Risk factors for Toxoplasma gondii infection in mothers of infants with congenital toxoplasmosis: Implications for prenatal management and screening

OBJECTIVE: The purpose of this study was to determine whether demographic characteristics, history of exposure to recognized transmission vehicles, or illness that was compatible with acute toxoplasmosis during gestation identified most mothers of infants with congenital toxoplasmosis. STUDY DESIGN: Mothers of 131 infants and children who were referred to a national study of treatment for congenital toxoplasmosis were characterized demographically and questioned concerning exposure to recognized risk factors or illness. RESULTS: No broad demographic features identified populations that were at risk. Only 48% of mothers recognized epidemiologic risk factors (direct or indirect exposure to raw/undercooked meat or to cat excrement) or gestational illnesses that were compatible with acute acquired toxoplasmosis during pregnancy. CONCLUSION: Maternal risk factors or compatible illnesses were recognized in retrospect by fewer than one half of North American mothers of infants with toxoplasmosis. Educational programs might have prevented acquisition of Toxoplasma gondii by those mothers who had clear exposure risks. However, only systematic serologic screening of all pregnant women at prenatal visits or of all newborn infants at birth would prevent or detect a higher proportion of these congenital infections.     

Association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth

OBJECTIVE: To determine the association between congenital toxoplasmosis and preterm birth, low birthweight and small for gestational age birth. DESIGN: Multicentre prospective cohort study. SETTING: Ten European centres offering prenatal screening for toxoplasmosis. POPULATION: Deliveries after 23 weeks of gestation in 386 women with singleton pregnancies who seroconverted to toxoplasma infection before 20 weeks of gestation. Deliveries after 36 weeks in 234 women who seroconverted at 20 weeks or later, and tested positive before 37 weeks. METHODS: Comparison of infected and uninfected births, adjusted for parity and country of birth. MAIN OUTCOME MEASURES: Differences in gestational age at birth, birthweight and birthweight centile. RESULTS: Infected babies were born or delivered earlier than uninfected babies: the mean difference for seroconverters before 20 weeks was -5.4 days (95% CI: -1.4, -9.4), and at 20 weeks or more, -2.6 days (95% CI: -0.5, -4.7). Congenital infection was associated with an increased risk of preterm delivery when seroconversion occurred before 20 weeks (OR 4.71; 95% CI: 2.03, 10.9). No significant differences were detected for birthweight or birthweight centile. CONCLUSION: Babies with congenital toxoplasmosis were born earlier than uninfected babies but the mechanism leading to shorter length of gestation is unknown. Congenital infection could precipitate early delivery or prompt caesarean section or induction of delivery. We found no evidence for a significant association between congenital toxoplasmosis and reduced birthweight or small for gestational age birth.     

Too late prenatal diagnosis of fetal toxoplasmosis: a case report

OBJECTIVE: We describe a case of severe fetal hydrocephalus due to toxoplasmosis which could not be diagnosed until late gestational age due to the lack of a serologic surveillance program during pregnancy; moreover, this case points to the usefulness of molecular biology tools in the diagnostic process. Abnormal ultrasound in the 2nd trimester was noticed and Toxoplasma gondii was demonstrated in amniotic fluid at the 28th week of gestation both by PCR and by mice inoculation. Fansidar and folinic acid were administered. The newborn suffered from progressive hydrocephalus, seizures, and pathological muscular tonus; ultrasound examination showed massive cerebral calcifications. Ophthalmologic examination revealed bilateral choroidoretinitis. Congenital toxoplasmosis was confirmed by the detection of anti- T. gondii IgM and IgA in the neonatal serum. CONCLUSION: The presented case is an example of severe fetal toxoplasmosis diagnosed and treated in utero.     

Granulomatous villitis formed by inflammatory cells with maternal origin: a rare manifestation type of placental toxoplasmosis

We present a case of placental toxoplasmosis with granulomatous villitis. The patient was a 26-year-old gravida 1 female with the findings of intrauterine death at 16th week of gestation. The pregnancy was terminated. Pathological examination revealed an autolysed fetus and a placenta with necrotizing granulomas within the villous stroma. Encysted Toxoplasma gondii was rarely observed within the granulomas and serologic examination of the mother confirmed acute toxoplasmosis. A fluorocein in situ hybridization examination, using sex chromosome probes, revealed that the villous granulomas were formed by inflammatory cells, originated from the maternal immune system. In conclusion, T. gondii should be taken into consideration as a rare cause of placental granulomatous inflammation. To the best of our knowledge, this is the first case of granulomatous villitis due to toxoplasmosis, in which formation by maternal inflammatory cells has been demonstrated.     

