Prenatal infection with the rubella virus may cause fetal death, miscarriage or still birth. If the fetus survives, they may develop symptoms of CRS. Congenital malformations observed in children whose mother contracted rubella during pregnancy depend on the time of maternal infection. Ophthalmologic alterations are typically associated with an early infection, i.e., with exposure to the pathogen before the end of the first trimenon. In contrast, hearing impairment may be caused by infection during the fourth or fifth month of pregnancy. If a pregnant woman is exposed to the rubella virus during the second half of pregnancy, the risk of the child developing CRS is significantly reduced.

The most common symptoms present at birth or developing within the first weeks of life are:

• Microcephaly and meningoencephalitis
• Microphthalmia, glaucoma, retinopathy, cataract and corneal opacity
• Hearing impairment or deafness
• Cardiac malformations, e.g., isolated valve defects, pulmonary artery stenosis, ventricular septal defect, tetralogy of Fallot or patent ductus arteriosus
• Interstitial pneumonia
• Hepatitis, hepatomegaly, jaundice
• Petechiae
• Hemolytic anemia, thrombocytopenia
• Stunted growth

An infant born with cataract, hearing impairment and cardiac malformations - also referred to as Gregg triad - is highly suspicious for CRS.

During infancy and childhood, previously detected symptoms may exacerbate and additional symptoms may manifest:

• Mental retardation
• Psychiatric disorders, autism [10]
• Progressive rubella panencephalitis
• Strabismus
• Permanent and complete, bilateral hearing loss

Even in adulthood, diseases related to prenatal infection with the rubella virus may develop [1]:

• Diabetes mellitus
• Hypothyroidism
• Growth hormone deficiency
• Early menopause
• Osteoporosis
• Peripheral vascular disease
• (Auto-)immune disorders

• Developmental Delay

  delay (OR, 4.4; 95% CI, 1.75-11.1). [ncbi.nlm.nih.gov]

  Delayed effects of Congenital Rubella Syndrome DeafBlind.com Helen Keller National Center [en.wikipedia.org]

  Pregnant women who contracted rubella in the first trimester of their pregnancy could pass the rubella virus to their developing fetus, causing the child to be born deaf, blind, with cardiac problems, developmental delays and other medical conditions. [helenkeller.org]

  Symptoms Babies born with congenital rubella syndrome may have some or all of the following symptoms: Heart problems Eye problems, including cataracts and glaucoma Intellectual disabilities Growth retardation Low birth weight Developmental delays Learning [childrenshospital.org]

• Atrial Septal Defect

  She was detected to have an ostium secundum atrial septal defect (ASD) and a large patent ductus arteriosus (PDA) on echocardiography. On ophthalmic examination, she was diagnosed with bilateral cataract. [ncbi.nlm.nih.gov]

  He also had atrial septal defect. He was diagnosed with diabetes at 18 years of age. He later developed type 1 diabetes and is being treated with insulin. He had antibodies to ICSA and anti-GAD65Ab. [care.diabetesjournals.org]

  Echocardiography may be essential for diagnosis of heart defects. 16.  Surgical treatment may be required for congenital heart anomalies, including patent ductus arteriosus (PDA), coarctation of aorta, ventricular septal defect (VSD), atrial septal defect [slideshare.net]

  The classic triad of Congenital Rubella Syndrome (also called the Greg's Triad) [ 5 ] involves-Sensorineural deafness (~58%), Eye abnormalities like microphthalmia, cataract and retinopathy (~43%) and Congenital Heart Diseases like PDA, VSD, Atrial Septal [annexpublishers.co]

  Keywords Congenital rubella syndrome Hospital-based surveillance Vaccine Immunization Indonesia Abbreviations ABR Auditory brainstem response ASD Atrial septal defect CRS Congenital rubella syndrome DORV Double outlet right ventricle F Female Ig Immunoglobulin [link.springer.com]

• Cerebral Palsy

  The other patient had cerebral palsy. [ijo.in]

  palsy, which generally results from an abnormal intrauterine environment or peri-/postnatal insult rather than a genetic condition. [pediatrics.aappublications.org]

