1967;77(4):434–439.Find this resource:

                  25. Arnold J. Ocular manifestations of congenital rubella. Curr Opin Ophthalmol 1995;6(3):45–50.Find this resource:

                  26. Cooper LZ. The history and medical consequences of rubella. Rev Infect Dis 1985;7(Suppl 1):S2–S10.Find this resource:

                  27. Ginsberg-Fellner F, Witt ME, Fedun B, Taub F, Dobersen MJ, McEvoy RC, et al. Diabetes mellitus and autoimmunity in patients with congenital rubella syndrome. Rev Infect Dis 1985;7(Suppl 1):S170–176.Find this resource:

                  28. Forrest JM, Turnbull FM, Hawker SGFRE, Martin FJ, Doran TT, Burgess MA. Gregg’s congenital rubella patients 60 years later. Med J Aust 2002;177(11–12):664–667.Find this resource:

                  29. Cooper LZ, Green RH, Krugman S, Giles JP, Mirick GS. Neonatal thrombocytopenic purpura and other manifestations of rubella contracted in utero. Am J Dis Child 1965;110(4):416–427.Find this resource:

                  30. Menser MA, Harley JD, Hertzberg R, Dorman DC, Murphy AM. Persistence of virus in lens for three years after prenatal rubella. Lancet 1967;2:7512, 387–388.Find this resource:

                  31. World Health Organization (WHO). Introduction of Rubella Vaccine into National Immunization Programmes. Geneva, Switzerland: World Health Organization, 2015.Find this resource:

                    32. Christianson A, Howson CP, Modell B. March of Dimes Global Report of Birth Defects: The Hidden Toll of Dying and Disabled Children. White Plains, NY: March of Dimes Birth Defects Foundation, 2006.Find this resource:

                      33. Cradock-Watson JE, Ridehalgh MK. Specific immunoglobulins in infants with congenital rubella syndrome. J Hyg (Lond) 1976;76(1):109–123.Find this resource:

                      34. Best JM, Icenogle JP, Brown DWG. Rubella. In Zuckerman AJ, Banatvala JE, Schoub BD, Griffiths PD, Mortimer P, eds. Principles and Practice of Clinical Virology, Sixth Edition. John Wiley & Sons, Ltd., Chichester, UK. 2009.Find this resource:

                      35. Sever JL, Monif G. Limited persistence of virus in congenital rubella. AM J Dis Child 1965;110(4):452–454.Find this resource:

                      36. American Academy of Pediatrics. Rubella. In Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2012 Report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics, 2012, 629–634.Find this resource:

                        37. McLean HQ, Fiebelkorn AP, Temte JL, Wallace GS. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013;62(RR-04):1–34.Find this resource:

                        38. Soares R, Siqueira M, Toscano C, Maia Mde L, Flannery B, Sato H, et al. Follow-up study of unknowingly pregnant women vaccinated against rubella in Brazil, 2001–2002. J Infect Dis 2011;204(Suppl 2):S729–S736.Find this resource:

                        39. Badilla X, Morice A, Avila-Aguero ML, Saenz E, Cerda I, Reef S, Castillo-Solórzano C. Fetal risk associated with rubella vaccination during pregnancy. Pediatr Infect Dis J 2007;26:9, 830–835.Find this resource:

                        40. Lanzieri TM, Parise MS, Siqueira MM, Fortaleza BM, Segatto TC, Prevots DR. Incidence, clinical features, and estimated costs of congenital rubella syndrome after a large rubella outbreak in Recife, Brazil, 1999–2000. Pediatr Infect Dis J 2004;12:1116–1122.Find this resource:

                        41. Saad de Owens C, Tristan de Espino R. Rubella in Panama: still a problem. Pediatr Infect Dis J 1989;8(2):110–115.Find this resource:

                        42. Al-Awaidy S, Griffiths UK, Nwar HM, Bawikar S, Al-Aisiri MS, Khandekar R, et al. Costs of congenital rubella syndrome (CRS) in Oman: evidence based on long-term follow-up of 43 children. Vaccine 2006;24(40 –41):6437–6445.Find this resource:

                        43. Hinman AR, Irons B, Lewis M KK. Economic analyses of rubella and rubella vaccines: a global review. Bull World Health Organ 2002;80(4):264–270.Find this resource: