Pediatric Annals

Congenital Rubella: The Teenage Years

Philip R Ziring, MD

Abstract

The large-scale epidemic of rubella in the United States in 1964-65 resulted in the birth of approximately 20,000 children with serious related congenital defects.

The spectrum of transient and permanent clinical findings seen in the newborn period in children with congenital rubella has been well characterized. Transient disorders most commonly include such features as thrombocytopenic purpura, bone "lesions," and pneumonitis. Permanent disorders include serious eye defects (cataract, glaucoma), sensorineural hearing loss, congenital heart disease, and various manifestations of brain injury wrought by congenital rubella encephalitis, including mental retardation and cerebral palsy.1

It was found that infants with these disorders were likely to shed rubella viruses from many sites - especially the throat - during the first weeks of life. Many continued to excrete virus for months afterward. This rubella shedding occurred despite the presence of high levels of circulating rubella antibody, much of it in the IgM class.2 Specimens obtained from abortion would frequently yield rubella virus from virtually all fetal tissues; this was also true of newborns.

Sophisticated techniques now available for measuring cell-mediated immunity were not readily available a decade ago, but unpublished studies by me and my colleagues demonstrated that some infants with congenital rubella could not be sensitized to customary doses of dinitrofluoro benzene as compared with age-matched controls. Children with this defect appeared to revert to normal after a few months, and they would then respond appropriately to dinitrofluorobenzene on patch testing. This suggested that although the child's B-cell function was intact, there may have been some early, nonspecific deficit in T-cell function, brought about by infection in utero and manifested by transient impairment of delayed-type hyper sensitivity.

Besides the transient disorders of the newborn and the permanent sequelae of congenital rubella described above, we have recently been made aware of additional new problems such children may encounter that are directly attributable to rubella infection in utero but whose clinical expression may be delayed until the adolescent years. The endocrine and neurologic disorders among this group have been best characterized, and it may well be that other diseases of late onset, such as malignancies, are related to this congenital infection.

Children with congenital rubella who are the product of the rubella epidemic of 196465 in the United States are only now beginning to go through adolescence, and they are presenting a host of problems for the medical community and society at large. The Rubella Project currently has approximately 600 children with this disease in active longitudinal follow-up, most of whom are adolescents. The purpose of this report is to inform the pediatrie community of some of our experiences with the problems now facing this group in the light of new scientific information.

Since the licensure of five rubella virus vaccines in the United States in 1969, more than 70 million doses have been administered, principally to a target population of infants and preschool children. This immunization effort seems, for the present at least, to have brought a halt to rubella as an epidemic menace in the United States. Nonetheless, sporadic new cases of congenital rubella continue to be reported, and scattered outbreaks of rubella continue to occur in unimmunized females of childbearing age. We expect, then, that children with congenital rubella will continue to be born, albeit at a rate greatly reduced from that existing before the "vaccine era," and that pediatricians will have to remain informed about the problems such patients may have throughout early childhood and adolescence. Congenital rubella continues to serve as the prototype for the study of congenital viral infection in general, and the information gained from the study of children…

The large-scale epidemic of rubella in the United States in 1964-65 resulted in the birth of approximately 20,000 children with serious related congenital defects.

The spectrum of transient and permanent clinical findings seen in the newborn period in children with congenital rubella has been well characterized. Transient disorders most commonly include such features as thrombocytopenic purpura, bone "lesions," and pneumonitis. Permanent disorders include serious eye defects (cataract, glaucoma), sensorineural hearing loss, congenital heart disease, and various manifestations of brain injury wrought by congenital rubella encephalitis, including mental retardation and cerebral palsy.1

It was found that infants with these disorders were likely to shed rubella viruses from many sites - especially the throat - during the first weeks of life. Many continued to excrete virus for months afterward. This rubella shedding occurred despite the presence of high levels of circulating rubella antibody, much of it in the IgM class.2 Specimens obtained from abortion would frequently yield rubella virus from virtually all fetal tissues; this was also true of newborns.

