TERATOGEN UPDATE
Congenital Rubella-an Encapsulated Review SHELDON B. KORONES Department of Pediatrics, Section on the Newborn, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee 381 63
Although postnatal rubella is generally a mild, self-limited disease fetal infection during the early months of gestation is often devastating. Fetal disease is associated with major anomalies, with destruction of normal tissue, and with chronic infection that persists for months or years after birth. Rubella virus has been recovered from the abortus, placenta, and amniotic fluid, and from liveborn infants from the throat, urine, meconium, and conjunctival and cerebrospinal fluids. At necropsy the virus has been recovered from virtually every organ of the body. It has been grown from a surgically extirpated ductus arteriosus, a cataractous lens, and from liver tissue obtained by biopsy. The risk of fetal involvement in the presence of maternal disease has been variably estimated. During the 1st gestational month fetal infection occurs in up to 50% of infected mothers, during the 2nd month in approximately 3 0 %, and in the 3rd and 4th months 10 and 5 % , respectively.
to maternal disease during pregnancy, being associated with recovery of virus from affected infants. s v e r et al. (‘69) labeled the newly appreciated clinical entity the “expanded rubella syndrome.” The commonest cardiovascular lesions are pulmonary arterial hypoplasia (peripheral pulmonic stenosis) and persistent patency of the ductus arteriosus. Coarctation of the aorta and septal defects have also been observed. Severe myocardial damage (necrosis) with congestive failure (usually refractory to vigorous medical therapy) has occurred in a few infants. ]Electrocardiograms resemble those of adults with myocardial infarction; in some instances the myocardial destruction seems to have originated in utero. Active encephalitis is the most frequent neonatal manifestation of central nervous system disease; microcephaly ordinarily appears after the neonatal period. In the eyes unilateral or bilateral cataracts are the most common lesions noted at birth, or very soon thereafter. Occasionally cataracts are first seen weeks Clinical signs in the neonate later. So-called “salt and pepper” retinoThe clinical manifestations are as pathy and glaucoma are not quite so frewidespread as the infection itself. They quent. Corneal clouding that clears in a have been noted in the cardiovascular few weeks, and is not associated with and central nervous systems, eyes, ears, other ocular involvement, has been noted blood, liver, and bones. In severe disease occasionally. Purpura and thrombocytopenia occur hypoplastic intrauterine growth retardation is almost the rule; in most organs in 4 0 4 0 % of affected infants. Hepatothere are in fact fewer cells than normal. splenomegaly is common; obstructive jaunThe triad of cataracts, patency of the dice and abnormal liver enzymes due ductus arteriosus, and deafness was regu- to hepatitis may also be present. Hepalarly described in earlier literature as titis may culminate in cirrhosis beyond composing the congenital rubella syn- the neonatal period. Interstitial pneumonitis has been noted drome. Lundstrom’s (‘62) milestone epidemiological study during the 1950s un- at birth. It may clear in a week or 2 or earthed an extensive variety of additional it may persist for months. Occasionally abnormalities, some of which had been it makes its first appearance at a few previously reported by others. Then, dur- months of age. In either event it is someing the pandemic of 1964, when isolation times fulminating. of the virus was feasible, most of these Reprint requests to: Dr. S. B. Korones, 42 N. Dunlap abnormal signs were clearly attributed St., Fifth Floor, Memphis, Tennessee 38163. TERATOLOGY. 14: 111-114.
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SHELDON B. KORONES
Fig. 1
Fig. 3
Bilateral cataracts.
Fig. 2 Congenital glaucoma. Note ground-glass megalocornea.
Ovoid radiolucency in metaphysis of right humerus-beyond
Long-bone X-rays reveal ovoid or longitudinal radiolucencies in the metaphyses that apparently are not a direct result of infection. These lesions are most frequently identifiable in the distal femur and proximal tibia.
Diagnosis A combination of several of the clinical signs described above strongly suggests
the point of the arrow.
the disease, particularly if maternal infection is documented. As a rule cardiovascular and opthalmological signs are associated with other abnormalities. A valid history of maternal disease during the 1st trimester is usually obtainable during epidemics, but sporadic maternal disease cannot be unequivocally identified by history. Furthermore approximately half of infected mothers are asympto-
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113
Fig. 4 Myocardial necrosis. Note loss of cross-striation, swelling of muscle fibers, and beginning fatty degeneration
Fig. 5 Interstitial pneumonitis. Note discxete thickening of alveolar septa by round-cell infiltrates.