• Multiple Congenital Anomalies

  In the fetus, there may be no effects, death in utero, or multiple anomalies referred to as congenital rubella syndrome (CRS). [merckmanuals.com]

• Pulmonary Valve Stenosis

  valve stenosis, VSD, hepatosplenomegaly, interstitial pneumonia, LBW, congenital cataracts, deafness, microcephaly, petechia, purpura, CNS Sx–eg, mental retardation, lethargy, irritability, dystonia, bulging fontanelles, ataxia Lab Viral isolation, IgM [medical-dictionary.thefreedictionary.com]

  Complications noted at birth included pulmonary valve stenosis, patent ductus arteriosus, thrombocytopenia, congenital cataracts, intracranial calcifications, and probable hearing deficits. [immunize.org]

  stenosis, and pulmonary valve stenosis, respectively. 5 In contrast, our first echocardiographic examinations detected PDA most frequently, whereas pulmonary valve stenosis was detected in only 2 patients, and none had branch pulmonary artery stenosis [pediatrics.aappublications.org]

• Respiratory Distress

   Babies with congenital rubella syndrome who develop respiratory distress may require supportive treatment in the ICU.  Hepatosplenomegaly is monitored clinically. [slideshare.net]

• Heart Murmur

  PDA or pulmonary artery stenosis associated with PH may also be easily overlooked because of the absence or diminution of heart murmurs. The etiology and pathogenesis of PH associated with CRS remain unknown. [pediatrics.aappublications.org]

• Hepatosplenomegaly

  A premature newborn male was clinically diagnosed as CRS with cataracts, congenital heart defects, microcephaly, hepatosplenomegaly, and thrombocytopenia. The infection was confirmed serologically and molecularly. [ncbi.nlm.nih.gov]

• Hepatomegaly

  The infant may be small for gestational age and exhibit hyperbilirubinemia, thrombocytopenia, and hepatomegaly. [medical-dictionary.thefreedictionary.com]

  Other manifestations are spleen, liver and bone marrow involvement, mental retardation, microcephaly, Low Birth Weight, hepatomegaly, micrognathia and thrombocytopenic purpura leading to the characteristic Blueberry Muffin Rash. [annexpublishers.co]

  […] failed brain development (called oligocephaly) Encephalitis (inflammation of brain) Meningitis (inflammation of the covering of the brain) Other complications may include: Deafness Low blood platelet count (thrombocytopenia) Enlarged liver and spleen (hepatomegaly [dovemed.com]

  […] cataract and corneal opacity Hearing impairment or deafness Cardiac malformations, e.g., isolated valve defects, pulmonary artery stenosis, ventricular septal defect, tetralogy of Fallot or patent ductus arteriosus Interstitial pneumonia Hepatitis, hepatomegaly [symptoma.com]

• Small Head

  Symptoms in the infant may include: Cloudy corneas or white appearance of pupil Deafness Developmental delay Excessive sleepiness Irritability Low birth weight Below average mental functioning (intellectual disability) Seizures Small head size Skin rash [nlm.nih.gov]

  head size (microcephaly) Eye defects Low birth weight Thrombocytopenic purpura Extramedullary hematopoiesis (presents as a characteristic blueberry muffin rash) Enlarged liver Small jaw size Skin Lesions Children who have been exposed to rubella in the [en.wikipedia.org]

  The individual features of the syndrome include growth retardation, microcephaly (abnormally small head), cataracts, glaucoma, microphthalmia (abnormally small eyes), cardiovascular malformations, hearing loss, and mental retardation. [medicinenet.com]

  ASD and VSD) 8 evidence of intra-uterine growth restriction sub-ependymal cysts : on cranial ultrasound 2 CT Brain manifestations 8 : small head circumference/microcephaly periventricular calcifications white matter hypodensity ventriculomegaly Promoted [radiopaedia.org]

• Corneal Opacity

  Ophthalmic examination showed right corneal opacity and left corneal haziness. Fundus examination could not be done because of corneal pathology bilaterally. [annexpublishers.co]

