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Previous Volume 330:1858-1863 June 30, 1994 Number 26 Next

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ABSTRACT

Background Most infants with congenital Toxoplasma gondii infection have no symptoms at birth, but many will have retinal disease or neurologic abnormalities later in life. Early detection and treatment of congenital toxoplasmosis may reduce these sequelae.

Methods In Massachusetts since January 1986, and in New Hampshire since July 1988, newborns have been screened for intrauterine infection with T. gondii by means of an IgM capture immunoassay of blood specimens routinely collected for screening for metabolic disorders. Congenital infection is confirmed by assays for specific IgG and IgM antibodies in serum from infants and their mothers. For this study, infants with serologic evidence of infection underwent extensive clinical evaluation and received one year of treatment.

Results Through June 1992, 100 of 635,000 infants tested had positive screening tests. Congenital infection was confirmed in 52 infants, 50 of whom were identified only through neonatal screening and not through initial clinical examination. However, after the serologic results became available, more detailed examinations revealed abnormalities of either the central nervous system or the retina in 19 of 48 infants evaluated (40 percent). After treatment, only 1 of 46 children had a neurologic deficit (hemiplegia attributable to a cerebral lesion present at birth). Thirty-nine treated children had follow-up ophthalmologic examinations when one to six years old; four (10 percent) had eye lesions that may have developed postnatally (a macular lesion in one child and minor retinal scars in three).

Conclusions Routine neonatal screening for toxoplasmosis identifies congenital infections that are subclinical, and early treatment may reduce the severe long-term sequelae.

Because congenital toxoplasma infection does not usually produce recognizable signs of infection at birth, we were concerned by the fact that most cases remain untreated because they are not detected by routine clinical examination. Therefore, we have used serologic screening to identify infants who should receive therapy, adding a toxoplasma-specific IgM assay to the battery of screening tests carried out on the universally collected newborn "filter-paper" specimens. We report the results of our serologic screening for congenital toxoplasma infection, the spectrum of initial clinical and laboratory findings in infected newborns, and the clinical outcome of empirical treatment with antitoxoplasma chemotherapy.

Methods

Study Population

In January 1986 the New England Regional Newborn Screening Program began screening all infants born in Massachusetts (about 90,000 births per year) for congenital toxoplasma infection. In July 1988 screening was extended to include infants born in New Hampshire (about 15,000 births per year). Infants screened before July 1, 1992, are described in this report.

Screening Assay

All assays for toxoplasma antibody were performed by one laboratory (New England Regional Newborn Screening Program) on a heel-stick blood specimen that had been adsorbed onto a filter-paper card, routinely obtained for all newborns before hospital discharge. The specimens are typically collected on the second to third day of life and delivered to the laboratory for testing. The assays for toxoplasma IgM and IgG have been described in detail elsewhere^3,4,5,6. In brief, a 6-mm disk saturated with dried blood was punched from the filter-paper card, and the specimen was eluted in 0.2 ml of buffer overnight. The eluate was tested by an IgM-specific enzyme-linked immunosorbent assay with a reported sensitivity of at least 75 percent⁶. Test results were usually available one to two weeks after birth. If the optical density indicating the IgM reaction was greater than 0.080, tests for IgM were repeated, with and without the inclusion of toxoplasma antigen, on blood from two additional 6-mm disks. If the optical density representing the toxoplasma-specific reactivity was greater than 0.100, we contacted the infant's physician by telephone to request specimens of serum from the infant and mother for further serologic testing.

In addition to the laboratory studies outlined in Table 1, tissue cultures and peritoneal inoculation of mice with blood or cerebrospinal fluid (or both) from the infants were performed by the laboratory in a subgroup of the study population in an attempt to demonstrate the presence of Toxoplasma gondii^7,8. Mouse 3T3 fibroblast cells were used for culture. Serum obtained from the mice six weeks after inoculation was assayed for toxoplasma-specific antibody by enzyme-linked immunosorbent assay.

View this table: [in this window] [in a new window]   Table 1. Initial and Follow-up Evaluations for Congenital Toxoplasma gondii Infection.