Antenatal diagnosis of congenital toxoplasmosis: evaluation of the biological parameters in a cohort of 286 patients

Objective To evaluate the biological parameters obtained by cordocentesis and amniocentesis in the antenatal diagnosis of congenital toxoplasmosis.
Design Nine-year retrospective study.
Setting Parasitology Laboratory, Department of Obstetrics and Gynaecology and Department of Paediatrics, Centre Hospitalo-Universitaire, Montpellier, France.
Participants Two hundred and eighty-six pregnant women infected with toxoplasmosis between 7 and 34 weeks of gestation.
Methods Detection of abnormalities by ultrasound examination. Detection in fetal blood of Toxoplasma , of specific IgM and IgA and of nonspecific biological markers. Detection in amniotic fluid of Toxoplasma.
Results Out of 286 antenatal diagnoses, 211 were negative (1st group), 40 were positive (2nd group) and led to 8 medical abortions, and 35 were uncertain (3rd group). In the 1st and 3rd groups respectively, 7 (3.3 %) and 5 (14.3 %) cases of congenital toxoplasmosis were observed. Overall, 52 cases of congenital toxoplasmosis were detected: 12 were clinically apparent, 36 subclinical (of which 12 were in groups 1 and 3) and 4 were lost to follow up.
Conclusion There is substantial importance in making the diagnosis of toxoplasmosis antenatally in order to limit the number of medical abortions. In our series, the most accurate predictor was the detection of the fetal antibody response (specific IgM and IgA) to Toxoplasma.     

Serodiagnosis of toxoplasmosis developing during pregnancy and of congenital toxoplasmosis

During the first prenatal serodiagnosis of toxoplasmosis, the test must permit to differentiate between immunized and non-immunized patients and to screen recently contracted toxoplasmosis. In a group of 33 women affected with toxoplasmosis during pregnancy a critical study of serodiagnosis criteria is carried out by comparing the theoretical protocol of the evolution of the serology during acquired toxoplasmosis with the situations observed under usual prenatal monitoring. Seroconversion was noted in 26 women and the variability of the results emphasizes the difficulties in determining the date of the contamination when an evolutive form of toxoplasmosis is suspected at the first examination, which is the case in 7 other patients. In children, 11 congenital toxoplasmosis were diagnosed, all on laboratory examinations. It must be emphasized that 16 children were prematurely lost to follow-up. It should be necessary to devote our energies to screening and information in order to validate the protocol of prevention of congenital toxoplasmosis.     

Pure fetal blood samples obtained by cordocentesis: technical aspects of 322 cases

Three hundred and twenty-two percutaneous umbilical blood samplings were performed over 4 years in our prenatal diagnostic centre. A 3.5 MHz sector ultrasound transducer was used to guide a 22.5-gauge needle under local anaesthesia. Sampling was performed for rapid fetal karyotyping (within 72 h) in 120 cases, for diagnosis of fetal toxoplasmosis in 133 cases, for determination of the severity of Rh immunization in 15 cases, and for diagnosis of congenital rubella in 4 cases. Pure fetal blood was obtained in 98.7 per cent of the cases after two attempts. The approach to the cord was either transamniotic or transplacental. Puncturing was preferentially done at the placental insertion of the cord (72.2 per cent of the cases) and the mean blood sample volume was 3.5 ml. The rate of fetal death in utero was 1.9 per cent, including two cases of amnionitis, one trisomy 18, and one severe bradycardia. The failures were due to sampling at an early stage of pregnancy (before gestation week 18), to maternal obesity, oligohydramnios, and the inexperience of the operator.     

Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies

OBJECTIVE: This study was undertaken to estimate the cumulative risk of perinatal death associated with delivery at each gestational week both at term and post term. STUDY DESIGN: The numbers of antepartum stillbirths, intrapartum stillbirths, neonatal deaths, and surviving neonates delivered at between 37 and 43 weeks' gestation in Scotland, 1985-1996, were obtained from national databases (n = 700,878) after exclusion of multiple pregnancies and deaths caused by congenital abnormality. The numbers of deaths at each gestational week were related to appropriate denominators: antepartum stillbirths were related to ongoing pregnancies, intrapartum stillbirths were related to all births (excluding antepartum stillbirths), and neonatal deaths were related to live births. The cumulative probability of perinatal death associated with delivery at each gestational week was estimated by means of life-table analysis. RESULTS: The gestational week of delivery associated with the lowest cumulative risk of perinatal death was 38 weeks' gestation, whereas the perinatal mortality rate was lowest at 41 weeks' gestation. The risk of death increased more sharply among primigravid women after 38 weeks' gestation because of a greater risk of antepartum stillbirth. The relationships between risk of death and gestational age were similar for the periods 1985-1990 and 1991-1996. CONCLUSION: Delivery at 38 weeks' gestation was associated with the lowest risk of perinatal death.     

