The acronym Torch is derived from the first letters of four nonbacterial diseases (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex) that may infect the fetus and cause a variety of teratogenic changes. All of these have several characteristics in common. Potentially severe fetal infection, often leading to congenital anomalies, is acquired following maternal infection. None of these are amenable to specific therapy (except on an experimental basis) following delivery. Only rubella is largely preventable through widespread programs of active immunization, although an experimental vaccine for cytomegalovirus has been developed.
In 1941, Gregg discovered that maternal rubella during the first trimester of pregnancy was associated with an increased incidence of cataracts, deafness, and congenital heart disease.1 Most of our knowledge of the pathophysiology of congenital rubella was gathered during the major epidemic of 1964, and it was shortly after this that the vaccine against rubella became commercially available.
Basic properties. The rubella virus is considered a member of the myxovirus family and is inactivated by extremes of pH, heat, and various chemical reagents. The pathologic effects caused by the virus are mitotic inhibition, increased number of chromosomal breaks, and interference with cell division, which leads to organ hypoplasia.
Fetal transmission. Illness in the mother is often mild and nonspecific, and may be overlooked in the absence of an epidemic.
Transplacental passage of the virus from mother to fetus usually occurs early in the first trimester, although transmission during the second trimester has been reported. -
Although the disease is generally mild in older children and adults, fetal infection is usually severe and all organ systems may be affected.3 The reason for the extreme virulence of fetal infection compared with postnatally acquired infection is not clear; it may be related to a virusantibody-host interaction. In postnatally acquired infections, there is a rapid rise of serum antibody concentration, which is followed by rapid disappearance of virus from the tissues. However, despite the rising antibody concentrations observed in fetal infection, the virus may be recovered months or years following infection. The mechanism for this phenomenon is not known.
Clinical manifestations. The major findings in congenital rubella include hepatomegaly and hepatitis, splenomegaly with extramedullary hematopoeisis, congenital heart disease (patent ductus arteriosus, ventricular septal defect, atrial septal defect, pulmonic stenosis), myocardial necrosis, hypoplastic abdominal aorta, cataracts, glaucoma, thrombocytopenia, interstitial pneumonia, adenopathy, bone lesions, microcephaly, encephalitis, loss of hearing, abnormal dermatoglyphic skin patterns, and genitourinary and gastrointestinal anomalies.
Microcephaly, severe growth retardation, and thrombocytopenia are observed in the most severely affected infants. The overall mortality is about 10 per cent in infants with normal platelet counts and about 35 per cent in those with thrombocytopenia.
Surviving infants with severe intrauterine growth retardation usually have microcephaly and neurologic defects.4
Diagnosis. The diagnosis of congenital rubella is made primarily on a clinical basis, but laboratory tests may be of great value. Recovery of the rubella virus from the throat, urine, or cerebrospinal fluid of the infant confirms the diagnosis.
As in other nonbacterial fetomaternal infections, elevated cord blood concentrations of IgM antibody reflect fetal infection and active antibody response.
Treatment. There is no specific treatment for congenital rubella. If the diagnosis of maternal rubella is made in the first trimester (by a fourfold or greater increase in the maternal hemagglutination-inhibition antibody titer),"* therapeutic abortion may be the most satisfactory approach. Administration of gamma globulin to the pregnant woman exposed to rubella is of no proven value.
Treatment of the newborn infant with this disorder is supportive. Digitalization is indicated if there is congestive heart failure. Platelet transfusions are of limited value for bleeding secondary to thrombocytopenia. Isolation of the affected infant is indicated, since rubella is highly contagious.
Prevention. With widespread use of effective live vaccines for the past decade, rubella is now largely a preventable disease. There have been no major epidemics of rubella in the United States since 1964, and only sporadic cases of congenital rubella are now seen.
It must be pointed out that pregnant women should not be actively immunized, since the attenuated virus may affect the fetus.11
Cytomegalovirus (CMV) is a medium-size virus belonging to the herpesvirus family that grows in human fibroblast and myometrial tissue cultures. Infected cells contain a characteristic eosinophilic or basophilic inclusion body, and can be recovered from the urine and saliva of affected neonates.
The virus can affect the fetus from the fourth week to the third trimester/ probably by the hematogenous route. Maternal illness is usually unapparent or mild, and presents a mononucleosislike clinical picture. It is observed most commonly during the first pregnancies of young women.
Clinical manifestations in the neonate.8 The illness is most severe if infection has occurred early in pregnancy, the period of greatest susceptibility of the developing central nervous system. Encephalitis occurring at this time may result in microcephaly, with subsequent mental retardation. Jaundice and hepatomegaly reflect liver involvement, while thrombocytopenia and petechiae are hematologic manifestations.
There is a wide teratogenic range of this disease, including the first branchial arch syndrome, high arched palate, congenital cardiac disease, club foot, inguinal hernia, abdominal wall defects, and central nervous system malformations other than microcephaly.