 
Clinical and Laboratory Assessment and Treatment

If serologic testing confirmed the presence of toxoplasma IgM in the infant and demonstrated findings consistent with recent toxoplasma infection in the mother, specialists in pediatric infectious diseases coordinated evaluation and follow-up (Table 1) and treatment of the infants. Treatment consisted of combination antibiotic therapy with pyrimethamine, sulfadiazine, and leucovorin (folinic acid) for one year (Table 2). Spiramycin was also given to two infants. The study did not contain an untreated control group, because of the expected high rate of sequelae of congenital toxoplasma infection.

View this table: [in this window] [in a new window]   Table 2. Treatment Regimens of 49 Infants with Congenital T. gondii Infection.

 
Results

Identification of Infants for Treatment and Follow-up

From January 1986 through June 1992, 5 infants were identified independently of the screening program as having congenital toxoplasma infection, and 50 were identified solely through screening. The antenatal or neonatal findings that suggested congenital infection in the five infants before their filter-paper specimens were tested are summarized in Table 3. When the routine filter-paper testing was performed, two of these infants were found to be positive for toxoplasma IgM antibody and three were negative. Tests of follow-up serum specimens showed that all five infants were positive for toxoplasma IgG antibody, and that their mothers were positive for both IgM and IgG antibodies. In addition, toxoplasma parasites were isolated from two infants. All five infants had severe disease and were treated with pyrimethamine, sulfadiazine, and leucovorin for one year.

View this table: [in this window] [in a new window]   Table 3. Clinical and Serologic Findings in Five Infants Known before Screening to Have Severe Disease Caused by Congenital T. gondii Infection.

 
A total of 100 infants were positive for toxoplasma IgM on filter-paper testing (Table 4), including 2 of those in Table 3. Fifty of the 100 had serologic confirmation of infection, as determined by a positive IgM test and consistent maternal serologic results. The other 50 infants were not confirmed to be infected, either because of their follow-up serum test results or those of their mothers.

View this table: [in this window] [in a new window]   Table 4. Criteria for Selecting 54 Infants for Treatment from among 100 Infants with Toxoplasma IgM Antibody According to Filter-Paper Testing.

 
The 50 infants in whom infection was not confirmed included 19 whose mothers were positive for toxoplasma IgM and IgG. Four of the 19 infants were treated -- 2 solely because of the attending physician's preferences, and 2 because they had intracranial calcifications. The other 15 infants were not treated because mothers who were positive on serologic testing might not necessarily have transmitted the infection. Some of these infants underwent more extensive clinical evaluations, which were negative. Serologic follow-up of 9 of these 15 infants was sufficient to demonstrate that IgG toxoplasma antibody had been lost in 8 of them. In summary, 54 infants shown to be positive on filter-paper screening were treated, 50 of whom had confirmed infection detected by serologic testing alone.

Initial Physical Findings

All 50 infants identified solely by neonatal screening were normal on routine neonatal examination by pediatricians who evaluated them while the serologic studies were in progress. All were term infants ( 37 weeks of gestation), and their respective weights and head circumferences were within the normal range for their gestational age. The ratio of male to female infants was nearly 1:1.

Central Nervous System Involvement and Neurologic Assessment

Of the 50 infants identified by neonatal screening, 32 underwent evaluation of cerebrospinal fluid during the neonatal period. Eight infants (25 percent) had elevated levels of protein in cerebrospinal fluid (range, 100 to 569 mg per deciliter). Nine of the 46 infants (20 percent) who underwent cranial computed tomography (CT) had intracranial calcifications in either the cerebral cortex or the periventricular regions (or both), and 1 of the 9 also had a large parietal toxoplasma lesion that appeared cystic. Of 47 infants who had either cranial CT scanning or cranial ultrasonography to assess ventricular size, 1 (2 percent) had ventriculomegaly. Thus, of the 48 infants who underwent cerebrospinal fluid examination, cranial CT, or cranial ultrasonography, 14 (29 percent) had objective evidence of central nervous system disease (Table 5).

