Safety profile of rubella vaccine administered to pregnant women: A systematic review of pregnancy related adverse events following immunisation,including congenital rubella syndrome and congenital rubella infection in the foetus or infant

BackgroundData on the safety of inadvertent rubella vaccination in pregnancy is important for rubella vaccination programs aimed at preventing congenital rubella syndrome.MethodsThe association between monovalent rubella or combination vaccinations in or shortly before pregnancy and potential harm to the foetus was examined by conducting a systematic review and meta-analysis using fixed effect methods and simulation.ResultsFour cohort studies of inadvertently vaccinated and unvaccinated women were found, 15 cohorts of pregnant women who were rubella susceptible at time of inadvertent vaccination and 9 cohort studies with no information on susceptibility and case series. No case of vaccine associated congenital rubella syndrome (CRS) was identified. Cohort studies with an unvaccinated comparison group were limited in number and size, and based on these only a theoretical additional risk of 6 or more cases of CRS per 1000 vaccinated women (0% observed, upper 95% CI 0.6%) could be excluded. Based on cohorts of vaccinated rubella susceptible pregnant women a maximum theoretical risk of 1 CRS case in 1008 vaccinated women (0% observed, upper 95% CI 0.099%) was estimated. Asymptomatic rubella vaccine virus infection of the neonate was also noted (fixed effects estimate of risk overall 1.74%, 95% CI 1.21, 2.28).ConclusionThere is no evidence that CRS is caused by rubella-containing vaccines but transplacental vaccine virus infection can occur. CRS is effectively prevented by vaccination, thus the risk/benefit balance is unequivocally in favour of vaccination. The data confirm previous recommendations that inadvertent vaccination during pregnancy is not an indication for termination of pregnancy.     

Estimating the burden of rubella virus infection and congenital rubella syndrome through a rubella immunity assessment among pregnant women in the Democratic Republic of the Congo: Potential impact on vaccination policy

BackgroundRubella-containing vaccines (RCV) are not yet part of the Democratic Republic of the Congo’s (DRC) vaccination program; however RCV introduction is planned before 2020. Because documentation of DRC’s historical burden of rubella virus infection and congenital rubella syndrome (CRS) has been minimal, estimates of the burden of rubella virus infection and of CRS would help inform the country’s strategy for RCV introduction.MethodsA rubella antibody seroprevalence assessment was conducted using serum collected during 2008–2009 from 1605 pregnant women aged 15–46 years attending 7 antenatal care sites in 3 of DRC’s provinces. Estimates of age- and site-specific rubella antibody seroprevalence, population, and fertility rates were used in catalytic models to estimate the incidence of CRS per 100,000 live births and the number of CRS cases born in 2013 in DRC.ResultsOverall 84% (95% CI 82, 86) of the women tested were estimated to be rubella antibody seropositive. The association between age and estimated antibody seroprevalence, adjusting for study site, was not significant (p = 0.10). Differences in overall estimated seroprevalence by study site were observed indicating variation by geographical area (p ⩽ 0.03 for all). Estimated seroprevalence was similar for women declaring residence in urban (84%) versus rural (83%) settings (p = 0.67). In 2013 for DRC nationally, the estimated incidence of CRS was 69/100,000 live births (95% CI 0, 186), corresponding to 2886 infants (95% CI 342, 6395) born with CRS.ConclusionsIn the 3 provinces, rubella virus transmission is endemic, and most viral exposure and seroconversion occurs before age 15 years. However, approximately 10–20% of the women were susceptible to rubella virus infection and thus at risk for having an infant with CRS. This analysis can guide plans for introduction of RCV in DRC. Per World Health Organization recommendations, introduction of RCV should be accompanied by a campaign targeting all children 9 months to 14 years of age as well as vaccination of women of child bearing age through routine services.     