Sophisticated techniques now available for measuring cell-mediated immunity were not readily available a decade ago, but unpublished studies by me and my colleagues demonstrated that some infants with congenital rubella could not be sensitized to customary doses of dinitrofluoro benzene as compared with age-matched controls. Children with this defect appeared to revert to normal after a few months, and they would then respond appropriately to dinitrofluorobenzene on patch testing. This suggested that although the child's B-cell function was intact, there may have been some early, nonspecific deficit in T-cell function, brought about by infection in utero and manifested by transient impairment of delayed-type hyper sensitivity.

Besides the transient disorders of the newborn and the permanent sequelae of congenital rubella described above, we have recently been made aware of additional new problems such children may encounter that are directly attributable to rubella infection in utero but whose clinical expression may be delayed until the adolescent years. The endocrine and neurologic disorders among this group have been best characterized, and it may well be that other diseases of late onset, such as malignancies, are related to this congenital infection.

Children with congenital rubella who are the product of the rubella epidemic of 196465 in the United States are only now beginning to go through adolescence, and they are presenting a host of problems for the medical community and society at large. The Rubella Project currently has approximately 600 children with this disease in active longitudinal follow-up, most of whom are adolescents. The purpose of this report is to inform the pediatrie community of some of our experiences with the problems now facing this group in the light of new scientific information.

Since the licensure of five rubella virus vaccines in the United States in 1969, more than 70 million doses have been administered, principally to a target population of infants and preschool children. This immunization effort seems, for the present at least, to have brought a halt to rubella as an epidemic menace in the United States. Nonetheless, sporadic new cases of congenital rubella continue to be reported, and scattered outbreaks of rubella continue to occur in unimmunized females of childbearing age. We expect, then, that children with congenital rubella will continue to be born, albeit at a rate greatly reduced from that existing before the "vaccine era," and that pediatricians will have to remain informed about the problems such patients may have throughout early childhood and adolescence. Congenital rubella continues to serve as the prototype for the study of congenital viral infection in general, and the information gained from the study of children with congenital rubella may have much broader applicability to children with other types of congenital infections who may have obvious birth defects or other manifestations of disease of late onset.

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

CLINICAL MANFESTATIONS

Hearing loss. Sensorineural hearing loss is the most common clinical manifestation of congenital rubella and a leading etiologic factor among children attending large public schools for deaf children. For example, of the 650 children attending the New York City School for the Deaf, 22 per cent have been diagnosed as having congenital rubella. Hearing impairment secondary to congenital rubella results from destruction of the hair cells in the organ of Corti, the extent of which may vary considerably from child to child. Consequently, hearing loss may be bilateral or unilateral and can vary from mild (with no clinically significant impact on speech development) to profound in degree. Early detection and characterization of the extent of hearing impairment in the young infant are crucial to the determination of the need for hearing aids and the potential for development of oral communication. Audiometrie testing of the young multihandicapped deaf child (deaf-retarded, deaf-blind) remains more of an art than a science, and the procedure requires ongoing reassessment and modification (Figure 1). The treatment plan is best developed by an interdisciplinary staff, which may include physicians, special educators, social workers, psychologists, and speech and hearing personnel. It has become increasingly clear that many children with congenital rubella have difficulty with speech and language that is far out of proportion to the severity of hearing loss. These children illustrate the special problems of rubella-induced injury to the language centers of the brain. Such central auditory impairment may accompany the hearing loss or may be present as an isolated deficit and may require referral to special educational programs for "aphasie" children.

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

Figure 1. This boy was born deaf and blind as a result of congenital rubella. At a prevocationat workshop at the New York Institute for the Education of the Blind, he is learning how to punch a time clock (left), stock parts (center), and assemble machine components (right).

