Congenital Rubella Syndrome

Infectious embryofetopathy caused by rubella virus, the leading vaccine-preventable cause of birth defects and an environmental phenocopy of genetic syndromes with cataract, sensorineural deafness, heart disease, microcephaly and intracranial calcifications.

Literature and regulatory information updated: 29 October 2026.

0. Initial Reference Table

1. Introduction

1.1. The place of congenital rubella in a medical genetics manual

Rubella is a benign viral illness in children, with a fine, transient macular rash, post-auricular and suboccipital lymphadenopathy and, in adults, arthralgia or arthritis; its clinical diagnosis is unreliable because other viruses produce the same picture [11]. The medical importance of the infection lies in its teratogenic potential: maternal infection in early pregnancy can cause miscarriage, fetal death, stillbirth or a set of birth defects termed congenital rubella syndrome (CRS), and rubella is recognised as the leading vaccine-preventable cause of birth defects [23, 25]. The geneticist encounters CRS in three settings: in the consultation of a pregnant woman with a rash or contact with rubella, where fetal risk depends on gestational age; in the assessment of a child with cataract, sensorineural deafness, heart disease or microcephaly, where congenital infection is an environmental cause to be excluded before genomic investigation; and in the assessment of an infant with intracranial calcifications, where monogenic disorders of the pseudo-TORCH group mimic congenital infection [39–41]. Before vaccination programmes, CRS was an important cause of congenital deafness, and in non-immunised populations rubella mainly affects children aged 4 to 9 years [11].

1.2. Historical milestones

In 1941, the Australian ophthalmologist Norman McAlister Gregg linked an increase in cases of congenital cataract in Sydney, after the 1940 epidemic, to maternal rubella in early pregnancy, documenting this history in 78 cases; the original article was not consulted and the information comes from reviews and from the follow-up cohort of his patients [5, 24, 27]. The virus was isolated in cell culture in 1962 [4, 5]. The 1962–1965 pandemic in the United States of America (USA), with about 12.5 million cases, caused about 2000 cases of encephalitis, 11,250 spontaneous or therapeutic abortions, 2100 neonatal deaths and 20,000 infants with CRS, including more than 8000 with deafness, 3580 with deaf-blindness and 1800 with intellectual disability [5, 27]. Live attenuated vaccines were licensed in the USA in 1969; the Wistar RA 27/3 strain, grown in human diploid fibroblasts, was licensed in 1979 and is the basis of most current vaccines [4, 25, 27]. The combination with measles and mumps appeared in the USA in 1971 and the tetravalent vaccine with varicella in 2005 [28]. In the United Kingdom, vaccination began in 1970 with prepubertal girls and non-immune women, the combined vaccine for both sexes was introduced in 1988 and the 2-dose schedule in 1996 [12]. The USA declared the elimination of endemic rubella in 2004, and the World Health Organization (WHO) Region of the Americas was the first to be declared free of rubella and CRS, in April 2015 [23, 27, 42].

1.3. Nomenclature and operational definitions

CRS designates the infant with compatible clinical signs and laboratory evidence of congenital infection; congenital rubella infection (CRI) designates the infant with laboratory evidence of infection without the signs of the main group, who is reclassified as CRS if these signs appear later, for example hearing loss [2, 3]. Fetal infection without signs of CRS is more likely when maternal infection occurs after 20 weeks, and these infants also shed virus [3]. Reinfection is infection in a person with previous documented natural infection or effective immunisation; it is usually subclinical and diagnosed only by a change in antibodies [12]. The surveillance case definitions of the WHO and of the Council of State and Territorial Epidemiologists (CSTE) with the US Centers for Disease Control and Prevention (CDC) distinguish suspected, probable or clinically compatible, and laboratory-confirmed cases; they serve uniform case counting and do not replace individual clinical judgement [2, 3]. Progressive rubella panencephalitis is a slowly progressive and fatal disease of the central nervous system associated with persistence of the virus [43].

1.4. Scope

This article covers CRS and CRI, rubella in pregnancy from the perspective of fetal risk, prenatal and postnatal diagnosis, prevention by vaccination and long-term follow-up. The differential diagnosis includes the other congenital infections and the genetic disorders that mimic congenital infection. Congenital cytomegalovirus infection, Aicardi-Goutières syndrome and the type I interferonopathies, which include pseudo-TORCH syndromes 2 and 3, enter the differential diagnosis; only the features that distinguish them from CRS are given here.

2. Molecular Genetics and Pathophysiology

2.1. The virus

Rubella virus has a single-stranded, positive-sense RNA genome, a pleomorphic nucleocapsid surrounded by a lipid membrane of cellular origin and particles of 50 to 85 nm [5]. The surface glycoproteins E1 and E2 are anchored in the envelope: E1 mediates receptor-dependent endocytosis and is the immunodominant antigen, and antibodies directed against its neutralising domain serve as a correlate of protection [5]. The cellular receptor has not been defined; E1 binds to myelin oligodendrocyte glycoprotein (MOG), whose ectopic expression renders non-permissive cells infectable, and MOG is present in the central nervous system, the gastrointestinal tract and the placenta, which makes it a plausible candidate for fetal infection, but not for primary respiratory infection [5]. There is a single antigenic type, and sequencing distinguishes vaccine and wild-type strains and genotypes with geographical distribution, such as 1E and 2B, which accounted for 56% and 43% of the 6792 sequences submitted to the global database between 2012 and 2024 [4, 23].

2.2. Transmission, viraemia and infectiousness

Transmission is respiratory, by droplets or direct contact, and subclinical cases also transmit [4]. The virus replicates in the nasopharynx and regional lymph nodes; viraemia occurs 5 to 7 days after exposure and disseminates the virus to several organs, including the placenta [4, 25]. The virus is present in nasopharyngeal secretions from one week before until two weeks after the rash, with maximum shedding up to day 5 [25]. The window of infectiousness given by different sources varies: about one week before and one week after the rash (Oxford Desk Reference, CDC), or from 7 days before to 10 days after (UK Health Security Agency, UKHSA) [4, 11, 12]. The attack rate in close household contacts is estimated at 90% [12]. The basic reproduction number has been estimated at 3 to 8 in Europe and up to 12 in densely populated developing countries, corresponding to herd immunity thresholds of 85–88% in the United Kingdom and the USA and of 67–87% in other European countries [5].

2.3. Pathogenesis of fetal lesions

In the pregnant woman, the virus infects the placenta and reaches the fetal circulation; fetal damage results from cell destruction and disruption of cell division, and fetal infection tends to become persistent [4, 5]. A 2025 review describes tropism for rapidly dividing cells (neuroectoderm, vascular endothelium, cardiac and ocular precursors), induction of apoptosis, inhibition of mitosis with organ hypoplasia and endothelial injury interfering with angiogenesis [42]. Immunohistochemical study of three autopsies of fatal CRS identified viral antigen in interstitial fibroblasts of the heart, adventitial fibroblasts of large vessels, alveolar macrophages, progenitor cells of the external granular layer of the brain, and capillary endothelium and basal plate of the placenta, a distribution consistent with inflammatory vascular injury and systemic dissemination [44]. This distribution corresponds to the typical clinical lesions: heart disease and arterial stenoses, damage to the neuroepithelium, cataract due to infection of differentiating lens fibres, and destruction of the hair cells and organ of Corti with vascular injury of the inner ear [42, 44]. The reference textbook describes, in addition to the structural defects, inflammatory lesions of the brain, liver, lungs and bone marrow [11].

2.4. Viral persistence and prolonged shedding

Fetal infection persists after birth. Infants with CRS or CRI shed large amounts of virus in pharyngeal secretions and urine: about 60% shed during the first 4 months, most for about 3 months, and some for more than a year [3, 25, 27]. Persistence can last decades: viral RNA was detected in the aqueous humour of a 28-year-old patient with CRS and Fuchs uveitis [5]. Intrathecal production of anti-rubella antibodies was demonstrated at autopsy in a patient with progressive rubella panencephalitis, with disproportionately high specific IgG and IgA antibodies in the cerebrospinal fluid (CSF) and brain tissue [43].

2.5. Timeline of fetal risk

The risk of infection and of damage depends on gestational age at the time of maternal infection. The prospective cohort of Miller and colleagues, with more than a thousand pregnant women with confirmed rubella in England and Wales, of whom 40% continued the pregnancy and whose children were followed clinically and serologically up to 2 years of age, remains the basis of the figures used in counselling [26]. Table 2.1 brings these data together with those of the guidelines.

Table 2.1. Fetal risk according to gestational age at maternal infection

The sources differ in detail: the WHO surveillance standards consider the risk low after 18 weeks, whereas the WHO position paper and the UKHSA allow for deafness with infection up to 20 weeks [3, 12, 25]. Fetal infection late in pregnancy, which is frequent, is not accompanied by structural defects [12, 26].

2.6. Maternal reinfection

Reinfection can occur after natural or vaccine-induced immunity [11]. The UKHSA estimates that the risk of congenital damage after subclinical reinfection in the first 16 weeks is less than 10% and probably less than 5%, and that reinfection with rash, which is very rare, carries a significant unquantified risk, because viraemia has occurred [12]. The WHO considers the risk of congenital infection after reinfection in the first 12 weeks to be low [25]. In the United Kingdom, 5 of the 31 infections in pregnancy diagnosed between 2003 and 2016 were considered reinfections [12]. A Japanese case illustrates the problem: CRS with intracranial calcifications in the daughter of a woman vaccinated at age 13 years and with positive serology on day 34 of pregnancy [45].

2.7. Natural and vaccine-induced immunity

Antibodies become detectable 14 to 18 days after infection, at approximately the time the rash appears; IgM usually disappears by 8 weeks, IgG persists and cellular immunity appears to be lifelong [25]. An IgG concentration ≥10 IU/ml is generally considered protective, but there is no formal correlate and assay sensitivity and thresholds vary [25]. The response to the vaccine is partly heritable: in a study of 100 twin pairs (45 monozygotic and 55 dizygotic), the heritability of antibody levels after vaccination was 45.7% [5]. Human leucocyte antigen (HLA) alleles and haplotypes (for example B*2705, DPA1*0201, DPB1*0401 and the B27 supertype, in the notation of the source) and polymorphisms in innate immunity genes, such as DDX58 (RIG-I), TRIM5, TRIM22, RARB and OAS genes, are associated with variation in the humoral or cellular response; HLA variation explains about 20% of the genetic variation in humoral immunity [5]. These associations have no individual clinical use.

