Congenital Rubella Syndrome Surveillance After Measles Rubella Vaccination Introduction in Yogyakarta, Indonesia.

BACKGROUND: Congenital rubella syndrome (CRS) is a fatal disease causing severe congenital defects. Indonesia had the highest CRS cases in the world in 2016 with a commitment to achieve elimination of rubella disease by 2020, through the campaign and introduction of measles rubella (MR) national vaccination program in 2017 and 2018. This study aimed to describe the impact of the national vaccination campaign by conducting surveillance of CRS cases and comparing the incidence of new CRS cases before and after the MR vaccination campaign. METHODS: From July 2015 to July 2020, we conducted surveillance of CRS in Yogyakarta. Suspected patients underwent complete clinical examinations. Serology was tested for the presence of IgM and IgG antibodies against rubella. Descriptive analysis was used to characterize the demographic and clinical characteristics of the cases before and after the MR vaccination campaign. RESULTS: The study involved 229 infants who were suspected for CRS. Laboratory-confirmed cases were found in 47 of them (20.86%). Most of the laboratory-confirmed cases (55.3%) were reported among 1-5 months old infants. Common clinical features among laboratory-confirmed cases included structural heart defects in 43 (91.4%). There was a significant decrease (60.9%) of CRS incidence from 0.39 per 1000 live births in the precampaign era to 0.08 in the postcampaign era (P = 0.00). CONCLUSION: There has been a significant declining number of CRS cases based on pre- and post-MR vaccination campaign in Yogyakarta, Indonesia. An effective surveillance system will help monitor the number of CRS cases.

Spatiotemporal proximity of rubella cases to the occurrence of congenital rubella syndrome in Yogyakarta, Indonesia.

INTRODUCTION: Rubella infection during early pregnancy may cause fatal consequences such as congenital rubella syndrome (CRS). The incidence rate (IR) of CRS confirmed cases in Yogyakarta, Indonesia between July 2008 and June 2013 was high at 0.05 per 1,000 live births. This study aimed to discover the spatiotemporal pattern of rubella and CRS and also identify whether the proximity of rubella cases was associated with the occurrence of CRS cases. METHODS: This observational research used a spatiotemporal approach. We obtained CRS and rubella surveillance data from Dr. Sardjito Hospital, Provincial, and District Health Offices in Yogyakarta, Indonesia during January-April 2019. The home addresses of rubella and CRS cases were geocoded using the Global Positioning System. Average of the nearest neighbour and space-time permutation analyses were conducted to discover the spatiotemporal patterns and clusters of rubella and CRS cases. RESULTS: The peak of rubella cases occurred in 2017 (IR: 22.3 per 100,000 population). Twelve confirmed cases of CRS were found in the 2016-2018 period (IR: 0.05 per 1,000 live births). The occurrence of CRS in Yogyakarta was detected 6-8 months after the increase and peak of rubella cases. The spatiotemporal analysis showed that rubella cases were mostly clustered, while CRS cases were distributed in a dispersed pattern. Rubella cases were found within a buffer zone of 2.5 km from any CRS case. CONCLUSIONS: Rubella cases were spatiotemporally associated with the occurrence of CRS in Yogyakarta. We recommend strengthening the surveillance system of CRS and rubella cases in order to contain any further spreading of the disease.

Rubella immune status of neonates - a window towards seroprevalence among childbearing women.