matic and totally unaware of their infection. Among these women however, half may be aware of exposure to infection. In the neonate isolation of the virus is the most certain diagnostic modality; demonstration of specific IgM antibody is equally reliable. Short of these signs abnormally increased concentrations of total serum IgM in an infant with a com-
bination of clinical signs attributable to intrauterine rubella is strongly suggestive. Since maternal IgG antibodies are passively acquired by the fetus across the placenta their presence in neonatal serum is of no diagnostic value. However, persistence of the neonatal titer to approximately 6 months of age or later is diagnostic. Demonstration of specific IgG
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SHELDON B. KORONES
antibody in a single specimen at these later ages is also diagnostic if clinical signs of congenital infection are present. Epidemiology Since rubella is preponderantly a disease of school-age children (5-14 years) infection during the childbearing years is not frequent except during epidemics. Vertical transmission of the virus in utero results in chronic fetal infection, Postnatally virus is shed for variable time periods. At 1 month of age virus has been recovered from the throats of 85% of babies with congenital rubella, at 5-8 months from 33 % . Shedding of virus is rare beyond these ages. Virus has been recovered from urine and from an extirpated lens past 2Y2 years of age. These infants constitute a source of infection, small outbreaks among hospital personnel having been attributed to them during their hospitalization. Prevention Live attenuated rubella vaccine is an effective means of protection against the disease. The demonstration of antibodies several years after vaccination suggests that permanent immunity has been imparted. Clinically inapparent reinfection
has been documented after childhood vaccination; i t has also been noted among individuals with natural immunity, but less frequently. Vaccine virus is known to cross the placenta; it has been recovered from the fetus, hence the need for extreme caution in vaccinating women during their fertile years. There should be rigid adherence to the widely stated precaution that conception should not occur until at least 2 months following vaccination. Small outbreaks of rubella continue to occur despite availability of the vaccine. It appears doubtful that herd immunity can protect susceptible individuals. Efforts toward mass vaccination of susceptible individuals should thus not be relaxed if a widespread epidemic and its tragic aftermath are to be avoided. LITERATURE CITED Lundstrom, R. 1962 Rubella during pregnancy: a follow-up study of children born after an epidemic of rubella in Sweden, 1951, with additional investigation on prophylaxis and treatment of maternal rubella. Acta Paediat. Supp., 133: 1110. Rubella Symposium 1965 Am. J. Dis. Child., 110: NO.4. Sever, J. L., J. B. Hardy, K. B. Nelson and M. R. Gilkeson 1969 Rubella in the collaborative perinatal research study. 11. Clinical and laboratory findings in children through 3 years of age. Am. J. Dis. Child., 118: 123-132.
The Editors welcome contributions to “Teratogen Update.” Manuscripts should be sent to Dr. John L . Sever, Teratology Update Editor, Building 36, Room 50-04, National lnstitutes of Health, Bethesda, Maryland 20014. Articles should concisely summarize the clinical manifestations, etiology, pathogenesis, treatment, and prevention of the phenomena; and be accompanied by high-quality photographs of affected individuals. Color illustrations will be at the author’s expense. Please address reprint requests to the author.
Congenital Rubella-an Encapsulated Review SHELDON B. KORONES Department of Pediatrics, Section on the Newborn, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee 381 63
Although postnatal rubella is generally a mild, self-limited disease fetal infection during the early months of gestation is often devastating. Fetal disease is associated with major anomalies, with destruction of normal tissue, and with chronic infection that persists for months or years after birth. Rubella virus has been recovered from the abortus, placenta, and amniotic fluid, and from liveborn infants from the throat, urine, meconium, and conjunctival and cerebrospinal fluids. At necropsy the virus has been recovered from virtually every organ of the body. It has been grown from a surgically extirpated ductus arteriosus, a cataractous lens, and from liver tissue obtained by biopsy. The risk of fetal involvement in the presence of maternal disease has been variably estimated. During the 1st gestational month fetal infection occurs in up to 50% of infected mothers, during the 2nd month in approximately 3 0 %, and in the 3rd and 4th months 10 and 5 % , respectively.
to maternal disease during pregnancy, being associated with recovery of virus from affected infants. s v e r et al. (‘69) labeled the newly appreciated clinical entity the “expanded rubella syndrome.” The commonest cardiovascular lesions are pulmonary arterial hypoplasia (peripheral pulmonic stenosis) and persistent patency of the ductus arteriosus. Coarctation of the aorta and septal defects have also been observed. Severe myocardial damage (necrosis) with congestive failure (usually refractory to vigorous medical therapy) has occurred in a few infants. ]Electrocardiograms resemble those of adults with myocardial infarction; in some instances the myocardial destruction seems to have originated in utero. Active encephalitis is the most frequent neonatal manifestation of central nervous system disease; microcephaly ordinarily appears after the neonatal period. In the eyes unilateral or bilateral cataracts are the most common lesions noted at birth, or very soon thereafter. Occasionally cataracts are first seen weeks Clinical signs in the neonate later. So-called “salt and pepper” retinoThe clinical manifestations are as pathy and glaucoma are not quite so frewidespread as the infection itself. They quent. Corneal clouding that clears in a have been noted in the cardiovascular few weeks, and is not associated with and central nervous systems, eyes, ears, other ocular involvement, has been noted blood, liver, and bones. In severe disease occasionally. Purpura and thrombocytopenia occur hypoplastic intrauterine growth retardation is almost the rule; in most organs in 4 0 4 0 % of affected infants. Hepatothere are in fact fewer cells than normal. splenomegaly is common; obstructive jaunThe triad of cataracts, patency of the dice and abnormal liver enzymes due ductus arteriosus, and deafness was regu- to hepatitis may also be present. Hepalarly described in earlier literature as titis may culminate in cirrhosis beyond composing the congenital rubella syn- the neonatal period. Interstitial pneumonitis has been noted drome. Lundstrom’s (‘62) milestone epidemiological study during the 1950s un- at birth. It may clear in a week or 2 or earthed an extensive variety of additional it may persist for months. Occasionally abnormalities, some of which had been it makes its first appearance at a few previously reported by others. Then, dur- months of age. In either event it is someing the pandemic of 1964, when isolation times fulminating. of the virus was feasible, most of these Reprint requests to: Dr. S. B. Korones, 42 N. Dunlap abnormal signs were clearly attributed St., Fifth Floor, Memphis, Tennessee 38163. TERATOLOGY. 14: 111-114.