山东省实施儿童风疹疫苗免疫后风疹发病年龄变化趋势的分析

目的分析山东省自1995年开始实施儿童风疹疫苗免疫后风疹发病年龄的变化趋势。方法对1999—2004年通过麻疹疫情专报系统得到的风疹疫情资料以及风疹疫苗接种情况进行分析。结果1999—2004年山东省风疹年平均报告发病率为0．59／10万，多为暴发（占总病例数的81．17％）；发病主要集中在7～15岁学龄儿童（77．77％），7岁以下发病较少（占7．93％），发病年龄中位数分别为10．37岁、11．66岁、11．41岁、12．81岁、14．28岁和13．96岁，发病高峰年龄逐年后移，成人发病有所增加；学龄前儿童风疹疫苗基础免疫估算接种率约为60％，学龄儿童约为20％。结论风疹发病年龄后移，将威胁育龄期妇女，增加发生先天性风疹综合征的危险性；应在继续做好儿童风疹免疫的同时，积极开展育龄期妇女风疹抗体筛查及疫苗接种工作。     

Rubella in Orkney: seroepidemiology and vaccination

Rubella haemagglutination inhibiting (HAI) antibody titres were determined in 54 seronegative women and 31 naturally immune women after vaccination and revaccination with Wistar RA27/3 strain rubella vaccine administered by the intranasal or subcutaneous routes or revaccination with the Cendehill strain administered subcutaneously. In addition, HAI antibody titres were determined in 46 seronegative schoolgirls after vaccination with the Cendehill strain and revaccination with the RA27/3 strain.     

Modelling the incidence of congenital rubella syndrome in developing countries

BACKGROUND: As of 1997, less than one-third of developing countries included rubella vaccine in their national immunization programme. In countries that have achieved high coverage of measles vaccine, an ideal opportunity exists to include control of rubella and congenital rubella syndrome (CRS) in enhanced measles control activities. Data on the burden of congenital rubella syndrome are important to guide rubella vaccination policies. METHODS: We reviewed the literature to identify studies of rubella antibody prevalence in developing countries that were conducted on populations with no major selection bias, prior to wide-scale rubella vaccination in the country. We used a simple catalytic model to describe the age-specific prevalence of susceptibility to rubella virus infection in given populations. Estimates of the incidence of infection among pregnant women were calculated using expressions for the average prevalence of susceptibility to infection and the incidence of infection during gestation. To estimate the number of cases of CRS, we assumed an overall risk of 65% after infection in the first 16 weeks of pregnancy and zero risk thereafter. These estimates were derived for each country for which data were available, then for each World Health Organization region, excluding Europe. RESULTS: The estimated mean incidence of CRS per 100,000 live births was lowest in the Eastern Mediterranean region (77.4, range 0-212) and highest in the Americas (175, range 0-598). The mean of the estimates of the total number of cases of CRS in developing countries in 1996 was approximately 110,000. The range was, however, very wide, from as few as 14,000 to as many as 308,000 cases. CONCLUSIONS: Congenital rubella syndrome is an under-recognized public health problem in many developing countries. There is an urgent need for collection of appropriate data to estimate the cost-effectiveness of a potential global rubella control programme.     

2005年山东省部分孕期妇女风疹易感性调查

[目的]了解山东省孕期妇女风疹易感性水平,为调整风疹疫苗免疫策略提供依据。[方法]2005年,采集不同地区到医院准备分娩的20~40岁孕妇血清,采用间接酶联免疫吸附定量法检测风疹IgG抗体。[结果]检测标本3 788份,风疹抗体阳性(>20 IU/ml)的2 942人,阴性(<10 IU/ml)的314人,临界值(10~20 IU/ml)的532人,易感(临界值和阴性者)合计846人,易感率为22.33%。几何平均抗体含量(CMT)为34.93 IU/ml。不同地区风疹易感率和CMT的差异均有统计学意义(P<0.01);风疹易感率有随年龄增长而增高的趋势(P<0.01)。[结论]山东省近1/4的孕妇为风疹的易感者,有必要对育龄期妇女开展风疹疫苗接种。     

Last cases of rubella and congenital rubella syndrome in Spain, 1997–2016: The success of a vaccination program