2.8. Molecular basis of the genetic phenocopies

The disorders that mimic congenital infection share two main mechanisms. The first is damage to the blood-brain barrier and small vessels: loss of occludin, a tight-junction protein encoded by OCLN, causes perivascular calcification and polymicrogyria, probably through an ischaemic or vascular insult in utero, and loss of JAM3 causes haemorrhagic destruction of the brain with subependymal calcification and congenital cataracts [10, 46]. The second is dysregulated activation of type I interferon, which reproduces the immune response to a viral infection: in Aicardi-Goutières syndrome through deficiency of nucleases or nucleic acid sensors and, in pseudo-TORCH syndromes 2 and 3, through failure of negative regulation of the late interferon response, because USP18 no longer blocks the access of Janus kinase 1 (JAK1) to the IFNAR2 receptor or the variant STAT2 no longer brings USP18 to the receptor [9, 47–50]. The variants described include the homozygous substitutions of arginine 148 of STAT2 (NM_005419.4:c.442C>T p.(Arg148Trp) and NM_005419.4:c.443G>A p.(Arg148Gln)) [49, 50]. Conversely, loss of function of STAT2 or IFNAR2 abolishes the interferon response and causes severe disease after live attenuated vaccines, including MMR [15, 17, 51].

3. Clinical Spectrum and Manifestations by System

3.1. Acquired rubella in women and children

The incubation period is 14 to 21 days (mean 14 days, range 12 to 23 days according to the CDC; 14 to 23 days according to the WHO) [4, 11, 25]. Up to half of infections are subclinical, a proportion that one review places between 25% and 50% [4, 42]. In young children the rash is often the first sign; in older children and adults there is a prodrome of 1 to 5 days with low-grade fever, malaise, lymphadenopathy and upper respiratory symptoms [4]. The maculopapular rash appears 14 to 17 days after exposure, begins on the face, progresses craniocaudally, lasts about 3 days, is fainter than that of measles and does not coalesce [4]. Post-auricular and suboccipital lymphadenopathy, resolution of the rash also in a craniocaudal direction and the absence of Koplik spots help to distinguish rubella from measles [28]. Arthralgia and arthritis are rare in children and men but common in adult women (up to 70% according to one review), affect the fingers, wrists and knees and last up to about a month [4, 28]. Complications include encephalitis in about 1 in 6000 cases (with reports of 1 in 500 and 1 in 1600), haemorrhagic manifestations such as thrombocytopenic purpura in 1 in 3000, orchitis, neuritis and, rarely, granulomas in primary immunodeficiencies [4, 25]. In the pregnant woman, the risk to the woman herself is generally limited to arthritis [12].

3.2. Pregnancy outcomes

Infection in early pregnancy can end in miscarriage, fetal death or stillbirth, or in a newborn with CRS [4, 23]. In Miller's cohort, defects attributable to rubella occurred in all infants infected before the 11th week, mainly heart disease and deafness, and in 35% of those infected at 13–16 weeks, in these with isolated deafness [26]. Some affected newborns appear normal at birth and sensorineural deafness is detected only later [11]. The most frequent signs of CRS are cataract, congenital heart disease, hearing impairment and developmental delay; many children have more than one, but the most frequent single sign is hearing impairment [27]. The only defects that frequently occur in isolation are sensorineural deafness and pigmentary retinopathy [11].

3.3. Frequency of manifestations

The evidence on frequencies comes mainly from cohorts identified in the 1960s and 1970s in developed countries, before standardised definitions existed and before widespread use of the vaccine [52]. Table 3.1 brings together the frequency classes assigned by Orphanet and the figures from a prospective surveillance series cited in a 2025 review.

Table 3.1. Frequency of the manifestations of CRS

Sources: [1, 42]. The two columns are not comparable with each other: the Orphanet classification summarises the literature, and the prospective series included infants identified by suggestive signs, with a selection bias towards severe forms [42]. Congenital heart disease occurs in 35% of newborns exposed to rubella in the teratogen table of the Oxford Desk Reference, which compares it with alcohol (up to 25–30%) and retinoic acid (10–20%) [53].

3.4. Eye

Ocular lesions include cataract, congenital glaucoma, microphthalmia, pigmentary retinopathy and chorioretinitis [5, 25]. The retinopathy has a "salt and pepper" appearance, with alternating areas of hypo- and hyperpigmentation, and autofluorescence shows irregular hypoautofluorescent dots; it is accompanied by myopia, hypermetropia, strabismus and nystagmus, and visual loss may be mild or absent despite the findings [42]. Corneal opacification requires exclusion of glaucoma and rubella embryopathy, and rubella is among the infectious causes of microphthalmia, together with varicella [54, 55]. The virus can be detected in lens tissue removed at cataract surgery, which in an Indonesian study was the material with the highest positivity for viral RNA [5, 56]. Intraocular persistence manifests decades later as Fuchs uveitis [5].

3.5. Hearing

Sensorineural deafness is the most frequent and persistent sequela, usually bilateral and moderate to profound, and may appear or worsen after the neonatal period [11, 42, 57]. It can result from infection up to 20 weeks, later than the structural defects [5, 25]. Before vaccination, CRS was an important cause of congenital deafness, and congenital rubella and cytomegalovirus infections remain among the environmental causes of severe deafness, which account for about 35% of the total [11, 39].

3.6. Heart and vessels

The typical cardiovascular lesions are PDA, peripheral pulmonary artery branch stenosis and septal defects, especially ventricular septal defect (VSD) [11, 25]. PDA is frequently associated with progressive pulmonary hypertension, a cause of death at around 6 months in series of unoperated patients and reversible in many cases with surgical closure of the duct [42]. Follow-up of Gregg's cohort at 60 years found mild aortic valve sclerosis in 68% [24]. Cardiomyopathy and arrhythmias are also described [42].

3.7. Central nervous system and neurodevelopment

Microcephaly, meningoencephalitis, intracranial calcifications and developmental delay are part of the picture [2, 25]. The calcifications described are periventricular and in the basal ganglia, a pattern close to that of cytomegalovirus infection and distinct from the subcortical pattern of Zika virus [42, 45, 58]. Prenatal ultrasound may show ventriculomegaly and calcifications [42]. In the two-year follow-up of surviving Vietnamese children, 95% had suspected delay in at least one domain of the Ages and Stages Questionnaire (ASQ), mainly communication (82%) and language (76%); 41% screened positive for autism spectrum disorder (ASD) on the Modified Checklist for Autism in Toddlers (M-CHAT), and assessment according to DSM-IV confirmed ASD in 3 of 17 children assessed, all with hearing and visual impairment [42]. The WHO and the reviews include autism among the developmental disabilities of CRS, and a 2015 review describes rubella as a vaccine-preventable cause of autism [5, 25]. In severe cases, motor milestones are greatly delayed (head control at 14 months, inability to sit at 22 months in described cases), and in later childhood deafness, motor abnormalities, balance and behaviour may worsen [42].

3.8. Neonatal systemic manifestations

The newborn may have IUGR, hepatosplenomegaly, hepatitis, jaundice, thrombocytopenia with purpura and dermal erythropoiesis with a "blueberry muffin" appearance, anaemia, interstitial pneumonitis and metaphyseal radiolucencies of the long bones, a characteristic radiological pattern [1, 25, 28]. Thrombocytopenia can be severe and recurrent: in the 2024 Dutch case, platelets were 16×10⁹/L at birth and fell again on days 4 and 8, requiring several transfusions [59]. In the Canadian series, one newborn had jaundice with total bilirubin of 307 µmol/L, radiolucent bone disease, platelets of 70×10⁹/L and PDA [60]. Reported mortality in infants with CRS reaches 33% [44]. A series with photographic documentation described facial dysmorphism in 54% (broad forehead, low anterior hairline with a whorl, triangular face, prominent nose, micrognathia), associated with heart disease [42].

3.9. Late manifestations

CRS is associated with late-onset endocrinopathies, mainly insulin-dependent diabetes mellitus and thyroiditis, and with a progressive encephalopathy resembling subacute sclerosing panencephalitis [3, 5]. One review also includes growth hormone deficiency [61]. In Gregg's cohort, 50 patients born in 1939–1944 were reassessed in 1967, 1991 and 2000–2001; of the 32 people examined at 60 years, 22% had diabetes, 19% thyroid disease, 73% early menopause and 12.5% osteoporosis, values higher than those of the Australian population, and 41% had no detectable anti-rubella antibodies; the HLA-A1, B8, DR3 haplotype was present in 25% [24]. In a Finnish group of 37 adults exposed in utero (mean age 22.5 years), one had diabetes and four clinical hypothyroidism, none had beta-cell autoantibodies and five had thyroid peroxidase antibodies, which suggests that the diabetes of CRS may not be autoimmune [62]. In a group of 16 young people with CRS, the CD4/CD8 T-lymphocyte ratio was reduced (1.57 versus 2.3 in controls) and about 20% had antimicrosomal antibodies [63]. The deficits of children with CRS appear in variable combinations and severity, and some appear or worsen later in life [57]. In adolescence and adulthood, learning difficulties, behavioural changes and deterioration of motor coordination are described [42]. Progressive rubella panencephalitis runs a course with raised CSF IgG, oligoclonal bands and a raised CSF:serum antibody ratio, and is fatal [43].

4. Clinical Recognition and Warning Signs

4.1. In pregnancy

Rubella should be considered in any pregnant woman with a non-vesicular rash illness, regardless of vaccination status, and in any pregnant woman who has had significant contact with a person with a rash [11, 12]. Significant contact was defined by the British guidelines as being in the same room for more than 15 minutes or face-to-face contact [64]. Clinical diagnosis is unreliable and infection is often subclinical, so laboratory confirmation is mandatory [11, 12]. The risk is higher in women born in countries without rubella vaccine in the schedule or with recent introduction: in a neonatal dried blood spot study in North Thames (England), mothers born in sub-Saharan Africa and South Asia were 4.2 and 5.0 times more likely to be seronegative than those born in the United Kingdom, and mothers under 20 years of age were also more susceptible [65]. Between 2003 and 2016, all women with primary infection in pregnancy in the United Kingdom with known country of birth had been born outside the country, and 14 of 22 with a known place of acquisition were infected abroad [12]. A positive IgG serology in early pregnancy does not exclude infection in women without a vaccination record from these countries: in the two Canadian cases, the mothers had antenatal IgG of 256.6 and >500 IU/ml, interpreted as immunity, and the children were born with CRS [60].

