Symptomatic Congenital Congenital Cytomegalovirus Research Articles

Assessment of patients’ characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease

IntroductionInsurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing. Materials and methodsWe performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants’ baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count. ResultsOf the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm3 occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019). ConclusionsInfants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Treatment of congenital cytomegalovirus infection.

Congenital cytomegalovirus (CMV) is the most common cause of congenital infection worldwide, the most common nongenetic cause of sensorineural hearing loss in children, and a cause of neurodevelopmental disorders in the brain. Infants with symptomatic congenital CMV infection may benefit from hearing and neurodevelopmental outcomes, particularly if antiviral treatment is initiated within the first month of life. Infants with life-threatening symptoms are recommended to receive 2-6 weeks of intravenous ganciclovir and then switch to oral valganciclovir, and those without life-threatening symptoms are recommended to use oral valganciclovir during the entire 6-month period. During antiviral drug treatment, absolute neutrophil count, platelet count, blood urea nitrogen, creatinine, and liver function tests were performed to identify neutropenia, thrombocytopenia, renal failure, and liver failure. This review investigated the evidence to date of treating congenital CMV infection.

Long-term ocular and visual outcomes following symptomatic and asymptomatic congenital CMV infection: a systematic review protocol

IntroductionCytomegalovirus (CMV) is one of the most common congenitally acquired infections worldwide. Visual impairment is a common outcome for symptomatic infants, with long-term ophthalmic surveillance often recommended. However, there are...

Assessment of mitochondrial toxicity in newborns and infants with congenital cytomegalovirus infection treated with valganciclovir

BackgroundGanciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity...

Hearing Loss in Congenital CMV Disease Post-Ganciclovir

Source: Lanzieri TM, Caviness AC, Blum P, et al. Progressive, long-term hearing loss in congenital CMV disease after ganciclovir therapy. J Pediatric Infect Dis Soc. 2021;piab095. doi:10.1093/jpids/piab095Investigators from the CDC, Atlanta, GA, and Baylor College of Medicine, Houston, TX, conducted a study to assess long-term hearing outcomes in children with symptomatic congenital cytomegalovirus (CMV) infection, and the impact of ganciclovir therapy on hearing loss. For the study, they analyzed data from children born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. All study participants had CMV infection detected in urine samples in the first 3 weeks of life and had microcephaly, chorioretinitis, neurologic abnormalities or evidence of reticuloendothelial system involvement (eg, petechiae/purpura). Study children had longitudinal assessments of hearing with auditory brainstem response testing and behavioral audiometry; those with hearing thresholds >20 dB were classified as having sensorineural hearing loss (SNHL). SNHL was defined as congenital if diagnosed in the first month of life. Study children were placed into 3 groups: Group A included patients who had been enrolled in a clinical trial and received ganciclovir; group B included children with SNHL, microcephaly and/or chorioretinitis but who were untreated; and group C comprised those without any of these findings who also were not treated with ganciclovir. The primary study outcome was long-term assessment of hearing loss among children in these 3 groups.Data were analyzed on 76 children; 17 (22%) in group A, 27 (36%) in group B, and 32 (42%) in group C. Among the 17 children in group A, 16 had microcephaly, chorioretinitis, or congenital SNHL; median duration of ganciclovir treatment in these patients was 40 days. Overall, the most common findings in study patients when they were neonates were purpura/petechiae (82% of those in group A, 78% in group B, and 63% in group C); 71% and 70%, respectively, of those in groups A and B had microcephaly. Congenital SNHL was diagnosed in 65% of patients in group A and 56% for those in group B, although hearing was not assessed in the first month of life in all study participants. The median age at last hearing assessment was 13 years for children in groups A and C and 11 years for those in group B. At that time, 16 (94%) patients in group A, 24 (89%) children in group B, and 16 (50%) group C patients had SNHL. SNHL was categorized as severe (>70 dB) in 12 (71%), 16 (59%), and 7 (22%) children, respectively, in groups A, B, and C.The authors conclude that most children in this study with congenital CMV infection developed substantial SNHL with or without ganciclovir treatment.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The current investigators provide long-term hearing outcomes for infants born 1983–2005 who were enrolled in the Congenital CMV Longitudinal Study. Participants were selected based on having severe disease as newborns.1,2 Not surprisingly, most developed substantial SNHL. As previously discussed, symptomatic congenital CMV infection at birth is a risk factor for SNHL. (See AAP Grand Rounds. 2019;42[5]:57.)3 Many infants also had microcephaly and/or head CT scan findings suggesting tissue destruction or dysplastic growth, which also are associated with an increased risk of SNHL.4 The results of early clinical trials of intravenous ganciclovir1,2 had suggested short-term stabilization or improvement in hearing at 6 months but were not borne out by the current investigation.With the introduction of oral valganciclovir, a phase III, randomized, placebo-controlled clinical trial, conducted during 2008– 2011, evaluated 6 weeks versus 6 months of therapy with valganciclovir.5 There was modest improvement in hearing and developmental outcomes at 12 and 24 months. Based on this trial, the AAP currently recommends 6 months of oral valganciclovir for infants with moderately to severely symptomatic congenital CMV infection who can start treatment in the first month of life.6 The current authors state that their findings cannot be extrapolated to infants who receive current standard of care therapy. Infants receiving valganciclovir are being followed to determine their long-term hearing outcomes.Another area that is not addressed is the role of valganciclovir for infants with congenital CMV infection who have isolated SNHL. The 2017 consensus guidelines do not routinely recommend valganciclovir for these infants based on insufficient evidence. Pasternak et al reported that 12 months of antiviral therapy for infants with congenital CMV infection and isolated SNHL led to improved hearing, but their study did not include a control group.(See AAP Grand Rounds. 2018;40[5]:55.)8Infants with congenital CMV infection are at risk for SNHL despite receipt of antiviral therapy. These infants deserve close audiology follow-up.The apparent lack of major benefit of antiviral therapy in children with symptomatic congenital CMV infection underscores the need for prevention. Neither CMV-IGIV nor investigational vaccines have yet proven efficacious.6