View this table: [in this window] [in a new window]   Table 5. Incidence of Central Nervous System and Retinal Abnormalities among Infants in Whom T. gondii Infection Was Diagnosed Solely by Neonatal Screening.

 
Of the 50 infants who completed therapy, 46 had one or more formal neurologic evaluations in the first year of life, followed by routine pediatric evaluations every 6 to 12 months. One infant had hemiplegia, which was attributed to a large parietal cystic toxoplasma lesion noted on the initial cranial CT scan. Four infants had abnormal muscle tone at a few months of age, but their tone became normal by the age of one year. One infant had normal neurologic development during the second year of life but subsequently had severe lead intoxication and developmental delays. His symptoms improved after chelation therapy. The other 40 infants had normal neurologic development when evaluated after one year of age by their primary pediatrician, although 1 infant had an attention deficit disorder of unknown cause that was first noted at the age of four years. Thus, only 1 of the 46 infants had a persistent neurologic deficit, a hemiplegia with severe cognitive and motor-function impairment.

Ophthalmologic Assessment

Table 5 summarizes the results of the initial ophthalmologic examinations performed during the neonatal period in 48 of the 50 infants identified by neonatal screening. Two of these 48 infants (4 percent) had active chorioretinitis, and 7 others (15 percent) had retinal scars without active inflammation, for a total of 9 with retinal disease (19 percent). The follow-up findings in these nine infants are shown in Table 6. Seven of them had macular lesions that caused unilateral visual impairment, although none of the macular lesions progressed. Only one infant had new peripheral retinal scars. These lesions, noted for the first time when the child was six years old, involved a portion of the retina not previously visualized and may have represented old scars that were present at birth.

View this table: [in this window] [in a new window]   Table 6. Ophthalmologic Follow-up Examination of 39 Children More Than One Year of Age in Whom T. gondii Infection Was Diagnosed by Neonatal Screening.

 
Table 6 also shows the ophthalmologic findings in the 30 infants who did not have evidence of retinal disease on initial ophthalmologic examination and who were examined when one year old or older. New lesions were detected in three children. Two of the three were noted to have small scars in portions of the retina that were believed to have been poorly visualized on examination in infancy; the third child had been examined twice during the first year of life by an ophthalmologist who acknowledged having great difficulty in visualizing the retinas. This child had persistent strabismus that required a complete ophthalmologic examination under general anesthesia, which revealed a macular lesion in one eye. The lesion has remained stable, with no other lesions noted up to six years of age. Thus, a total of four children (10 percent) had ocular lesions that may have developed after birth.

Treatment and Toxicity

A one-year course of treatment was recommended for the infants with confirmed congenital toxoplasma infection, but the choice of regimens was left to the discretion of each infectious-disease consultant (Table 2). Compliance was good as assessed by interviews with parents, the number of refills of prescriptions, and the occurrence of hematologic side effects (see below). All infants completed a one-year treatment course except for four infants whose parents discontinued treatment after six to eight months and one infant who died of a viral infection at two months of age.

Data on drug toxicity were available for 47 infants. Thirty-two infants tolerated treatment without difficulty and had no abnormal hematologic findings. Six infants had anemia (mean [±SD] hematocrit, 26.5 ±1.8 percent; range, 24 to 29), six had absolute neutrophil counts below 500 cells per cubic millimeter on at least one occasion, and one had both neutropenia and anemia. These children received more dietary iron, a larger dose of leucovorin, or a reduced dose of pyrimethamine. Specific interventions were individualized for each patient, with close monitoring of complete blood counts. Bone marrow depression responded rapidly to these interventions except in one infant with severe neutropenia (absolute neutrophil count, <100 per cubic millimeter), which resolved only after sulfadiazine had been discontinued for three weeks; the drug was reintroduced without a recurrence of neutropenia. One infant with asthma and a family history of atopy had a recurrent rash of the face and extremities that resembled atopic dermatitis; because of the possibility of drug hypersensitivity, sulfadiazine was discontinued and pyrimethamine alone was administered during the last three months of therapy. Another infant inadvertently received 20 times the dose of pyrimethamine and had an acute tonic-clonic seizure that required hospitalization; the seizure resolved on the first day of admission, without sequelae. All infants had normal patterns of growth, head circumferences, and weight.

