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Detection of cytomegalovirus (CMV)-specific immunoglobulin M (IgM) antibodies as first-line serologic diagnosis plays an important role in identifying CMV primary infection during pregnancy. The performance characteristics of eight commercially available CMV IgM assays were compared. Sensitivity and IgM antibody kinetics were assessed using 100 acute phase and follow-up sera from 39 pregnant women with a well-defined onset of CMV primary infection. Specificity was analyzed using 50 well-characterized serum samples from pregnant women not infected or latently infected with CMV and from patients with other acute infections. Until 12 weeks after the onset of primary infection, four assays showed sensitivities of 100%, whereas the others had individual gaps to detect all primary infections in this time period. All assays showed a time-dependent decrease of IgM levels. More than 12 weeks after the onset of infection, the IgM-positive rates varied considerably between tests. The specificity was between 92% and 98% in all but one assay. The observed differences in the performance characteristics must be taken into account in CMV screening and diagnosis of primary infection during pregnancy., Competing Interests: The authors declare no conflict of interest.

Introduction: Nonrandomized studies support the potential of cytomegalovirus hyperimmunoglobulin (CMV-HyperIg) in preventing maternofetal CMV transmission, but prospective interventional studies show equivocal results. We pre-sent a prospective phase-III international randomized open-label trial on the potential effect of CMV-HyperIg following serial monitoring of CMV serostatus., Methods: CMV-seronegative pregnant women (gestational age [GA] <14 weeks) were 1:1 randomized to monthly CMV-serostatus monitoring and CMV-HyperIg upon seroconversion (treatment), or routine prenatal care with CMV-serostatus testing at end of pregnancy (control). Ethical considerations required that control subjects with confirmed seroconversion be offered Cytotect®. The primary endpoint was the proportion of fetuses/newborns with congenital CMV infection. Secondary endpoints included neonatal CMV disease and safety during the 24-month follow-up., Results: The treatment arm counted 4,800 randomized subjects: 52 seroconverted (median GA 24 [11-35] weeks), of which 45 completed follow-up. The control arm counted 4,735 randomized subjects: 42 seroconverted, of which 34 completed follow-up (evaluable data for 28 newborns) and 8 subjects chose off-label Cytotect®. Congenital CMV rates were 13/28 newborns (46.4% [CI 27.51; 66.13]) vs. 16/45 newborns (35.6% [CI 21.87; 51.22]) in control and treated arms, respectively (p = 0.46). Newborn CMV disease was mostly mild and spontaneously resolving. There were no major safety concerns. The target sample was not reached within an acceptable time frame., Conclusions: Serial monitoring of CMV serostatus with CMV-HyperIg treatment was associated with a mild nonsignificant reduction in the vertical CMV transmission rate. Studies on the optimal preventive strategy are hampered by epidemiological and ethical challenges and should focus on GA-dependent transmission rates and accurate dating of infection., (The Author(s). Published by S. Karger AG, Basel.)