Protection against Congenital CMV Infection Conferred by MVA-Vectored Subunit Vaccines Extends to a Second Pregnancy after Maternal Challenge with a Heterologous, Novel Strain Variant.

Maternal reinfection of immune women with novel human cytomegalovirus (HCMV) strains acquired during pregnancy can result in symptomatic congenital CMV (cCMV) infection. Novel animal model strategies are needed to explore vaccine-mediated protections against maternal reinfection. To investigate this in the guinea pig cytomegalovirus (GPCMV) model, a strictly in vivo-passaged workpool of a novel strain, the CIDMTR strain (dose, 1 × 107 pfu) was used to infect dams that had been challenged in a previous pregnancy with the 22122 strain, following either sham-immunization (vector only) or vaccination with MVA-vectored gB, gH/gL, or pentameric complex (PC) vaccines. Maternal DNAemia cleared by day 21 in the glycoprotein-vaccinated dams, but not in the sham-immunized dams. Mean pup birth weights were 72.85 ± 10.2, 80.0 ± 6.9, 81.4 ± 14.1, and 89.38 ± 8.4 g in sham-immunized, gB, gH/gL, and PC groups, respectively (p < 0.01 for control v. PC). Pup mortality in the sham-immunized group was 6/12 (50%), but reduced to 3/35 (8.6%) in combined vaccine groups (p = 0.0048). Vertical CIDMTR transmission occurred in 6/12 pups (50%) in the sham-vaccinated group, compared to 2/34 pups (6%) in the vaccine groups (p = 0.002). We conclude that guinea pigs immunized with vectored vaccines expressing 22122 strain-specific glycoproteins are protected after a reinfection with a novel, heterologous clinical isolate (CIDMTR) in a second pregnancy.

The Current Challenges in Developing Biological and Clinical Predictors of Congenital Cytomegalovirus Infection.