4.2. In the newborn

CRS should be suspected in an infant under 12 months with congenital heart disease, suspected hearing impairment or an ocular sign (cataract visible as a white pupil, congenital glaucoma visible as an enlarged eyeball, pigmentary retinopathy), and in any infant whose mother had suspected or confirmed rubella in pregnancy, even without signs [3]. In neonatal practice, the combination of IUGR, purpura or "blueberry muffin", thrombocytopenia, hepatosplenomegaly, early jaundice, microcephaly and metaphyseal radiolucencies directs screening for congenital infection [2, 28, 59]. The differential diagnosis of "blueberry muffin" includes TORCH infections and neoplasms such as leukaemia and neuroblastoma [59]. The initial assessment includes the timeline of any maternal exposure or rash, growth parameters with head circumference, cardiac examination and eye examination for cataract and pigmentary retinopathy [11].

4.3. In the infant and child beyond the neonatal period

Isolated sensorineural deafness or pigmentary retinopathy may be the only manifestations [11]. Rubella is part of the TORCH screen (toxoplasmosis, others, rubella, cytomegalovirus, herpes simplex) that the Oxford Desk Reference recommends in early-onset deafness, in which rubella serology is useful mainly in children under 6 months, in microcephaly and in intracranial calcification [39–41]. A history of maternal rubella infection is part of the history taking for any congenital heart disease [53]. After 6 months, detection of IgG that persists or rises in the absence of vaccination suggests congenital infection, and detection of viral RNA in cataract surgery material can confirm the diagnosis even after the first year [3, 27, 56].

4.4. Warning and emergency signs

Emergency signs are severe thrombocytopenia with bleeding, respiratory failure due to pneumonitis or heart failure, pulmonary hypertension associated with PDA, and seizures or meningoencephalitis [42, 58, 59]. Timely cardiac intervention can be life-saving [57]. From a public health perspective, suspicion of CRS is an immediate alert: the infant sheds virus and can infect susceptible pregnant women, and the CDC require immediate investigation of each suspected case with provisional notification within 24 hours, whereas the WHO requires investigation within 48 hours and contact and droplet precautions [3, 27]. In a country with elimination, a single locally acquired case of CRS is a sentinel event indicating unrecognised transmission, because up to half of rubella cases are asymptomatic [27].

4.5. Signs suggesting a genetic phenocopy

When screening for congenital infection is negative, genetic disorders should be considered: consanguinity or an affected sibling, progressive microcephaly, band-like cortical calcification with symmetrical polymicrogyria, chilblains, fever without a focus, recurrent hepatosplenomegaly and thrombocytopenia, raised interferon signature, photosensitivity, retinal telangiectasias, cataract with destructive cerebral haemorrhage or porencephaly [6, 10, 40, 41]. The Oxford Desk Reference advises caution regarding genetic conditions that mimic environmental causes, with pseudo-TORCH as an example [41].

4.6. Newborn screening and prenatal screening

There is no newborn screening directed at congenital rubella. Deafness detected by newborn hearing screening prompts investigation for congenital infection, now centred on cytomegalovirus [39]. Antenatal screening for rubella susceptibility ceased in England on 1 April 2016, after more than 40 years [11, 12]. The Brazilian Ministry of Health does not recommend routine antenatal serology for rubella, reserving it for symptomatic or exposed pregnant women, whereas other countries (USA, Canada, Australia) maintain determination of immunity before or during pregnancy, according to a 2025 review [42]. The WHO does not recommend serology before vaccination [25].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Case definitions

The surveillance definitions of the WHO (2018), of the CSTE with the CDC (2010) and of Canada differ in wording, but share the structure of two groups of signs and the requirement for laboratory evidence to confirm the case (Table 5.1).

Table 5.1. Case definitions of CRS and CRI

Sources: [2, 3]. The Canadian definition includes microphthalmia and late-onset conditions, such as diabetes and progressive panencephalitis, among the compatible manifestations [60]. The definitions serve surveillance and are not intended to decide individual clinical diagnosis [2].

5.2. Diagnosis of rubella in the pregnant woman

The UKHSA recommends that all pregnant women with a rash be investigated simultaneously for rubella and parvovirus B19, that the request state the pregnancy, the possibility of rubella and the date of the rash, and that IgG (or total antibody) and IgM be determined together [12]. No pregnant woman should be diagnosed with rubella on the basis of an isolated positive IgM: in an elimination setting, most positive IgM results do not reflect recent rubella, and all positive results should be confirmed in a reference laboratory with a second sample, IgM by two assay formats, RT-PCR and IgG avidity [12]. IgG avidity is low soon after primary infection and increases over weeks; in a recent infection, IgM reactivity changes within a few weeks rather than persisting at the same level [12]. The WHO adds that, when prevalence is low, the positive predictive value of IgM (especially by indirect method) is low, and that RT-PCR detects RNA only up to about one week after symptom onset, so a negative result does not exclude rubella [25].

The French national reference laboratory illustrates the scale of the problem: between 2013 and 2019 it received samples from 4104 pregnant women for IgG seroconversion (899) or positive IgM (3205); primary infection was excluded in 3724 (90.8%) and confirmed in only 46 (1.1%), with a positive predictive value of 0.2% for seroconversion and 1.4% for positive IgM [66]. IgM can remain positive for months without recent infection or reinfection, and in these cases IgG avidity is not low [67]. Oral fluid methods are not suitable for confirming or excluding rubella in the pregnant woman, and when investigation begins 4 or more weeks after the rash, an IgG-positive and IgM-negative profile does not exclude infection without earlier sera to demonstrate seroconversion [12].

5.3. Exposed pregnant woman

If the pregnant woman has at least two documented doses of vaccine or at least one positive IgG before or at the time of exposure, the probability of rubella is remote and no specific investigation is needed, but she should return if a rash develops [12]. Otherwise, serum is collected soon after the contact for IgM and IgG and, if she is susceptible, a second sample 4 weeks later; any seroconversion or positive IgM goes on for confirmation [12]. The CDC recommend collecting blood as early as possible from all exposed women of childbearing age, regardless of symptoms, for IgG, IgM and avidity, and storing the sample for repeat testing; a US review indicates repetition at 2–3 and at 6 weeks, testing the frozen initial serum in parallel [27, 28]. The 2002 British guidelines advised against specific testing for asymptomatic reinfection [64].

5.4. Fetal diagnosis

Before any invasive procedure, the maternal serological status should be established [11]. Ultrasound may show IUGR, microcephaly, ventriculomegaly or calcifications, hydrops, heart disease (ASD, VSD, PDA, pulmonary artery stenosis), hepatosplenomegaly, effusions, cataract and microphthalmia, hepatic hypoechogenicity, hyperechogenic bowel, polyhydramnios and placentomegaly; the findings most often described and accessible to prenatal diagnosis are septal defects, pulmonary artery stenosis, microcephaly, cataract, microphthalmia and hepatosplenomegaly, and the ultrasound signs of CRS are poorly known [11, 42, 68]. Fetal infection can be demonstrated by RT-PCR on amniotic fluid or by PCR and specific IgM on fetal blood obtained by cordocentesis [11, 42]. In a French study of 45 pregnant women with confirmed primary infection, RT-PCR on amniotic fluid had a specificity of 100% and a sensitivity of 83–95% compared with fetal or neonatal IgM [69]. In a London case of rash at 15 weeks, RNA and IgM were detected in fetal blood at 23 weeks, but RNA was not detected in the amniotic fluid samples at 19 and 23 weeks, which led the authors to prefer fetal blood [70]. Demonstration of fetal infection is not equivalent to fetal damage, especially in the second trimester, when the risk of damage is low [26, 70]. In the United Kingdom, fetal virological techniques are not widely available and should be discussed with the reference laboratory [12].

5.5. Diagnosis in the newborn and infant

The newborn of a mother with confirmed rubella, or in whom infection could not be excluded, should be investigated at birth with cord blood, placenta, urine and oral fluid [12]. Maternal IgM does not cross the placenta, so a positive IgM in the newborn supports congenital infection; IgG at birth includes maternal antibody and does not confirm the diagnosis [27]. Table 5.2 summarises the interpretation by age.

Table 5.2. Laboratory tests for congenital infection by age

IgM can persist for up to a year, rarely beyond [3, 42]. The 2019–2021 Indonesian study shows the limited sensitivity of RT-PCR outside the neonatal period: among 22 infants with laboratory-confirmed CRS (WHO definition), RNA was detected in only 42.1%, and lens material had the highest positivity [56]. In the Canadian series, urine was negative or inconclusive in the first samples and only nasopharyngeal swabs were positive, which the authors attribute to the difficulty of obtaining an adequate urine volume (more than 10 ml) in infants [60]. Culture is slower and is not a first-line method [28].

5.6. Assessment after confirmation

Once infection is confirmed, each system is assessed: ophthalmological examination for cataract, glaucoma and retinopathy; audiometry; echocardiography; brain imaging, with computed tomography (CT) if calcifications need to be demonstrated, because magnetic resonance imaging (MRI) is less sensitive; full blood count and liver function; radiography of the long bones when radiolucent bone disease is suspected [11, 25, 40, 57, 60]. These examinations should be repeated during follow-up, because some deficits appear later [57]. In the 2024 Dutch case, the complete assessment (echocardiography, transfontanellar ultrasound, brain MRI, audiology and ophthalmology) was normal despite purpura and severe thrombocytopenia [59].

5.7. Limitations of the tests

Immunity serology has its own limitations. In a panel of 322 sera from pregnant women that were negative or equivocal on screening, immunoblot and neutralisation agreed in 267; of the 182 positive by these reference methods, 25.3–61.5% were classified as equivocal and 6–64.8% as positive by the eight commercial assays studied, with wide variation of titres in IU/ml [71]. In another study, 52.2% of 186 pregnant women considered susceptible had anti-E1 IgG by immunoblot, and all of these mounted a secondary response to postpartum vaccination [72]. Serological false positives may be due to previous parvovirus or Epstein-Barr virus infection and to rheumatoid factor [5]. A high IgG titre does not distinguish old immunity from recent infection [60]. RT-PCR may prolong the isolation period compared with culture, because it detects RNA from inactive virus [60]. Avidity tests are not widely available and their performance varies [5].

5.8. Genetic investigation when infection is not confirmed

When an infant has the phenotype of congenital infection and tests for rubella, cytomegalovirus, toxoplasmosis and other infections are negative, or when neuroimaging has an atypical pattern, investigation should proceed to genetic causes [6, 40]. The Oxford Desk Reference proposes, in the presence of intracranial calcifications, electrolytes, calcium, phosphate and parathyroid hormone, congenital infection serology, cytomegalovirus PCR on the Guthrie card, organic acids and amino acids, lactate, CSF with cells, protein, lactate, interferon alpha and pterins, and genomic analysis (array, panel or exome or genome sequencing), storing DNA [40]. Detection of OCLN variants requires copy number analysis in addition to sequencing, because the spectrum includes intragenic deletions and the gene has a nearby pseudogene [46, 73]. A blood interferon signature (expression of interferon-stimulated genes) supports an interferonopathy, but does not identify the gene [74]. The coexistence of a confirmed infection does not exclude another cause, and a diagnosis of CRS with negative genetic screening should rest on clear laboratory evidence.