The aim of this study is to report on the specificity in the low-positive range of the Liaison CMV IgG II assay for determination of cytomegalovirus immune status in pregnancy. Sera with test results between 12.0 and 40.0 U/mL were retested with the Enzygnost Anti-CMV/IgG assay. Enzygnost-negative samples were analyzed by the Serion ELISA classic Cytomegalovirus IgG assay and, if positive or equivocal, also with the Mikrogen recomLine CMV IgG assay. A total of 12,117 sera were tested with the Liaison assay. Sixty sera were equivocal (12.0-13.9 U/mL), and 400 of 4295 positive sera were low-positive (14.0-40.0 U/mL). Based on consensus, at least 14% of the low-positives and 1.3% of all Liaison-positives can be considered as misclassified. The proportion of misclassified sera increased with lower Liaison IgG results. We suggest that the range for equivocal results in the Liaison assay should be revised., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Due to its ease of collection saliva was recently recommended as the preferred specimen, not only for screening, but also for diagnosis of congenital cytomegalovirus (CMV) infection., Objective: To compare the diagnostic performance of saliva PCR to urine PCR in infants born to mothers with primary CMV infection during pregnancy., Study Design: We retrospectively analyzed available data of infants tested for CMV DNA in urine and saliva at birth. PCR was performed with RealStar® CMV-PCR Kit 1.0 (altona Diagnostics). Infectious virus was detected in urine by rapid culture., Results: A total of 133 newborns were eligible for final analysis. Saliva swabs and urine were collected at birth with a time interval of 0-8 days (median 0; IQR 0-1). In 55% of newborns, cord blood was also tested. The overall concordance of saliva and urine PCR was 91% (27 positive, 94 negative). In 12 cases with discordant findings the discrepancy was due to false-negative (n = 2) or false-positive (n = 10) PCR results in saliva. Compared to urine, PCR in saliva showed a positive predictive value of 73%. Viral load in saliva was significantly lower (p < 0.0001; Mann-Whitney test) in the 10 false-positive cases than in the 27 cases with concordantly positive results., Conclusions: Positive CMV PCR results in saliva, especially low positive, have to be confirmed by urine testing. In our opinion detection of CMV by PCR in neonatal urine remains the gold standard for diagnosing congenital CMV infection in infants of mothers with primary infection in pregnancy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To determine the frequency of obstetrical adverse events and clinical outcome in infants following antenatal hyperimmune globulin (HIG) treatment for primary cytomegalovirus (CMV) infection in pregnancy., Methods: Data from 50 women including three twin pregnancies were retrospectively evaluated. Primary infection was defined by seroconversion or the presence of CMV-specific IgM and low IgG avidity. All women received two or more infusions of HIG (200 U/kg). Congenital CMV (cCMV) infection was diagnosed by detection of CMV in amniotic fluid and/or neonatal urine. We compared gestational age (GA) at birth, head circumference (HC) and birth weight (BW) of infants in our study cohort with those of live-born infants delivered in our clinic between 2015 and 2016., Results: Median gestational age at time of maternal CMV diagnosis was 13 weeks. One-hundred-forty-one maternal HIG doses were given. No HIG-related severe adverse reactions occurred. Preterm birth rate was 4.2% (2/47) in singleton pregnancies. None of the neonates had birth weight or head circumference < 3rd percentile (< 3P) for gestational age. There was no statistically significant difference regarding GA, BW and HC between our study cohort and the total population of live-born infants. The frequency of CMV-related sequelae in infants with cCMV infection was 10.5% (2/19) (one with bilateral hearing loss and one with mild motoric delay), both cases following first trimester maternal infection., Conclusion: Antenatal HIG treatment was well tolerated and not associated with prematurity or decreased birth weight. HIG application might have a favorable effect on the clinical course of congenital CMV infection.

Background: Primary CMV infections in pregnancy are usually asymptomatic and only detected by serology. Estimating the onset of infection is a major diagnostic goal, since primary infections around conception and in early gestation hold a higher risk for congenital disease than those in later pregnancy., Objectives: To assess the ability of serological supplementary CMV assays to date the onset of primary infection., Study Design: From our routine diagnosis we identified 61 pregnant women (n=188 serum samples) with precisely determined onset of CMV primary infection either by IgG seroconversion (n=24) or by significant IgG antibody rise (n=37). One hundred and forty-seven sera were investigated using the VIDAS(®) CMV IgG avidity EIA (BioMèrieux) and 83 sera using the recomBlot CMV IgG with avidity (Mikrogen)., Results: Both assays proofed to be reliable in terms of timing the onset of CMV primary infection. An avidity index (AI) in the VIDAS avidity EIA of <40% indicated primary infection within the last 20 weeks (positive predictive value 93.4%; 99/106), whereas an intermediate AI excluded primary infection within the last 12 weeks (negative predictive value 88.2%; 15/17). The recomBlot showed high reliability (PPV 96.9%; 31/33) for timing the onset of infection within the last 14 weeks. Avidity testing by blot however could not be interpreted in 11 of 47 sera (23.4%)., Conclusion: For timing the onset of infection (before or in early pregnancy) CMV avidity testing is most helpful if carried out within the first trimester up to the beginning of second trimester., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In Germany, studies on the IgG seroprevalence in pregnancy and in women of childbearing age are rare. Therefore, we retrospectively evaluated the CMV IgG seropositive rate in 40,324 pregnant women as well as in 31,093 female and male bone marrow donors over 15 consecutive years (1996-2010). Furthermore, the result of a study conducted in 1999 investigating 1,305 healthy adolescents with known ethnicity was included. The overall CMV IgG seroprevalence in pregnant women (15-50 years) was 42.3%. Age-dependent analysis revealed a significantly higher seropositive rate (55.6%) in young women (15-25 years) than in those aged 26-40 years (37-42%) and in women older than 40 years (48.3%). Over the study period of 15 years, the rate of seroprevalence in pregnant women declined significantly (χ(2) test < 0.01) from 44.3% in the first interval period (1996-2000), to 42.8% (2001-2005) and to 40.9% (2006-2010). The most influencing factor on CMV seropositivity appeared to be the socioeconomic status (SES), which we characterized by type of health insurance: Seroprevalence in women with low, middle and upper SES was 91.8, 46.9 and 33.7%, respectively. Female bone marrow donors of childbearing age (15-45 years) showed a significantly higher seropositive rate of 36.5% than age-matched male donors (28.6%). In adolescents aged 13-16 years, no gender-specific differences were recognized. Concerning ethnicity, youngsters with German descent had a significantly lower seroprevalence (29.9%) than those with non-German descent (67.4%).