There have been occasional anecdotal reports of children with congenita) rubella who developed progressive hearing loss as they reached later childhood and adolescence. The reasons for this are unclear, but fortunately such experiences seem to be very uncommon. Eye disorders. Congenital cataracts (uniocular or bilateral) and glaucoma are the most common serious eye defects in children whose mothers contracted rubella during early pregnancy. Longitudinal follow-up of the group affected by the 1964 epidemic has indicated that children who had a successful outcome from bilateral cataract surgery performed at approximately one year of age at the Rubella Project continue to have useful stable residual vision and function with partial sight. Since children with cataracts and congenital rubella most commonly have additional associated handicaps, such as hearing loss and evidence of brain injury, this residual vision has often been an important channel for rehabilitation efforts, such as the use of sign language in appropriately selected subjects. As with normal children going through adolescence, the eyes of children with congenital rubella undergo a growth spurt in globe diameter, which may lead to myopia. Since such sensorally impaired children are so dependent on their vision, it is imperative that careful vision testing be performed on at least an annual basis for early detection and remediation of refractive errors. There still appears to be no evidence that the characteristic "salt and pepper" retinopathy seen in many children with congenital rubella has any effect on visual functioning.

Cardiovascular disease. Since the various stages of embryologie development of the heart are largely completed by the eighth week of pregnancy, rubella contracted after that time generally does not result in the manifestation of congenital heart disease. On the other hand, a variety of anomalies can be present as a result of rubella contracted before this period - most commonly patent ductus arteriosus or anomalies involving the pulmonary artery or its branches. In general, we have been principally concerned with patent ductus arteriosus as the lesion of greatest hemodynamic significance. Increased attention has been focused on the management of children with stenosis of the pulmonary infundibulum and valve after a few adolescent children have come to surgery for evidence of clinical and laboratory signs of cardiac difficulty. Though our patient population is being followed closely for the possible appearance of systemic hypertension, this condition does not appear to be associated with an increased incidence beyond that seen in the general population.

Urogenital disorders. Congenital rubella is associated with a significant likelihood of the appearance of urogenital anomalies. Of 316 boys in our program, 111 have some anomaly. These include 39 with cryptorchidism, 35 with inguinal hernias, 12 with hypospadias, 31 with meatal stenosis, and 18 with other urologie abnormalities (hydrocele, abnormalities of the vas or testes, hydrometer, and hydronephrosis). It has been our practice to perform a careful urologie examination of any child with congenital rubella presenting with even minor genitourinary abnormalities, because of the probability of finding more significant occult disorders.

Endocrine disturbances. One of the most provocative aspects of this longitudinal study has been the sporadic occurrence of diseases of low incidence, especially endocrine disturbances. Among our population we have identified six children with overt diabetes mellitus, one with Addison's disease, one with Graves' disease,3 and one with hypothyroidism secondary to Hashimoto's thyroiditis.4 A population of older persons with congenital rubella has been studied in Australia in which the incidence of diabetes mellitus was found to be 20 per cent.5 Statistically, then, there is an increased probability of development of some endocrine disorder in the child with congenital rubella.

In an attempt to explain this association, we had the opportunity to perform a biopsy of the goitrous thyroid gland of our sixyear-old patient with Hashimoto's thyroiditis. The specimen was subjected to fluorescent antibody staining, with resultant demonstration of rubella virus antigen in the germinal centers of the lymphoid follicles. Our hypothesis is that this infection may have interfered with the normal development of immunologie maturity, specifically that related to cell-mediated immunity. The patient's immunologie defense mechanisms were later turned against the rubella virus antigens, which had taken up long-term residence in the thyroid. The result of this immunologie response was inflammatory disease causing the goiter and the hypothyroid state. It is interesting to speculate about the possible viral cause of juvenile diabetes mellitus as potentially following the same sequence, since it has been demonstrated that this disease may have its onset following viral infections, and histopathologic sections of the pancreas may show round-cell infiltration of the islets of Langerhans.

Additional immunologie studies are under way in our laboratory to extend these observations. For example, although lymphocytes from normal persons following natural rubella or rubella vaccine regularly respond to rubella antigen with blast formation and development of various lymphokines, our patient with Hashimoto's thyroiditis failed to respond in this fashion. On the other hand, B-cell function was intact as manifested by high levels of antibodies to various components of thyroid tissue and moderate levels of circulating rubella HI antibody, some of which was in the IgM fraction.