Congenital cytomegalovirus (CMV) infection may cause severe long-term sequelae. Recent studies have demonstrated that early antiviral therapy for infants with symptomatic congenital CMV (cCMV) infection may improve neurological outcomes; thus, accurate identification of newborns at high risk of cCMV infection may contribute to improved outcomes in affected children. However, maternal serological screening for cCMV infection by diagnosing primary infection during pregnancy, which is a popular screening strategy, is inefficient, because the number of cCMV infections with nonprimary causes, including reactivation of or reinfection with CMV, is larger than that of cCMV infections with primary causes. Low levels of neutralizing antibodies against pentameric complex and potent CMV-specific T cell-mediated immune responses are associated with an increased risk of cCMV infection. Conversely, our prospective cohort studies revealed that the presence of maternal fever/flu-like symptoms, threatened miscarriage/premature delivery, or actual premature delivery are risk factors for cCMV infection among both women with normal pregnancies and those with high-risk ones, regardless of whether the infection is primary or nonprimary. This review focused on host immune responses to human CMV and current knowledge of potential biological and clinical factors that are predictive of cCMV infection.

Progressive, Long-Term Hearing Loss in Congenital CMV Disease After Ganciclovir Therapy.

Long-term hearing outcomes among children with symptomatic congenital cytomegalovirus (CMV) disease who received 6-week ganciclovir therapy early in life are unknown. Longitudinal study of 76 children with symptomatic congenital CMV disease, born 1983-2005, who were categorized into three groups: group A treated with ganciclovir; group B untreated who had microcephaly, chorioretinitis, or sensorineural hearing loss (SNHL; ≥25 dB) diagnosed in the first month of life (congenital); and group C untreated who did not meet criteria for group B. Patients in groups A (n = 17), B (n = 27), and C (n = 32) were followed to median age of 13, 11, and 13 years, respectively. In group A, patients received ganciclovir for median of 40 (range, 11-63) days; 7 (41%) had grade 3 or 4 neutropenia. Congenital SNHL was diagnosed in 11 (65%) patients in group A, 15 (56%) in group B, and none in group C. Early-onset SNHL was diagnosed between ages ≥1-12 months in an additional 4 (24%), 6 (22%), and 8 (25%) patients in groups A, B, and C, respectively. By the end of follow-up, 12 (71%), 16 (59%), and 7 (22%) of patients in groups A, B, and C, respectively, had severe (>70 dB) SNHL in the better-hearing ear. In this study, most patients with symptomatic congenital CMV disease and congenital or early-onset SNHL eventually developed hearing loss severe enough to have been potential candidates for cochlear implantation, with or without 6-week ganciclovir therapy. Understanding long-term hearing outcomes of patients treated with 6-month oral valganciclovir (current standard of care) is needed.

Ganciclovir Treatment in Symptomatic Congenital CMV Infection at Siriraj Hospital: 11 Year-Review (2008 to 2019)

Background: Congenital cytomegalovirus (CMV) infection is the most common non-genetic cause of permanent sensorineural hearing loss in infants and children. A 6-month course of intravenous ganciclovir or valganciclovir is recommended for treatment of patients with moderate to severe symptomatic congenital CMV disease. Hearing status improvement has been reported in those that received treatment within the first month of life. In Thailand, there has been no data of antiviral treatment in symptomatic congenital CMV patients. Objective: To determine the incidence of symptomatic congenital CMV infection in the past 11 years and to evaluate the hearing, neurological, and developmental outcomes of the antiviral treatment and factors associated with hearing outcomes. Materials and Methods: A retrospective observational study was performed at Siriraj Hospital, between January 2008 and December 2019. The medical records of the patients diagnosed of symptomatic congenital CMV infection (ICD10-P351) were reviewed. Results: The incidence of symptomatic congenital CMV infection was 0 to 1.01 case per 1,000 livebirths. Of the 52 patients, 18 received 6-week course of ganciclovir and five continued with oral valganciclovir for three to six months. Developmental delayed was found in 69.2% (36). No difference in hearing outcomes at 6 and 12 months of age between the patients who did or did not receive treatment. Among 24 (46.1%) children who underwent hearing test at two to three years of age, the birth characteristics, as well as antiviral treatment (attributable risk 0.007, 95% CI –0.4 to 0.4, p=0.973), had no difference in hearing outcome. Long-term disability was diagnosed in the lower proportion among the patients receiving antiviral treatment (attributable risk –0.3, 95% CI –0.5 to –0.1, p=0.030). Conclusion: Symptomatic congenital CMV infection resulted in poor hearing and developmental outcomes. Antiviral treatment reduced risk of disability but did not improve hearing outcomes. The results underscore the need for early diagnosis and initiation of antiviral treatment in infants with symptomatic congenital CMV. Keywords: Congenital infection; CMV; Hearing loss; Ganciclovir; Valganciclovir; Disability