Aims: The aim of this study was to investigate the current prenatal "off-label use" of cytomegalovirus hyperimmunoglobulin (CMV-HIG) in the prevention and treatment of congenital CMV (cCMV) infection, including the long-term outcome of the children., Methods: This retrospective observational study comprised mothers and their children, born between January 1, 2006, and October 30, 2010. Prenatal CMV-HIG was administered after diagnosis of primary CMV infection of the mother. Clinical and virological data were collected from maternal and pediatric medical and laboratory reports. Follow-up was 12-36 months after birth., Results: Forty-two women and 43 children met the study criteria. In total, 40 mothers and six unborn infants received 115 doses of CMV-HIG. The treatment group (TG; CMV-DNA polymerase chain reaction-positive amniotic fluid) included four mothers; the multinomial group (MG; CMV-positive mother and unknown CMV status of fetus) included 38 mothers (39 infants). For the four unborn infants in TG, CMV-HIG was administered either intraumbilically or into the amniotic fluid; three of the four mothers received intravenous CMV-HIG. Three children in TG remained CMV-positive and were asymptomatic at birth and during follow-up. One infant in TG had symptomatic cCMV infection in utero, at birth, and during follow-up. In MG, 37 of 38 women received intravenous CMV-HIG and two of 39 infants received CMV-HIG in utero. In total, 9 (23.1%) of 39 children in MG were positive for cCMV (including a terminated pregnancy). All eight instances of cCMV infection at birth in MG were asymptomatic at birth and during follow-up. The fetus from the terminated pregnancy showed no sonographic symptoms of cCMV infection. No severe side effect occurred in 115 CMV-HIG applications., Conclusion: CMV-HIG was well tolerated. Compared with published untreated mother-child pairs, we observed a trend toward a smaller risk for intrauterine CMV transmission following CMV-HIG application. Signs of prenatal cCMV disease were not reversed after CMV-HIG.

Background: The risk of intrauterine cytomegalovirus (CMV) infection and disease in the fetus or newborn largely depends on time of primary maternal infection during pregnancy., Objectives: Prospective cohort study of pregnancy outcome in relation to gestational age at primary maternal CMV infection., Study Design: In a total of 248 pregnancies with primary infection the onset of infection was determined by IgG seroconversion, IgG avidity and/or onset of clinical symptoms. Congenital infection was diagnosed by CMV detection in amniotic fluid, fetal tissue or urine of the neonate in the first 2 weeks of life. Clinical symptoms were retrieved from ultrasound and medical records., Results: The intrauterine transmission rates following primary CMV infection in the pre- and periconceptional period were 16.7% (4/24) and 34.5% (10/29), respectively. For the first, second and third trimester of pregnancy transmission rates were 30.1% (25/83), 38.2% (29/76) and 72.2% (26/36), respectively. The rate of symptomatically infected fetuses or newborns at birth was 22.8% for any symptoms and 10.3% for severe manifestations. No symptoms were observed in infected newborns of mothers with primary infection in the preconceptional period and in the third trimester., Conclusions: The risk of intrauterine transmission following primary maternal infection in the third trimester is high, but the risk of neonatal disease is low. The highest risk of severe symptoms in the fetus and newborn exists around conception and in the first trimester of pregnancy., (Copyright © 2011 Elsevier B.V. All rights reserved.)