6. Differential Diagnosis

6.1. Comparative table

Table 6.1. Differential diagnosis of CRS

Sources: [6–10, 12, 15, 17, 40–42, 46, 47, 51, 55, 75–77]. AR, autosomal recessive; AD, autosomal dominant.

6.2. Other congenital infections

Intracranial calcification is common, but not constant, in congenital infections, and has been described after cytomegalovirus, rubella, Zika, toxoplasma, parvovirus, varicella, herpes, lymphocytic choriomeningitis virus and human immunodeficiency virus (HIV) [40]. A 2025 review compares the patterns: in rubella the calcifications are periventricular and in the basal ganglia, as in cytomegalovirus, whereas in Zika they are predominantly subcortical; rubella has the highest risk at around the 10th week, Zika between 7 and 13 weeks, cytomegalovirus in all trimesters and toxoplasmosis in late pregnancy [42]. Cataract, "salt and pepper" retinopathy and the specific cardiac lesions point to rubella, whereas chorioretinitis and hydrocephalus suggest toxoplasmosis [42]. Rubella is the only one of these infections preventable by vaccination [42]. Diagnosis is simple when there is active infection with virus identified by serology or PCR in the neonatal period; after this period the distinction becomes difficult and neuroimaging may recognise specific genetic disorders [40].

6.3. Pseudo-TORCH 1 (OCLN)

Band-like calcification with simplified gyration and polymicrogyria, formerly called pseudo-TORCH syndrome, is an autosomal recessive disorder that mimics intrauterine infection without evidence of infection: congenital microcephaly, intracranial calcifications, simplified gyration with polymicrogyria and severe developmental delay [6]. The phenotype presents at birth or shortly afterwards with seizures, feeding difficulties, microcephaly, tetraparesis and bulbar palsy; on CT the calcification forms a continuous or semicontinuous symmetrical cortical band, with thalamic and sometimes pontine calcification, a pattern distinct from cytomegalovirus, which is the most common cause of the combination of calcification and polymicrogyria [40]. O'Driscoll and colleagues identified intragenic deletions and mutations of OCLN in 9 patients from 6 families, using autozygosity mapping and copy number analysis [46]. Thrombocytopenia, liver dysfunction and hepatosplenomegaly are more associated with pseudo-TORCH than with Aicardi-Goutières syndrome, although there is overlap [6]. The deletion of exons 3 and 4 behaves as a founder allele in the Egyptian population [73].

6.4. Type I interferonopathies: Aicardi-Goutières syndrome and pseudo-TORCH 2 and 3

Aicardi-Goutières syndrome is a genetically heterogeneous encephalopathy with cerebral atrophy, leukodystrophy, calcifications, chronic lymphocytosis and raised CSF interferon alpha, with negative prenatal serology, phenotypically similar to a viral infection in utero [9]. The neonatal form presents with fever, seizures, hepatosplenomegaly, thrombocytopenia and anaemia, and the infantile form appears after a period of apparently normal development [40]. Pseudo-TORCH 2, due to USP18 deficiency, has prenatal onset with intracranial haemorrhage and calcification, brain malformations, liver dysfunction and thrombocytopenia, and patients usually die in infancy [7, 47]. A newborn with a USP18 splicing variant responded to ruxolitinib, a Janus kinase (JAK) inhibitor used off-label [48]. Pseudo-TORCH 3, due to homozygous STAT2 variants that prevent negative regulation of the interferon response, runs a course with episodes of fever, coagulopathy, thrombotic microangiopathy and progressive calcifications, and death in early childhood is frequent [8, 49, 50].

6.5. Other phenocopies

Haemorrhagic destruction of the brain with subependymal calcification and cataracts, due to biallelic JAM3 variants, deserves particular attention because it combines congenital cataract with severe brain injury and calcifications, a combination that also occurs in CRS; it was described in a highly consanguineous Saudi family with 8 affected individuals and a catastrophic neurological course [10]. COL4A1- and COL4A2-related disease combines cerebral vascular injury, porencephaly and cataract [40]. Cystic leukoencephalopathy without megalencephaly due to RNASET2 can be indistinguishable from congenital cytomegalovirus, and Coats plus, leukoencephalopathy with calcifications and cysts and Cockayne syndrome complete the group [40]. In the context of congenital Zika, Aicardi-Goutières syndrome, pseudo-TORCH and variants of JAM3, NDE1 and ANKLE2 produce a fetal brain disruption sequence phenotype [76].

6.6. Genetic causes of cataract, deafness and heart disease

When the picture is limited to one of the main signs, the differential widens to the genetic causes of congenital cataract, sensorineural deafness and congenital heart disease. In developed countries, about 35% of severe childhood deafness has an environmental cause, including congenital infections, and at least 60% has a genetic origin, with more than 60 autosomal dominant and more than 90 recessive loci in non-syndromic deafness [39]. Pigmentary retinopathy with deafness also suggests Usher syndrome, and the Oxford Desk Reference recommends complete ophthalmological assessment in all children with severe deafness [39]. The heart disease associated with rubella (PDA, peripheral pulmonary artery branch stenosis, septal defects) is distinguished from the conotruncal heart defects associated with retinoic acid and from the predominance of ventricular and atrial septal defects with alcohol exposure [53].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no antiviral treatment or other specific therapy for acquired or congenital rubella; management is supportive, directed at the anomalies, and prevention depends on vaccination [3, 28, 42]. Children with CRS need multidisciplinary follow-up (paediatrics, cardiology, ophthalmology, audiology, neurology and rehabilitation) and early intervention with speech and language therapy, occupational therapy, physiotherapy and behavioural intervention [42, 57].

7.2. Treatment of the manifestations

Timely cardiac intervention can be life-saving: PDA is associated with progressive pulmonary hypertension, and surgical closure of the duct reversed this course in many described cases [42, 57]. Congenital cataract and the other ocular lesions require early surgery and lifelong ophthalmological follow-up [42]. In severe or profound deafness, auditory rehabilitation includes assessment for cochlear implantation, and children with hearing impairment depend heavily on vision, so complete ophthalmological assessment is essential [39]. Severe neonatal thrombocytopenia may require repeated platelet transfusions, and respiratory distress may require continuous positive airway pressure [59]. In the Somali case, heart failure with an ejection fraction of 40% was treated with enalapril and furosemide, stopped after improvement, and the seizures with phenobarbital; these measures are specific to the case and do not constitute a protocol [58]. Late endocrinopathies are treated according to the standards for each disease [24].

7.3. Infection control of the infant with CRS or CRI

Infants with CRS or CRI shed live virus for a long time and can infect susceptible carers and pregnant women [3, 27]. Table 7.1 compares the recommendations.

Table 7.1. Infection control in the infant with CRS or CRI

A US review recommends droplet precautions in hospital up to 1 year, unless two RT-PCR tests 1 month apart after 3 months are negative [28]. The Canadian experience describes practical application: monthly nasopharyngeal swabs and urine at home visits, release from isolation at the 12th month in the first case, a dedicated team with confirmed immunity, checking and catch-up vaccination of household and non-household contacts, restriction of visits to immune persons, surveillance of unvaccinated visitors for 12 to 23 days, advice against day care and air travel, and cleaning with low-level disinfectants, effective because the virus is enveloped [60]. In these cases, urine remained positive longer than the nasopharyngeal swab in one patient and the reverse in the other [60].

7.4. Immunoglobulin after exposure

Administration of immunoglobulin to an exposed person is not recommended as routine prophylaxis, and vaccine administered after exposure does not prevent infection, although it protects against future exposures [28]. A Cochrane review of 12 studies (430 participants, all in high-income countries, only one with pregnant women) found a reduction in rubella cases with polyvalent gamma globulin (relative risk 0.61; 95% CI 0.45–0.83), with a greater effect for higher volumes and when given within 5 days of exposure; no study measured congenital infection, and the evidence is insufficient to draw conclusions on the prevention of CRS, not least because the anti-rubella antibody concentration of current products is unknown [78].

7.5. Management of the pregnant woman with confirmed rubella

Management depends on gestational age, the woman's circumstances and the probability of anomalies; decisions in the first 20 weeks should be taken in a fetal medicine unit, and asymptomatic reinfection in the first 16 weeks may justify fetal investigation by PCR [12]. The possible intervention is counselling for an informed decision on continuation of the pregnancy [12]. Between 2003 and 2016 there were 4 terminations of pregnancy associated with rubella in the United Kingdom, and records of rubella-associated terminations ceased to be published after 2000 because of very low numbers [11, 12].

7.6. Vaccination: products and dosage

Rubella vaccines are live attenuated, almost all with the RA 27/3 strain, and are given combined with measles vaccine (MR vaccine), with measles and mumps vaccine (MMR) or with measles, mumps and varicella vaccine [4, 25]. There is no monovalent rubella vaccine in the USA, and in Portugal MMR is the only presentation used in the National Vaccination Programme (Programa Nacional de Vacinação, PNV) [4, 29]. Table 7.2 summarises the presentations and dosage according to the labels and the PNV.

Table 7.2. Rubella-containing vaccines: dosage according to labels and national programme

Seroconversion after one dose of RA 27/3 vaccine is 95–100% in susceptible individuals aged 9 months or older; a meta-analysis of 26 trials recorded 99% (95% CI 98–99) at 9–18 months and the second dose reaches 100% [25]. Between 1% and 5% do not seroconvert after the first dose, because of concomitant infection or maternal antibodies [25]. Seropositivity persists in 92–100% between 1 and 21 years after one dose, and all children vaccinated at 14–18 months and at 4–6 years had antibodies 20 years after the second dose [25]. The CDC indicate protection against clinical disease in more than 90% for at least 15 years and probably lifelong protection with one dose; cohort studies estimate an effectiveness of 78.6–89% against infection [4, 28].

