Comparative Effects of Valganciclovir and Ganciclovir on the Congenital Cytomegalovirus Infection and Hearing Loss: A Randomized Controlled Trial

Background: Cytomegalovirus (CMV) is a highly specific herpes virus spreading only from person to person. Valganciclovir (VGCV) and ganciclovir (GCV) are effective in the treatment of neonatal congenital CMV infection. Objectives: This study aimed to compare the curative effects of VGCV and GCV among neonates with CMV infection and evaluate their effects on hearing. Methods: A total of 48 neonates with congenital CMV infection admitted to Huaian Maternal and Child Health Care Hospital, China, were selected from January 2016 to December 2019 and randomly divided into two equal groups of intervention and group (n = 24 each). While the control group received intravenous injection of GCV, the intervention group received oral VGCV. After a 6-week course of treatment, polymerase chain reaction (PCR) was applied to detect the CMV load in both urine and blood. We used the ELISA method to detect the serum CMV-IgM expression level before and after treatment. Moreover, we compared the positive rates of CMV-DNA and CMV-IgM, hyperbilirubinemia, retinitis, hepatosplenomegaly, thrombocytopenia, neutropenia, as well as the results of hearing screening and brainstem auditory evoked potentials (BAEP). Results: Before treatment, there was no statistical difference in blood/urine CMV-DNA expression level and positive expression rates of blood/urine CMV-DNA and CMV-IgM between the groups (P > 0.05). After treatment, blood/urine CMV-DNA expression and the positive expression rates of blood/urine CMV-DNA and CMV-IgM significantly decreased in both groups compared to before treatment (P < 0.05), but there was no statistical significance between the two groups (P > 0.05). Before treatment, there was no significant difference in hearing abnormality rates between the control (50%) and intervention (62.5%) groups (P > 0.05). After treatment, both the control (20.83%) and intervention (29.17%) groups had significantly decreased hearing abnormality rates, and the difference was statistically significant compared with before treatment (P < 0.05), but the difference between the two groups was not statistically significant (P > 0.05). After treatment, the results of comparing BAEP showed that both groups had no statistically significant differences in the number of neonates with normal hearing, mild hearing loss, moderate to severe hearing loss, severe hearing loss, and extremely severe hearing loss (P > 0.05). Before treatment, both groups had no statistically significant differences in the number of neonates with hyperbilirubinemia, retinitis, hepatosplenomegaly, thrombocytopenia, and neutropenia (P > 0.05). After treatment, while the number of neonates with hyperbilirubinemia, retinitis, hepatosplenomegaly, and thrombocytopenia decreased, neutropenia cases increased, and the difference before and after treatment was statistically significant (P < 0.05); however, the difference between the two groups was not statistically significant (P > 0.05). Conclusions: VGCV is similar to GCV in the treatment of neonatal congenital CMV infection, but the oral route of administration of VGCV is more acceptable among neonates.

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.

First-line noninvasive management of cytomegalovirus primary infection in pregnancy

Objectives To introduce a first-line noninvasive antenatal management of maternal cytomegalovirus (CMV) primary infection based on ultrasound (US) and magnetic resonance imaging (MRI). Amniocentesis (AC) is used as a second-line tool in cases of abnormalities compatible with fetal CMV infection on US and/or MRI screening. Methods Between January 2011 and October 2018, pregnant women referred with a CMV primary infection on antibody screening were followed up by monthly US scans and a brain MRI at approximately 32 weeks. In cases with US and/or MRI abnormalities compatible with congenital CMV infection, AC was performed to confirm the diagnosis. Results Ninety pregnant women with a primary CMV infection were included (89 singleton and one twin pregnancy). The first-line screening by US and/or MRI was normal for 72 of 91 fetuses (79%). At birth, 19 of these 72 neonates (26%) had a positive urine sample for CMV but were asymptomatic. US and/or MRI abnormalities were identified in 19 fetuses (21%). AC confirmed a fetal CMV infection in 16 fetuses (84%); 12 pregnancies were terminated, and four were continued, with three symptomatic neonates at birth and one poor neurodevelopmental outcome at postnatal follow-up. Conclusions First-line noninvasive management of maternal CMV primary infection based on serial US scans and brain MRI can be offered to identify fetuses with severe symptomatic congenital CMV infection and reduce the number of ACs without compromising the fetal outcome.