With a highly immunized population, rubella infection in Spain is so low that the WHO has declared the elimination of rubella. Rubella in pregnant women is also very rare. The objective of this study is to describe the last cases of congenital rubella syndrome reported and recommend actions to maintain the status of the disease as eliminated.The CRS cases reported to the Spanish National Epidemiological Surveillance Network between 1997 and 2016 were studied, and the epidemiological, clinical, diagnostic and maternal characteristics of newborns with CRS described. The incidence of CRS was calculated using Birth Statistics from the Spanish National Statistics Agency (INE).Twenty-three cases of CRS were reported, 70% of which were associated with rubella outbreaks. The most common clinical conditions were heart disease (52.2%), deafness (39.1%) and cataracts (30.4%); 91.3% of cases were confirmed by laboratory testing. 70.0% were born from a non-vaccinated foreign mother, resident in Spain (cumulative rate incidence (CR): 1.1/100,000 births), with mothers coming from Africa (36.0%), Latin America (29.0%), Eastern Europe (21.0%) and Asia (14.0%). Six were born to Spanish mothers (CR: 0.08/ 100,000 births), the last of which were in 2005.The majority of CRS cases were born to unvaccinated immigrant women infected in Spain during rubella outbreaks. Universal vaccination in childhood is the most efficient strategy to prevent rubella. The limited circulation of the virus will, however, quickly lead to a loss of awareness about rubella among clinicians and epidemiologists. It is necessary to maintain protocols capable of identifying signs consistent with rubella in pregnant women and signs suggestive of congenital rubella in newborns.     

Sero-epidemiology of rubella in the urban population of Addis Ababa, Ethiopia

We conducted a community-based cluster sample survey of rubella sero-epidemiology in Addis Ababa, Ethiopia in 1994. Among 4666 individuals for whom complete data were available, rubella antibody prevalence was 91% (95% confidence interval: 90, 92). On multivariable analysis, seroprevalence was lower among individuals who were resident in Addis Ababa for 1 year or less. Approx. 50% seroprevalence was attained by age 4 years, and the estimated average age at infection was 5.2 years. The highest age-specific force of infection was estimated to occur in 5- to 9-year-olds. The early age at infection corresponded with a low estimated incidence of congenital rubella syndrome (CRS) of 0.3 per 1000 live births, equivalent to nine cases of CRS in 1994. The predicted critical level of immunity for elimination of rubella via vaccination was 85-91%, requiring 89-96% coverage with a vaccine of 95% effectiveness. Unless very high coverage of rubella vaccine could be guaranteed, the introduction of childhood vaccination could increase the incidence of CRS in Addis Ababa.     

Seroprevalence of rubella in the cord blood of pregnant women and congenital rubella incidence in Nha Trang,Vietnam

To investigate susceptibility to and factors associated with rubella infection among pregnant mothers and to estimate the burden of congenital rubella infection (CRI) in Vietnam where rubella-containing vaccine (RCV) is not included in the routine immunization program, we conducted a prospective cohort study in Nha Trang, Vietnam between 2009 and 2010. Rubella-specific immunoglobulin-M and immunoglobulin-G were investigated in cord blood samples by enzyme immunoassay. Corresponding clinical–epidemiological data were analyzed and the national congenital rubella syndrome (CRS) incidence was estimated using modeling. We enrolled 1988 pairs of mothers aged 17–45 years and their newborn babies. No mothers had received RCV. Multivariate analysis revealed that mothers aged 17–24 (aOR 2.5, 95% CI: 1.7–3.8) or 25–34 (1.4, 1.0–2.1) years were more likely to be susceptible than those aged 35–45 years. Overall 28.9% (574/1988, 95% CI: 26.9–30.9%) of mothers were seronegative. The CRI rate was 151 (95% CI: 0–322) per 100,000 live births. Modeling estimated that 3788 babies (95% CI: 3283–4143) were born with CRS annually in Vietnam with an overall CRS incidence of 234 (95% CI: 207–262) cases per 100,000 live births. A substantial proportion of women of childbearing age (WCBA) are at risk of rubella infection during pregnancy and this can result in a high frequency of miscarriage or burden of CRS across Vietnam. Prompt introduction of RCV into national immunization program with catch-up vaccination to children and WCBA will reduce CRI in Vietnam.     

Persistence of antibody induced by rubella vaccine (Wistar RA 27/3 strain) after six years.

A total of 21 rubella seronegative children vaccinated subcutaneously with Wistar RA 27/3 strain live attenuated rubella vaccine in a family study of vaccine virus transmissibility were reviewed after 6 years. Haemagglutinating inhibiting (HAI) antibody titres of sera collected 46 days, 2 years and 6 years after vaccination were compared. Antibody titres in the vaccinated subjects were not significantly influenced by time, infection in susceptible siblings or revaccination.     