7.7. Schedules and recommendations by jurisdiction

Table 7.3. Recommended schedules

Since the 2024 meeting of the Strategic Advisory Group of Experts on Immunization (SAGE), the WHO has recommended introduction of the vaccine in all countries, without the previous condition of ≥80% coverage with the first dose of measles vaccine, which was intended to avoid the paradoxical effect of shifting infection to childbearing ages [5, 23, 25]. The sources converge on three points: serology is not needed before vaccinating, absence of a vaccination record should be treated as susceptibility, and women identified as susceptible in pregnancy should be vaccinated after delivery [12, 25, 29]. They differ in the number of doses required as proof of a woman's immunity (one for the WHO and ACIP; two for the PNV and the UKHSA) and in the usefulness of antenatal serology [4, 12, 25, 29, 42].

7.8. Contraindications, precautions and adverse effects

Table 7.4. Contraindications and precautions for rubella vaccine

Adverse effects of MMR include local pain and redness; fever ≥39.4 °C in 5–15% of susceptible individuals between 7 and 12 days after the vaccine; rash in about 5%; febrile seizures in about 1 per 3000 to 4000 doses; anaphylaxis in 1.8 to 14.4 per million doses; rare transient thrombocytopenia; and arthralgia in up to 25% of adult women, attributed to the rubella component, between 1 and 3 weeks after vaccination [4, 29]. The tetravalent vaccine increases the risk of fever (21.5% versus 14.9%) and of febrile seizures after the first dose at 12–23 months (one additional seizure per 2300 to 2600 children) [4]. Thrombocytopenic purpura is twice as frequent after natural infection as after the vaccine, and the National Academy of Medicine reviews found no causal relationship with autism or with inflammatory bowel disease [4, 28]. Vaccine and wild-type virus have been identified in cutaneous granulomas, sometimes at the site of an old vaccination, in patients with and without immunodeficiency [28].

7.9. Inadvertent vaccination in pregnancy

The contraindication in pregnancy is based on a theoretical risk. Table 7.5 summarises the safety data.

Table 7.5. Data on rubella vaccination shortly before or during pregnancy

Termination of pregnancy after inadvertent vaccination is not indicated, according to the WHO, the CDC, the British Department of Health and the 2020 systematic review; individual counselling is recommended [4, 11, 25, 83]. The 2023 French case, the first published case of CRS after vaccination in pregnancy and now mentioned in the M-M-R II and PRIORIX labels, does not change this recommendation, but reinforces the rule of not vaccinating pregnant women and of avoiding pregnancy for one month [80, 81, 84]. In Portugal, inadvertent vaccination of a pregnant woman with a contraindicated vaccine should be reported to the National Pharmacovigilance System (Portal RAM) [29]. Vaccination of a breastfeeding woman does not interfere with the infant's vaccination schedule; women vaccinated postpartum may shed vaccine virus in breast milk and transmit it, without severe disease in the infants described (one had mild disease) [29, 80].

7.10. Regulatory status

Table 7.6. Regulatory status of rubella-containing vaccines

Sources: [4, 79–81].

7.11. Trials and main evidence

Table 7.7. Intervention studies and systematic reviews

These studies are not comparable with one another. The microneedle patch trial is phase 1/2, with safety and immunogenicity objectives and not clinical efficacy, and the product is not authorised [85]. The Cochrane review assessed mainly old trials, with high heterogeneity (I² 73%) and products of unknown antibody concentration [78]. The reviews of safety in pregnancy are based on small cohorts with comparator and do not exclude a very low risk, which the 2023 case confirms to be possible [83, 84].

7.12. Developments in the last 12 months

As of 29 October 2026, the developments identified concern surveillance, labelling and development, with no new authorisations. The July 2026 MMWR report updated global progress to 2024 (117 countries with verified elimination and 26,859 estimated CRS cases) and recorded the introduction of the vaccine in Nigeria and the Democratic Republic of the Congo in 2025–2026 [23]. The WHO fact sheet was updated on 15 July 2026 [87]. The US labels of PRIORIX (21 May 2026) and M-M-R II (15 October 2026) include the CRS case associated with the vaccine strain genotype, a labelling change [80, 81]. The microneedle patch with MR vaccine has completed phase 1/2, with no application for authorisation identified in the sources consulted [85, 86]. The absence of other results in the searches performed does not prove that none exist.

8. Reproductive Options and Family Counselling

8.1. CRS is not inherited

CRS results from an infection acquired during gestation and carries no genetic recurrence risk. A woman who has had primary infection is usually immune, and subsequent pregnancies are protected, except for the low risk of reinfection [12, 25]. A person with CRS does not transmit the disease to their offspring genetically. Counselling of a family with an affected child focuses on prognosis, rehabilitation, the risk of viral transmission while the infant sheds virus and vaccination of contacts [3, 60].

8.2. Counselling the pregnant woman with confirmed rubella

Counselling uses the risks by gestational age in Table 2.1: a risk of fetal infection of about 90% and of defects of about 90% before 11 weeks; 55% and 20% between 11 and 16 weeks; minimal risk, limited to deafness, between 16 and 20 weeks; and no documented risk before the estimated conception or after 20 weeks [12, 26]. Prenatal diagnosis by RT-PCR on amniotic fluid or fetal blood can help parents make an informed decision, especially in second-trimester infection, when the risk of damage is low [69, 70]. The decision to continue or terminate the pregnancy rests with the woman after counselling in a fetal medicine unit [12]. In reinfection, the risk of damage in the first 16 weeks is probably less than 5%, and reinfection with rash carries a significant unquantified risk [12].

8.3. Inadvertent vaccination and pregnancy planning

Inadvertent vaccination before or during pregnancy is not an indication for termination; the estimated maximum theoretical risk in susceptible women is 1 in 1008, with a single published case of vaccine-associated CRS [25, 83, 84]. Women planning pregnancy, including those undergoing fertility treatment, should check their vaccination status and, without two documented doses, be vaccinated and avoid conception for one month [11, 12, 29].

8.4. Counselling when infection is not confirmed

When an infant with a congenital infection phenotype has negative infection tests, counselling changes. Pseudo-TORCH syndromes are autosomal recessive, with a recurrence risk of 25% for each pregnancy of the same parents and the possibility of prenatal or preimplantation diagnosis once the variants are identified [6–8, 73]. In Aicardi-Goutières syndrome, inheritance is recessive for most genes and dominant for some, including TREX1-related forms, and counselling depends on the gene [9]. In apparently sporadic microcephaly without an identified cause, the Oxford Desk Reference proposes an empirical recurrence risk of 15–20%, and of 25% when there is consanguinity [41]. A mistaken diagnosis of congenital infection leads to underestimation of the recurrence risk, which is why laboratory confirmation of CRS is essential [40, 41].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Global situation

The global surveillance report published in 2026 describes the period from 2012 to 2024 (Table 9.1) [23]. The number of countries with rubella-containing vaccine in the schedule rose from 132 (68%) to 179 (92%) of the 194 Member States, and first-dose coverage at 12–23 months from 39% to 73%, with regional variation between 37% (African Region) and 96% (South-East Asia) [23]. Reported rubella cases fell from 94,277 in 2012 to 18,881 in 2022 and rose to 31,593 in 2024, owing to transmission in Chad and Nigeria, without vaccine, and in South Africa during introduction [23]. The number of countries with verified elimination rose from 84 (43%) in 2019 to 117 (60%) in 2024, and no country that eliminated rubella has had endemic transmission again [23]. In 2024, about 21 million infants aged 12–23 months (16% of the birth cohort) lived in the 15 countries without vaccine, almost all in Africa and the Eastern Mediterranean [23].

Table 9.1. Rubella and CRS by WHO region, 2024

Source: [23]. Estimated CRS fell from 101,381 cases in 2012 to 26,859 in 2024 (−73.5%); the increase in reported cases (302 in 2012, 611 in 2024) reflects the expansion of surveillance in populous countries such as Afghanistan, Bangladesh, India, Indonesia and Pakistan [23]. The WHO fact sheet of July 2026 maintains the estimate of about 100,000 births with CRS per year, which differs from the 2026 model, and the CDC surveillance manual cites about 30,000 per year; the difference results from different bases and years, and the model-based estimate published in 2026 is the most recent [23, 27, 87]. Reported numbers underestimate CRS, because surveillance relies on sentinel referral sites [3, 23].

9.2. Europe

In 2024, the WHO European Region had 50 of 53 countries with verified elimination and one reported case of CRS [23]. EUVAC.NET network data for 2000–2008 showed a fall in median rubella incidence from 7.2 to 0.3 per million inhabitants; in 2008, 98% of the 21,475 cases were reported by Poland, Italy and Romania, only 1.5% were laboratory-confirmed, and there were 20 cases of CRS in 5 countries [22]. The birth prevalence values used by Orphanet derive from that study: Romania 2.18, Italy 0.8, the Netherlands 0.64, France 0.29, Austria 0.27, Germany 0.24, Spain 0.22 and Turkey 0.02 per 100,000 births, and 0.35 per 100,000 for Europe (non-validated value) [1, 22]. In 2023, 345 rubella cases were reported in 17 European countries, mainly in Poland, Kyrgyzstan, Tajikistan, Turkey and Ukraine, of which 23% were laboratory-confirmed [88]. Between February 2024 and January 2025, 29 European Union and European Economic Area countries reported 224 cases to the European Centre for Disease Prevention and Control (ECDC), 28 laboratory-confirmed (Germany 13, Poland 7, Sweden 3, Latvia 2, France, Lithuania and Italy 1 each) [59]. Poland and Romania had outbreaks in 2012 that mainly affected men, a consequence of initial strategies directed only at women [5].

In the United Kingdom, rubella is rare: between April 2013 and March 2018, 7 of about 1500 oral fluid samples were confirmed; between 2003 and 2016 there were 31 infections in pregnancy (0.23 per 100,000 pregnancies) and 12 infants with CRS; seronegativity on antenatal screening rose from about 3% in 2006 to 7% and varies with country of origin [12]. The British national register shows the fall in births with CRS and in rubella-associated terminations since the 1970s, after the introduction of the combined vaccine [11].

9.3. The Americas, the USA and Brazil

The Region of the Americas was the first to eliminate rubella and CRS, with verification in 2015, and the 35 countries maintained this status in 2024 [23, 42]. Between 2010 and 6 October 2026, after interruption of endemic circulation, 136 rubella cases in several countries and 19 cases of CRS were reported in the Americas, 14 in the USA and 5 in Canada [89]. In the USA, elimination was declared in 2004 and reconfirmed in 2011 and 2014; since 2004 there have been fewer than 10 rubella cases and fewer than one case of CRS per year, and since 2012 all cases have been acquired outside the country [4, 27]. Between 1998 and 2017, 41 of 47 CRS cases (89%) occurred in children of mothers born outside the USA, and between 2005 and 2017 all confirmed cases but one were linked to international travel [27]. In Canada, the vaccine was licensed in 1969 and rubella incidence fell from 37 per 100,000 inhabitants (1969–1973) to less than 1 per 100,000 in 2005, the year of elimination; since then cases have been imported [60].

