Introduction
     Rubella is a systemic viral infectious disease with mild symptoms compared to measles and accompanied by rash and fever. Also dubbed "three-day measles" in Japan, it afflicts children primarily. However, it is known that when it infects pregnant women at the early stage of their pregnancy, the newborns may acquire congenital rubella syndrome (CRS).
     In Japan, the rubella vaccine was incorporated into the routine vaccination of girls in junior high schools from 1977 (age: 12~14 years) following the model adopted in the UK. Twenty seven years have elapsed since then and with the popularization of the vaccine large-scale rubella epidemics have been brought under control. Nevertheless the number of reports of rubella cases from sentinel pediatric medical institutions in charge of infectious disease surveillance in Oita, Kagoshima, Miyazaki, Tochigi, Gunma and Miyagi prefectures increased at the beginning of the year 2004; 2,278 cases have been reported up to May 9 this year, accounting for 80% of the total number of reports for the whole year 2003. In the meantime three children suffering from CRS were reported. Therefore on April 9, the Ministry of Health, Welfare and Labour sent a notification to all the prefecture authorities to draw their attention to the prevention of CRS and recommending in particular immunization of women who intend to become pregnant and who have no history of rubella. In this article, we will discuss the current status of rubella and the reasons for its re-emergence.
1 Rubella and CRS
     Rubella is normally endemic from March through June and it infects primarily children aged 1~4 years. However this year a high proportion of infected subjects are aged 10~14 years and 20 years and over.
     The incubation period of rubella is 2~3 weeks. Over half of the patients develop a rash, following a prodrome consisting of swelling of the lymph nodes of the retroauricular region, low-grade fever, malaise and conjunctivitis. The virus is excreted from the upper respiratory tract notably for one week before and after the onset of a rash and becomes the source of infection. Re-infection may occur when the level of antibodies decreases and this occurs more often in those who aguired immunity by vaccination than natural infection. In general re-infection remains symptomless during its course.
     Pregnant women afflicted with rubella may in some cases experience natural abortion or stillbirth. CRS occurs through vertical infection to the fetus by the rubella virus. Nevertheless intrauterine infection does not inevitably induce defects in newborn children. The incidence of defects and their nature are closely related to the time of the infection during pregnancy. (Miller E. et al. Lancet 2: 788-784, 1982). The frequency of defects in the newborn varies with the reports. Generally speaking, cataract, cardiac diseases and deafness occur in a multiple form in 33~90% in infection in women during the first trimester of pregnancy, deafness occurs in 11~24% during the following three months, and anomalies are practically not observed after 18 weeks. Besides there are no defects due to infection before conception. Immediately after birth, symptoms that are not always clinically evident, such as retinopathy, mental retardation, deafness and endocrinal anomalies may sometimes appear.
2 Diagnosis of rubella in pregnant women
     There is apparently a great number of cases of induced abortion in pregnant women who fear CRS simply because they have been infected with rubella. In order to avoid unneeded induced abortions, it is important to estimate the time of infection. Since IgM antibodies rise rapidly from the 4th day after the rash before IgG antibodies and they decline more rapidly than IgG antibodies, the detection of IgM antibodies by means of enzyme immunoassay (EIA) is widely used for the diagnosis at the acute stage. However, the detection of rubella antibodies in pregnant women is often done in a set combining hemagglutination inhibition (HI) and determination of EIA-IgM antibodies, not only in case acute infection is suspected but also in general during examination ten weeks or more after becoming pregnant. The sensitivity of IgM detection kits has been improved, and a low level of IgM antibodies may be detected one year later or even during re-infection. Thus the estimation of the time of infection in asymptomatic cases becomes difficult. A slightly positive IgM antibody titer will not suffice to determine the early stage after the infection or primary infection. If the level of HI antibodies is high, re-infection may be suspected, and in case the level is low, IgM antibodies remaining from a previous infection many years ago will be suspected. With EIA, the decision is made often by determining one specimen, but it is also necessary to observe the variations in the antibody titer through simultaneous measurement in pairs with the sera collected after several weeks.
     In case of re-infection, the incidence of CRS is reportedly extremely low compared to primary infection. Therefore in case a low level of IgM antibody is detected, making a distinction between primary infection and re-infection by checking the avidity of EIA-IgG antibody and the antigen will be helpful for the diagnosis.
     On the other hand, it is possible to check up for the presence of rubella infection by detecting directly the genes of the rubella virus from specimens of fetal origin (placenta villus, amniotic fluid, cord blood) by means of RT-PCR and nested PCR. According to Shigetaka Kato and coworkers, no anomalies were observed in the newborn except for two cases out of 254 in whom the fetal PCR result was negative in pregnant women in whom rubella infection was suspected (Review of the Japanese Society for Obstetrics and Gynecology, 52 (2) 366,2000). In these two cases, cold blood was not collected and the specimens were obtained only from amniotic fluid whose reliability is inferior. Since the PCR technique allows to know infection in the fetus more directly than antibody tests in pregnant women, it should contribute to reduce the number of unneeded induced abortions. However, this test is not currently done in ordinary laboratory test facilities.