BACKGROUND: When contracted in pregnancy, rubella may cause serious chronic infection of the fetus and development of Congenital Rubella Syndrome. Despite widespread application of rubella vaccination, periodical outbreaks are still being reported worldwide. The aim of this study was to determine rubella seroprevalence and antibody levels in neonates in Serbia as a proxy of maternal serostatus. METHODS: ELISA based serological testing for rubella was done in 599 neonates treated at the Institute of Neonatology in Belgrade, from January 2010 to December 2011. All individuals with rubella IgG concentration ≥10 IU/ml were considered seropositive for rubella. RESULTS: The mean age of enrolled neonates was 18 ± 6 days. The overall seroprevalence of rubella IgG antibodies among the tested neonates was 540/599(90.2 %, 95 % CI: 87.5-92.3). Seropositivity rate among sera of the neonates enrolled in 2010 was significantly higher than those collected in 2011 (p < 0.0001). There was no difference in average maternal age, gestational age or frequency of receiving blood products among the two study years. Significant high seropositivity rate was observed among neonates from mother aged >30 as compared to those from mothers aged <20 years (p = 0.02). Significant difference was also found between average IgG titers in the two study years (79 IU/mL in 2010 vs. 46 IU/mL in 2011, p < 0.0001). CONCLUSION: We report on high rubella seroprevalence among newborns in Serbia, as a proxy of rubella serostatus of childbearing aged women. Notably, declining trend of rubella antibodies toward diminishing titers suggest the importance of sustained rubella serosurvey and antenatal screening at the national level.

Associated systemic and ocular disorders in patients with congenital unilateral cataracts: the Infant Aphakia Treatment Study experience.

PurposeFive-year prospective data on children enrolled in the Infant Aphakia Treatment Study (IATS) provided an opportunity to explore ocular and systemic associations in patients with a unilateral congenital cataract.MethodsInfants <7 months of age with a unilateral cataract were eligible for IATS screening. We reviewed data pertaining to the exclusion of patients as well as data collected on standardized study forms used at any time for documentation of ocular or systemic disorders.ResultsOverall, 227 infants were referred for possible enrollment. Of these, 10 had insignificant cataracts and 32 refused to participate. Of those excluded, 3 were premature, 27 had significant ocular disease (usually persistent fetal vasculature (PFV) or corneal diameter <9 mm), and 4 had systemic disorders. An additional 26 were excluded at the time of the first EUA, most often because of PFV or variants thereof. On follow-up, in the 114 enrolled patients, the following disorders were diagnosed: Stickler syndrome (1), mitochondrial disease (1), autism (1), and presumed congenital rubella syndrome (1). No patient developed a cataract in the fellow eye.DiscussionSome conditions that can feature unilateral cataracts are diagnosed at birth or very early in life, but others may be diagnosed at varying periods thereafter. PFV and its variants are the most common associated ocular findings in about a quarter of cases of unilateral congenital cataracts.ConclusionAlthough patients with a unilateral cataract may have significant associated abnormalities in the affected eye, most commonly PFV and its variants, the prevalence of associated significant systemic disease is quite low.

Evolution and Use of Dynamic Transmission Models for Measles and Rubella Risk and Policy Analysis.

The devastation caused by periodic measles outbreaks motivated efforts over more than a century to mathematically model measles disease and transmission. Following the identification of rubella, which similarly presents with fever and rash and causes congenital rubella syndrome (CRS) in infants born to women first infected with rubella early in pregnancy, modelers also began to characterize rubella disease and transmission. Despite the relatively large literature, no comprehensive review to date provides an overview of dynamic transmission models for measles and rubella developed to support risk and policy analysis. This systematic review of the literature identifies quantitative measles and/or rubella dynamic transmission models and characterizes key insights relevant for prospective modeling efforts. Overall, measles and rubella represent some of the relatively simplest viruses to model due to their ability to impact only humans and the apparent life-long immunity that follows survival of infection and/or protection by vaccination, although complexities arise due to maternal antibodies and heterogeneity in mixing and some models considered potential waning immunity and reinfection. This review finds significant underreporting of measles and rubella infections and widespread recognition of the importance of achieving and maintaining high population immunity to stop and prevent measles and rubella transmission. The significantly lower transmissibility of rubella compared to measles implies that all countries could eliminate rubella and CRS by using combination of measles- and rubella-containing vaccines (MRCVs) as they strive to meet regional measles elimination goals, which leads to the recommendation of changing the formulation of national measles-containing vaccines from measles only to MRCV as the standard of care.