  The most common symptoms present at birth or developing within the first weeks of life are: Microcephaly and meningoencephalitis Microphthalmia, glaucoma, retinopathy, cataract and corneal opacity Hearing impairment or deafness Cardiac malformations, [symptoma.com]

  The corneal opacity was central in all the patients [Figure - 2]. In our series, rubella retinopathy was seen in 33 (37.9%) eyes. Except in three eyes this was associated with cataract and microphthalmos. [ijo.in]

• Corneal Edema

  A viral infiltration of endothelium is postulated as the mechanism of the corneal edema and keratitis. [ncbi.nlm.nih.gov]

  edema and corneal opacification  Secondary glaucoma  Intense inflammation, uveitis  May require prolonged postoperative steroids  Probably best to avoid primary implantation of IOL’s 18.  Rubella vaccine is given to children at 15 months of age [slideshare.net]

• Hearing Impairment

  CONCLUSIONS: The incidence of CRS in infants in Yogyakarta Indonesia is considered high, with most clinical manifestations being CHD, hearing impairment and congenital cataract. [ncbi.nlm.nih.gov]

  […] three had cataract, 20 had congenital heart disease, and 12 had hearing impairment. [niid.go.jp]

  In contrast, hearing impairment may be caused by infection during the fourth or fifth month of pregnancy. [symptoma.com]

• Petechiae

  […] susceptible period extends to ±20 th wk; infection in late pregnancy carries little fetal morbidity Clinical Cardiac defects–eg PDA, pulmonary valve stenosis, VSD, hepatosplenomegaly, interstitial pneumonia, LBW, congenital cataracts, deafness, microcephaly, petechia [medical-dictionary.thefreedictionary.com]

  […] opacity Hearing impairment or deafness Cardiac malformations, e.g., isolated valve defects, pulmonary artery stenosis, ventricular septal defect, tetralogy of Fallot or patent ductus arteriosus Interstitial pneumonia Hepatitis, hepatomegaly, jaundice Petechiae [symptoma.com]

• Profound Intellectual Disability

  In a previous study by Chess 5, children with congenital rubella had overlapping signs and symptoms such as unspecified, borderline, mild, moderate, severe, or profound intellectual disability (37%); hard signs (44%) of physical neurological defects such [nature.com]

• Delayed Milestone

  Developmental and neurological defects were seen in 16 (34.8%) children, which included microcephaly with mental retardation, seizure disorder and delayed milestones, emphasising the need for multi-speciality management in these infants. [ijo.in]

If a pregnant woman presents with rubella, the initial workup should aim at verifying if the fetus has been infected or not. In order to do so, amniotic fluid may be obtained by amniocentesis and should be analyzed for the presence of the pathogen applying molecular biological methods. Cord blood samples may be tested for IgM antibodies against rubella virus. However, these tests may not yield positive results until up to two months after maternal infection and the risk of false-negative results should not be underestimated either, particularly if less than 20 weeks of pregnancy have passed at the time of testing.

Even though fetal infection can be proven, the extent of fetal developmental defects can not be easily assessed and the decision for or against a therapeutic abortion may be very difficult to make.

Any neonate presenting with cataract, hearing impairment and cardiac malformations is highly suspicious for CSR. Both direct and indirect tests, i.e., virus culture, molecular biological verification of infection, and serology, are helpful in confirming this tentative diagnosis. Virus particles can most easily be isolated from pharynx smears, conjunctival smears and cerebrospinal fluid. Serology is still considered the gold standard for diagnosis of CSR. Of note, neonates primarily produce IgM and titers of maternal IgG should decrease over time.

If this diagnosis is confirmed by any of the aforementioned tests, the child needs to undergo a thorough workup to detect possible additional CSR-related pathologies. Complete ophthalmologic, otologic, neurologic and cardiac exams are required. Blood samples should be analyzed since they may indicate anemia, thrombocytopenia, pneumonia or hepatitis. Further diagnostic measures, particularly diagnostic imaging, may be necessary if blood parameters are altered.

There are neither specific treatments for rubella infection nor for the majority of developmental defects. Certain CSR-associated pathologies, e.g., glaucoma, cataract, cardiac malformations and inflammatory diseases, should be treated according to standard medication and surgical procedures.