2006年山东省风疹暴发地区孕妇风疹病毒早期感染状况调查

[目的]了解风疹暴发地区孕妇风疹病毒早期感染状况,为监测与预防先天性风疹综合症（CRS）提供依据。[方法]2006年4月,在山东省5处近期风疹暴发地区采集部分未发生风疹的孕妇血清,检测风疹IgM抗体,并对阳性孕妇所生儿童进行追踪观察。[结果]调查孕妇1030名,风疹IgM抗体阳性5例,阳性率为0．49％;5例孕妇孕周分别为16周、19周、20周、21周和40周,其中2例（孕周16周、20周）流产,3例均顺利生产,跟踪观察1年,儿童未发现出生缺陷。[结论]山东省风疹暴发地区孕妇风疹病毒早期感染率不高。     

2010-2014年哈尔滨市先天风疹综合征监测分析

目的 分析2010-2014年哈尔滨市先天风疹综合征（CRS）的监测结果。方法 采用描述流行病学方法,对监测的CRS病例进行分析,并对监测指标进行评价。结果 2010-2014年,哈尔滨市共报告CRS疑似病例611例,诊断为CRS的37例,发病率在6.88/10万~15.23/10万之间,年平均发病率为10.05/10万活产儿童;临床表现主要为先天性心脏病、听力损失和眼部疾病,患儿母亲均无明确风疹疫苗接种史;实验室诊断病例感染风疹病毒的时间集中在孕4~6周。结论 我市CRS发病率仍在较高水平。应继续加强疫苗接种,开展育龄期妇女血清抗体水平监测,继续开展CRS病例监测,为制定CRS防控策略提供依据。     

Seroepidemiology study of rubella antibodies among pregnant women from seven Asian countries: evaluation of the rubella vaccination program in Taiwan

During 2003-2004, approximately 13% of birth in Taiwan was given by foreign-born females. The aims of this study were to compare the seroprevalence of rubella antibodies between Taiwan-born and foreign-born pregnant women and evaluate the effect of rubella vaccination program in Taiwan. We reviewed the rubella antibody test results of 5007 women during routine pregnancy check-ups at Fooyin University Hospital during 1999-2002. In Taiwan-born women, rubella antibody was undetectable in 29.2%, 7.3%, and 8.3% of the cohorts born before 1971, between 1971 and 1976, and after 1976, respectively. In the cohorts born between 1971 and 1976 and after 1976, pregnant women born in China, Vietnam, Indonesia, and Philippines had significant higher chances of being susceptible. Our results suggested that the voluntary adult vaccination program was not as effective as the school or wipe-out programs. Both Taiwanese women born before 1971 and foreign-born women were more likely to be susceptible to rubella. The introduction of 'catch-up' immunization program and enforcement of the checking of immunization record and/or blood test before pregnancy for these women are necessary in preventing CRS.     

Rubella infection during pregnancy in the 1985–86 epidemic: Follow-up after seven years

The study covered 310 pregnant women from southern Poland who were exposed to rubella during the 1985–86 epidemic, none of whom had been vaccinated against rubella. Rubella specific antibodies were detected by hemagglutination –inhibition (HI) tests, and IgM antibodies by enzyme immunoassay (ELISA) (Organon Teknika). Clinical symptoms according to anamnesis were recorded. The consequences of serologically confirmed maternal rubella on the course of pregnancy and on fetal outcome were evaluated. IgM antibodies could be examined in only 10 newborns at delivery or in the first days of life. After seven years, follow-up studies of children born to infected mothers were done. The mental development of 14 of these children was evaluated with Terman-Merrill test. Among 310 women examined during pregnancy, rubella infection was confirmed serologically in 46 cases (14.8%). All but 3 of those had clinical symptoms. The course of pregnancy was observed in 36 of the infected mothers. Only 5 women (22.7%) who had the infection in the first trimester of pregnancy delivered a healthy child. The rate of complications in pregnancy among women infected in the second trimester was lower, and 8 (66.7%) bore healthy children. All the children born to mothers infected in the third trimester were healthy. Eight of the 10 newborns examined at delivery were IgM positive. Of 29 children congenital rubella syndrome (CRS) was confirmed in 5 cases, CRS compatible or CRS possible in 7 and 3 had congenital infection only confirmed serologically (IgM-positive) without defects or symptoms. Seventheen (58.6%) children were found healthy including the 3 who had congenital infection only. The mental development of 14 children at age 7 was assessed; 10 cases (72%) fell within rank II 130-85, and 4 (28%) were of borderline intelligence. The study indicates that congenital rubella is still a serious problem in Poland. Immunization was introduced only in 1988–89, for 13-year-old girls. Women of child- bearing age should be screened for rubella antibodies and those susceptible to rubella infection should be vaccinated.     