Characterization of the Risks of Adverse Outcomes Following Rubella Infection in Pregnancy.

Although most infections with the rubella virus result in relatively minor sequelae, rubella infection in early pregnancy may lead to severe adverse outcomes for the fetus. First recognized in 1941, congenital rubella syndrome (CRS) can manifest with a diverse range of symptoms, including congenital cataracts, glaucoma, and cardiac defects, as well as hearing and intellectual disability. The gestational age of the fetus at the time of the maternal rubella infection impacts the probability and severity of outcomes, with infection in early pregnancy increasing the risks of spontaneous termination (miscarriage), fetal death (stillbirth), birth defects, and reduced survival for live-born infants. Rubella vaccination continues to change the epidemiology of rubella and CRS globally, but no models currently exist to evaluate the economic benefits of rubella management. This systematic review provides an overall assessment of the weight of the evidence for the outcomes associated with rubella infections in the first 20 weeks of pregnancy. We identified, evaluated, and graded 31 studies (all from developed countries) that reported on the pregnancy outcomes of at least 30 maternal rubella infections. We used the available evidence to estimate the increased risks of spontaneous termination, fetal death, infant death, and CRS as a function of the timing of rubella infection in pregnancy and decisions about induced termination. These data support the characterization of the disability-adjusted life years for outcomes associated with rubella infection in pregnancy. We find significant impacts associated with maternal rubella infections in early pregnancy, which economic analyses will miss if they only focus on live births of CRS cases. Our estimates of fetal loss from increased induced terminations due to maternal rubella infections provide context that may help to explain the relatively low numbers of observed CRS cases per year despite potentially large burdens of disease. Our comprehensive review of the weight of the evidence of all pregnancy outcomes demonstrates the importance of including all outcomes in models that characterize rubella-related disease burdens and costs.

Targeting rubella for elimination.

Rubella is an acute, usually mild viral disease. However, when rubella infection occurs just before conception or during the first 8-10 weeks of gestation, it causes multiple fetal defects in up to 90% of cases, known as Congenital Rubella Syndrome (CRS). It may result in fetal wastage, stillbirths and sensorineural hearing deficit up to 20 weeks of gestation. Rubella vaccine (RA 27/3) is highly effective and has resulted in elimination of rubella and CRS from the western hemisphere and several European countries. Review of several studies documents the duration of protection over 10-21 years following one dose of RA27/3 vaccination, and persistent seropositivity in over 95% cases. Studies in India show seronegativity to rubella among adolescent girls to vary from 10% to 36%. Although due to early age of infection resulting in protection in the reproductive age group, incidence of rubella in India is not very high. However, due to severity of CRS coupled with introduction of RCV in private sector and in some of the states which is likely to lead to sub-optimal coverage and resulting higher risk of rubella during pregnancy in the coming decades, it is imperative to adopt the goal of rubella elimination. As in order to control measles, the country has adopted strategy of delivering second dose of measles through measles campaigns covering children 9 months to 10 years of age in 14 states, it is recommended to synergize efforts for elimination of rubella with these campaigns by replacing measles vaccine by MR or MMR vaccine. Other states which are to give second dose of measles through routine immunization will also have to adopt campaign mode in order to eliminate rubella from the country over 10-20 years. Subsequently, measles vaccine can be replaced by MR or MMR vaccine in the national schedule.

Rubella vaccination of unknowingly pregnant women during mass campaigns for rubella and congenital rubella syndrome elimination, the Americas 2001-2008.