Current practices of management of maternal and congenital Cytomegalovirus infection during pregnancy after a maternal primary infection occurring in first trimester of pregnancy: Systematic review

Introduction Congenital CMV infection is the first worldwide cause of congenital viral infection but systematic screening of pregnant women and newborns for CMV is still debated in many countries. Objectives This systematic review aims to provide the state of the art on current practices concerning management of maternal and congenital CMV infection during pregnancy, after maternal primary infection (PI) in first trimester of pregnancy. Data sources Electronically searches on databases and hand searches in grey literature. Study eligibility criteria and participants Primary outcome was listing biological, imaging, and therapeutic management interventions in two distinct populations: population 1 are pregnant women with PI, before or without amniocentesis; population 2 are pregnant women with congenitally infected fetuses (after positive amniocentesis). Secondary outcome was pregnancy outcome in population 2. Results Out of 4,134 studies identified, a total of 31 studies were analyzed, with 3,325 pregnant women in population 1 and 1,021 pregnant women in population 2, from 7 countries (Belgium, France, Germany, Israel, Italy, Spain and USA). In population 1, ultrasound (US) examination frequency was 0.75/month, amniocentesis in 82% cases, maternal viremia in 14% and preventive treatment with hyperimmune globulins (HIG) or valaciclovir in respectively 14% and 4% women. In population 2, US examination frequency was 1.5/month, magnetic resonance imaging (MRI) in 44% cases at 32 weeks gestation (WG), fetal blood sampling (FBS) in 24% at 28 WG, and curative treatment with HIG or valaciclovir in respectively 9% and 8% patients. Conclusions This systematic review illustrates management of maternal and congenital CMV during pregnancy in published and non-published literature, in absence of international consensus. Systematic review registration PROSPERO CRD42019124342

Clinical case of congenital CMV neuroinfection in a child with selective IgA deficiency

Congenital CMV infection is thought to occur in at least 1 % of infants, although recent clinical studies indicate that these lesions account for 8 % of all neonates. The severity of clinical symptoms of nervous system damage of CMV-etiology depends on the duration of intrauterine infection. In early infection, during the first trimester of the fetal period, severe CNS malformations develop, including anencephaly, porencephaly, schizencephaly, lissencephaly, micropolygyria, and pachygyria. At later infection, during the 2nd–3rd trimesters of pregnancy, there are milder manifestations — ventriculomegaly, impaired myelination of the white matter of the brain, cysts in the poles of the temporal lobes, hypogenesis of the corpus callosum, periventricular calcifications, and lesions of the cochleovestibular nerves. The article presents the medical history of a 5-year-old boy with typical clinical and instrumental signs of congenital CMV infection. The child had deep spastic tetraparesis, severe mental retardation, refractory epileptic syndrome with polymorphic seizures, disorders of pelvic organs, inability to move independently. MRI of the brain showed typical radiological signs of congenital CMV infection: cortical atrophy, ventriculomegaly, periventricular gliosis, demyelination fields in the white matter of the hemispheres, cysts in the poles of the temporal lobes, hypoplasia of the corpus callosum. During the neonatal period, specific IgM to CMV in serum was observed. Blood leukocyte PCR revealed the CMV DNA in a 5-year-old child at the time of admission to the clinic. This infection led to genera-lized lymphadenopathy, hepatosplenomegaly, thrombocytopenia, and lymphomonocytosis. The assessment of immune status showed the presence of selective IgA deficiency, which was associated with the development of this opportunistic infection. Typical mistakes in the clinical management of children with congenital CMV infection and ways to avoid them are discussed.