Rapid prenatal determination of fetal sex by polymerase chain reaction on amniocyte DNA.

Sex determination in early gestation is important for fetuses at risk for X-linked disorders or congenital adrenal hyperplasia. One hundred and seventy consecutive samples of amniocytes were collected between the 12th and 31st gestational week. Seven women received early amniocentesis before the 14th week. Fetal sex was determined by amplification of Y-specific DNA fragments within five hours. All results of the polymerase chain reaction, except for one false-negative, were compatible with cytogenetic analyses. Polymerase chain reaction of amniocyte DNA provides a rapid technique for sex determination in early gestation with high specificity and sensitivity.     

Postnatal therapy for congenital toxoplasmosis: a comparison of 2 different treatment approaches

Protocols recommended in the USA and Germany for the postnatal treatment of congenital toxoplasmosis are mainly based on the National Collaborative Chicago-based Congenital Toxoplasmosis Study that calls for daily administration of pyrimethamine in combination with sulfadiazine for several months, then 3 times a week. The recommended total duration of treatment is 12 months. This scheme necessitates frequent white blood cell counts that often result in the discontinuation of treatment because of severe neutropenia even with the concomitant administration of folinic acid. In contrast, the administration of pyrimethamine with sulfadoxine every 2 weeks for 2 years, as used by a referral centre in Toulouse, France, is associated with less toxicity. The efficacy may even be improved, as judged by the rate of new chorioretinal lesions. In the absence of larger randomised studies the Toulouse protocol appears to have several advantages when a decision has to be made to treat infants with congenital toxoplasmosis.     

Prenatal diagnosis using polymerase chain reaction on amniotic fluid for congenital toxoplasmosis

OBJECTIVE: To evaluate sensitivity, specificity, and predictive values of a prenatal amniotic fluid (AF) polymerase chain reaction (PCR) test for diagnosis of congenital toxoplasmosis. METHODS: A multicenter prospective study was done on 271 women with proved primary Toxoplasma infection during pregnancy and who had amniocentesis for prenatal diagnosis by PCR. Live-born infants were eligible for analysis only if a serologic follow-up could assess a definitive infection status. RESULTS: Of the 270 evaluable cases, 75 were congenitally infected, 48 of whom had a positive PCR at prenatal diagnosis. Overall sensitivity of PCR on AF was estimated at 64% (95% confidence interval [CI] 53.1%, 74.9%), negative predictive value of 87.8% (95% CI 83.5%, 92.1%), whereas specificity and positive predictive value were 100% (95% CIs 98%, 100% and 92.3%, 100%, respectively). Among cases with congenital toxoplasmosis, there were no significant differences between those with positive or negative PCR with regard to median gestational age at maternal infection, interval between maternal infection and amniocentesis, or duration of treatment before amniocentesis. However, sensitivity of PCR was found to be significantly higher for maternal infections that occurred between 17 and 21 weeks' gestation (P <.02). CONCLUSION: A negative PCR of AF cannot rule out congenital infection. In this case, continuation of treatment with spiramycin combined with ultrasonographic follow-up and postnatal follow-up are warranted. Our results also suggest presumptive treatment combining pyrimethamine and sulfonamides in case of maternal infection occurring late in pregnancy.     

Congenital hereditary hypothyroidism--prenatal diagnosis and treatment

Intrauterine diagnosis of congenital hypothyroidism was established on the basis of TSH concentration in amniotic fluid in the 22nd week of gestation for the offspring of a couple both known to have an iodide organification defect. Prenatal treatment consisted of intramniotic injections of 500 mcg Na-1-thyroxine, which was administered from the first amniocentesis until one week before delivery. Following delivery, the diagnosis was confirmed by the elevated level of TSH, 60.5 uU/ml, and a gradual decrease of fT4 to 0.8 ng/ml. Regular substitution therapy was commenced on the third day of life. The normal shape and location of the thyroid gland was demonstrated by Technetium scintiscan. At 18 months the infant revealed no significant deviation from normalcy in growth or mental capacity. This experience indicates that testing of amniotic fluid for TSH in the 22nd week of gestation can be diagnostic for congenital primary hypothyroidism. Furthermore, it is suggested that the treatment approach described is warranted in all cases in which there is a high risk of congenital primary hypothyroidism.     

Treatment and results of chronic toxoplasmosis. Analysis of 33 cases.