Cytomegalovirus-A Risk Factor for Childhood Hearing Loss: A Systematic Review.

Permanent hearing loss is an important public health issue in children with consequences for language, social, and academic functioning. Early hearing detection, intervention, and monitoring are important in mitigating the impact of permanent childhood hearing loss. Congenital cytomegalovirus (CMV) infection is a leading cause of hearing loss. The purpose of this review was to synthesize the evidence on the association between CMV infection and permanent childhood hearing loss. We performed a systematic review and examined scientific literature from the following databases: MEDLINE, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), Embase, and CINAHL. The primary outcome was permanent bilateral or unilateral hearing loss with congenital onset or onset during childhood (birth to 18 years). The secondary outcome was progressive hearing loss. We included studies reporting data on CMV infection. Randomized controlled trials, quasi-experimental studies, nonrandomized comparative and noncomparative studies, and case series were considered. Data were extracted and the quality of individual studies was assessed with the Qualitative Assessment Tool for Quantitative Studies (McMaster University). The quality and strength of the evidence were graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A narrative synthesis was completed. Sixty-five articles were included in the review. Prevalence of hearing loss at birth was over 33% among symptomatic CMV-infected newborns and less than 15% in asymptomatic infections. This difference in prevalence was maintained during childhood with more than 40% prevalence reported for symptomatic and less than 30% for asymptomatic CMV. Late-onset and progressive hearing loss appear to be characteristic of congenital CMV infections. Definitions of hearing loss, degree of loss, and reporting of laterality varied across studies. All degrees and both bilateral and unilateral loss were reported, regardless of symptomatic and asymptomatic status at birth, and no conclusions about the characteristics of hearing loss could be drawn. Various patterns of hearing loss were reported including stable, progressive, and fluctuating, and improvement in hearing (sometimes to normal hearing) was documented. These changes were reported in children with symptomatic/asymptomatic congenital CMV infection, presenting with congenital/early onset/late-onset hearing loss and in children treated and untreated with antiviral medication. Symptomatic and asymptomatic congenital CMV infection should be considered a risk factor for hearing loss at birth and during childhood and for progressive hearing loss. Therefore, CMV should be included as a risk factor in screening and surveillance programs and be taken into account in clinical follow-up of children with hearing loss.

Maternal cytomegalovirus immune status and hearing loss outcomes in congenital cytomegalovirus-infected offspring.