Studies such as these highlight the importance of continued monitoring of children with congenital rubella through adolescence for the appearance of any symptom suggestive of endocrine disorders.

NEUROLOGIC MANIFESTATIONS

The invasion of rubella virus into the developing central nervous system during fetal development results in direct killing of some brain cells and an inflammatory process that results in ischemia and further inhibition of normal brain maturation. There is great variability in both the amount and the site of injury dealt to portions of the brain, with the result that the form of neurologic disorder and magnitude of impairment may vary considerably from one child to the next. Another variable that is a determinant of the neurologic manifestation of disease is the time of fetal development when rubella infection takes place. In general, the earlier in pregnancy that rubella is contracted, the greater the likelihood that some clinical manifestation of brain injury in the child will occur and the more severe the impairment will be.

One of the most striking aspects of our longitudinal study has been that of the continuously evolving character of the neurologic aspects of children with congenital rubella. There have been countless examples among our patients of the great plasticity of the central nervous system and its capacity for utilization of relatively undamaged portions of the brain. On the basis of our experience, we wish to urge extreme caution to pediatricians providing counseling to families and agencies serving this group of children to avoid predictions of a hopeless prognosis, and we advise early institution alizat ion in residential facilities for the mentally retarded until a full range of rehabilitative services are brought to bear on each of the child's impairments.

In a study carried out in collaboration with Dr, Stella Chess of 74 children with mental retardation secondary to congenital rubella, 21 children considered to be retarded by standard criteria at four to five years of age were no longer classified as retarded at eight to nine years of age.7 Many children with spastic diplegia have had a successful outcome from orthopedic surgery, enabling them to enter special education programs previously closed to them because of difficulties in ambulation. Children seen during infancy with extreme irritability, tremulousness, and frank opisthotonic behavior reflect an ongoing meningoencephalitis secondary to rubella infection. Such children generally have considerable delay in all developmental milestones. With clearing of this encephalopathic process, which may take place between three and five years of age, there is often a gratifying spurt in development with improvement in ambulation and self -care skills. Language development usually lags behind because of the frequent association of severe or profound hearing loss and "central language impairment" with mental retardation.

By the time this group of children reached early adolescence, their neurologic picture seemed to have stabilized. Recently, however, available information has disturbed this relatively complacent attitude. For example, seizure disorders have been appearing in this population with greater frequency and seem to be present in a much higher percentage than would be expected in a random population. Whereas most surveys seem to indicate that seizure disorders affect approximately 0.5 per cent of the general population, we have identified 11 children in our population of 517 with congenital rubella who have clinical and elect roencephalographic evidence of a seizure disorder clinically significant enough to come to a physician's attention.

In this connection, our experience with psychoactive medication is worth mentioning. The phenothiazine group of drugs (e.g., chlorpromazine, thioridazine) are often the drugs of choice for management of severe hyperactivity and distractibility in these children. Caution is advised, however, because of their prediliction for lowering the seizure threshold and unmasking latent convulsive disorders. Stimulant drugs (dextroamphetamine, methylphenidate) may be worth trying, but in our hands they have often increased the very anxiety and hyperactivity we have been trying to reduce. Similarly, barbiturates should be used with caution in the treatment of seizure disorders because of their frequent side effects (restlessness, irritability, and hyperactivity}.

Recently, a new problem has surfaced regarding neurologic sequelae in children with congenital rubella. A group of children with congenital rubella have been described in California with a progressive, unrelenting degenerative disease of the central nervous system with onset around the time of puberty.8 The disease, termed progressive rubella panencephalitis, is characterized by progressive ataxia, spasticity, behavioral and intellectual deterioration, and seizures, leading to death in two of eight patients. Results of laboratory studies include abnormal electroencephalogram and elevated levels of rubella Hl antibody in serum and detectable rubella antibody in spinal fluid. Rubella virus has been isolated from the brain biopsy of one patient with the use of cocultivation techniques. Fortunately, this late-appearing complication of congenital rubella appears to be rare, and we have not observed it in any patient in the group we have been following. Nevertheless, with approximately 20,000 children with congenital rubella in the United States who represent the survivors of the 1964 epidemic now entering puberty, pediatricians should be especially vigilant for the appearance of the signs of this disorder.

