Congenital toxoplasmosis in Austria: Prenatal screening for prevention is cost-saving.

BACKGROUND: Primary infection of Toxoplasma gondii during pregnancy can be transmitted to the unborn child and may have serious consequences, including retinochoroiditis, hydrocephaly, cerebral calcifications, encephalitis, splenomegaly, hearing loss, blindness, and death. Austria, a country with moderate seroprevalence, instituted mandatory prenatal screening for toxoplasma infection to minimize the effects of congenital transmission. This work compares the societal costs of congenital toxoplasmosis under the Austrian national prenatal screening program with the societal costs that would have occurred in a No-Screening scenario. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively investigated data from the Austrian Toxoplasmosis Register for birth cohorts from 1992 to 2008, including pediatric long-term follow-up until May 2013. We constructed a decision-analytic model to compare lifetime societal costs of prenatal screening with lifetime societal costs estimated in a No-Screening scenario. We included costs of treatment, lifetime care, accommodation of injuries, loss of life, and lost earnings that would have occurred in a No-Screening scenario and compared them with the actual costs of screening, treatment, lifetime care, accommodation, loss of life, and lost earnings. We replicated that analysis excluding loss of life and lost earnings to estimate the budgetary impact alone. Our model calculated total lifetime costs of €103 per birth under prenatal screening as carried out in Austria, saving €323 per birth compared with No-Screening. Without screening and treatment, lifetime societal costs for all affected children would have been €35 million per year; the implementation costs of the Austrian program are less than €2 million per year. Calculating only the budgetary impact, the national program was still cost-saving by more than €15 million per year and saved €258 million in 17 years. CONCLUSIONS/SIGNIFICANCE: Cost savings under a national program of prenatal screening for toxoplasma infection and treatment are outstanding. Our results are of relevance for health care providers by supplying economic data based on a unique national dataset including long-term follow-up of affected infants.

Placental pathologies on fetal MRI are associated with high impairment rates: a prospective long-term outcome study.

OBJECTIVE: Placental anomalies visualized at midgestation by MRI are shown to be related to pregnancy outcome. We performed a prospective cohort study to investigate the influence of placental pathologies diagnosed with fetal MRI on long-term neurodevelopmental outcome. METHODS: In our hospital-based, cross-sectional study, all fetal MRI examinations of pregnancies with vascular placental pathology (i.e. infarction with/without hemorrhage, subchorionic thrombi/hemorrhages, intervillous thrombi/hemorrhages or retroplacental hematoma) between 2003 and 2007 were included. The extent of the pathology was expressed as the percentage of abnormality related to the whole placental volume. Pathohistological reports were correlated to MRI findings. Infants were prospectively investigated using Bayley developmental scales at the age of 2-3.5 years. Impairment was categorized as a Bayley scale two SDs below normal (<85 points). RESULTS: There were 31 singletons and 25 offspring of multiple pregnancies included in the analyses. Impairment rates were 32.2% in singletons and 32.0% in multiple births. No correlation between neuro/motor developmental outcome at 2-3.5 years and the type, extent or gestational week at the time of diagnoses of placental vascular pathologies was found. CONCLUSION: The long-term outcome of children with vascular placental pathologies on fetal MRI was associated with a high impairment rate after 2-3.5 years, both on motor- and neurodevelopmental Bayley scales. Neurological impairment did not correlate with the extent of placental involvement, intrauterine growth restriction, gestational age at birth or multiple state.

The Austrian Toxoplasmosis Register, 1992-2008.