Laboratory diagnosis. The diagnosis of CMV infection is based on virologie, serologic, and cytologic findings.
Isolation of the virus from body fluids following inoculation into appropriate tissue culture media is the method of choice in establishing the diagnosis. Viruria may, however, be present in asymptomatic infants.9 Elevated concentrations of specific complement fixation and neutralizing antibody (which are of the IgG class) may represent either fetal infection or passive transfer from the mother. Cord blood IgM concentrations of more than 20 mg. /100 ml. are nonspecific indications of fetal infection. A specific IgM immunofluorescent antibody test has also been described. I0
Cytologic studies of cells in urinary sediment for typical inclusion bodies are important in establishing the diagnosis. It should be kept in mind that diagnostic cells are shed intermittently and that adenoviruses also produce intranuclear inclusions, which may cause some confusion in interpretation.
Prevention and treatment. Treatment of CMV infection in the neonate is essentially symptomatic. Experimental antiviral agents have been used, but their efficacy has not been satisfactorily determined.
A live vaccine is currently undergoing field trials and is a promising new approach to the prevention of this disorder. ' '
Congenital toxoplasmosis is caused by an organism, T. gondii, that is usually considered to be a protozoon. It can be readily grown in tissue culture, but not in artificial media.
Maternofetal infection. Maternal illness may occur at any time during pregnancy and is usually accompanied by fever and posterior cervical lymphadenopathy .
Maternal infection occurring between the second and sixth months most often leads to fetal infection. In contrast, the fetus is usually spared if maternal infection occurs during the third trimester. Congenital toxoplasmosis usually does not occur in subsequent pregnancies.
Maternal illness may be acquired from contact with infected cats or by the ingestion of raw or poorly cooked meat.
It is estimated that the incidence of congenital toxoplasmosis is about one in every 400 live births in the United States, and the disease may be responsible for about 2 per cent of the severe mental retardation in this country.
Neonatal illness. The signs of congenital toxoplasmosis include hepatosplenomegaly, jaundice, petechiae, pneumonia, anemia, hydrocephalus, chorioretinitis, and a maculopapular rash. Although clinical manifestations may be apparent at birth, the onset may be delayed for several months.
The triad of chorioretinitis, CNS calcifications, and hydrocephaly occur in about 60 per cent of infants with the illness. The single most common finding is bilateral chorioretinitis. With CNS involvement, severe neurologic sequelae, such as convulsions and mental retardation, are common.12
Laboratory diagnosis. The SabinFeldman dye titer,13 complement fixation, hemagglutination inhibition, and neutralization tests all measure IgG antibody and may therefore show either fetal infection or passive transfer of maternal antibodies. If the Sabin-Feldman test titer is 1:128 or less in both umbilical cord and maternal serum, the probability of fetal infection is unlikely. If it is 1:256 or higher, toxoplasmosis becomes a strong diagnostic possibility.
As in congenital rubella and CMV, a cord blood IgM concentration greater than 20 mg./100 ml. is suggestive of fetal infection. The indirect fluorescent antibody-IgM test described by Remington suggests active infection and is more specific than any of the IgG-related antibody tests.14
There is considerable variation in the temporal course of each of the IgG-related antibody titers. The dye titer develops promptly and lasts for several years, whereas the complement fixation titer does not begin to rise until a few months after infection.
Therapy. Avoidance of undercooked meat and contact with pet cats may be helpful in preventing this potentially lethal disease. Treatment of the infected pregnant woman with spiramycin may prevent spread of the disease to the fetus. This drug does not cross the placenta, however, and it is of no value to an already infected fetus.
Two chemotherapeutic agents, pyrimethamine and sulfisoxazole, have been used for treating the disease, but there is no proof of their efficacy among neonates. No active immunization is available.
Neonatal infection from Herpesvirus hominis (HVH) occurs in 1:3,200 to 1:30,000 live births in the United States. Most are due to the genital (type 2) rather than the oral (type 1) variety.
Transmission. There are three possible routes of infection. Transplacental passage early in pregnancy may lead to fetal death, abortion, and congenital anomalies, such as microcephaly, microphthalmia, and skin involvement.15*16 Transmission may also occur during parturition if the virus is present in the maternal genital tract. Secondary systemic spread may follow cutaneous and mucous membrane involvement. A third possibility is postnatal droplet transmission from another infant or mother or from a member of the nursery staff.
While cesarean section has been used as a means of preventing transmission of infection in the presence of maternal genital lesions, it has not always been successful.
Immune mechanisms. Antibodies against HVH, which are of the IgG type, are nearly always present in umbilical cord sera at a titer comparable with that in maternal sera. These antibodies, however, are incompletely protective against clinical infection in the infant. This may be due to the fact that the virus is disseminated by infected white blood cells. IgM antibody synthesis in infected infants may not begin for two weeks to two months, and may have poor neutralizing capacity. However, elevated levels of IgM may be present in cord blood in cases of first-trimester infection.