111
112
SHELDON B. KORONES
Fig. 1
Fig. 3
Bilateral cataracts.
Fig. 2 Congenital glaucoma. Note ground-glass megalocornea.
Ovoid radiolucency in metaphysis of right humerus-beyond
Long-bone X-rays reveal ovoid or longitudinal radiolucencies in the metaphyses that apparently are not a direct result of infection. These lesions are most frequently identifiable in the distal femur and proximal tibia.
Diagnosis A combination of several of the clinical signs described above strongly suggests
the point of the arrow.
the disease, particularly if maternal infection is documented. As a rule cardiovascular and opthalmological signs are associated with other abnormalities. A valid history of maternal disease during the 1st trimester is usually obtainable during epidemics, but sporadic maternal disease cannot be unequivocally identified by history. Furthermore approximately half of infected mothers are asympto-
CONGENITAL RUBELLA - AN ENCAPSULATED REVIEW
113
Fig. 4 Myocardial necrosis. Note loss of cross-striation, swelling of muscle fibers, and beginning fatty degeneration
Fig. 5 Interstitial pneumonitis. Note discxete thickening of alveolar septa by round-cell infiltrates.
matic and totally unaware of their infection. Among these women however, half may be aware of exposure to infection. In the neonate isolation of the virus is the most certain diagnostic modality; demonstration of specific IgM antibody is equally reliable. Short of these signs abnormally increased concentrations of total serum IgM in an infant with a com-
bination of clinical signs attributable to intrauterine rubella is strongly suggestive. Since maternal IgG antibodies are passively acquired by the fetus across the placenta their presence in neonatal serum is of no diagnostic value. However, persistence of the neonatal titer to approximately 6 months of age or later is diagnostic. Demonstration of specific IgG
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SHELDON B. KORONES
antibody in a single specimen at these later ages is also diagnostic if clinical signs of congenital infection are present. Epidemiology Since rubella is preponderantly a disease of school-age children (5-14 years) infection during the childbearing years is not frequent except during epidemics. Vertical transmission of the virus in utero results in chronic fetal infection, Postnatally virus is shed for variable time periods. At 1 month of age virus has been recovered from the throats of 85% of babies with congenital rubella, at 5-8 months from 33 % . Shedding of virus is rare beyond these ages. Virus has been recovered from urine and from an extirpated lens past 2Y2 years of age. These infants constitute a source of infection, small outbreaks among hospital personnel having been attributed to them during their hospitalization. Prevention Live attenuated rubella vaccine is an effective means of protection against the disease. The demonstration of antibodies several years after vaccination suggests that permanent immunity has been imparted. Clinically inapparent reinfection
has been documented after childhood vaccination; i t has also been noted among individuals with natural immunity, but less frequently. Vaccine virus is known to cross the placenta; it has been recovered from the fetus, hence the need for extreme caution in vaccinating women during their fertile years. There should be rigid adherence to the widely stated precaution that conception should not occur until at least 2 months following vaccination. Small outbreaks of rubella continue to occur despite availability of the vaccine. It appears doubtful that herd immunity can protect susceptible individuals. Efforts toward mass vaccination of susceptible individuals should thus not be relaxed if a widespread epidemic and its tragic aftermath are to be avoided. LITERATURE CITED Lundstrom, R. 1962 Rubella during pregnancy: a follow-up study of children born after an epidemic of rubella in Sweden, 1951, with additional investigation on prophylaxis and treatment of maternal rubella. Acta Paediat. Supp., 133: 1110. Rubella Symposium 1965 Am. J. Dis. Child., 110: NO.4. Sever, J. L., J. B. Hardy, K. B. Nelson and M. R. Gilkeson 1969 Rubella in the collaborative perinatal research study. 11. Clinical and laboratory findings in children through 3 years of age. Am. J. Dis. Child., 118: 123-132.
The Editors welcome contributions to “Teratogen Update.” Manuscripts should be sent to Dr. John L . Sever, Teratology Update Editor, Building 36, Room 50-04, National lnstitutes of Health, Bethesda, Maryland 20014. Articles should concisely summarize the clinical manifestations, etiology, pathogenesis, treatment, and prevention of the phenomena; and be accompanied by high-quality photographs of affected individuals. Color illustrations will be at the author’s expense. Please address reprint requests to the author.