BACKGROUND: Due to the significant teratogenicity of rubella virus and the use of a live-attentuated vaccine, pregnancy is a contraindication of receipt of rubella vaccine (RCV). Data collected from several countries that have observed susceptible women who had received RCV during pregnancy documented that no infant with congenital rubella syndrome (CRS) has been born, so the risk is theoretical. As part of the regional initiative to eliminate rubella and CRS in the Americas, one of the key strategies was the vaccination of women of childbearing age. The implementation of mass vaccination campaigns targeting women of childbearing age in Argentina, Brazil, Costa Rica, Ecuador, El Salvador, and Paraguay provided an opportunity to further increase the body of knowledge on the safety of rubella vaccine if an unknowingly pregnant woman is vaccinated in early pregnancy. METHODS: Using a standard protocol, women who were unknowingly pregnant or become pregnant ≤ 30 days after receiving RCV were evaluated to determine immunity status (eg, susceptible, immune, and unknown) at the time of vaccination. Susceptible pregnant women were observed to determine the outcome of the pregnancy. For pregnancies that resulted in live births, serum samples were obtained from the newborn for rubella immunoglobulin (Ig) M antibody testing. If the newborn's serum sample was IgM positive, the infant was evaluated for manifestations of CRS. RESULTS: During the period 2001-2008, 48748253 women of childbearing age were vaccinated in the region of the Americas, 39542253 (81%) of whom were vaccinated in the 6 selected countries. Of these women, 30139 (0.07%) were pregnant or became pregnant ≤1 month after receiving vaccine and were followed up. On the basis of serological evaluation, 2894 (10%) women were classified as susceptible at the time of vaccination; of their pregnancies, 1980 (90%) resulted in a live birth. Sera from 70 (3.5%) of these infants were rubella IgM antibody positive, but none of the infants had features of CRS as a result of rubella vaccination. The maximum theoretical risk for CRS following rubella vaccination of susceptible pregnant women was 0.2%. Conclusions. The results of these studies from 6 select countries provides additional evidence showing an absence of risk of CRS associated with administering rubella vaccine shortly before or during pregnancy.

Causes of birth defects: lessons from history.

Environmental causes of birth defects have increasingly been recognized since the mid-20th century. The teratogenic effects of maternal infections such as rubella and therapeutic drugs such as thalidomide were first reported by alert clinicians. Among clinicians and researchers who have contributed significantly to our knowledge of these environmental causes, Norman Gregg was a Sydney ophthalmologist whose seminal study in 1941 identified maternal rubella as a cause of birth defects. The teratogenic effects of thalidomide were first noted in 1961 by William McBride, a Sydney obstetrician, and independently confirmed by Widukind Lenz, a German pediatrician. Marsh Edwards, an Australian veterinary scientist, showed experimentally that maternal hyperthermia caused birth defects in various animal species. While it is likely that alert individual clinicians or researchers will continue to signal the first clues about new environmental causes of birth defects, especially therapeutic drugs, it is now usually teams of laboratory researchers and epidemiologists who are more likely to provide definitive evidence of these new teratogens.

Congenital rubella syndrome after rubella vaccination in 1-4 weeks periconceptional period.

OBJECTIVE: To examine weather exposure to rubella vaccine during 1-4 wk periconceptional period can cause congenital rubella syndrome (CRS). METHODS: This prospective study was performed in 60 pregnant women who received rubella vaccine inadvertently 1-4 wk pre or post conception. Time of conception was determined by last menstrual period (LMP) and first trimester sonography. In addition to gathering mother's obstetric and demographic information, all neonates were evaluated for CRS signs by systemic physical examination and anti rubella IgG and IgM antibody titers in cord blood samples. RESULTS: A total of 60 pregnant women with the median gestational age of 38 weeks were studied. The mean maternal age was 22 years and 58.3% of pregnancies were unintended. In 90% of mothers there were no post vaccination side effects (fever, lymphadenopathy, arthritis, arthralgia). None of the mothers had a history of drug abuse, smoking or teratogenic exposures. Mean neonatal weight was 3100grs and 6.7% of them were premature. No signs of CRS were found in the neonates based on systemic physical exam at birth and one month later. Mean value of cord blood anti rubella IgG titere was 148/28+/-67/26 lu/ml. cord blood anti rubella IgM was negative in all of the neonates. CONCLUSION: In this study inadvertent rubella vaccination 1-4 wk before and after conception did not cause CRS in neonates and according to all reasearches pregnancy termination is not indicated in these cases.