Family Perceptions of Newborn Cytomegalovirus Screening: A Qualitative Study

Objectives: We sought to understand long-term retrospective parental perceptions of the utility of newborn screening in a context where many affected children never develop sequelae but where intensive support services and ongoing healthcare were provided. Study design: Qualitative study. Methods: Focus groups and interviews among parents (N = 41) of children with congenital CMV who had been enrolled in a long-term follow-up study at a large medical college for a mean of 22 years following diagnosis. Groups included parents whose children were: symptomatic at birth; initially asymptomatic but later developed sensorineural hearing loss; and who remained asymptomatic into adulthood. Results: With proper follow-up support, newborn CMV screening was viewed positively by parents, who felt empowered by the knowledge, though parents often felt that they and healthcare providers needed more information on congenital CMV. Parents in all groups valued newborn CMV screening in the long term and believed it should be embedded within a comprehensive follow-up program. Conclusions: Despite initial distress, parents of CMV-positive children felt newborn CMV screening was a net positive. Mandatory or opt-out screening for conditions with variable presentations and treatment outcomes may be valuable in contexts where follow-up and care are readily available.

In vivo magnetic resonance imaging evidence of olfactory bulbs changes in a newborn with congenital Citomegalovirus: a case report

Background Citomegalovirus (CMV) infects approximately 1% of live newborns. About 10% of the infants affected by congenital CMV infection are symptomatic at birth and up to 60% of these infants will develop permanent neurological disabilities. Depending on gestational age (GA) at the time of infection, the involvement of central nervous system (CNS) can lead to malformations of cortical development, calcifications, periventricular white matter lesions and cysts, ventriculomegaly and cerebellar hypoplasia. Case presentation We report the MRI findings in a Caucasian female born at 32 weeks of post-menstrual age with post-birth diagnosis of congenital CMV infection showing an unusual and peculiar marked T2 hyperintensity of the inner part of olfactory bulbs in addition to the CMV related diffuse brain involvement. Despite the known extensively described fetal and neonatal Magnetic Resonance Imaging (MRI) findings in CMV infected fetuses and newborns, any in vivo MRI depiction of olfactory system damage have never been reported so far. Nevertheless, in murine studies CMV is known to infect the placenta during pregnancy showing particular tropism for neural stem cells of the olfactory system and previous neuropathologic study on CMV infected human fetal brains from 23 to 28 weeks of GA reported damage in the olfactory bulbs (OB) consisting in disseminated cytomegalic cells, inflammation, necrosis and neuronal and radial glial cell loss. Therefore, we assume an OB involvement and damage in congenital CMV infection. Conclusion To our knowledge this is the first in vivo MRI evidence of OB damage in a newborn with congenital CMV infection that may give new insights on CMV infection.

The association between maternal cytomegalovirus urinary excretion and congenital infection rate

Background In utero Cytomegalovirus (CMV) vertical transmission occurs predominantly during primary maternal infection. There are no known non-invasive methods for diagnosis of fetal infection before delivery, however some risk factors have been suggested. We aimed to evaluate the association between maternal CMV urinary excretion and congenital CMV infection. Methods A retrospective cohort study of all women who were diagnosed with primary CMV infection during pregnancy in a single university affiliated tertiary medical center, between 2012 and 2016. We examined congenital CMV infection and disease rates among infants born to women with and without CMV urinary excretion. Results Overall, 126 women were included, 77 in the positive urinary excretion group, and 49 in the negative urinary excretion group. There was no difference in maternal symptoms between the groups. We found no difference in congenital CMV infection and disease rates between infants born to women with and without urinary excretion of CMV (congenital infection rate 37.1% vs. 24.4%, p = 0.209, congenital disease rate of 18.2% vs. 22.4%, p = 0.648). Women with positive urinary CMV excretion had lower IgG avidity values (36.7% vs 54.6%, p = 0.007), with no additional difference in serology pattern. Compared to asymptomatic women, those with CMV related symptoms did not have significantly higher rates of urinary excretion of CMV (70% vs. 60.5%, p = 0.38) or congenital infection rates (40.7% vs. 31.2%, p = 0.48). Conclusion Among infants of women with primary CMV infection in pregnancy, we did not find an association between urinary excretion of CMV and congenital CMV infection.

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