This study showed that the rubella-specific IgM antibody prevalence in Japanese pregnant women was approximately 1.0%, and almost all of them were not acutely infected. The study also showed that a few patients retained high rubella-specific IgM antibody titers. Furthermore, there was a weak positive correlation between rubella HI and rubella-specific IgM antibody titers; however, more than 70% of patients who tested positive for rubella-specific IgM had rubella HI antibody titers of less than 1:256.
Rubella-specific IgM antibodies are detectable 4 days after the onset of illness, persist for 1 month, and are used with IgG antibodies measured in paired sera to diagnose acute-phase infection [11]. False-positive IgM antibody test results can be detected in patients with other viral infections or rheumatoid factor positivity, and IgM antibodies can be persistently positive after immune acquisition [12], which is termed “persistent IgM” in the Japanese obstetric guidelines [9]. Given that the positive predictive value is relatively low because of the frequency of false-positive and persistent IgM antibody carriers and the low prevalence of rubella infection, it is important to assess the frequency of false-positive and persistent IgM antibody carriers for the diagnosis of rubella infection by using IgM antibodies. In our survey [10] of 1,850 deliveries between 2003 and 2006, the prevalence of rubella-specific IgM antibody positivity was reported at 1.1%. Although data on the number of rubella cases in Japan before 2007 are unavailable, the exact number of all cases of congenital rubella syndrome is known. There were 13 cases (an average of 3.25 cases/year) in the 4 years at that time and 53 cases (an average of 3.79 cases/year) in the 14 years of the present study period with no significant difference [13], suggesting that the rubella-specific IgM antibody positivity rate also remained unchanged. The rubella-specific IgM antibody positivity rate was 1.3% in the year 2013, which was slightly higher than that in the non-epidemic years. Therefore, it can be reasonably estimated that the rubella-specific IgM antibody positivity rate in pregnant women in Japan is approximately 1%, although it is expected to vary from time to time and among different regions, depending on the degree of an outbreak. In addition, the epidemic year 2013 did not significantly affect the rubella-specific IgM antibody positivity rate.
This study also showed that the rubella-specific IgM antibody titer of persistent IgM can be high.
In Japan, HI antibody titers have traditionally been used to diagnose rubella infection because of their simplicity and cost. Japanese obstetric guidelines recommend HI antibody measurement in the first trimester of pregnancy to alert pregnant women with low antibody titers for possible rubella infection or to diagnose rubella infection with high antibody titers [9]. In pregnant women with high HI antibody titers, rubella-specific IgM antibody measurement is recommended for the diagnosis of rubella infection for recent infection. However, owing to the false-positive/persistent IgM titers, a rubella-specific IgM positive result does not always indicate a recent infection. Although there were many reports of false-positive/persistent IgM [14–19], the levels of IgM antibody titers of false-positive/persistent IgM are not known.
Banatvala et al. [14] reported low levels of rubella-specific IgM positivity over a long period but did not provide specific antibody titers. In the present study, several pregnant women had rubella-specific IgM antibody titers as high as those at the start of rubella infection and rubella vaccination [20]. However, these patients did not show a recent clinical infection. This finding suggests that even patients with rubella-specific IgM antibody titers markedly higher than the cutoff, in the absence of risk factors for rubella infection, should be advised that persistent IgM or false-positive results are very likely. The measurement of rubella-specific IgM antibodies should be performed in women with a history of contact or when symptoms are observed during pregnancy [21], which is supported by the present study’s findings.
The study found a weak positive correlation between rubella HI antibody titer and rubella-specific IgM antibody titer; however, more than 70% of rubella-specific IgM-positive patients had rubella HI antibody titers less than 1:256. The HI assay measures total IgG, IgM, and IgA antibody titers, and immunity against rubella infection is associated with the levels of these antibodies [22]. The rubella HI assay is known to correlate with rubella-specific IgG antibody titers in the EIA assay [23]; however, in several patients rubella HI antibody titers did not correlate with rubella-specific IgG antibody titers in the EIA assay [24]. This may be due to high rubella-specific IgM antibody titers, as shown in this study, and measurement error in the HI assay [25]. The results of this study indicate that it is difficult to estimate the time point of rubella infection using only the combination of rubella HI antibody measurement and rubella-specific IgM antibody measurement. Hence, it is important to consider the medical history of the patient and the measurement of rubella-specific IgG antibody titers using paired sera for the diagnosis of rubella. The measurement of rubella-specific IgM antibody titers should be considered an auxiliary diagnostic method. In the absence of risk factors for rubella infection, the measurement of rubella-specific IgM antibodies based on the rubella HI antibody titers is not essential because almost all rubella-specific IgM antibody-positive patients and rubella-specific IgM antibody-high patients were not acutely infected and more than 70% of rubella-specific IgM positive patients have HI antibody titers of less than 1:256.
This is the largest study reporting rubella-specific IgM prevalence in pregnant women and is the first to report a correlation between rubella HI antibody titer and rubella-specific IgM antibody titer using rubella-specific IgM antibody levels, regardless of whether the rubella HI antibody titer was high or low.
There are a few limitations of this study. First, this study did not rule out rubella infection among patients who were rubella-specific IgM-negative, so it is not possible to calculate the sensitivity and specificity of rubella-specific IgM measurements for the diagnosis of rubella infection. During the study period, there were no cases of congenital rubella syndrome in our hospital, and none of the rubella-specific IgM-negative patients had an induced abortion because of rubella infection. However, the study could not confirm the presence or absence of rubella infection in patients with interrupted hospital visits who tested negative for rubella-specific IgM. Second, the study did not examine the subclinical infection. In Japan, 70 cases of congenital rubella syndrome were reported between 2000 and 2021, including 10 cases in women with no history of rubella during pregnancy, and 14 cases in women with an unknown history of rubella during pregnancy [13]. Congenital rubella syndrome caused by subclinical infection is still unclear [26], and it is unknown how serological changes are detected in subclinical infection. Therefore, further future studies are warranted in that direction to achieve the complete eradication of rubella in Japan.