BACKGROUND: We aimed to determine the incidence of primary gestational infections with Toxoplasma gondii and congenital toxoplasmosis in Austria, a country with a nationwide prenatal serological screening program since 1974. METHODS: We analyzed retrospective data from the Austrian Toxoplasmosis Register of pregnant women with Toxoplasma infection and their offspring with births between 1992 and 2008, identified by the prenatal mandatory screening program. Treatment was administered to women from diagnosis of a Toxoplasma infection until delivery. Infected infants were treated up to 1 year of life routinely. Clinical manifestations in infected infants were monitored at least for 1 year and documented in the register. RESULTS: The Austrian Toxoplasmosis Register included 2147 pregnant women with suspected Toxoplasma infection. Annually, 8.5 per 10 000 women acquired Toxoplasma infection during pregnancy, and 1.0 per 10 000 infants had congenital toxoplasmosis (13% mean transmission rate). Our data showed that women treated according to the Austrian scheme had a 6-fold decrease in the maternofetal transmission rate compared to women without treatment. CONCLUSIONS: Results from the Austrian Toxoplasmosis Register show the efficiency of the prenatal screening program. Our results are of clinical relevance for infants, healthcare systems, and policy makers to consider preventive Toxoplasma screening as a potential tool to reduce the incidence of congenital toxoplasmosis.

Less invasive surfactant administration in extremely preterm infants: impact on mortality and morbidity.

BACKGROUND: A new mode of surfactant administration without intubation - less invasive surfactant administration (LISA) - has recently been described for premature infants. OBJECTIVE: We report single-center outcome data of extremely premature infants who have been managed by LISA in our department. Mortality and morbidity rates of the cohort were compared to historical controls from our own center and to data of the Vermont-Oxford Neonatal Network (VONN). PATIENTS AND METHODS: All infants born at 23-27 weeks' gestational age during 01/2009 and 06/2011 (n = 224) were managed by LISA and included in the study group. RESULTS: LISA was tolerated by 94% of all infants. 68% of infants stayed on continuous positive airway pressure on day 3. The rate of mechanical ventilation was 35% within the first week and 59% during the entire hospital stay. Compared to historical controls, we found significantly higher survival rates (75.8 vs. 64.1%) and significantly less intraventricular hemorrhage (IVH) (28.1 vs. 45.9%), severe IVH (13.1 vs. 23.9%) and cystic periventricular leukomalacia (1.2 vs. 5.6%); only persistent ductus arteriousus (PDA) (74.7 vs. 52.6%) and retinopathy of prematurity (ROP) (40.5 vs. 21.1%) occurred significantly more often. Compared to VONN data, we found significantly less chronic lung disease (20.6 vs. 46.4%), severe cerebral lesions (IVH 3/4 + cystic PVL; 9.4 vs. 16.1%) and ROP (all grades) (40.5 vs. 56.5%); only PDA (74.7 vs. 63.1%) and severe ROP (> grade 2) (24.1 vs. 14.1%) occurred significantly more often in our cohort. CONCLUSION: Surfactant can be effectively and safely delivered via LISA and this is associated with low rates of mechanical ventilation and various adverse outcomes in extremely premature infants.

Evaluation of serological prenatal screening to detect Toxoplasma gondii infections in Austria.

BACKGROUND: In Austria, a nationally mandated prenatal serological congenital toxoplasmosis screening program was introduced in 1974 in response to a high incidence of 7.8 per 1,000 infected infants. Maternal prenatal recognition of acute gestational infection and early treatment of infants with congenital infection are important because prenatal and accurate postnatal antibiotic therapy improves the outcomes of infected infants. OBJECTIVE: To determine the impact of additional maternal and/or fetal cord blood serology at birth on improving current prenatal maternal screening in detecting congenital toxoplasmosis. METHODS: In this prospective observational study, 5,545 consecutive women were included over a 19-month period. Routine prenatal maternal toxoplasmosis serology screening was performed along with additional cord blood serology screening at delivery. Fetal cord blood serology included Sabin-Feldman dye and IgM immunosorbent agglutination assay testing. RESULTS: Based on the initial prenatal maternal screening serology results, there was evidence of a prior chronic infection manifest in 1,830 (33.0%) women and 3,708 (66.9%) were not infected. Seven (0.13%) were diagnosed with acute toxoplasma infection based on seroconversion. Of these, 4 manifested transmission, and 3 did not. Of the seven infected women, routine prenatal maternal screening identified acute infection in only 2 of the women, 1 of whom had an infected fetus with abnormal prenatal ultrasound. Fetal cord blood serology screening identified an additional 5 women, 3 with infected fetuses. CONCLUSIONS: Identification of Toxoplasma gondii infection by prenatal maternal serological testing is significantly improved by the addition of maternal and/or fetal serological testing at birth.