Rötelsituation in Deutschland Ergebnisse der seroepidemiologischen Überwachung von 1990 bis 1998

The present situation regarding rubella is reflected in seroprevalence studies performed between 1990 and 1998. By selective immunisation of girls and young women (the female population >13 years of age) it was possible to a wide extent to close immunity gaps in young adults which occurred in the pre-vaccination era. In 1998 in the cohort of the 18–30-year-old population only 0.8–3% of the women were seronegative for rubella, compared to 5–13% of the men. Differences regarding immunity between old and new federal Länder are no longer existent, although vaccination against rubella was only introduced in the new Länder after the reunification. Above all, a potential risk for pregnant women without protection against rubella is conferred by the high percentage of pre-school children without rubella immunity. This is due to the delay in starting to vaccinate small children, but also to a lower acceptance of the combined vaccination. Compared to countries like Finland, Sweden or the United States, which have almost achieved the elimination of congenital rubella syndrome (CRS), in Germany a considerable number of individuals remain susceptible to this infection. Continuous endemic virus circulation endangers the main target group of rubella vaccination, i. e. women in the early stages of pregnancy. Only when MMR vaccination rates of more than 90% are achieved in small children in the course of their second year of life, there will be a real chance in Germany to eradicate not only measles, but also the CRS over the next 10 years.     

The predicted impact of private sector MMR vaccination on the burden of Congenital Rubella Syndrome

In many developing countries, Measles-Mumps-Rubella (MMR) vaccine is available through the private but not the public sectors, and there is no systematic rubella vaccination among adult women. In this paper, we extend previous modeling studies to demonstrate that in developing countries with a medium-high force of infection (200-400/1000 per year), current levels of private sector MMR coverage (<60%) would lead to increases in the incidence of Congenital Rubella Syndrome (CRS) both among unvaccinated individuals and the general population even when mixing between vaccinated and unvaccinated individuals is fairly minimal. Our findings highlight the need for countries to establish surveillance of trends in susceptibility to rubella and CRS incidence and perhaps introduce rubella vaccination among women of child-bearing age.     

上海市麻疹、流行性腮腺炎、风疹抗体水平调查分析

[目的 ]　了解本市健康人群麻疹、腮腺炎、风疹的抗体水平。　 [方法 ]　采集 0～ 5 0岁健康人群血标本 5 43份 ,检测麻疹、腮腺炎、风疹抗体。　 [结果 ]　小于 8月龄组麻疹抗体GMT最低 ,接种麻疹疫苗后抗体GMT显著升高 (P<0 .0 0 1) ;小于 8月龄组及 8月龄组风疹抗体水平最低 ,1岁接种疫苗后风疹抗体显著升高 (P <0 .0 0 1) ,但随着年龄的增长抗体水平有所下降 ,抗体阳性率维持在 85 %以上 ;小于 8月龄组及 8月龄组流行性腮腺炎抗体水平最低 ,1岁以上各年龄组抗体水平显著上升 (P <0 .0 0 1)。　 [结论 ]　上海市现阶段实行麻疹疫苗、MMR疫苗的接种程序比较合理和有效 ,但应该进一步开展上海市育龄期妇女风疹抗体水平调查和MMR疫苗免疫持久性观察 ,研究预防未及龄儿童麻疹疫苗免疫策略、育龄期妇女接种风疹疫苗免疫策略 ,预防先天性风疹综合征     