In Brazil, rubella has been notifiable since 1996 and has had integrated surveillance with measles since 1999; after campaigns directed mainly at women of childbearing age, including the 2008 national campaign, the country received the rubella elimination certificate from the Pan American Health Organization (PAHO) in 2015 and, in 2024, regained joint certification for measles, rubella and CRS [42, 90]. Admissions coded as congenital rubella (ICD-10 P35.0) in the public hospital system are not equivalent to confirmed cases in the surveillance system, because they may reflect suspected cases, provisional diagnoses or coding errors [90].

9.4. Portugal

The Portuguese PNV includes two doses of MMR, at 12 months and 5 years, and requires two doses of rubella vaccine in women of childbearing age; vaccination of health professionals is part of the strategy for consolidating the elimination of measles and rubella in the country [29]. The 2015/2016 National Serological Survey showed immunity to measles in 99.6% of those born before 1970 [29]. The sources consulted do not include data on the incidence of rubella or CRS in Portugal; the European Region, to which Portugal belongs, had 94% of countries with verified elimination in 2024 [23].

9.5. Asia and at-risk populations

Japan had epidemics in 1965–1969, 1975–1977, 1982, 1987–1988 and 1992–1993; a survey of schools for the deaf identified 83, 232, 77 and 167 children with CRS after the first four, and the hypothesis that Japanese strains were less teratogenic was refuted [91]. Selective vaccination of girls from 1977 left men susceptible, and the 2013 outbreak had more than 11,000 cases in the first half of the year, 70% in men aged 20 to 39 years, and at least 13 cases of CRS [5, 91]. In Vietnam, a large outbreak in 2011 gave rise to a cohort of children with CRS followed between 2011 and 2015 [57]. In the African pre-vaccine era (2002–2009), the median age of confirmed cases was 7.3 years [5].

The populations at greatest risk in countries with elimination are migrant women born in countries without vaccine or with recent introduction, adult men from selectively vaccinated cohorts and communities that refuse vaccination [5, 59, 65]. In the Netherlands, outbreaks since 2000 have occurred in unvaccinated children from communities that refuse vaccination for religious reasons, and the 2024 case was born to a Somali asylum seeker [59]. The recent Canadian and British cases occurred in children of women recently arrived from sub-Saharan Africa or born outside the country [12, 60].

9.6. Reference networks and patient organisations

There is no ERN dedicated to congenital infections. Relevant to the sequelae and the differential are ERN-EYE for rare eye diseases, including congenital cataract and glaucoma (https://www.ern-eye.eu/), ERN CRANIO for rare ear, nose and throat disorders (https://www.ern-cranio.eu/), ERN-ITHACA for malformation syndromes and intellectual disability (https://ern-ithaca.eu/), ERN GUARD-Heart for rare heart diseases (https://guardheart.ern-net.eu/) and ERN RITA for the interferonopathies and immunodeficiencies of the differential (https://ern-rita.org/) [31–35]. Organisations include Sense, in the United Kingdom, dedicated to people with deafblindness and complex disabilities (https://www.sense.org.uk/), and Deafblind International (https://www.deafblindinternational.org/); the Measles & Rubella Partnership is the international partnership referred to in the elimination progress reports (https://www.measlesrubellapartnership.org/) [23, 36–38].

10. Illustrative Clinical Case

10.1. Main case: congenital rubella syndrome in Somalia

Ismail and colleagues described in 2024 a male term infant referred to a Somali hospital at 35 days for seizures, fever and bilateral cataract present since birth [58]. The 33-year-old multiparous mother, without vaccination or antenatal care, had had a rash, headaches and fever in the first months of pregnancy, without seeking care; the parents were consanguineous with no history of hereditary disease, and the three siblings were healthy [58]. The newborn had required resuscitation and oxygen at birth. At 35 days he weighed 3.55 kg, measured 55 cm and had a head circumference of 35.8 cm; he was hypotonic but alert, with respiratory distress without cyanosis, involuntary eye movements, bilateral cataract, a continuous murmur at the upper left sternal border and clonic seizures, without hepatosplenomegaly [58]. Figure 1 of the article documents the bilateral cataract (https://pmc.ncbi.nlm.nih.gov/articles/PMC11338173/figure/f0001/) [58].

The full blood count showed leucocytes 9×10⁹/L, haemoglobin 16.6 g/dl and platelets 181×10⁹/L, with no thrombocytopenia on any measurement; sodium was 129 mmol/L, albumin 2.7 g/dl and C-reactive protein 29 mg/L, with normal renal, liver and thyroid function and coagulation [58]. Anti-rubella IgM was 50.2 AU/ml, and serology for herpes simplex virus, cytomegalovirus and toxoplasma was negative; RT-PCR was not available at the hospital [58]. Chest radiography showed cardiomegaly and mild bilateral infiltrates (Figure 2), echocardiography an ejection fraction of 40% and PDA, and brain CT symmetrical periventricular calcifications with hypodensity and loss of grey-white matter differentiation (Figure 3); hearing assessment revealed bilateral sensorineural deafness [58]. The patient received empirical antibiotic therapy, enalapril and furosemide, stopped after improvement in ejection fraction, and phenobarbital, and was referred for cataract surgery [58].

The case brings together the classic triad of cataract, heart disease (PDA) and sensorineural deafness, with periventricular calcifications and seizures, in a child from a country that, in 2024, had not yet introduced rubella vaccine [23, 58, 59]. By the WHO definition, a positive IgM with group A signs in an infant under 6 months is sufficient to confirm the case, but the lack of RT-PCR prevented genotyping; in a country with elimination, confirmation would include oropharyngeal and urinary RT-PCR, genotyping and isolation until negative [3, 27]. The parents' consanguinity, in an infant with cataract, seizures and calcifications, would make it relevant to consider the autosomal recessive phenocopies (for example JAM3 or pseudo-TORCH) if the evidence of infection were less clear [6, 10]. The pharmacological measures described are those of the report and do not constitute a routine recommendation.

10.2. Complementary cases in countries with elimination

In the Netherlands, in May 2024, a Somali asylum seeker without antenatal care until 33 weeks gave birth to a term female newborn with diffuse "blueberry muffin" purpura, platelets of 16×10⁹/L, hepatosplenomegaly and respiratory distress; urinary RT-PCR and the child's IgM and IgG were positive, the mother had very high IgG and negative IgM and recalled a facial rash in the 5th month of pregnancy, while still in Somalia; echocardiography, brain imaging, audiology and ophthalmology were normal, and the child was placed in contact and droplet isolation [59]. In Canada, two newborns of mothers who had arrived from sub-Saharan Africa, whose high antenatal IgG had been interpreted as immunity, were born with CRS (IUGR, jaundice, thrombocytopenia, PDA and radiolucent bone disease in one case; microcephaly, desquamating skin and radiolucent bone disease in the other), were confirmed by nasopharyngeal RT-PCR and IgM, and shed virus for several months [60]. These cases show that maternal infection may have occurred in the country of origin or in transit, that antenatal serology can be misleading and that the public health response lasts throughout the first year of life.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Reported mortality in infants with CRS reaches 33%, and pulmonary hypertension associated with an unclosed PDA is a frequent cause of death at around 6 months [42, 44]. Survivors have sensory, motor and cognitive disabilities of variable severity, often combined, which may appear or worsen later [25, 57]. A systematic review estimated between about 19 and 39 disability-adjusted life years lost per case in high-income countries with optimal treatment, and between 29 and 39 in low-income countries with minimal treatment [52]. More than 90% of children followed for two years in a Vietnamese cohort had developmental delays, mainly in communication and language, which tend to persist [42]. In Gregg's Australian cohort, followed up to 60 years, 10 of the 50 patients had died since 1967 (4 from cardiovascular causes, 4 from neoplasms, 1 from acquired immunodeficiency syndrome and 1 from hepatitis C-associated cirrhosis), and the survivors had more diabetes, thyroid disease, early menopause and osteoporosis than the general population [24]. CRI without signs has a better prognosis, but requires reassessment, because hearing loss may appear later and prompt reclassification as CRS [2, 11].

11.2. Surveillance

The sources consulted recommend paediatric, cardiac, hearing, ophthalmological and neurological assessments after birth, repeated during follow-up, but do not set specific intervals for CRS beyond those for testing for viral shedding; the intervals in Table 11.1 indicate this limitation where it exists [42, 57].

Table 11.1. Surveillance of the infant and child with CRS or CRI

11.3. Transition to adulthood

The person with CRS reaches adulthood with sensory deficits, frequently deafblindness, and with an increased risk of diabetes, thyroid disease, early menopause and osteoporosis [5, 24]. Viral persistence may manifest decades later as Fuchs uveitis, and 41% of the adults in Gregg's cohort had no detectable antibodies at 60 years [5, 24]. Learning difficulties, behavioural changes and deterioration of motor coordination are accompanied by educational and social needs that require prolonged multidisciplinary support [42].

12. Summary and Final Considerations

Congenital rubella syndrome is an embryofetopathy caused by transplacental passage of rubella virus during maternal viraemia. The risk of defects is greatest when infection occurs before 11 weeks, when up to 90% of fetuses are damaged, falls to about 20% between 11 and 16 weeks, is limited to deafness between 16 and 20 weeks and is not documented thereafter. The classic picture combines cataract, pigmentary retinopathy, sensorineural deafness, patent ductus arteriosus and peripheral pulmonary artery branch stenosis, with microcephaly, growth restriction, purpura, hepatosplenomegaly and metaphyseal radiolucencies in the newborn, and with diabetes, thyroid disease and progressive encephalopathy as late manifestations. Deafness and retinopathy may be isolated and of late onset.

Diagnosis in the pregnant woman rests on simultaneous determination of IgM and IgG, with confirmation of any positive IgM by avidity and RT-PCR in a reference laboratory, because in an elimination setting most positive IgM results do not correspond to recent infection. In the infant, IgM in the first 6 months, RT-PCR on oropharyngeal swab and urine in the first 3 months and persistence of IgG after 6 months confirm infection, according to the WHO and CDC case definitions. A negative result does not exclude infection, and a high IgG titre does not prove old immunity in a woman without a vaccination record.