     Thus since there are limits to definitely identify the time of the asymptomatic infection in pregnant women even with any of these techniques and to precisely predict occurrence of CRS, it is important to make an overall decision, after taking into consideration the contacts with persons infected with rubella and of an outbreak in their surroundings.
3 Vaccination and status of antibody carriage
     Routine vaccination against rubella that began in Japan in 1977 was focused on junior high school female students in order to immunize them during their puberty before pregnancy, the primary objective being the prevention of CRS. At that time all children in the US were receiving the vaccine. The measles-mumps-rubella combined vaccine (MMR) was given on an option basis to children receiving routine measles vaccination (12~72 months of age) from 1989 in parallel to routine immunization of these junior high school female students. However, MMR vaccination was suspended in 1993 due to the occurrence of meningitis caused by a constituent of the mumps vaccine. Then in 1994 the Prophylaxis Vaccination Act was amended, and the target of immunization against rubella was changed from simply focussing protection against CRS to prevention of rubella epidemics. Afterward from 1995 the target for routine vaccination was changed from junior high school female students to both male and female children aged from 12 months to 90 months. At the same time boys and girls aged 12 to less than 16 years who were born between April 2, 1979 and October 1st, 1983 and who lost the chance to be vaccinated because the vaccination schedule had been implemented earlier were subjected to routine vaccination as a temporary measure until September 2003, so that they could be immunized at the age of 12 to less than 16 years. Likewise the vaccination method was also changed from mass immunization to individual immunization. This resulted in a decrease in the vaccination coverage in that age group. Therefore the Prophylaxis Vaccination Act was amended again in 2001. Indeed the upper age limit was removed without changing the regulations on the birth date specified in the temporary measure, and children aged 14 years and over became eligible for vaccination during the period up to September 2003. However, according to a calculation made by the Ministry of Health, Welfare and Labour, the vaccination rate during the temporary measure fluctuated around 50% it decreased notably to 39% in 2001 and to 15% in 2002, although the vaccination coverage in children was as high as 92% and over from 1995 onward. As a result, approximately half of the people who have now reached the age of 16~25 years and who were eligible for the temporary measure have not been immunized. In addition, according to a survey of the prediction of infectious disease epidemics in 2002, the antibody-positive rate of males aged 25 to 39 years who were not vaccinated fell to 64%. Since the antibody-positive rate of vaccinated females of the same age is as high as 90%, and over there exisis a vast number of antibody-negative males.
4 Rubella epidemics and occurrence of CRS
     According to Infectious Agents Surveillance Reports(IASR), the annual number of reports of rubella patients from 1999 to 2003 is below 4,400, and large-scale nationwide rubella outbreaks that occurred so far every five years have not been observed any longer (IASR 24, 3, 2003). This is apparently due to the decrease in the incidence thanks to the immunization of susceptible children, who were the main victims of the outbreaks, following the amendment of the Prophylaxis Vaccination Act in 1994. At the same time CRS that struck a total of 301 subjects in parallel to outbreaks from 1978 to 1993 fell remarkably (Shigetaka Kato, "Clinical Virology" in Japanese 23 (3): 148~154, 1955), and only one case was reported each year during the last four years. However, regional rubella outbreaks continued to occur, and two CRS cases out of three in 2004 occurred in Okayama when rubella broke out two years ago and last year. These current regional outbreaks are not restricted to these areas and show a tendency to spread to neighboring regions. The decrease in the vaccination rate of adolescents and the accumulation of susceptible subjects are apparently the reasons for these recent outbreaks and the high age at which the disease is contracted. It will be necessary to pay attention to the changes in the age at which the disease is contracted. In former years the majority of children were the source of infection to pregnant women who had no antibodies. However, now there is a high possibility that their husbands may be the source of infection. The shedding of the virus from the pharynx of vaccinees is observed after immunization. However, since it does not spread to their contacts, the husbands who have no antecedents of rubella infection are advised to be vaccinated immediately.
5 Control measures
     Rubella is a vaccine preventable disease. We have described the great merits of immunizing small children. However, it has been pointed out that in sufficient immunization of children against rubella will decrease the antibody carriage rate in women of child-bearing age and consequently increase the incidence of CRS. The UK and the US have achieved results in the control of both rubella and CRS by implementing a two-dose vaccination schedule with the MR or the MMR vaccine. It will be necessary to take radical control measures as rapidly as possible in order to prevent CRS, the most serious problem with rubella.
Conclusion
     CRS can be avoided by immunization against rubella at the child-bearing age. Maintaining at a high level the vaccination rate in children and in women of child-bearing age is essential for the control of CRS.