Women who grew up in Turkey, where undercooked meat is part of the usual diet, have an increased risk of toxoplasmosis. This study covers treatment and prognosis of 33 cases with chronic toxoplasmosis. The study group was selected among the patients with a history of repeated abortions, recurrent preterm labor, stillbirths and babies with congenital anomaly after all other causative reasons were ruled out. IgG and IgM antibody titers were detected by Sabin-Feldman's dye test and indirect fluorescence antibody test. 33 patients, who had negative IgM and IgG antibody titers above 1/64, were accepted as having chronic toxoplasmosis and were included in our study group. These patients were treated with our pyrimethamine treatment protocol (Din?er Formula) for 36 days before their pregnancies. IgG antibody titers were repeated in the 8th and the 20th week of pregnancy. With the exception of 7 cases, 24 patients (72.7%) still had IgG antibody titers of more than 1/64 and were given the same treatment protocol in the 8th week of pregnancy. Very early abortions occurred in 2 cases. Of 24 patients, 8 had antibody titers still above 1/64 and were treated with spiramycine. While 28 cases (84.8%) had healthy and living infants, pregnancies of 3 cases are still continuing. No teratogenic effects of pyrimethamine on the fetuses were seen. As a result, we can say that a patient who presents with complaints of repeated abortions, recurrent preterm labor or stillbirth should be investigated for toxoplasmosis during pregnancy; even if the IgG antibody test is normal before pregnancy, she should be treated with the protocol mentioned above before pregnancy and in the 8th week of pregnancy when chronic toxoplasmosis is diagnosed.     

Maternal serologic screening for toxoplasmosis

Congenital toxoplasmosis is a rare, but potentially serious, problem during pregnancy. Toxoplasmosis is caused by a protozoal parasite that can be found in warm-blooded animals (including humans); dried cat feces, contaminated soil, or contaminated water; and raw or undercooked meat containing infective tissue cysts. Although cats play a role in the epidemiology of the disease, there is no statistical correlation between toxoplasmosis infection and cat ownership. Toxoplasmosis can be transmitted to the fetus in utero through transplacental transmission. Both the incidence of placental transmission and severity of congenital disease depend on gestational age at which maternal seroconversion occurs. Although transmission rates from mother to fetus tend to be low early in pregnancy, fetal disease severity is highest when the fetus is infected early in gestation. Serological tests to determine maternal seroconversion are available, but their use can pose ethical and practical dilemmas. Universal maternal screening is not currently warranted in the United States because disease prevalence is low.     

Congenital acquired immunodeficiency syndrome and congenital toxoplasmosis: pathologic support for a chronology of events

We report a case of congenital acquired immunodeficiency syndrome (AIDS) with congenital opportunistic toxoplasmosis. The thymic histopathology was that seen in childhood AIDS cases and not that seen in primary congenital toxoplasmosis. The toxoplasma infection was selectively localized to the brain and the serum titers were paradoxically low as reported in most adult cases of AIDS with secondary infection by the parasite. These findings strongly suggest that the infection by the human immunodeficiency virus (HIV) preceded the toxoplasma infection in the fetus.     

Congenital toxoplasmosis: a review

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. In the United States, approximately 85% of women of childbearing age are susceptible to acute infection with T. gondii. Acute infections in pregnant women may cause serious health problems when the organism is transmitted to the fetus (congenital toxoplasmosis), including mental retardation, seizures, blindness, and death. An estimated 400 to 4000 cases of congenital toxoplasmosis occur in the U.S. each year. Manifestations of congenital toxoplasmosis may not become apparent until the second or third decade of life. Serologic tests are used to diagnose acute infection in pregnant women, but false-positive tests occur frequently, therefore, serologic diagnosis must be confirmed at a reference laboratory before treatment with potentially toxic drugs should be considered. Much of congenital toxoplasmosis can be prevented by educating women of childbearing age and pregnant women to avoid eating raw or undercooked meat, to avoid cross-contamination of other foods with raw or undercooked meat, and to use proper cat-litter and soil-related hygiene.     

Fetal toxoplasmosis and negative amniocentesis: necessity of an ultrasound follow-up

Prenatal diagnosis of congenital toxoplasmosis relies on the PCR test on amniotic fluid and ultrasound follow-up of the fetus. We report two cases of toxoplasma infection during the first trimester of gestation with a discrepant diagnosis of fetal infection. PCR performed more than four weeks after the estimated date of contamination was negative. Ultrasound follow-up was normal up to the third trimester when major hydrocephalus was detected, leading to pregnancy termination. In both cases, post-mortem examination revealed a diffuse infection with severe brain lesions. These observations confirm the necessity to continue a monthly ultrasound follow-up, even if amniocentesis is negative, in case of fetal toxoplasma infection in pregnancy.     