Congenital rubella syndrome in infants of women vaccinated during or just before pregnancy with measles-rubella vaccine.

BACKGROUND & OBJECTIVE: Measles and Rubella Control Campaign was conducted in Iran in December 2003 targeting both males and females 5 to 25 yr old using measles-rubella vaccine. During the campaign, some pregnant women received vaccine during the first trimester of pregnancy or some others became pregnant shortly thereafter. The goal of this study was to evaluate the risk of congenital rubella syndrome (CRS) among the infants born to the vaccinated mothers. METHODS: A total of 106 pregnant women, who had received vaccine during the first trimester of pregnancy or become pregnant less than three months after vaccination were included in the study for comparison 40 pregnant women without rubella vaccine were also included. The mothers' blood samples at the time of delivery, infants' cord blood and blood samples at the end of the second month of birth of sixty children whose parents agreed about blood sampling, were tested for rubella IgM and IgG antibodies using ELISA method. RESULTS: There were 107 live births in the exposed group and 42 in the control group. Serological study showed no IgM rubella antibody in the maternal and infant cord blood; it was not found in the second blood specimens of 60 infants tested at 8 wk of age. IgG rubella antibody was positive in all infants' cord blood but it decreased in the second blood specimens of the infants. None of the children exhibited signs of congenital rubella syndrome. INTERPRETATION & CONCLUSION: Finding of our study showed that none of the infants born to mothers vaccinated by MR vaccine during the first trimester of pregnancy or had become pregnant within three months after vaccination, had CRS.

O conhecimento das gestantes sobre a síndrome da rubéola congênita / The knowledge of pregnant patients about the congenital rubella syndrome

A rubéola congênita é uma doença viral preocupante, principalmente quando acomete a gestante no primeiro trimestre gestacional. Vários estudos descrevem que a rubéola, ocorrendo precocemente na gravidez, geralmente leva a malformações congênitas variadas. A chamada Tétrade de Gregg, com alterações visuais, auditivas, cardíacas e mentais, é a mais conhecida, porém outras alterações podem ocorrer. Este trabalho mostra o grau de conhecimento das gestantes quanto aos riscos da rubéola durante a gestação e as orientações sobre o assunto recebidas do médico durante o pré-natal.

Congenital rubella syndrome in a child born to Liberian refugees: clinical and public health perspectives.

We describe a case of congenital rubella syndrome with typical stigmata in an infant born in New Hampshire to Liberian refugees. The infant's clinical specimens were tested for rubella. Rubella immunity status was sought for contacts. The infant's specimen cultures grew wild-type rubella virus; serum immunoglobulin M and G were positive. Eighteen of 20 contacts were rubella-immune. Family's transit history, mother's vaccination history, and infant's estimated gestational age supported congenital infection acquired overseas. Clinicians should maintain vigilance for congenital rubella syndrome in infants with relevant stigmata, particularly those whose mothers are from countries with nonexistent or recently implemented rubella vaccination programs.

A resurgence of congenital rubella in Australia?

Two infants with congenital rubella defects (congenital rubella syndrome) have been reported from Queensland in 2003, after an increase in rubella in that State in 2001-2002. The national Measles Control Campaign in 1998 aimed to give measles-mumps-rubella (MMR) vaccine to all unvaccinated preschoolers and a second dose to primary schoolchildren. Following the Campaign no children with congenital rubella defects were born to Australian-born mothers during the five years 1998 to 2002, according to reports to the Australian Paediatric Surveillance Unit. However, three imported cases occurred. Broad immunisation coverage and detection and vaccination of susceptible women of child-bearing age before they become pregnant are necessary to prevent further cases.