For the geneticist, CRS is a phenocopy to be confirmed or excluded before genomic investigation of an infant with cataract, deafness, heart disease, microcephaly or calcifications. When infection is not confirmed, the pseudo-TORCH syndromes due to OCLN, USP18 and STAT2, Aicardi-Goutières syndrome and JAM3-related disease have autosomal recessive inheritance in most cases and a recurrence risk of 25%, which makes the aetiological diagnosis decisive for counselling.

There is no antiviral treatment. Management comprises surgical correction of heart disease and cataract, auditory and visual rehabilitation, early developmental intervention and endocrine surveillance, with contact precautions until two samples one month apart are negative. Prevention depends on the live attenuated vaccine, with seroconversion of 95–100% after one dose; the vaccine is contraindicated in pregnancy, pregnancy should be avoided for one month, and inadvertent vaccination does not justify termination, although a case of CRS associated with the vaccine strain was published in 2023. In 2024, 117 of the 194 countries had verified elimination and estimated CRS had fallen to about 27,000 cases per year, almost 90% in Africa; in countries with elimination, cases occur mainly in children of unvaccinated migrant women, which justifies vaccination of all women of childbearing age without two documented doses.

13. References

1. Orphanet. Congenital rubella syndrome (ORPHA:290). https://www.orpha.net/en/disease/detail/290
2. Council of State and Territorial Epidemiologists; Centers for Disease Control and Prevention. Rubella, congenital syndrome (CRS): 2010 case definition (CSTE position statement 09-ID-61). Atlanta: CDC NNDSS; revised 16 Apr 2021. https://ndc.services.cdc.gov/case-definitions/rubella-congenital-syndrome-2010/
3. World Health Organization. Vaccine-preventable diseases surveillance standards: congenital rubella syndrome. Geneva: WHO; 2018 (updated 5 Sep 2018). https://www.who.int/publications/m/item/vaccine-preventable-diseases-surveillance-standards-crs
4. Centers for Disease Control and Prevention. Rubella. In: Epidemiology and Prevention of Vaccine-Preventable Diseases (Pink Book). 14th ed. Atlanta: CDC; 2021. Chapter 20. https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-20-rubella.html
5. Lambert N, Strebel P, Orenstein W, Icenogle J, Poland GA. Rubella. Lancet. 2015;385(9984):2297-307. doi:10.1016/S0140-6736(14)60539-0. PMID: 25576992. PMC4514442.
6. Online Mendelian Inheritance in Man, OMIM. #251290 PSEUDO-TORCH SYNDROME 1; PTORCH1. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/251290
7. Online Mendelian Inheritance in Man, OMIM. #617397 PSEUDO-TORCH SYNDROME 2; PTORCH2. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/617397
8. Online Mendelian Inheritance in Man, OMIM. #618886 PSEUDO-TORCH SYNDROME 3; PTORCH3. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/618886
9. Online Mendelian Inheritance in Man, OMIM. #225750 AICARDI-GOUTIERES SYNDROME 1; AGS1. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/225750
10. Online Mendelian Inheritance in Man, OMIM. #613730 HEMORRHAGIC DESTRUCTION OF THE BRAIN, SUBEPENDYMAL CALCIFICATION, AND CATARACTS; HDBSCC. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/613730
11. Firth HV, Hurst JA. Rubella. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 782–783.
12. UK Health Security Agency. Guidance on the investigation, diagnosis and management of viral illness (plus syphilis), or exposure to viral rash illness, in pregnancy. Version 6.0. London: UKHSA; 2 Aug 2024. https://www.gov.uk/government/publications/viral-rash-in-pregnancy
13. Online Mendelian Inheritance in Man, OMIM. *602876 OCCLUDIN; OCLN. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/602876
14. Online Mendelian Inheritance in Man, OMIM. *607057 UBIQUITIN-SPECIFIC PROTEASE 18; USP18. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/607057
15. Online Mendelian Inheritance in Man, OMIM. #616636 IMMUNODEFICIENCY 44; IMD44. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/616636
16. Online Mendelian Inheritance in Man, OMIM. *600556 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 2; STAT2. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/600556
17. Online Mendelian Inheritance in Man, OMIM. #616669 IMMUNODEFICIENCY 45; IMD45. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/616669
18. Online Mendelian Inheritance in Man, OMIM. *606871 JUNCTIONAL ADHESION MOLECULE 3; JAM3. Baltimore: Johns Hopkins University; accessed 29 Oct 2026. https://omim.org/entry/606871
19. Orphanet. Pseudo-TORCH syndrome type 1 (ORPHA:1229). https://www.orpha.net/en/disease/detail/1229
20. Orphanet. Pseudo-TORCH syndrome type 2 (ORPHA:481665). https://www.orpha.net/en/disease/detail/481665
21. Orphanet. Pseudo-TORCH syndrome type 3 (ORPHA:714429). https://www.orpha.net/en/disease/detail/714429
22. Muscat M, Zimmerman L, Bacci S, Bang H, Glismann S, Mølbak K, et al. Toward rubella elimination in Europe: an epidemiological assessment. Vaccine. 2012;30(11):1999-2007. doi:10.1016/j.vaccine.2011.12.016. PMID: 22178098.
23. Dahlke M, Dautel KA, Vynnycky E, Still C, Papadopoulos T, Kabore HJ, et al. Progress Toward Rubella and Congenital Rubella Syndrome Elimination - Worldwide, 2012-2024. MMWR Morb Mortal Wkly Rep. 2026;75(28):356-363. doi:10.15585/mmwr.mm7528a1. PMID: 42490629. PMC13395318.
24. Forrest JM, Turnbull FM, Sholler GF, Hawker RE, Martin FJ, Doran TT, et al. Gregg's congenital rubella patients 60 years later. Med J Aust. 2002;177(11-12):664-7. doi:10.5694/j.1326-5377.2002.tb05003.x. PMID: 12463994.
25. World Health Organization. Rubella vaccines: WHO position paper – July 2020. Wkly Epidemiol Rec. 2020;95(27):306–24. https://www.who.int/publications/i/item/WHO-WER9527
26. Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed maternal rubella at successive stages of pregnancy. Lancet. 1982;2(8302):781-4. doi:10.1016/s0140-6736(82)92677-0. PMID: 6126663.
27. Centers for Disease Control and Prevention. Manual for the surveillance of vaccine-preventable diseases. Chapter 15: Congenital rubella syndrome. Atlanta: CDC. https://www.cdc.gov/surv-manual/php/table-of-contents/chapter-15-congenital-rubella-syndrome.html
28. Gailani AE, Dehority W, Katz SE. Clinical progress note: Rubella. J Hosp Med. 2026;21(2):179-182. doi:10.1002/jhm.70169. PMID: 40938300. PMC12865257.
29. Direção-Geral da Saúde. Programa Nacional de Vacinação 2020. Norma n.º 018/2020 de 27/09/2020. Lisboa: DGS; 2020. https://www.dgs.pt/normas-orientacoes-e-informacoes/normas-e-circulares-normativas/norma-n-0182020-de-27092020-pdf.aspx
30. Brasil. Ministério da Saúde. Calendário Nacional de Vacinação. Brasília: Ministério da Saúde; 2025. https://www.gov.br/saude/pt-br/vacinacao/calendario
31. European Reference Network for Rare Eye Diseases (ERN-EYE). https://www.ern-eye.eu/
32. European Reference Network for rare craniofacial anomalies and ear, nose and throat disorders (ERN CRANIO). https://www.ern-cranio.eu/
33. European Reference Network ITHACA. https://ern-ithaca.eu/
34. ERN GUARD-Heart. https://guardheart.ern-net.eu/
35. ERN RITA (immunodeficiency, autoinflammatory and autoimmune diseases). https://ern-rita.org/
36. Sense (charity for people with complex disabilities, including deafblindness), United Kingdom. https://www.sense.org.uk/
37. Deafblind International. https://www.deafblindinternational.org/
38. Measles & Rubella Partnership. https://www.measlesrubellapartnership.org/
39. Firth HV, Hurst JA. Deafness in early childhood. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 122–124.
40. Firth HV, Hurst JA. Intracranial calcification. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 200–201.
41. Firth HV, Hurst JA. Microcephaly. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 228–230.
42. De Melo LC, Rugna MM, Durães TA, Pereira SS, Callado GY, Pires P, et al. Congenital Rubella Syndrome in the Post-Elimination Era: Why Vigilance Remains Essential. J Clin Med. 2025;14(11):3986. doi:10.3390/jcm14113986. PMID: 40507747. PMC12156454.
43. Wolinsky JS, Waxham MN, Hess JL, Townsend JJ, Baringer JR. Immunochemical features of a case of progressive rubella panencephalitis. Clin Exp Immunol. 1982;48(2):359-66. PMID: 7105489. PMC1536479.
44. Lazar M, Perelygina L, Martines R, Greer P, Paddock CD, Peltecu G, et al. Immunolocalization and Distribution of Rubella Antigen in Fatal Congenital Rubella Syndrome. EBioMedicine. 2016;3:86-92. doi:10.1016/j.ebiom.2015.11.050. PMID: 26870820. PMC4739417.
45. Numazaki K, Fujikawa T. Intracranial calcification with congenital rubella syndrome in a mother with serologic immunity. J Child Neurol. 2003;18(4):296-7. doi:10.1177/08830738030180040601. PMID: 12760434.
46. O'Driscoll MC, Daly SB, Urquhart JE, Black GC, Pilz DT, Brockmann K, et al. Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria. Am J Hum Genet. 2010;87(3):354-64. doi:10.1016/j.ajhg.2010.07.012. PMID: 20727516. PMC2933344.
47. Meuwissen ME, Schot R, Buta S, Oudesluijs G, Tinschert S, Speer SD, et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 2016;213(7):1163-74. doi:10.1084/jem.20151529. PMID: 27325888. PMC4925017.
48. Alsohime F, Martin-Fernandez M, Temsah MH, Alabdulhafid M, Le Voyer T, Alghamdi M, et al. JAK Inhibitor Therapy in a Child with Inherited USP18 Deficiency. N Engl J Med. 2020;382(3):256-265. doi:10.1056/NEJMoa1905633. PMID: 31940699. PMC7155173.