ObjectivesThe purpose of this study is to determine the relationship between maternal primary and recurrent CMV infection during pregnancy, symptoms at birth in the newborn, and long term hearing loss through18 years of age.Patients and methods237 mother-infant pairs in the Houston, Texas area identified through maternal CMV IgG and IgM antibody serologic screening and newborn screening using urine CMV culture to identify congenital CMV infection were enrolled in the Houston Congenital CMV Longitudinal Study. Mothers were categorized as having primary or recurrent or unknown maternal CMV infections, and newborns were categorized at birth as having symptomatic or asymptomatic congenital CMV infection, or as uninfected controls. All three newborn groups were followed longitudinally with serial hearing evaluations up to 18 years of age. The relationship between type of maternal CMV infection, newborn classification, and the occurrence of hearing loss over time was determined through Kaplan-Meier survival analysis, life table analysis, and a simulated ascertainment of maternal infection type for the unknown categories.ResultsOf 77 newborns with symptomatic congenital CMV infection, 12 (16%) of mothers had a primary CMV infection during pregnancy; 4 (5%) had a non-primary infection, and the type of infection in 48 (79%) could not be determined and were classified as unknown type of maternal infection. Fifty Seven (74%) of the 77 symptomatic children had hearing loss by 18 years of age, including 9 of the 12 (75%) who were born to mothers with primary infection and 48 (79%) of the 61 with unknown type of maternal infection. Of the 109 newborns with asymptomatic congenital CMV infection, 51 (47%) were born to mothers with a primary CMV infection during pregnancy, 18 (17%) to mothers with a recurrent infection; and 40 (37%) had unknown type of infection. Of these 109 asymptomatic cases, 22 (20%) developed hearing loss, including 14 out of 51 (28%) of those born to mothers with primary infection, two out of the 18 (11%) born to mothers with recurrent infection, and 6 out of the 40 (15%) to mothers of unknown infection type. Of the 51 uninfected newborn controls, 10 (20%) of mothers had a primary CMV infection during pregnancy, 5 (10%) had a non-primary infection, 10 (20%) were never infected, and 26 (51%) were assigned unknown type of infection. Three controls (6%) developed hearing loss, with 1 being born to a mother with primary infection and 1 to a mother never infected with CMV.ConclusionsBoth primary and non-primary maternal CMV infections during pregnancy resulted in symptomatic and asymptomatic congenital CMV infection. Symptomatic congenital CMV infection was more likely to occur after primary maternal CMV infection. Sensorineural hearing loss occurred in children born to mothers with both primary and non-primary CMV infections, and in both asymptomatic and symptomatic congenital CMV infection, but was more common after maternal primary infection. Most, but not all, hearing loss in children with cCMV associated hearing loss was first detected within the first year of life.

A cohort study of the universal neonatal urine screening for congenital cytomegalovirus infection

ObjectivesThis prospective cohort study aimed to evaluate the efficacy of the universal neonatal urine screening, followed by diagnosis, workup and antiviral therapy for symptomatic congenital cytomegalovirus (CMV) infection to reduce neurological impairments and sequelae. MethodsNeonates born in three facilities underwent the universal urine screening of PCR analyses for CMV-DNA. Neonates with symptomatic congenital CMV infection (cCMV) received oral valganciclovir (VGCV) of 32 mg/kg/day for six weeks or six months, and were evaluated for neurological outcomes including developmental quotient (DQ) and hearing function at around 18 months of corrected age. ResultscCMV was diagnosed in 56 (0.48%) of 11,736 neonates, consisting of 23 neonates with symptomatic and 33 with asymptomatic cCMV. The incidence of cCMV in the general perinatal medical center (0.69%) was higher than that in the primary maternity hospital (0.23%, p<0.01%). Twenty of the 23 infants with symptomatic cCMV received VGCV therapy, and 19 underwent neurological assessment. Eight neonates (42%) had severe sequelae of DQ < 70, bilateral hearing dysfunction, and/or epilepsy. Four neonates (21%) had mild sequelae of DQ 70–79 or unilateral hearing dysfunction only, and seven (37%) showed normal development without any impairment. ConclusionsThis study on a large scale demonstrated that a series of universal neonatal urine screening, diagnosis, workup, and VGCV therapy for neonates with symptomatic cCMV may decrease neurological impairments, because 58% of the treated infants had normal development or mild sequelae. The universal urine screening likely identifies subclinical symptomatic cCMV. Mothers with fetuses of cCMV seem to be selectively transferred to perinatal medical centers before deliveries.