Evaluation of the liaison automated testing system for diagnosis of congenital toxoplasmosis.

Congenital toxoplasmosis is a worldwide health problem, and different screening strategies exist. Testing of toxoplasma-specific antibodies in infants identifies congenital toxoplasmosis during the first year of life. However, experience with commercial available immunoassays is limited. The aim of this study was to evaluate both the performance and analytical characteristics of the Liaison diagnostic system in infants. In a retrospective study, serum Toxoplasma gondii antibodies were measured in samples from 333 infants, including 212 noninfected infants and 121 infants with congenital toxoplasmosis. A total of 1,157 umbilical cord blood and peripheral serum samples were analyzed. Liaison toxoplasma-specific IgG and IgM antibodies and the IgG avidity index were compared to the infection status of the infant, determined by the Sabin-Feldman dye test and immunosorbent agglutination assay--IgM. All noninfected infants were seronegative by Liaison IgG within the first year of life. The Liaison system showed a sensitivity of 81.8%, a specificity of 100.0%, a positive predictive value of 100.0%, a negative predictive value of 90.6%, and overall agreement of 84.4% by comparison with the dye test. Overall agreement of both IgM test systems was 96.0%. In this study cohort, avidity did not show a potential diagnostic benefit for the detection of congenital infection. In conclusion, the Liaison system is a valuable tool to monitor the serologic course of infants at risk. A final serologic confirmatory test is recommended to improve the rate of detection of congenital toxoplasmosis at 1 year of life. Protocols of routine follow-up testing in infants and accurate diagnostic tools after acute gestational infections are needed to improve medical care.

Tetanus immunity in neonates in a developed country.

OBJECTIVE: In consideration of comprehensive and well-established vaccination programmes in industrialized countries, it is expected that immunity against tetanus among expectant mothers and their offspring is complete. Our study evaluated seroprotection against tetanus among newborns in Austria, who may gain passive immunity by transplacental transfer of maternal tetanus antibody. METHODS: Cord blood samples from 99 deliveries were analyzed for antibody concentration against tetanus toxoid by standardized ELISA. RESULTS: 85/99 (85.8%) individuals presented with levels of tetanus immunity having a protective antibody concentration ≥0.1 IU/ml. 9/99 (9.1%) samples showed low seropositivity, while in 5/99 (5.1%) samples no tetanus antibodies could be detected. The median antibody concentration was 0.95 IU/ml. CONCLUSIONS: Our data provide evidence for a lack of adequate tetanus immunity in 14.2% of newborns delivered in an Austrian University Hospital. This investigation is emphasizing the importance of stringent regimens concerning prenatal vaccination care, even in countries with generalized immunization programs. If indicated, maternal immunization during pregnancy should be initiated for protection of newborns.

Evaluation of the Roche Elecsys Toxo IgG and IgM electrochemiluminescence immunoassay for the detection of gestational Toxoplasma infection.

Unidentified gestational infection with Toxoplasma gondii may lead to fetal infection with severe complications later in childhood. Because diagnosis of maternal infection solely depends on serology, routine tests with high sensitivity and specificity are required. In this study, the new Roche Elecsys Toxo IgG and IgM immunoassay was compared with Sabin-Feldman dye test and immunosorbent agglutination assay-IgM as reference test. Serum samples were analyzed from 927 pregnant women, including 100 negative, 706 chronic, and 121 acute infections. The combination of both Elecsys IgG and IgM assays demonstrated high sensitivity and specificity of 97.1% and 100.0%, respectively, and a positive and negative predictive value of 100.0% and 81.3%, respectively. The Elecsys assay is a useful tool as a first-line screening method to detect gestational infections. However, if gestational infection is assumed, confirmatory testing by a reference laboratory might be necessary to discriminate between pre- and postconceptional infection to start antiparasitic treatment to avoid mother-to-fetus transmission and severe sequelae.

