Congenital cytomegalovirus infection

Each year, thousands of children are born with or develop permanent disabilities such as hearing loss, vision loss, motor and cognitive deficits from congenital CMV infection (cCMV). However, awareness of cCMV and its associated sequelae is very low in pregnant women and healthcare providers. Both targeted and universal approaches to screen newborns for CMV infection are now achievable due to recent scientific advances including the development of a rapid, high-throughput method for detecting CMV in saliva, the efficacy of antiviral treatment in symptomatic infants, and the demonstration of cost effectiveness of CMV screening. Future studies are needed to address gaps in our understanding on the role of non-primary maternal CMV infections, the evaluation of antiviral treatment in asymptomatic infants, and the implementation of prevention strategies for cCMV.     

Neonatal screening for congenital CMV infection stresses the importance of maternal nonprimary infection even in an area where prenatal serology testing is common

Aim and Methods: Dried blood spots from 2149 newborns were examined to diagnose congenital cytomegalovirus (cCMV).

Results: Prenatal CMV-IgG antibodies had been measured during prenatal care in 1287 (60.3%) of mothers and 980 (76.1%) of them were found seropositive. cCMV incidence was 0.47%. All newborns were asymptomatic; 9/10 were born post nonprimary maternal infection; two developed sensorineural hearing loss.

Conclusions: In a country where prenatal CMV testing is common and therefore a false sense of control might prevail, nonprimary maternal infection should not be overlooked. Indeed, women of childbearing age should be educated on CMV prevention measures irrespectively to their serostatus.     

Prevention and treatment of fetal cytomegalovirus infection with cytomegalovirus hyperimmune globulin: a multicenter study in Madrid

Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection.

Materials and methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009–2015, CMV-HIG (Cytotect^® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy.

Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38–40) and two children (5.5%) were premature (born at 28 and 34 weeks’ gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3–1185; p?=?.007).

Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.     

Anti-viral therapy for congenital cytomegalovirus infection: pharmacokinetics,efficacy and side effects

Congenital cytomegalovirus (CMV) infection is the most common congenital infection in the world with approximately 0.5–2% of all live born infants, and can cause early or late severe neurological and neurisensorial damage. Although no drug has been licensed for therapy of congenital CMV infection, ganciclovir (GCV) and its oral pro-drug, valganciclovir (val-GCV), is increasingly being administrated to symptomatic infants, to improve neurodevelopmental and auditory outcome. Other potentially efficacious for therapy of congenital CMV disease are foscarnet and cidofovir, which have only been administered in few cases. A literature search was performed to look for evidence based or scientific articles evaluating pharmacokinetics, efficacy, and side effects of GCV/val-GCVand the other two anti-viral drugs.     

Cytomegalovirus infection in infants admitted to a neonatal intensive care unit

Abstract

Objectives: To determine the incidence of congenital cytomegalovirus (CMV) infection and the frequency of postnatal infection in a neonatal intensive care unit (NICU).

Methods: Urine samples of 135 infants who were admitted to the NICU during a 6 month period were evaluated to detect CMV using a nested PCR assay. A breast milk sample was obtained to determine viral excretion. Clinical characteristics of infected and non-infected infants were compared.

Results: Congenital CMV infection was confirmed in two (1.48%) infants. Post-natal infection was documented in four of 36 (11.1%) infants that were evaluated. CMV excretion was detected in 43 of 116 mothers. Gestational age of infants born to mothers who excreted CMV was shorter than that of infants of mothers with negative results (33.1 versus 34.2 weeks; p?=?0.07).

Conclusions: CMV excretion in breast milk is frequent and is associated to congenital and postnatal infection. Further studies are necessary to assess the impact of CMV infection during pregnancy and neonatal outcomes.     