Discussion

There is no standard approach to the prevention of congenital toxoplasmosis in the United States,¹⁰ in contrast to the aggressive approach taken in France, where susceptible women undergo serial testing during pregnancy¹¹. The argument against such a program in the United States is based in part on the greater cost: previous infection and immunity are less common among pregnant women in the United States, and the proportion of seronegative women who would require serial testing would be much higher¹².

Although our approach to neonatal screening identified only about 1 infant with toxoplasma infection per 10,000 newborns, rather than the 1 per 1000 expected in view of earlier estimates by others,¹ we identified many infants whose infection probably would have remained unrecognized. Studies continue to determine whether the current incidence is truly lower than first thought, or whether IgM-based screening misses a substantial number of cases⁴.

The efficacy of our program in preventing sequelae is difficult to evaluate without a concurrent, untreated control group. It should be emphasized that the optimal duration of chemotherapy for congenital toxoplasma infection is unknown. Treatment failures have been described in infants receiving brief courses of therapy, arousing concern about the susceptibility of infants throughout the first year of life and later¹. This has led to the recommendation that infected infants be treated throughout the first year of life¹. Because we believed that a placebo-controlled trial was unacceptable when our study began, our results can only be compared with outcomes in other cohorts of infants^{2,13,14,15,16,17,18}.

The most common sequela of congenital toxoplasma infection is chorioretinitis. The reported incidence of this complication varies, but the risk of new retinal complications continues for many years. Koppe et al.^2,13. prospectively followed 11 infants with congenital infection. Only those who had retinal disease at birth (four infants) or toxoplasma cultured from the placenta or cerebrospinal fluid (one infant each) received therapy, which consisted of a three-week course of sulfadiazine and pyrimethamine. After 20 years of follow-up, nine subjects (82 percent) had evidence of chorioretinitis, including four with severe visual impairment and three with monocular blindness. Similar findings were made by Wilson et al.,¹⁴ who followed 13 infants with subclinical congenital toxoplasma infection diagnosed by measurement of specific IgM antibodies in cord blood who received either no chemotherapy or chemotherapy for less than one month. On periodic follow-up examinations over several years 11 children had chorioretinitis, 3 of whom had monocular blindness.

There is some suggestion that treating newborns during the entire first year of life may be useful. Couvreur et al.¹⁵. prospectively followed 108 infants with congenital toxoplasma infection diagnosed by postnatal screening; 26 infants (24 percent) had chorioretinitis on their initial examination. Although follow-up was reported for only a small number of these infants, 8 percent of those who did not receive therapy had new retinal lesions, whereas none of those treated had new retinal disease. In a separate report, Couvreur et al.¹⁶. described an inverse relation between the incidence of chorioretinitis and the duration of treatment. Nevertheless, there has been at least one case report of new retinal disease occurring in a child treated for toxoplasma infection for 11 months during the first year of life¹⁷.

The neurologic outcome in infants with mild or subclinical congenital toxoplasma infection remains less certain. In the studies by Koppe et al.,^2,13 the 11 infants followed prospectively were reported to have performed normally in school when compared with controls of their age, suggesting that they had no severe neurologic sequelae. In contrast, the study by Wilson et al.¹⁴. found serious long-term neurologic complications in 13 infants in whom toxoplasma infection was diagnosed in cord blood (IgM antibody). All 13 infants initially had normal findings on general physical and neurologic examinations. Their mean (±SE) IQ on follow-up examination was 88.6 ±23.4, but the mean for six children retested 5.5 years later fell from 97 to 74. Two of the children were severely retarded, with IQs of 36 and 62. Three children had sensorineural hearing loss, and five had other neurologic complications: psychomotor retardation, microcephaly, and seizures (one child); delayed psychomotor development, with eventual restoration of function (two children); and persistent cerebellar dysfunction (two children).