Quantitative real-time polymerase chain reaction for the accurate detection of Toxoplasma gondii in amniotic fluid.

Infection with Toxoplasma gondii during pregnancy is often asymptomatic and may cause severe fetal damage. A quantitative TaqMan minor groove binder real-time polymerase chain reaction (PCR) assay was developed for the specific and sensitive detection of the previously described 529-bp repeat element occurring up to 200 to 300 times in T. gondii genome. The qualitative and quantitative detection limits determined were 6 and 20 marker copies (1/30 to 1/50 of 1 parasite) per PCR, respectively. In addition to standard PCR cycling conditions, 3 different fast PCR protocols were evaluated to minimize run time. A higher variability but no loss of specificity was observed. For the evaluation of clinical applicability, a total of 135 amniotic fluid samples were analyzed targeting both 529-bp and B1 gene. The sensitivity and specificity were 88.0% and 100.0% for B1, and 100.0% and 98.2% for 529-bp PCR assay (positive predictive value and negative predictive value: 100.0% and 97.4%, and 92.6% and 100.0%, respectively). Our results demonstrated an increased sensitivity of the 529-bp PCR assay even in a faster protocol.

Evaluation of the Vitros ECiQ immunodiagnostic system for detection of anti-Toxoplasma immunoglobulin G and immunoglobulin M antibodies for confirmatory testing for acute Toxoplasma gondii infection in pregnant women.

Infection with Toxoplasma gondii is often asymptomatic and, when acquired during pregnancy, may lead to connatal toxoplasmosis in the offspring. The newly introduced Vitros anti-Toxoplasma immunoglobulin G (IgG) and IgM assays, designed for the Vitros ECiQ immunodiagnostic system, a fully automated system based on chemiluminescence, were evaluated as a screening method for the serological detection of acute and chronic Toxoplasma infections in the sera of 719 pregnant women. The combination of the Vitros IgG and IgM assays demonstrated a sensitivity and a specificity of 100% for the successful detection of all acute T. gondii infections by comparison with the Sabin-Feldman dye test as the reference test. The Vitros IgG assay parameter revealed a sensitivity of 95.0%, a specificity of 100.0%, a positive predictive value of 100.0%, a negative predictive value of 86.2%, and an overall agreement of 96.2% by comparison with the dye test. Comparison of the Vitros Toxoplasma IgM assay with the immunosorbent agglutination assay yielded values of 77.1%, 99.0%, 97.7%, 88.5%, and 91.1%, respectively. Subsequent receiver operating characteristic curve analysis for the accurate detection of Toxoplasma IgM in acute (n = 90) and chronic (n = 461) infections demonstrated high sensitivity (92.2%) and specificity (81.6%). The combination of a Toxoplasma-specific IgG assay with specific IgM antibody detection has improved the diagnosis of T. gondii infection by decreasing follow-up testing. Nonetheless, positive Toxoplasma IgM test results during pregnancy necessitate confirmatory testing by a reference laboratory to ensure fast and, above all, accurate test results.

Characterization and differentiation of iron status in anemic very low birth weight infants using a diagnostic nomogram.

BACKGROUND: In the early weeks of life, very low birth weight (VLBW) infants experience intense laboratory blood sampling leading to clinically significant anemia and the need for red blood cell transfusion. Although controversial, treatment with recombinant human erythropoietin (EPO) and iron has been recommended to stimulate erythropoiesis; optimal dosing of EPO and iron is still uncertain. OBJECTIVES: To assess the validity of a four-quadrant diagnostic plot of iron availability (ferritin index) versus iron demand for erythropoiesis (reticulocyte hemoglobin content, CHr) for differentiating iron status in anemic VLBW infants. METHODS: Study subjects were enrolled in a previously reported randomized controlled trial of clinically stable VLBW infants <31 weeks' gestation and <1,300 g at birth to receive 18 days of treatment with: group 1: oral iron; group 2: EPO + oral iron, and group 3: EPO + intravenous + oral iron. RESULTS: At the end of treatment the ferritin index was significantly higher in both EPO groups compared to the control group. By day 18, CHr of the control group declined into the quadrant of the diagnostic plot characteristic of functional iron deficiency and anemia of chronic disease. Both EPO groups ended in the quadrants that are characteristic for latent iron deficiency and iron deficiency anemia, respectively. CONCLUSIONS: The diagnostic plot for differentiating anemia in VLBW infants may be an informative, clinically useful tool for iron status assessment under different physiologic and therapeutic erythropoietic states. Larger additional studies in difficult patient populations are needed before the clinical utility of this diagnostic procedure can be unequivocally confirmed.