Knowledge of Congenital CMV,Risk Behaviours for CMV Acquisition,and Acceptance of an Educational Infographic Among Postpartum Women: A Pilot Study

Congenital cytomegalovirus (cCMV) infection in the newborn can present with sensorineural hearing loss and microcephaly. The objectives of this study were to determine baseline knowledge of cCMV and the acceptability of an infographic about cCMV among a group of postpartum women. Participants completed a questionnaire assessing their perceptions of an infographic as well as their knowledge and risk behaviours for acquisition of CMV. Of all 140 respondents, 119 (85%) had no prior knowledge of cCMV, and all 12 women (8.6%) who viewed the infographic indicated that it was helpful. Our study also demonstrated that passive dissemination of an infographic in clinics results in limited viewership.     

DNA-positive,IgM-negative symptomatic congenital cytomegalovirus infection: Two case reports

The characteristics of two newborns that had clinical symptoms of congenital cytomegalovirus have been presented here, whose CMV-DNA was found to be positive by the PCR method, despite serological analysis being negative for CMV IgM. In conclusion, when congenital CMV infection is suspected in newborns, it should not be forgotten that the sensitivity of serological CMV IgM assay is 70% and other methods such as CMV-DNA analysis should be performed in case of negative test results.     

Congenital and perinatal cytomegalovirus lung infection

Abstract

Background: Cytomegalovirus (CMV) pneumonitis may be severe, even lethal, following congenital infection or in premature infants with perinatal infection.

Objective: To review the epidemiological, pathogenetic, clinical and therapeutic features of prenatal and perinatal CMV lung diseases.

Methods: Evaluation of all published papers listed on PubMed describing CMV pneumonitis in infants.

Results: CMV is frequent and severe in immunosuppressed infants but infrequent in full-term neonates and occurs more frequently after perinatal than after congenital infection, particularly in premature infants. In premature infants, CMV infection is often protracted and causes a diffuse interstitial pneumonitis leading to fibrosis and bronchopulmonary dysplasia (BPD). Congenital CMV infection should also be considered in newborns with severe acute respiratory distress syndrome and refractory respiratory failure with progression to early chronic lung disease. The association between breast milk-transmitted CMV and development of cystic lung disease and Wilson–Mikity syndrome has also been reported. Data on the efficacy of antiviral therapy for infants with respiratory CMV diseases are lacking and only anecdotal case reports are available.

Conclusions: Persistent CMV infection appears to cause a diffuse necrotizing pneumonitis with fibrosis leading to BPD, in both immunocompromised or preterm infants and, less frequently in immunocompetent infants. The role of antiviral therapy remains to be elucidated.     

Fetal viral infection: a pragmatic approach to recognition and management

Viruses can be transmitted from a pregnant woman to her fetus via the placenta and can affect development and growth. Maternal infection is often asymptomatic or mild. The implications for the fetus are dependent on gestation, stage of organogenesis, the presence of maternal immunity and the virus type. Fetal infections are a potentially preventable cause of perinatal morbidity and mortality. Prenatal diagnosis is often initiated due to exposure of mother to an infectious contact. Management involves confirmation of maternal infection and careful consideration of the risks and benefits of fetal diagnosis, fetal surveillance, intrauterine treatment and possibly termination of pregnancy. Empathic and effective counselling of the parents is crucial and a multidisciplinary approach is important for optimal care. This case based review follows three pregnancies to illustrate a pragmatic approach to the prenatal diagnosis and management of three common fetal viral infections.     

Flow cytometric white blood differential using CytoDiff™ in the diagnosis of neonatal early-onset infection

Objective: Neonatal early-onset infection is a life-threatening disease, requiring early diagnosis and treatment. Newborns at risk are identified by a combination of risk factors, clinical signs of infection and laboratory parameters such as white blood cell count and C-reactive protein (CRP). This method is labor-intensive, time consuming and has a variable reproducibility. New reliable diagnostic markers are needed to identify neonatal infection. This study presents additional leukocyte differential parameters produced by the automated flow cytometry and processing software using CytoDiff? reagent (Beckman Coulter) in newborns suspected for early-onset infection.

Methods: An analytic prospective observational case–control study was performed in which 185 newborns were included and retrospectively allocated into two groups, “infection likely” and “infection unlikely”. Leukocyte parameters of the CytoDiff? technique were compared with microscopic slide differentiation and routine tests.