With regards to pregnant women who contract rubella, hyperimmune globulins that contain high levels of rubella-specific antibodies have been proposed as a possible treatment, but its efficacy has not yet been proven. Also, viremia occurs before onset of clinical symptoms and it is very unlikely that fetal infection can be prevented by such therapy. Depending on national laws and the calculated risk of severe malformations, an abortion with medical indication may be considered.

Of note, vaccination of pregnant women is contraindicated.

Morbidity and mortality associated with CRS are high. There is no causative treatment and children who are born with severe cardiac malformations, who suffer from meningoencephalitis, pneumonia or hepatitis have an unfavorable prognosis. About one third of CRS patients dies during infancy [9]. Specific treatments to improve vision, hearing and cardiac function may relieve symptoms but are often not available in developing countries.

The causative agent of rubella is the rubella virus, a single-stranded, positive RNA virus pertaining to the genus Rubivirus and the family of Togaviridae. In general, the virus is transmitted by droplet infection and primarily infects the upper respiratory tract. After an incubation period of about two weeks, flu-like symptoms manifest. These complaints are followed by generalized lymphadenopathy and a characteristic rash that spreads over the whole body. The latter is usually self-limiting within three days, while the remaining symptoms may last for a few weeks.

Viremia occurs even before generalized symptoms manifest and during this stage of the disease, the virus may reach uterus and placenta of pregnant women. It may pass the placental barrier and infect the unborn child. Indeed, observations made by the Australian ophthalmologist Sir Norman McAlister Gregg regarding rubella infections during pregnancy and congenital cataracts are often cited as the first evidence for the fact that certain pathogens are able to cause infections in utero [3].

Children who are born with CRS suffer from a chronic infection with the rubella virus, although long-term studies indicate that the pathogen is eventually eliminated [1].

The introduction of a vaccine against rubella in 1969 largely contributed to the reduction of rubella and CRS incidence. For instance, there was a rubella epidemic in the early 1960s that caused tens of thousands fetal deaths and cases of CRS in the United States. Today, less than ten cases of CRS are reported annually in this country [4]. These are usually associated to a lack of vaccination of the mother in her childhood.

However, there are still several countries that did not yet implement childhood immunization programs that include vaccination against rubella. Here, CRS incidence remains as high as 8 per 10,000 live births in the Eastern Mediterranean region and 18 per 10,000 live births in developing countries on the American continent [5].

Although the rubella virus initially infects the upper respiratory tract, viremia occurs about one week after infection. Thus, viremic spread takes place before the incubation period terminates and before a patient shows any symptoms of rubella. In non-pregnant patients, hematogenous spread eventually gives rise to generalized symptoms such as lymphadenopathy and rash; in pregnant women, however rubella virus-associated morbidity mainly results from placental passage of the pathogen and establishment of a persistent infection of the unborn child.

Hematogenous spread seems to account for the infection of multiple organs of the fetus, too. It has been suggested that the virus mainly causes cytopathic effects on endothelial cells [6]. According to that hypothesis, congenital malformations are a direct effect of virus-mediated lesions (in case of the cardiovascular system) or result from ischemia due to vascular damage (in case of the central nervous system and sense organs). An alternative theory states that endothelial infection inhibits cell division and thus causes the aforementioned developmental defects. Symptoms like microcephaly and microphthalmia argue for this hypothesis. Most likely, both cytopathology and inhibition of cell division contribute to deficient organogensis [7].

The infection persists and virus particles may be isolated from CRS patients months or even years later. Diabetes mellitus, a common long-term complication of prenatal infection with the rubella virus, is provoked by virus-mediated destruction of the pancreatic islets of Langerhans. Similar events are assumed to account for the increased prevalence of hypothyroidism among CRS patients, although additional research is required to shed more light on the pathophysiologic events that cause these endocrinologic diseases [8].

Prevention of CSR consists in prevention of rubella infections. Vaccines are readily available and are indeed part of childhood immunization schedules in many countries. Analysis of epidemiological data clearly shows the benefits of vaccination which generally takes place during the second year of life. Although later immunization is possible, the vaccine should not be administered to pregnant women.