The findings of Sever et al.¹⁸. are equally worrisome. These investigators reported the results of a seven-year study of 22,845 mothers and their infants in the Collaborative Perinatal Project (National Institutes of Health). Toxoplasma-antibody titers were positive in 38.7 percent of the mothers; the rate of acute toxoplasma infection during pregnancy was inferred to be 1.1 per 1000. The incidence of deafness among the children of women with toxoplasma IgG antibody was twice that among those of women without toxoplasma antibody. The incidence of microcephaly was 60 percent higher among the children of women with high toxoplasma titers, and the frequency of low IQs (<70) was 30 percent higher.

Our prospective screening program identified infants who appeared normal on routine neonatal examination but who had a surprisingly high incidence of retinal or central nervous system disease (40 percent). In all these infants, the retinal and cranial lesions present at birth remained stable or improved, and the incidence of new complications was low on follow-up evaluation. Although formal tests of hearing have been conducted in only about half the infants and children whom we have followed, no hearing abnormalities have been detected. These findings contrast with the high incidence of retinal disease and neurologic deficits among infants who received little or no chemotherapy for toxoplasma infection.

The costs of neonatal screening for congenital toxoplasmosis are relatively low because the program uses the systems for collection and processing specimens already in place for screening newborns for eight other diseases. The additional laboratory and personnel costs of screening and following approximately 100,000 infants per year for toxoplasma infection total $220,000, or less than $30,000 per infant identified. Considering the financial and social costs of rearing a single visually or intellectually impaired child, the cost-benefit ratio is quite favorable¹⁹.

We have shown that a screening program to identify newborns with congenital toxoplasma infection is feasible and that the treatment regimen is acceptable. Early clinical follow-up indicates that there has been little progression of disease in infants who were treated from birth. Because sequelae can occur into adulthood, more follow-up will be needed before the overall benefits of neonatal screening for toxoplasma infection can be accurately assessed.

We are indebted to Dr. Jack Remington (Palo Alto Research Foundation, Palo Alto, Calif.) for his early encouragement, advice, and laboratory reference services; to Dr. Rima McLeod (Michael Reese Hospital, Chicago) for sharing her experience with treatment protocols for congenital toxoplasmosis; and to the pediatricians who cared for the children in this study, without whose participation in treatment and monitoring this study would not have been possible.

Source Information

From the Divisions of Infectious Diseases and Newborn Medicine, Children's Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, and the Division of Neonatology, Newton-Wellesley Hospital, Newton, Mass. (N.G.G.); the New England Regional Newborn Screening Program, Massachusetts State Laboratory Institute, Boston (H.-W.H., R.L., R.H., R.B.E., G.F.G.); the Department of Pediatric Infectious Diseases, New England Medical Center, and the Department of Pediatrics, Tufts University School of Medicine, Boston (H.C.M.); the Department of Infectious Diseases, Brigham and Women's Hospital, and the Department of Medicine, Harvard Medical School, Boston (J.H.M.); the Pediatric Infectious Disease Unit, Massachusetts General Hospital, and the Department of Pediatrics, Harvard Medical School, Boston (R.L., M.S.P.); the Division of Pediatric Infectious Diseases, Baystate Medical Center, Springfield, Mass., and the Department of Pediatrics, Tufts University School of Medicine, Boston (B.S.); and the Department of Neurology, University of Massachusetts Medical Center, Worcester (I.A.). The other members of the New England Regional Toxoplasma Working Group are Sarah H. Cheeseman, M.D. (University of Massachusetts Medical Center, Worcester), Kenneth McIntosh, M.D. (Children's Hospital, Boston), Donald N. Medearis, Jr., M.D. (Massachusetts General Hospital, Boston), Richard Robb, M.D. (Children's Hospital, Boston), and Barbara J. Weiblen, M.S. (Massachusetts State Laboratory Institute, Boston).

Address reprint requests to Dr. Guerina at the Division of Newborn Medicine, New England Medical Center (NEMC #44), 750 Washington St., Boston, MA 02111.

References

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