Results: We showed significant lower numbers of monocytes, CD16(?) monocytes and lymphocytes (including T+/NK-lymphocytes) in neonates suspected for early-onset infection using CytoDiff? technique. The manual counting did not demonstrate changes with respect to the number of monocytes in these neonates.

Conclusions: The automated routine CytoDiff? leukocyte differential provides an interesting additional diagnostic tool, next to routine laboratory diagnostics, in the diagnosis of neonatal early-onset infection.     

Recent advances in the prevention and treatment of congenital cytomegalovirus infections

Continued but slow progress has led to recent advances in our understanding that congenital cytomegalovirus (CMV) infection has occurred. We understand that the most severe congenital disease occurs following a primary maternal infection during pregnancy. We now have the ability to accurately diagnosis a primary maternal infection using serologic studies of single serum sample. For pregnant women with young children, we know that child-to-mother CMV transmission can probably be prevented by hygienic intervention, and that for pregnant women who have acquired a primary CMV infection, mother-to-fetal transmission is probably preventable using CMV hyperimmune globulin. Although additional studies are needed, treatment of congenitally infected fetuses or newborns should be possible using either CMV hyperimmune globulin or antiviral agents such as ganciclovir or its derivates. Finally, recent evidence indicates that CMV replicates in the placenta, impairs development, and causes inflammation and dysfunction. This plus the reversibility of many manifestations of congenital infection in the fetus and newborn indicate that congenital CMV disease is in part a syndrome of placental insufficiency.     

Cytomegalovirus infection: perinatal implications

Cytomegalovirus (CMV), a member of the herpes virus family, is the most common cause of congenital infection in humans, affecting 0.5-3% of all newborns worldwide. Congenital cytomegalovirus infection is the leading infectious cause of deafness, learning disabilities, and mental retardation in children. The high prevalence of cytomegalovirus in the general population, unpredictability of transmission, and asymptomatic nature of the disease in otherwise healthy women challenge prevention and treatment efforts.     

Neuroimaging findings using transfontanellar ultrasound in newborns with microcephaly: a possible association with congenital Zika virus infection

Objective: The objective of this study is to determine the main neuroimaging findings of microcephalic newborns with possible Zika virus (ZIKV) intrauterine infection using transfontanellar cranial ultrasound.

Methods: We performed a retrospective study to describe the main neuroimaging findings in newborns with microcephaly and possible association with congenital ZIKV infection. Microcephaly was defined in the postnatal period using transfontanellar cranial examination which was performed using both two- (2D) and three-dimensional (3D) ultrasound.

Results: One hundred and fifty newborns with microcephaly were identified during the study period. The mean?±?(standard deviation - SD) of cephalic perimeter was 28.5?±?4.2?cm (range, 25–38?cm). Transfontanellar neuroimaging patterns detected cerebral calcifications, neuronal migrational abnormalities, dysgenesis of the corpus callosum, and cerebellar atrophy in 34.9%, 31.1%, 26%, and 16.2%, respectively. Hydrocephalus was seen in 28% of overall newborns. A history of maculopapular rash was present in almost half of the mothers (46.1%).

Conclusion: Neuroimaging patterns by means of transfontanellar ultrasound are accurate and diagnostic investigations of brain pathology in newborns affected by microcephaly and possible intrauterine ZIKV infection.     

Persistent intestinal bleeding due to severe CMV-related thrombocytopenia in a preterm newborn

The optimal threshold for neonatal platelet transfusions in sick newborns is still uncertain. We report a congenital cytomegalovirus (CMV) infection in a premature neonate with severe thrombocytopenia who subsequently presented with necrotizing enterocolitis and intestinal bleeding. The baby recovered after platelet transfusions were discontinued and the therapy was switched from intravenous ganciclovir to oral valganciclovir. We discuss both measures, speculating on the key role of platelet transfusions.     

