Nadia Gussetti

Early Primary Cytomegalovirus Infection in Pregnancy: Maternal Hyperimmunoglobulin Therapy Improves Outcomes Among Infants at 1 Year of Age

BACKGROUND Primary cytomegalovirus (CMV) infection during pregnancy is the leading infectious cause of congenital neurological disabilities. Early CMV infection carries a higher risk of adverse neonatal outcome (sensorineural hearing loss or neurological deficits). Intravenous hyperimmunoglobulin (HIG) therapy seems to be promising, but its efficacy needs further investigation. METHODS Since 2002, we have enrolled consecutively all pregnant women with early (ie, before gestational week 17) CMV infection. Beginning in 2007, all women were offered treatment with HIG (200 UI per kilogram of maternal weight, in a single intravenous administration). Outcome of infants was evaluated at the age of 1 year. RESULTS Of the 592 women with early primary CMV infection, amniocentesis for CMV DNA detection was performed for 446. Of the 92 CMV-positive fetuses, pregnancy was terminated for 24, HIG was administered to mothers of 31, and no treatment was received by mothers of 37. Fetuses of treated mothers did not differ from fetuses of nontreated mothers according to mothers age, gestational week of infection, CMV load, or detection of abnormal ultrasonography findings. At the 1-year evaluation, 4 of 31 infants with treated mothers (13%; 95% confidence interval [CI], 1%-25%) and 16 of 37 infants with nontreated mothers (43%; 95% CI, 27%-59%) presented with poor outcomes (P < .01, by the 2-tailed Fisher exact test). CONCLUSIONS HIG treatment improved the outcome of fetuses from women who had primary CMV infection before gestational week 17.

High Cytomegalovirus (CMV) DNAemia Predicts CMV Sequelae in Asymptomatic Congenitally Infected Newborns Born to Women With Primary Infection During Pregnancy

OBJECTIVE We investigated the kinetics of cytomegalovirus (CMV) clearance in blood and urine and the relationship between the viral load in blood at birth and the development of late-onset sequelae in asymptomatic congenital CMV infection. METHODS Thirty-three newborns with congenital asymptomatic CMV infection born to women with primary CMV infection during pregnancy were enrolled. CMV infection was monitored by polymerase chain reaction analysis of blood and urine. The follow-up examination was concluded at 6 years of age. RESULTS Ten infants developed postnatal sequelae, whereas twenty-three infants remained asymptomatic. Fifty percent of babies cleared CMV in blood and urine within 3 and 36 months, respectively. Logistic multivariate regression revealed that the risk of neonatal clinical disease crossed the level of 50% with a DNAemia at birth of ≥ 12,000 copies/mL (P = .0002). The risk of hearing deficit crossed the level of 50% with a DNAemia at birth of ≥ 17,000 copies/mL (P = .0001). No significant difference was found between the kinetics of CMV clearance in asymptomatic children as compared to babies with late-onset disease. CONCLUSIONS Asymptomatic newborns with a CMV DNAemia at birth of ≥ 12,000 copies/mL were more likely to experience CMV-related sequelae. The risk of hearing deficit increased with a viral load in blood of ≥ 17,000 copies/mL.

Strong Cell-Mediated Immune Response to Human Cytomegalovirus Is Associated With Increased Risk of Fetal Infection in Primarily Infected Pregnant Women

BACKGROUND Human cytomegalovirus (CMV) represents one of the leading causes of congenital infections worldwide. Early diagnosis of fetal infection and consequent rapid therapeutic intervention with immunoglobulin treatment may prevent fetal transmission and virus-related sequelae. In this study, the cell-mediated immunity and immunoglobulin avidity were evaluated as potential predictors of congenital transmission of the infection. METHODS CMV immunoglobulin G (IgG) avidity and CMV enzyme-linked immunospot (ELISpot) assays were employed in 80 pregnant women including 57 primary and 23 nonprimary CMV infections. Congenital infection was assessed using CMV DNA quantitative polymerase chain reaction on amniotic fluid or offspring urine. Logistic regression and receiver operating characteristic statistical methods were employed to determine the association with congenital infection. RESULTS Low CMV IgG avidity (25%) alone correlated with a probability of congenital transmission of 18.2% (95% confidence interval, 7.7%-28.8%). In contrast to the expectations, an increase in CMV ELISpot levels was statistically associated with congenital transmission (P = .006). The combined use of CMV ELISpot and low CMV IgG avidity resulted in a higher level of association than either method alone with the incidence of fetal transmission (area under the curve, 0.8685). CONCLUSIONS CMV-specific cell-mediated immunity represents a relevant marker in assessing the likelihood of congenital CMV transmission, particularly in combination with CMV IgG avidity.

Comparison of the Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot and CMV QuantiFERON Cell-Mediated Immune Assays in CMV-Seropositive and -Seronegative Pregnant and Nonpregnant Women.