Efficacy of Valganciclovir Versus Ganciclovir in Treatment of Symptomatic Cytomegalovirus Infection in Infants: An Open- Labeled Randomized Controlled Trial

Introduction: Congenital cytomegalovirus (CMV) infection is the most common viral infection transmitted via the placenta, causing significant neurodevelopmental impairment in infants and children. Gancyclovir and Valgancyclovir are two drugs used in the treatment of symptomatic CMV infected case which have limited comparative study. This study compared the efficacy and tolerability of these two drugs on symptomatic CMV infected infants.Methodology: This was an open-label randomized controlled trial done to compare oral valganciclovir(VGCV) with injectable ganciclovir (GCV) in the treatment of symptomatic congenital CMV infected infants. A total of 72 patients were included; 12 patients discontinued the treatment due to noncompliance or side effects. Pre and post-treatment CMV virus levels and adverse effects were monitored. Psychological, visual, and hearing assessments were performed at baseline and six months post-treatment.Results: The mean age of the infants in VGCV and GCV group was 7.10±3.58 and 7.50±3.99 months, respectively. Nineteen infants presented with developmental delay, 13 with seizure, 4 with a movement disorder. Twenty-one percent of the infants were preterm, and 38% were low birth weight. Eighteen infants had a neonatal seizure. Twenty-eight infants of VGCV and 24 infants of the GCV group showed clearance of the virus after six weeks of treatment. No statistical difference was found in virus clearance. Regarding ophthalmological assessment, infants had chorioretinitis, optic atrophy, squint, and cortical blindness. On hearing assessment, none of the infants deteriorated after drug administration, while some showed improved hearing. None of the infants showed deterioration of cognition, while some of the infants showedimprovement in cognitive assessment, but there was no significant difference in two groups. The side effects of GCV were significantly greater than VGCV (P&lt;0.05). Conclusion: In symptomatic congenital CMV infection in infants, VGCV is as efficient as GCV, and the former has fewer side effects.

Clinical and Microbiological Diagnosis of Nonprimary Cytomegalovirus Infection in Pregnancy With Symptomatic Congenital Cytomegalovirus Infection

Abstract Cytomegalovirus (CMV) infection is the most common cause of congenital infection in developed countries. It is thought that symptomatic congenital CMV (cCMV) infections are produced by a primary CMV infection in the majority of the cases, but recent case series published show a similar prevalence and severity of clinical findings and long-term sequels in nonprimary and primary cCMV infection. We report a case of nonprimary CMV infection in pregnancy with fetal neurological alterations. A positive quantitative polymerase chain reaction in amniotic fluid (AF) confirmed the diagnosis of cCMV infection that triggered a voluntary termination of pregnancy. Quantitative polymerase chain reaction assays of AF are used to confirm a fetal cCMV infection, and the invasive amniocentesis procedure is justified when abnormalities are found in ultrasound control, although they are not validated to use in AF.

Inattention and Hyperactivity in Children with Symptomatic and Asymptomatic Congenital Cytomegalovirus.

To explore the relationship between congenital cytomegalovirus (CMV) and inattention and hyperactivity among school-aged children. The Behavior Assessment System for Children, Second Edition, parent- and self-report, was completed among children with symptomatic congenital CMV (ScCMV) (n = 36), asymptomatic congenital CMV (AcCMV) (n = 76), and controls (n = 29) enrolled in a longitudinal cohort. The proportions of children with ScCMV, AcCMV, and controls with Attention Problems or Hyperactivity T-scores ever ≥ 65 were compared. Mean T-scores in these domains were also compared and adjusted for IQ. Children with AcCMV did not differ from controls in the proportion of children with elevated Attention Problems or Hyperactivity T-scores or in mean Attention Problems or Hyperactivity T-scores. Children with ScCMV had a higher proportion of elevated Attention Problems T-scores compared with the AcCMV group but not controls. There were no differences in the proportions of children with elevated Hyperactivity T-scores between ScCMV and AcCMV or control groups. Children with ScCMV had higher mean Attention Problems T-scores versus those with AcCMV and controls and higher mean Hyperactivity T-scores versus those with AcCMV but not controls. After adjustment for IQ, differences in mean Attention Problems or Hyperactivity T-scores were no longer significant. Children with AcCMV are not at increased risk of inattention or hyperactivity compared with controls. However, our study suggests an increased prevalence of inattention and hyperactivity among children with ScCMV. Differences in IQ were confirmed to have a confounding effect. Evaluation for attention-deficit/hyperactivity disorder may be warranted in this population.