Neonates born with CSR may shed the virus and should therefore not be handled by susceptible individuals, particularly not by not immunized pregnant women.

Rubella is an infectious disease whose causative agent is the rubella virus. In non-pregnant patients, rubella is primarily associated with a general lymphadenopathy and dermatological lesions. Symptomatic treatment may be provided, but rubella patients have a very good prognosis and otherwise healthy individuals are generally able to overcome the disease within a few days. Recovery from rubella infection provides life-long immunity.

However, if women that are not immune against the disease contract rubella during early pregnancy, the infection may have detrimental consequences for the unborn child. Rubella virus infection during pregnancy may cause spontaneous abortion or stillbirth; in case of live birth, the neonate may present a variety of congenital malformations. These often affect the central nervous system, the sense organs and the cardiovascular system, and are referred to as congenital rubella syndrome (CRS). Other designations for this disease are fetal rubella syndrome and rubella embryopathy.

The risk for a child to be affected by maternal infection with rubella virus is particularly high if the latter occurs during the first trimester of pregnancy. However, later infections may still interfere with fetal development. Frequently observed congenital symptoms are:

• Microcephaly and mental retardation
• Microphthalmia, glaucoma and cataracts
• Hearing impairment or deafness
• Cardiac malformations

CRS patients may develop additional pathologies throughout life. For instance, diabetes mellitus, hypothyroidism, early menopause and osteoporosis manifest much later [1].

CRS may be prevented by means of vaccination against rubella and thus, such an immunization should be included in national childhood immunization schedules. A child whose mother received rubella vaccine before pregnancy will not develop CRS even if the woman is exposed to the causative virus. Consequent application of this preventive measure has largely reduced the incidence of rubella and CRS and may even allow for the eradication of these diseases [2].

Rubella is an infectious disease whose causative agent is the rubella virus. In non-pregnant women, rubella is primarily associated with generalized lymphadenopathy and rash. While supportive treatment may be provided, the disease is generally self-limiting and sequelae are not to be expected. Recovery from rubella infection provides life-long immunity.

However, if a pregnant woman contracts rubella, the virus may affect fetal development. Such an infection may cause miscarriage, still birth or severe congenital malformations. The latter are referred to as congenital rubella syndrome (CRS).

Causes

CRS is generally triggered by an infection with the rubella virus during the first trimenon of pregnancy, although fetal development may also be hindered if maternal infection occurs later.

The virus is transmitted by droplet infection, primarily affects the upper respiratory tract of the mother and subsequently spreads hematogenously. This way, it reaches uterus and placenta and passes the placental barrier. It may interfere with vascular development and thus causes ischemia in distinct organs. Therefore, CSR patients present pathological alterations of the central nervous system, sense organs, heart and liver.

Symptoms

Many symptoms are recognizable at birth, while others develop during infancy or childhood. CSR may even cause health issues during adulthood.

The most common symptoms are:

• Impaired eye development, glaucoma and cataracts
• Hearing impairment or deafness
• Cardiac malformations

Additionally, CSR patients may suffer from:

• Mental retardation
• Psychiatric disorders
• Strabism
• Diabetes mellitus
• Hypothyroidism
• Stunted growth

Diagnosis

Prenatal diagnosis of fetal rubella infection may be achieved by analyzing amniotic fluid (obtained by amniocentesis) or cord blood samples (requires cordocentesis). However, the possibility of false results should be considered. Also, these tests allow for the detection of fetal rubella infection but don't provide any information regarding the extent of developmental defects.

If a child presents with several of the above mentioned symptoms, they are suspicious for CSR. Rubella infection may be proven by detection of virus particles or neonatal antibodies. Confirmation of such diagnosis should prompt complete ophthalmologic, otologic, neurologic and cardiac exams in order to reveal possible additional pathologies.

Treatment

There is no specific treatment for rubella infections. Certain congenital defects, e.g., ophthalmologic disorders and cardiac malformations, may require medication or surgery. Little can be done to relieve neurological symptoms or mental retardation. Therefore, it is of utmost importance to receive the corresponding vaccination before getting pregnant.

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