ABSTRACT Human cytomegalovirus (CMV) infection is a major cause of congenital infection leading to birth defects and sensorineural anomalies, including deafness. Recently, cell-mediated immunity (CMI) in pregnant women has been shown to correlate with congenital CMV transmission. In this study, two interferon gamma release assays (IGRA), the CMV enzyme-linked immunosorbent spot (ELISPOT) and CMV QuantiFERON assays, detecting CMV-specific CMI were compared. These assays were performed for 80 CMV-infected (57 primarily and 23 nonprimarily) pregnant women and 115 controls, including 89 healthy CMV-seropositive pregnant women without active CMV infection, 15 CMV-seronegative pregnant women, and 11 seropositive or seronegative nonpregnant women. Statistical tests, including frequency distribution analysis, nonparametric Kruskal-Wallis equality-of-populations rank test, Wilcoxon rank sum test for equality on unmatched data, and lowess smoothing local regression, were employed to determine statistical differences between groups and correlation between the assays. The CMV ELISPOT and CMV QuantiFERON assay data were not normally distributed and did not display equal variance. The CMV ELISPOT but not CMV QuantiFERON assay displayed significant higher values for primarily CMV-infected women than for the healthy seropositive pregnant and nonpregnant groups (P = 0.0057 and 0.0379, respectively) and those with nonprimary infections (P = 0.0104). The lowess local regression model comparing the assays on an individual basis showed a value bandwidth of 0.8. Both assays were highly accurate in discriminating CMV-seronegative pregnant women. The CMV ELISPOT assay was more effective than CMV-QuantiFERON in differentiating primary from the nonprimary infections. A substantial degree of variability exists between CMV ELISPOT and CMV QuantiFERON assay results for CMV-seropositive pregnant women.

Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot Assay but Not CMV QuantiFERON Assay Is a Novel Biomarker To Determine Risk of Congenital CMV Infection in Pregnant Women.

ABSTRACT Cytomegalovirus (CMV) enzyme-linked immunosorbent spot (ELISPOT) and CMV QuantiFERON assays were examined as potential biomarkers predictive of congenital CMV (cCMV) transmission. Fifty-seven pregnant women with primary CMV infection and 23 with nonprimary CMV infection were recruited in the study. Maternal age, CMV IgG avidity, viremia, and viruria were also included among the potential predictors. Spearmans statistical correlation analysis revealed a positive correlation between the CMV ELISPOT and CMV QuantiFERON assay results (P < 0.001), but only the CMV ELISPOT assay correlated with cCMV (P < 0.001). cCMV was positively correlated with maternal viremia and viruria (P < 0.05) and negatively correlated with CMV IgG avidity (P < 0.01). Maternal age and CMV QuantiFERON assay results were not statistically associated with cCMV. CMV-specific cell-mediated immunity detected by the CMV ELISPOT assay plays a critical role in cCMV.

GB virus C infection in pregnancy: maternal and perinatal importance of the infection.

OBJECTIVES The more effective way of transmission of GB virus C (GBV-C) is parenteral, but sexual and vertical transmission seem to be the main way of spreading. We evaluated the prevalence and the effect of GBV-C infection on pregnant women, vertical transmission and viral effects on the newborn. STUDY DESIGN This study has consecutively enrolled 879 pregnant women. All patients had blood sampling to determine GBV-C RNA, serologic tests for chronic viral infections and seric tests of hepatic damage. The newborns from infected mothers had blood sampling to detect the presence of GBV-C at birth, and after 3 and 6 months. Positive babies were checked until 18 months. RESULTS 36 (4.1%) women resulted GBV-C positive. Among the positive patients none presented complications during pregnancy. Neither embryonic-fetal abnormalities nor relevant differences in fetal birth weight and week of gestation at delivery were found. 20 out of 36 babies had a follow-up. At birth, 13 (65%) babies were positive. 4 out of 9 vaginal deliveries (44%) and 9 out of 11 cesarean sections (82%) resulted positive to GBV-C RNA. The risk of GBV-C vertical transmission was not significantly increased by type of delivery (p=0.274). At 3 months, 13 babies were GBV-C positive (65%) and 7 were negative (35%). At the end of the follow-up, 9 babies were positive (45%), while 11 were negative (55%). CONCLUSION The percentage of patients positive to GBV-C RNA was comparatively high (4.1%). This prevalence, in a population without particular risk factors, confirms that common ways of transmission, such as the sexual and vertical ones, might have an important role in viral diffusion. Our data suggest that the infection does not influence the course of pregnancy. The rate of transmission found in our study is high. Type of delivery does not seem to be actually involved in vertical transmission and the protective role of cesarean section has not been confirmed.