LB20. Valacyclovir to Prevent Vertical Transmission of Cytomegalovirus After Maternal Primary Infection During Pregnancy

BackgroundCytomegalovirus (CMV) is the most common cause of congenital infection in humans. The highest risk of fetal injury follows a maternal primary infection early in pregnancy. Despite the potential for severe fetal injury, to date there are no proven means to prevent viral transmission. Valacyclovir is an antiviral drug proven effective in decreasing the risk for CMV infection among transplant recipients. Valacyclovir is safe for use in pregnancy, and concentrates in the amniotic fluid without accumulating. A dose of 8 g/day creates therapeutic drug levels in the amniotic fluid and fetal blood.MethodsThis is a randomized, double-blind, placebo-controlled study comprising pregnant women with serologic evidence of primary CMV infection during the periconceptional period and first trimester. After informed consent, patients were randomly assigned to a treatment group (8 g/day of Valacyclovir) or control group (placebo). Treatment was initiated at the time of serological detection, and continued until amniocentesis. The primary endpoint was the rate of vertical transmission of CMV—determined by amniotic fluid CMV PCR. Secondary endpoints included evidence of symptomatic congenital CMV infection—in utero or postnatally.ResultsOne hundred women were recruited, 90 were included in the data analysis; 45 patients received Valacyclovir and 45 placebo. There were 2 twin pregnancies, and therefore 92 amniocentesis Amongst the Valacyclovir group, 5 (11.1%) amniocentesis were positive for CMV, compared with 14 (29.8%) in the placebo group (P GLMM = 0.03), corresponding with an odds ratio of 0.29 (95% CI: 0.09–0.90) for vertical CMV transmission. Amongst patients infected during the first trimester, a positive amniocentesis for CMV was significantly (P = 0.02) less likely in the Valacyclovir arm (2/19) compared with placebo (11/23). No significant differences (P = 0.91) in CMV-positive amniocentesis were observed between study arms amongst patients infected periconceptionally.ConclusionValacyclovir at a dose of 8 g/day is effective in reducing the rate of fetal CMV infection following early maternal primary infection during pregnancy. The drug reduces the rate of fetal infection by 71%.Disclosures All authors: No reported disclosures.

Therapy Options for Infants with Congenital Cytomegalovirus Infection - Implications for Setting Up Neonatal Screening Programs

The number of diseases covered by universal neonatal screening in Germany has risen steadily from 1 (phenylketonuria) in 1968 to 17 (with hearing impairment and congenital hip dysplasia) in 2018. Treatment, however, of disorders diagnosed by screening may harm children, as failed neuroblastoma screening has shown. There are several pilot studies to detect congenital cytomegalovirus (CMV) infection but no consensus as to the treatment of the infants identified. Systematic search for studies investigating therapy of congenital CMV infection, using PubMed and the WHO International Clinical Trials Registry Platform (ICTRP). We found only one controlled trial that randomized infants with symptomatic congenital CMV infection (involving the central nervous system) to treatment (intravenous ganciclovir for 6 weeks) or no treatment. Treatment was associated with significantly less hearing deterioration. A second trial comparing 6 weeks vs. 6 months of treatment with valganciclovir, an oral prodrug of ganciclovir, found no benefit for hearing but modestly improved developmental outcomes associated with 6 months of treatment. In contrast, an open-label registry reported benefits for infants with congenital CMV infection and isolated hearing who received valganciclovir for 12 months, with hearing improvement in 2/3 of cases after a median follow-up of 4½ years. Antiviral treatment of neonates with congenital CMV infection and few symptoms including isolated hearing loss remains controversial. A generally accepted therapy, however, is pivotal before introducing universal or targeted screening for congenital CMV infection.

Cortical Visual Impairment in Congenital Cytomegalovirus Infection.