PSYCHIATRIC DISORDERS

Serious behavior disorders in children with congenital rubella have been problems with which parents, educators, pediatricians, psychologists, and others have struggled for many years. Among the few publications in the medical literature that have dealt with this, probably the most comprehensive studies have been those of Chess.7 This group studied 223 patients with congenital rubella who comprised a population in our longitudinal study at approximately four and then again at eight years of age. Their studies demonstrated the higher frequency of psychiatric disturbances, especially autism, than is seen in the population at large.1 One important contribution of their work was the demonstration that a well-characterized biologic insult to the brain (in this case, congenital rubella) could be associated with a behavior disorder that had traditionally been viewed by many to be environmental in origin (autism).

During adolescence, children with congenital rubella have demonstrated their capacity to stir the same concerns among their parents as children without handicaps. Moodiness, rebelliousness, and other behavior considered so typical of children entering their teenage years are commonly seen in children with congenital rubella, but the ability of parents and other caretakers to cope with them are made much more complex by the associated defects, such as deafness or mental retardation. These factors tend to magnify such behavior in children who may already have considerable difficulty in impulse control and aggressiveness.

We have become increasingly concerned with developing approaches that deal with the children's emerging sexuality. After years of treating their growing children like infants, the parents suddenly find - to their dismay - that their handicapped child is no longer a child in the biologic sense. Parents need considerable support as their children seek sexual gratification or try to cope with menstruation and possible pregnancy. Parents and caretaking agencies at this stage are in special need of counseling from sympathetic pediatricians and other health professionals, so that such issues as masturbation, contraception, pregnancy, abortion, and sterilization can be discussed in order to reconcile the rights of the child with those of the parents and the rest of society. These issues are obviously quite complex and deserve a broad appreciation by pediatricians, who are so frequently sought by parents for such counseling.

CONCLUSION

It is now apparent that the problems of diagnosis and management in children with congenital rubella may not be resolved in the first few years of life, but the character of the disorder continues to evolve the longer we continue our longitudinal follow-up of the survivors of the rubella epidemic of 1964. With the administration of more than 70 million doses of rubella vaccine since licensure in 1969, large-scale epidemics of rubella have virtually been eliminated from the United States. The thousands of children with congenital rubella in the United States continue to occupy our attention, both for the ongoing care they require and for what they continue to teach us about the pathogenesis and clinical manifestations of congenital infections.

BIBLIOGRAPHY

1. Cooper, L. Z. Congenital rubella in the United States. In Krugman, S., and Gershon, A. A. (eds.). Infections of the Fetus and the Newborn Infant. New York: Alan R. Liss, 1 975.

2. Cooper, L. Z., e! al. Rubelte: Clinical manifestations and management. Am. J. Dis. Child. 118 (1969), 18-29.

3. Ziring, P. R., Fedun, B. A., and Cooper, L. Z. Letter: Thyrotoxicosis in congenital rubella. J. Pediatr. 87 (1975), 1002.

4. Ztring, P. R., et al. Chronic lymphocytic thyroiditis: Identification of rubella virus antigen in the thyroid of a child with congenital rubella. J. Pediatr. 90 (1977), 419.

5. Forrest, J. M., Menser, M. A., and Burgess, J. A. High frequency of diabetes mellitus in young adults with congenital rubella. Lancet2 (1971), 332-334.

6. Levy, A. L., and Notkins, A. L. Viral infections and diseases of the endocrine system. J. lnlect. Dis. 124 (1971), 94-103.

7. Chess, S. Behavior and learning of school-age rubella children. Final report, "Congenital Rubella - Behavior Studies (CRBS)," Project #MC-R-3601 83-03-0, December 31, 1974.

8. Weil. M. L, et al. Chronic progressive panencephalitis due to rubella virus stimulating SSPE. N. Engl. J. Med. 292 (1975), 994998.

10.3928/0090-4481-19771201-04

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