Results of a preventive program for congenital toxoplasmosis

All pregnant women followed during the period 1982-87 were screened for toxoplasmosis, and 35 patients had documented seroconversion or doubtful toxoplasmosis titers. One patient opted for pregnancy termination. The remaining were followed with a protocol that included serial ultrasound examinations and prophylactic antibiotic treatment of the mother and neonate. No fetal abnormalities related to congenital toxoplasmosis were found. All the infants had negative toxoplasmosis test titers at birth; at follow-up only one was found to have developed a subclinical infection, at 2 months of age. Our data suggest that antiparasitic treatment during pregnancy for those at risk for Toxoplasma infection may reduce the transmission rate.     

Prenatal diagnosis of congenital toxoplasmosis: a multicenter evaluation of different diagnostic parameters.

OBJECTIVE: Our purpose was to evaluate different methods of diagnosing congenital toxoplasmosis prenatally by amniocentesis and cordocentesis. STUDY DESIGN: In a retrospective multicenter study, we investigated consecutive women who had seroconversion for Toxoplasma gondii during pregnancy and who underwent either amniocentesis or cordocentesis or both to obtain a prenatal diagnosis of fetal toxoplasmosis. Data were obtained from 122 patients recruited in 6 different European Toxoplasma reference centers. Infants born to these mothers were followed up until 1 year of age to confirm or exclude congenital toxoplasmosis. Sensitivity, specificity, positive predictive value, and negative predictive value were measured for the following parameters: (1) detection of the parasite in amniotic fluid by mouse inoculation, (2) detection of the parasite in amniotic fluid by in vitro cell culture, (3) detection of Toxoplasma deoxyribonucleic acid in amniotic fluid by a polymerase chain reaction assay, (4) detection of the parasite in fetal blood by mouse inoculation, (5) detection of specific immunoglobulin M antibodies in fetal blood, and (6) detection of specific immunoglobulin A antibodies in fetal blood. RESULTS: The polymerase chain reaction test performed on amniotic fluid had the highest level of sensitivity (81%) and also a high level of specificity (96%). The combination of the polymerase chain reaction test and mouse inoculation of amniotic fluid increased sensitivity to 91%. The sensitivity of immunoglobulins M and A in fetal blood was 47% and 38%, respectively. In congenitally infected fetuses a negative correlation was observed between positive serologic parameters and gestational age at the time of maternal infection and at prenatal diagnosis. CONCLUSION: Congenital toxoplasmosis is best predicted by prenatal examination with the combination of T gondii polymerase chain reaction and mouse inoculation of amniotic fluid. The role of cordocentesis in the diagnosis of congenital toxoplasmosis is limited.     

Prediction of congenital toxoplasmosis by polymerase chain reaction analysis of amniotic fluid

OBJECTIVE: To determine the accuracy of polymerase chain reaction (PCR) analysis of amniotic fluid for fetal toxoplasmosis according to clinical predictors of outcome and study centre. DESIGN: Prospective cohort study. SETTING: Nine European centres. POPULATION: Women with suspected toxoplasma infection identified by prenatal screening. METHODS: Logistic regression was used to examine the effects of gestational age at maternal seroconversion, treatment and timing of amniocentesis, on PCR accuracy, and to calculate the post-test probability of congenital toxoplasmosis. MAIN OUTCOME MEASURES: Infants had congenital toxoplasmosis if specific IgG persisted beyond 11.5 months. Uninfected infants had undetectable IgG in the absence of anti-toxoplasma treatment. RESULTS: Of 593 PCR results, 64 were positive (57 confirmed infected), and 529 were negative (23 confirmed infected). The likelihood ratio for a positive PCR result decreased significantly with trimester at seroconversion, but did not change significantly for a negative result. Weak associations were detected between sensitivity and, inversely, with specificity, and gestational age at maternal seroconversion. There was no significant association between sensitivity and centre, type or duration of treatment, or timing of amniocentesis. Specificity differed significantly between centres (P < 0.001). The change in pre- to post-test probability of infection was maximal for a positive PCR after first trimester seroconversion, affecting 1% of women tested, and a negative PCR after third trimester seroconversion, affecting half the women tested. CONCLUSIONS: Prediction of the risk of congenital toxoplasmosis should combine estimates of test accuracy and maternal-fetal transmission, which take account of the gestational age at which the mother seroconverted. Local laboratory standards will affect the generalisability of these results.