Clinical manifestations. While diagnosis is made on clinical grounds by appearance of the characteristic vesicles, up to 25 per cent of cases may remain undetected until postmortem examination. Signs of disseminated infection include vomiting, anorexia, diarrhea, poor weight gain, lethargy, respiratory distress, bleeding, jaundice, and conjunctivitis. CNS findings include bulging anterior fontanelle, opisthotonos, convulsions, and coma. Microcephaly, microphthalmia, hydrocephaly, porencephalic cysts, intracranial calcifications, and chorioretinitis may reflect firsttrimester infection.
In about one-third of disseminated cases, vesicular skin lesions are found over various parts of the body; these may become secondarily infected with bacterial pathogens.
Localized infection may involve only the skin and mucous membranes. In addition to the vesicles, an erythema multiforme type of picture may be seen. These localized lesions may be delayed for 10 to 14 days, in contrast to a more rapid appearance in generalized HVH infection. The mortality is about 80 per cent in the latter form of the disease.17
Laboratory diagnosis. Cytologic findings of multinucleated giant cells and intranuclear inclusions in cell scrapings from vesicles and ulcers, as well as fluorescent antibody techniques for the detection of organisms in samples obtained by smear or biopsy, are useful in confirming the diagnosis.18
Pathologic characteristics. At postmortem examination, the liver and adrenal glands are most frequently affected, but involvement of other organs is often observed. Typical lesions include areas of focal necrosis surrounded by an inflammatory response. Epithelial cells show both nuclear and cytoplasmic changes.
Treatment. Supportive treatment consists of warmth, proper oxygenation, intravenous administration of fluids, heparinization in the presence of disseminated intravascular coagulation, and antibiotic administration to treat secondary infection.
Several experimental chemotherapeutic agents have been used, but their efficacy in the newborn period has not been demonstrated.
1. Gregg, N. M. Congenital cataract following German measles m the mother. Trans. Ophthalmol. Soc. Ausi 3 (1942), 35-46.
2. Hardy, J. B., et al. Adverse fetal outcome following maternal rubella after the first trimester of pregnancy. J. A.M. A. 207 (1969), 2414-2420.
3. Driscoll, S. H. Histopathology of gestational rubella. Am. J. Dis. Child. 118 (1969). 49-53.
4. Menser. M. ?., et al. Congenital rubella: Longterm follow-up study. Am. J. Dis. Child. 118 (1969), 32-34
5. Cooper, L. Z., et al. Experience with a modified rubella hemagglutination inhibition test. J. A.M. A. 207 (1969), 89-93.
6. Horstmann. D. M., Liebhaber, H., and Kohorn, E. I. Post-partum vaccination of rubella-susceptible women. Lancet 2 (1970), 1003-1006.
7. Monif, G. R. G, et al. The correlation of maternal cytomegalovirus infection during varying stages in gestation with neonatal involvement. J. Pediatr. 80 (1972). 17-20.
8. Weiler, T. H. The cytomegaloviruses: Ubiquitous agents with protean clinical manifestations. Part I. N. Engl. J. Med. 285 (1971). 203-214; Part II. N. Engl. J. Med. 285 (1971), 267-274.
9. Starr, J. G, Bart, R. D., Jr., and Gold, E. Inapparent congenital cytomegalovirus infection: Clinical and epidemiologic characteristics in early infancy. W. Engl. J. Med. 282 (1970), 1075-1078.
10. Hanshaw, J. B., Steinfield. H. J, and White. C. J. Fluorescent antibody test for cytomegalovirus macroglobulin, N. Engl. J. Med. 279 (1968), 566-570.
11. Elek, S. D., and Stern, H. Development of a vaccine against mental retardation caused by cytomegalovirus in utero. Lancet 1 (1974). 1-5.
12. Feldman, H. A. Toxoplasmosis. N. Engl. J. Med. 279 (1968), 1370-1375.
13. Sabin. A. B., and Feldman, H. A. Dyes as microchemical indicators of a new immunity phenomenon affecting a protozoan parasite (Toxoplasma). Science 108 (1948), 660-663.
14. Remington, J. S., and Desmonts, G. Variability in the IgM-fluorescent antibody response and some pitfalls in diagnosis. J. Pediatr. 83 (1973). 27-30.
15. Florman. A. L. et al. Intrauterine infection with herpes simplex virus. J.A.M.A. 225 (1973), 129-132.
16. South, M. A., et al. Congenital malformation of the central nervous system associated with genital type (type 2) herpesvirus. J. Pediatr. 75 (1969), 13-18.
17. Hanshaw, J. B. Herpesvirus hominis infections in the fetus and newborn. Am. J. Dis. Child. 126 (1973), 546-555.
18. Gardner. P. S.. et al. Rapid diagnosis of herpesvirus hominis infections in superficial lesions by immunofluorescent antibody technics. Br. Med. J. 4 (1968), 89-92.