To describe the presentation, evolution, and long-term outcome of cortical visual impairment (CVI) in patients with symptomatic congenital cytomegalovirus (CMV) infection, and to identify risk factors for the development of CVI in patients with symptomatic congenital CMV. Retrospective subanalysis of a long-term prospective cohort study with data gathered from 1982 to 2013. Eleven of 77 (14.3%) patients with symptomatic CMV, 0 of 109 with asymptomatic CMV, and 51 control patients had CVI. Overall, patients with symptomatic CMV had worse vision than patients with asymptomatic CMV, who in turn had worse vision than control patients. Microcephaly, intracranial calcification, dilatation of ventricles, encephalomalacia, seizure at birth, optic atrophy, chorioretinitis/retinal scars, strabismus, and neonatal onset of sensorineural hearing loss were risk factors associated with CVI. CVI may result from symptomatic congenital CMV infection. The relationship of CVI and its risk factors in patients with CMV suggests the potential to predict the development of CVI through predictive modeling in future research. Early screening of CVI in children born with symptomatic congenital CMV can facilitate educational, social, and developmental interventions. [J Pediatr Ophthalmol Strabismus. 2019;56(3):194-202.].

Histopathological analysis of placentas with congenital cytomegalovirus infection

IntroductionCytomegalovirus (CMV) infection is the most common cause of congenital viral infections in humans. The unusual structure of the placenta plays a pivotal role in CMV transmission from mothers to fetuses. The aim of this study was to evaluate the histopathological findings of placentas with congenital CMV infections. MethodsWe obtained placental specimens from 35 women who had newborns with congenital CMV infections. Placental specimens, extraplacental membranes, and umbilical cords were stained with hematoxylin and eosin, and subjected to immunohistochemical analysis. We evaluated the localization of CMV-infected cells and other histological parameters. ResultsThirty (86%) of the 35 placentas tested positive for CMV-infected cell proteins by immunohistochemistry. A majority of CMV-positive cells were present in fibroblasts and endothelial cells in the villi. The number of CMV-infected cells was inversely correlated to gestational age at delivery. The frequency of chronic villitis (65% vs. 11%; p < 0.01) and changes of the villi (38% vs. 0%; p < 0.05) in the placentas from mothers with symptomatic congenital CMV infections was higher than those observed in samples from mothers with asymptomatic congenital infections. The frequency of changes of the decidua (43% vs. 5%; p < 0.01) in the placentas from mothers with non-primary CMV infections was higher than those from mothers with primary infections. DiscussionChronic villitis and changes of the villi were associated with symptomatic congenital CMV infections. The changes of the decidua were associated with congenital CMV infections, in mothers with non-primary CMV infections.

Long-term hearing outcomes of children with symptomatic congenital CMV treated with valganciclovir

ObjectivesCongenital human cytomegalovirus (cCMV) is a leading cause of pediatric hearing loss. Recent literature has suggested that valganciclovir (VGCV) therapy can improve hearing outcomes. The objective of this study was to evaluate the long-term hearing outcomes among symptomatic CMV patients treated with VGCV. MethodsA retrospective chart review of symptomatic CMV patients treated with VGCV was completed. The primary endpoint was the change in best ear hearing scores prior to treatment and after follow-up audiograms. A paired-sample t-test was used to evaluate the data. ResultsA total of 16 children were included in the study and participants were followed for an average of 3.2 years. There was a measurable worsening, but not a statistically significant change in the best ear hearing scores, where the mean change was 11.9 dB (p-value = 0.070). However, 14/16 patients (87.5%, p-value<0.001) were found to have clinically significant worsening of hearing. The mean change in hearing scores for the left and right ear was 14.2 dB (p-value = 0.023) and 15.5 dB (p-value = 0.032), respectively. Mean elapsed time for progressive loss was 2.6 ± 0.2 years. When comparing the better or worse ear, there was no pattern for which ear deteriorated earlier or more frequently. ConclusionsOur data did show a measurable, but not a statistically significant worsening outcome in best ear hearing. There was a significant change in both left and right ear hearing. Our results suggest that VGCV may provide only a short-term improvement in hearing outcomes; however, these preliminary post-hoc findings suggest the need for a more rigorous evaluation.