Absence of maternal antibodies to hepatitis B core antigen and HBV vertical transmission: One case of infection notwithstanding passive-active prophylaxis

SummaryWe report the case of a newborn of an HBsAg carrier mother who was infected by vertical transmission and developed a subclinical hepatitis B at four months of age, notwithstanding the passive-active prophylaxis performed right after birth. The mothers HBV marker status was: HBsAg positive, HBeAg positive, anti-HBc IgM positive at low titer, anti-HBc IgG negative, anti-HBs negative, anti-HBe negative. It is assumed that the absence of anti-HBC antibodies might have favoured, perhaps in utero, the HBV infection whose antigenic expression was subsequently delayed by HBIg administered at birth. These findings suggest that the positivity for anti-HBc IgM must be considered an additional marker of maternal infectivity especially in the absence of anti-HBc IgG antibodies.ZusammenfassungWir berichten über das Neugeborene einer Mutter mit HBsAg-Trägerstatus, das durch vertikale Übertragung infiziert wurde und im Alter von vier Monaten trotz der sofort nach Geburt durchgeführten aktiv-passiven Impfprophylaxe eine subklinische Hepatitis B entwickelte. Bei der Mutter wurde folgender HBV-Marker-Status nachgewiesen: HBsAg-, HBeAg-positiv; niedrige Titer von anti-HBc IgM, anti-HBc IgG-, anti-HBs- und anti-HBe-negativ. Es wird angenommen, daß das Fehlen von anti-HBc-Antikörpern die möglicherweise in utero erfolgte HBV-Infektion begünstigt hat, deren antigene Expression anschließend durch die Gabe von HBIg bei Geburt verzögert wurde. Aus diesen Befunden ist zu schließen, daß der Nachweis von anti-HBc IgM, insbesondere bei Fehlen von anti-HBc IgG-Antikörpern, ein zusätzlicher Marker für mütterliche Infektiosität ist.

Testing for Cytomegalovirus in Pregnancy

ABSTRACT Congenital cytomegalovirus (CMV) infection represents a relevant cause of deafness and neurological damage in newborns. Intrauterine CMV transmission might result after primary or nonprimary infections, though at different rates (30% versus 0.2%, respectively). At present, a prenatal diagnosis of CMV infection is based mainly on maternal serology, the detection of CMV-DNA in amniotic fluid and fetal blood, and ultrasound (US) and magnetic resonance imaging (MRI). Recent evidences suggest that congenital CMV infection may be an immune-mediated disease and that evaluation of humoral and especially T-cell immunities may improve the overall prenatal diagnosis. This review summarizes the most recent advancements in the diagnosis of maternal and prenatal CMV infections.

OC10.05: Middle cerebral artery pulsatility index may predict fetal cerebral injury in pregnancy complicated by cytomegalovirus infection

Methods: Within our cohort of CCMV confirmed by positive amniotic fluid PCR, we excluded cases of severe encephalic anomalies diagnosed by ultrasound during mid-trimester follow-up. A MRI was systematically performed at 30–34 weeks in the remaining cases. White matter hyperintense T2 signal (WMHS) was defined as a signal ratio of temporal areas over basa ganglia and was considered abnormal when >1.4. Adverse pediatric outcomes included bilateral neurosensory hearing loss (NSHL) and neurological impairment. Over the last 5 years, fetal therapy by valacyclovir was systematically offered in moderately symptomatic fetuses. Results: An MRI was performed in 57 cases with a reassuring mid-trimester assessment, as part of final prognostic assessment: 33 cases were asymptomatic; 20 presented extracranial moderate symptoms such as hyperechoic bowel, IUGR, hepatosplenomegaly; 4 presented moderate intracranial anomalies such as posterior intraventricular adhesion or leucostriate vasculopathy. MRI confirmed ultrasound findings (normal or moderate anomalies) in all but one case. However, WMHS was found in 6/33 (18%) asymptomatic cases and was significantly associated with NSHL (3/6 vs. 0/27, P=0.004). In fetuses with extracranial anomalies, WMHS was found in 7/20 (35%) and was also associated with an adverse outcome (3/7 vs. 1/20, P=0.04). 3/4 fetuses with moderate intracranial anomalies prior to MRI showed WMHS, one of which suffered severe neurological impairment. Conclusions: WMHS is independently associated with an adverse outcome following a reassuring mid-trimester assessment for CCMV. In asymptomatic fetuses, such a finding would suggest a 50% risk of NSHL, whereas its absence strongly suggests a favourable outcome.

OC20.03: Sonographic findings before and after maternal administration of hyperimmune globulin in women with fetal cytomegalovirus infection

collected including bilateral tibial length and midforefoot width. Once defined the measurements and compared to normal control limbs, receiver operative characteristics (ROC) curves were plotted. Results: ROC curves showed that a difference of 33% in TAMV on pedial artery, between the two limbs would predict limb amputation with a sensitivity (S) of 71.1% and a Specificity (Sp) of 60.9%. When modifying this cut-off to 50%, the sensitivity was 48% but specificity reached the 85%, and negative predictive value (NPP) was 93.6%. In Popliteal artery, a difference of 20% in TAMV between the two limbs predicted amputation with a S of 45.4% and a Sp of 72.8%. In morphology, we found that a persistent severe oedema (healthy limb width under 20% of ligated one) acted as a predictor of NO amputation with a S of 67.6% and a Sp of 87.5%, and a NPP of 86.8%. Conclusions: Based on an experimental, well controlled, model, we suggest considering intervention in case of a comparative fall in TAMV in distal artery of more than 50% or more than 20% in the proximal one.