Knowledge-based generation of diagnostic hypotheses and therapy recommendations for toxoplasma infections in pregnancy.

Primary infection of pregnant women with the parasite Toxoplasma gondii results in infections of the unborn by transplacental transmission in about 50% of the cases. The degree of possible damage depends on the duration of parasitical impact on fetal tissues. The web-based software system ToxoNet processes the results of serological antibody tests performed during pregnancy by means of a knowledge base containing medical knowledge on the interpretation of toxoplasmosis serology findings. For this purpose, it matches the results of all serological investigations of maternal blood with the content of the knowledge base and generates interpretive reports consisting of a diagnostic hypothesis, recommendations for therapy, and proposals for further investigations. Fuzzy sets are used to formalize certain intervals between subsequent investigations to take the varying immune responses of individual patients into account. In a retrospective study, ToxoNet classified 100% of the trivial serological cases and about 87.8% of the more complex cases correctly. ToxoNet comprises a knowledge base, a system for interpretation, and a knowledge acquisition and modification program. It is available on the WWW by accessing a medical knowledge-base server via standard browsers.

Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling.

The impaired infection control related to the functional immaturity of the neonatal immune system is an important cause of infection in preterm newborns. We previously reported that constitutive Toll-like receptor (TLR) 4 expression and cytokine secretion on lipopolysaccharide (LPS) stimulation increases with gestational age. Here, we analyzed constitutive monocyte TLR2 expression and evaluated the expression profiles of the proximal downstream adapter molecule myeloid differentiation factor 88 (MyD88). We further investigated activation of protein kinases p38 and extracellular regulated kinsase (ERK) 1/2 in CD14 monocytes after ex vivo stimulation with bacterial TLR ligands (LPS and lipoteichoic acid [LTA]). The functional outcome of the stimulation was determined by cytokine secretion. Monocytes from 31 preterm newborns (<30 weeks of gestation, n=16; 30-37 weeks of gestation, n=15), 10 term newborns, and 12 adults were investigated. In contrast to TLR4 expression, TLR2 levels did not differ between age groups. However, MyD88 levels were significantly lower in preterm newborns. Activation of p38 and ERK1/2 was impaired in all newborn age groups after stimulation with TLR-specific ligands. Accordingly, after LTA stimulation, the levels of interleukin (IL)-1 beta , IL-6, and IL-8 cytokine production were substantially lower (P<.001) in preterm newborns than in adults. The reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose premature newborns to bacterial infection.

Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging.

Premature newborns are highly susceptible to severe bacterial infections. This is partially due to their immature innate immune system, characterized by decreased neutrophil and monocyte activity as well as by reduced concentrations of complement factors. However, additional mechanisms might be important for innate immunity and are still the subject of considerable debate. The importance of pattern recognition domains such as Toll-like receptors (TLR) has been fully acknowledged within the last few years. Therefore, we investigated age-related monocyte TLR4 expression and lipopolysaccharide-induced cytokine secretion from very low birth weight infants (VLBWI) and from newborns after wk 30 of gestation in comparison to healthy adults. In VLBWI, expression of TLR4 surface protein, detected by flow cytometry, and TLR4-specific mRNA, quantified by real time-PCR, were significantly reduced in comparison to mature infants and to adults. Reduced TLR4 expression was paralleled by significantly diminished ex vivo LPS stimulated IL-1beta, IL-6, and tumor necrosis factor-alpha secretion into whole blood. We conclude that, in VLBWI, the minimized expression of TLR4 contributes to the susceptibility of VLBWI to infections with Gram-negative bacteria due to the lack of cytokines to boost initial immune response.