49. Duncan CJA, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, et al. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Sci Immunol. 2019;4(42). doi:10.1126/sciimmunol.aav7501. PMID: 31836668. PMC7115903.
50. Gruber C, Martin-Fernandez M, Ailal F, Qiu X, Taft J, Altman J, et al. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy. J Exp Med. 2020;217(5):e20192319. doi:10.1084/jem.20192319. PMID: 32092142. PMC7201920.
51. GeneGuidance. STAT2: clinical curation of the gene and associated conditions. GeneGuidance database; accessed 29 Oct 2026.
52. 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. 2016;36(7):1332-56. doi:10.1111/risa.12263. PMID: 25115193.
53. Firth HV, Hurst JA. Congenital heart disease. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 112–115.
54. Firth HV, Hurst JA. Anterior segment eye malformations. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 62–64.
55. Firth HV, Hurst JA. Microphthalmia and anophthalmia. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 236–237.
56. Herini ES, Triono A, Iskandar K, Nurputra DK, Nugrahanto AP, Korompis M, et al. Diagnostic Challenges in Detecting Rubella Viral RNA in Cases of Congenital Rubella Syndrome Using RT-PCR in the Era of Elimination. Pediatr Infect Dis J. 2025;44(9):853-859. doi:10.1097/INF.0000000000004839. PMID: 40298435.
57. Toizumi M, Vo HM, Dang DA, Moriuchi H, Yoshida LM. Clinical manifestations of congenital rubella syndrome: A review of our experience in Vietnam. Vaccine. 2019;37(1):202-209. doi:10.1016/j.vaccine.2018.11.046. PMID: 30503658.
58. Ismail FA, Ali YK, Ali AM, Hirsi IM, Ali NA, Kassim MM, et al. Congenital Rubella Syndrome: A Case Report from Somalia. Int Med Case Rep J. 2024;17:751-755. doi:10.2147/IMCRJ.S472306. PMID: 39171203. PMC11338173.
59. Loeve LF, Sideridou VL, Schölvinck EH, Brandsema RB, van Leer-Buter CC, Zhou X. A Case of Congenital Rubella Syndrome in the Netherlands: A Brief Report on Rubella Virus Surveillance. Pediatr Infect Dis J. 2025;44(9):e350-e352. doi:10.1097/INF.0000000000004849. PMID: 40397485. PMC12333520.
60. Medu O, Mahajan P, Hennink M, Stang L, Anderson M, Tan B, et al. Congenital rubella syndrome, a case series. Can Commun Dis Rep. 2024;50(7-8):274-281. doi:10.14745/ccdr.v50i78a05. PMID: 39170592. PMC11323722.
61. Edlich RF, Winters KL, Long WB 3rd, Gubler KD. Rubella and congenital rubella (German measles). J Long Term Eff Med Implants. 2005;15(3):319-28. doi:10.1615/jlongtermeffmedimplants.v15.i3.80. PMID: 16022642.
62. Viskari H, Paronen J, Keskinen P, Simell S, Zawilinska B, Zgorniak-Nowosielska I, et al. Humoral beta-cell autoimmunity is rare in patients with the congenital rubella syndrome. Clin Exp Immunol. 2003;133(3):378-83. doi:10.1046/j.1365-2249.2003.02244.x. PMID: 12930364. PMC1808787.
63. Rabinowe SL, George KL, Loughlin R, Soeldner JS, Eisenbarth GS. Congenital rubella. Monoclonal antibody-defined T cell abnormalities in young adults. Am J Med. 1986;81(5):779-82. doi:10.1016/0002-9343(86)90344-x. PMID: 3490785.
64. Morgan-Capner P, Crowcroft NS. Guidelines on the management of, and exposure to, rash illness in pregnancy (including consideration of relevant antibody screening programmes in pregnancy). Commun Dis Public Health. 2002;5(1):59-71. PMID: 12070980.
65. Hardelid P, Cortina-Borja M, Williams D, Tookey PA, Peckham CS, Cubitt WD, et al. Rubella seroprevalence in pregnant women in North Thames: estimates based on newborn screening samples. J Med Screen. 2009;16(1):1-6. doi:10.1258/jms.2009.008080. PMID: 19349523.
66. Bouthry E, Perillaud-Dubois C, Lebraud P, Soutière MP, Grangeot-Keros L, Vauloup-Fellous C. Positive predictive value of seroconversion or positive rubella IgM in diagnosis of maternal rubella infection: Seven-years review of French National Reference Laboratory for Rubella. J Clin Virol. 2021;134:104708. doi:10.1016/j.jcv.2020.104708. PMID: 33316569.
67. Thomas HI, Morgan-Capner P, Roberts A, Hesketh L. Persistent rubella-specific IgM reactivity in the absence of recent primary rubella and rubella reinfection. J Med Virol. 1992;36(3):188-92. doi:10.1002/jmv.1890360308. PMID: 1314284.
68. Yazigi A, De Pecoulas AE, Vauloup-Fellous C, Grangeot-Keros L, Ayoubi JM, Picone O. Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature. J Matern Fetal Neonatal Med. 2017;30(3):274-278. doi:10.3109/14767058.2016.1169526. PMID: 27002428.
69. Macé M, Cointe D, Six C, Levy-Bruhl D, Parent du Châtelet I, Ingrand D, et al. Diagnostic value of reverse transcription-PCR of amniotic fluid for prenatal diagnosis of congenital rubella infection in pregnant women with confirmed primary rubella infection. J Clin Microbiol. 2004;42(10):4818-20. doi:10.1128/JCM.42.10.4818-4820.2004. PMID: 15472350. PMC522298.
70. Tang JW, Aarons E, Hesketh LM, Strobel S, Schalasta G, Jauniaux E, et al. Prenatal diagnosis of congenital rubella infection in the second trimester of pregnancy. Prenat Diagn. 2003;23(6):509-12. doi:10.1002/pd.631. PMID: 12813768.
71. Bouthry E, Furione M, Huzly D, Ogee-Nwankwo A, Hao L, Adebayo A, et al. Assessing Immunity to Rubella Virus: a Plea for Standardization of IgG (Immuno)assays. J Clin Microbiol. 2016;54(7):1720-1725. doi:10.1128/JCM.00383-16. PMID: 27147722. PMC4922105.
72. Picone O, Bouthry E, Bejaoui-Olhmann Y, Cordier AG, Nedellec S, Letourneau A, et al. Determination of rubella virus-specific humoral and cell-mediated immunity in pregnant women with negative or equivocal rubella-specific IgG in routine screening. J Clin Virol. 2019;112:27-33. doi:10.1016/j.jcv.2019.01.009. PMID: 30711798.
73. GeneGuidance. OCLN — band-like calcification with simplified gyration and polymicrogyria: clinical curation of the gene and associated conditions. GeneGuidance database; accessed 29 Oct 2026.
74. GeneGuidance. USP18 deficiency: clinical curation of the gene and associated conditions. GeneGuidance database; accessed 29 Oct 2026.
75. Firth HV, Hurst JA. Cytomegalovirus (CMV). In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 716–717.
76. Jones KL, Jones MC, del Campo M. Congenital Zika syndrome. In: Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 812–813.
77. Facundo RF, Ribeiro EM. Síndrome de fenilcetonúria materna. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 189–191.
78. Young MK, Cripps AW, Nimmo GR, van Driel ML. Post-exposure passive immunisation for preventing rubella and congenital rubella syndrome. Cochrane Database Syst Rev. 2015;2015(9):CD010586. doi:10.1002/14651858.CD010586.pub2. PMID: 26350479. PMC8761358.
79. European Medicines Agency. M-M-RVAXPRO: EPAR – medicine overview. Amsterdam: EMA; first EU authorisation 5 May 2006; page updated 30 Oct 2025. https://www.ema.europa.eu/en/medicines/human/EPAR/m-m-rvaxpro
80. Merck Sharp & Dohme LLC. M-M-R II (measles, mumps, and rubella virus vaccine live) [prescribing information]. DailyMed setid 0a9e384f-e717-436b-b9a0-15e53cef0862, version 44; 15 Oct 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0a9e384f-e717-436b-b9a0-15e53cef0862
81. GlaxoSmithKline Biologicals SA. PRIORIX (measles, mumps, and rubella vaccine, live) [prescribing information]. DailyMed setid 95c6fdb6-b587-4413-92f9-d592b9f7a23e, version 7; 21 May 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=95c6fdb6-b587-4413-92f9-d592b9f7a23e
82. Firth HV, Hurst JA. 22q11 deletion syndrome. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 624–627.
83. Mangtani P, Evans SJW, Lange B, Oberle D, Smith J, Drechsel-Baeuerle U, et al. 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. Vaccine. 2020;38(5):963-978. doi:10.1016/j.vaccine.2019.11.070. PMID: 31839467.
84. Bouthry E, Queinnec C, Vauzelle C, Vauloup-Fellous C. Congenital Rubella Syndrome Following Rubella Vaccination During Pregnancy. Pediatrics. 2023;152(3):e2022057627. doi:10.1542/peds.2022-057627. PMID: 37622237.
85. Adigweme I, Yisa M, Ooko M, Akpalu E, Bruce A, Donkor S, et al. A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial. Lancet. 2024;403(10439):1879-1892. doi:10.1016/S0140-6736(24)00532-4. PMID: 38697170. PMC11099471.
86. ClinicalTrials.gov. Measles and Rubella Vaccine Microneedle Patch Phase 1-2 Age De-escalation Trial (NCT04394689). https://clinicaltrials.gov/study/NCT04394689
87. World Health Organization. Rubella [fact sheet]. Geneva: WHO; 15 Jul 2026. https://www.who.int/news-room/fact-sheets/detail/rubella
88. Muscat M, Ben Mamou M, Reynen-de Kat C, Jankovic D, Hagan J, Singh S, et al. Progress and Challenges in Measles and Rubella Elimination in the WHO European Region. Vaccines (Basel). 2024;12(6):696. doi:10.3390/vaccines12060696. PMID: 38932424. PMC11209032.
89. Pan American Health Organization. Number of rubella and congenital rubella syndrome (CRS) cases after interruption of endemic circulation by year and country. The Americas, 2010–2026 (Measles/Rubella Bulletin 2026, epidemiological weeks 37–38; data as of 6 Oct 2026). Washington, DC: PAHO; 2026. https://www.paho.org/sites/default/files/body-data/2026/10/mrbulletin_2026-37-38-distribution-confirmed-rubella-crs-cases-2010-2026-e.pdf
90. Callado GY, Siqueira MM, Corrêa LH, Delpino FM, Marra AR, Santana EFM. Congenital rubella hospitalizations in Brazil: interpreting administrative data within the context of rubella elimination. Antimicrob Steward Healthc Epidemiol. 2026;6(1):e97. doi:10.1017/ash.2026.10361. PMID: 42038642. PMC13104557.
91. Ueda K. Epidemiology of rubella and congenital rubella syndrome in Japan before 1989. Vaccine. 2016;34(16):1971-4. doi:10.1016/j.vaccine.2015.10.010. PMID: 26469722.