An epidemiological assessment towards elimination of rubella and congenital rubella syndrome in Singapore

ObjectiveIn line with regional and global goals for the elimination of rubella and congenital rubella syndrome (CRS), we reviewed the epidemiological situation in Singapore, based on surveillance reports on rubella and CRS, national immunization coverage and seroprevalence surveys. The aim of our review was to identify current gaps and steps taken to achieve the targets set by the World Health Organization (WHO) Western Pacific Regional Office (WPRO).MethodsEpidemiological data on clinical and laboratory-confirmed rubella cases, including CRS, notified to the Communicable Diseases Division, Ministry of Health, Singapore, from 2003 to 2013 were collated and analyzed. Vaccination coverage against rubella was obtained from the National Immunization Registry and School Health Services of the Health Promotion Board. The changing prevalence of rubella was determined from periodic serological surveys.FindingsThe incidence of indigenous rubella cases per million population decreased from 37.2 in 2008 to 7.6 in 2013 and there had been no indigenous case of CRS in 2012 and 2013. Therapeutic abortions performed due to rubella infections had become uncommon. The annual measles, mumps, and rubella (MMR) vaccination coverage in childhood population remained high ranging from 93% to 96%. The overall susceptibility to rubella in women aged 18–44 years had reduced significantly from 15.8% in 2004 to 11.0% in 2010. The prevalence of IgG antibody against rubella among Singapore children aged 1–17 years was maintained at 87.3% in 2008–2010.ConclusionAll available data indicated that Singapore has made good progress towards the elimination of rubella and CRS. It has attained the targets set by the WHO WPRO for 2015. In preparation for verification of rubella elimination, an enhanced surveillance system has been implemented to ensure that all reported cases are laboratory confirmed, and genotyping of rubella virus strains isolated is carried out to provide evidence for interruption of endemic transmission.     

An audit of rubella IgG antibody status in antenatal women in a NHS Trust over 5 years (2005-2009)

Rubella, a vaccine-preventable infection. This study examined the antibody status of 11 987 pregnant women during 2005-2009. Results showed a non-significant decrease in those with antibody levels of <4·0 IU/ml from 29/2312 (1·3%) in 2005 to 21/2447 (0·9%) in 2009 (χ2 for linear trend=0·279, P=0·56) but a significant increase in those with levels of <10 IU/ml from 88/2312 (3·8%) in 2005 to 124/2447 (5·1%) in 2009 (χ2 for linear trend=10·27, P=0·001). In women born before 1983 (pre-pubertal vaccination) the proportion of first pregnancies with titres <4 IU was 1·1% (21/2002) compared to 3·4% (69/2022) in those born after 1983 (χ2=25·176, P<0·0001) and 2·2% (44/2002) for titres <10 IU compared to 14·0% (282/2022) for those born after 1983 (χ2=171·43, P<0·0001). The potential impact of the increase is difficult to determine, requiring further monitoring. This paper discusses the effect of changing immunization programmes on rubella susceptibility in pregnant women.     

Control of rubella and congenital rubella syndrome (CRS) in developing countries, Part 2: Vaccination against rubella.

In 1995-96 we conducted a review of rubella immunization strategies. Worldwide, 78 countries (more than one-third) reported a national policy of using rubella vaccine. This was closely related to country economic status. Based on the United Nations country classification, rubella vaccine is used in 92% of industrialized countries, 36% of those with economies-in-transition, and 28% of developing countries. Cases of congenital rubella syndrome (CRS) may be prevented as follows: by providing direct protection to women and/or schoolgirls (a selective vaccination strategy); by vaccinating boys and girls to provide indirect protection by reducing the transmission of rubella virus (a childhood vaccination strategy); or by a combination of these approaches (a combined strategy). A combined strategy was most commonly reported (60% of countries); seven countries (9%) reported a selective strategy; and 24 countries (31%) reported only childhood immunization. Experience has shown that it is essential to include vaccination of women of childbearing age in any rubella control strategy. Childhood vaccination alone may pose a risk of an increase in CRS cases. Although many countries have introduced rubella vaccine, few report any data on the impact of vaccination. Countries using rubella vaccine need to establish surveillance for rubella and CRS and monitor coverage in each of the target groups.