Is the use of early nasal CPAP associated with lower rates of chronic lung disease and retinopathy of prematurity? Nine years of experience with the Vermont Oxford Neonatal Network.

OBJECTIVE: The neonatal regional tertiary care center of the University of Vienna (VC) has been a member of the Vermont Oxford Neonatal Network (VONN) since 1994. During the period 1994--2002, important differences between the VC and the VONN in both pre- and postnatal management and in late morbidities such as chronic lung disease (CLD) and severe retinopathy of prematurity (ROP) were observed. We hypothesize that stabilization of very-low-birth-weight (VLBW) infants on nasal continuous positive airway pressure (NCPAP) immediately after birth, combined with a restrictive use of artificial ventilation, might be responsible for lower rates of CLD and ROP. PATIENTS AND METHODS: Obstetric and neonatal data for all 1299 VLBW infants (401-1500 g) from the VC were compared with corresponding data for the 201,167 VLBW infants from the VONN for the period 1994--2002 with regard to respiratory management and patient outcome. Morbidity criteria were in accordance with VONN definitions. RESULTS: The percentage range for treatment and morbidity criteria for the VC and VONN are related to differences among various years within the observation period. Infants were stabilized at birth on NCPAP in 45-86% of cases in the VC vs. 37-63% in the VONN, the rate of mechanical ventilation was 40-59% vs. 66-74%, and use of surfactant was 31-50% vs. 55-64%. CLD was diagnosed in 14-32% of cases in the VC vs. 27-39% in the VONN, discharge on supplemental oxygen took place in 2-4% vs. 12-17% of cases and ROP (stages III and IV) was found in 1-10% vs. 8-12%. CONCLUSION: The association of lower rates of CLD and ROP in the VC compared to the VONN might be related to differences in early respiratory management of VLBW infants at high risk of development of respiratory distress syndrome. This needs to be confirmed in a large multicenter trial.

Knowledge-based computer-aided decision support in prenatal toxoplasmosis screening (TempToxopert).

The development of TempToxopert aimed at assisting clinicians in analysing the results of prenatal toxoplasmosis screening tests. Expert knowledge about diagnostics, screening strategies, and treatment of toxoplasmosis during pregnancy was collected and represented as a rule-based decision graph. Based on actual and past individual findings, the system generates case-specific interpretative reports consisting of a diagnostic hypothesis, recommendations for further treatment, and interpretations of specific test results.

Association between prenatal treatment and clinical manifestations of congenital toxoplasmosis in infancy: a cohort study in 13 European centres.

AIM: To determine the effectiveness of prenatal treatment for clinical manifestations of congenital toxoplasmosis. METHODS: We prospectively identified 255 live-born infants with congenital toxoplasmosis using prenatal or neonatal screening. We determined the effect of prenatal treatment on the risks of intracranial or ocular lesions in infancy, accounting for gestational age at maternal seroconversion. RESULTS: Prenatal treatment within 4 wk of seroconversion reduced the risk of intracranial lesions compared with no treatment (odds ratio, OR 0.28; 95% CI: 0.08-0.75), but there was no significant effect when initiated after 4 wk (OR 0.76; 95% CI: 0.35-1.59; overall p-value 0.19). Compared to spiramycin alone, no treatment doubled the risk of intracranial lesions (OR 2.33; 95% CI: 1.04-5.50), but the risk did not differ with pyrimethamine-sulphonamide treatment (overall p-value 0.52). There was no consistent relationship between the type or timing of treatment and the risk of ocular lesions. Gestational age at maternal seroconversion was inversely associated with the risk of intracranial but not ocular lesions. CONCLUSION: Only early versus no prenatal treatment for intracranial lesions showed a statistically significant benefit. A large randomized controlled trial and/or meta-analysis of individual patient data from cohort studies is required to confirm these findings.