Maternal–fetal cytomegalovirus infection: From diagnosis to therapy

Cytomegalovirus (CMV) is the most common and serious congenital infection, because it occurs after both primary and recurrent infection in pregnancy and is a major cause of childhood deafness and neurological handicap. Fetal transmission generally occurs in 30–60% of women acquiring a primary infection or in 0.5–2% of women with preconceptional immunity. Following primary maternal infection, approximately one-third of the CMV-infected infants will have disease at birth or develop severe sequelae, which include convulsive or spastic syndromes, mental retardation and auditory and visual impairment. Routine antepartum and in pregnancy serological screening should be essential for avoiding doubtful interpretations of CMV-IgM results in pregnancy. Detection of quantitative CMV DNA in the amniotic fluid and accurate ultrasound examinations are needed in pregnant women with suspected primary infection. Being not yet available a vaccine and uncertain the results of postnatal ganciclovir therapy, CMV hyperimmunoglobulin appears to be the only safe and valid approach for prevention of congenital CMV disease.     

Seroepidemiologic study of human cytomegalovirus in pregnant women in Valiasr Hospital of Kazeroon,Fars, Iran

Background. Cytomegalovirus (CMV) is a common opportunistic infection among HIV-infected individuals, a major source of serious complications among organ-transplant recipients, and a leading cause of hearing loss, vision loss, and mental retardation among congenitally infected children. Women infected for the first time during pregnancy are especially likely to transmit CMV to their fetuses.

Objective. In this study, it was aimed to determine the rate of CMV seroprevalence in pregnant women, the prevalence of maternal CMV infection and also the incidence of congenital CMV infection in their newborns in the Kazeroon, south of Iran.

Methods. Between January 2007 and July 2007, all (n = 1472) pregnant women who attended the obstetric ward of Valiasr hospital in Kazeroon for delivery, were enrolled in this study, and according to the presence or absence of anti CMV-IgM and CMV-IgG, were classified as seropositive, seronegative and having active maternal CMV infection. Differentiation of primary and recurrent CMV infection in women with both CMV-IgM (+) and CMV-IgG (+) antibody was determined by the avidity index (AI) of anti-CMV IgG.

Results. The rate of seropositivity was found as 97.69% and the rate of seronegativity as 2.31% in pregnant women. The prevalence of active maternal CMV infection was found as 4.35% and among these pregnant women, the incidence of primary and recurrent maternal CMV infection was 34.4% and 65.6% respectively.

Conclusion. Seroprevalence rate of CMV in pregnant women is high and most infections are recurrent. Thus, it does not seem to be cost-effective to screen all pregnant women for CMV infection, as in the other countries with high seropositivity rate.     

ACOG Practice Bulletin No. 88, December 2007. Invasive prenatal testing for aneuploidy

Prenatal diagnosis of fetal chromosomal abnormalities is the most common indication for invasive prenatal testing. The prevalence of chromosomal abnormalities in clinically recognized early pregnancy loss is greater than 50%(1). Fetuses with aneuploidy account for 6-11% of all still births and neonatal deaths(2). Chromosomal abnormalities that are compatible with life but cause considerable morbidity occur in 0.65% of newborns, and structural chromosomal rearrangements that will eventually affect reproduction occur in 0.2% of newborns(3). Consequently, screening and diagnostic programs to detect the most common autosomal trisomies in liveborn infants, including Down syndrome, are well established. The purpose of this document is to provide clinical management guidelines for the prenatal diagnosis of these aneuploidies.     

Intrauterine therapy with cytomegalovirus hyperimmunoglobulin for a fetus congenitally infected with cytomegalovirus

Reported herein is a case of hydrops fetalis in which the cord blood expressed cytomegalovirus (CMV) antigen. Fetal ascites was removed from an infected fetus with hydrops in utero and 2.5 g CMV hyperimmunoglobulin was administered into the fetal abdominal cavity at 28 weeks gestation. After immunoglobulin administration, fetal ascites vanished, preload index of the inferior vena cava decreased and platelet count of the infant increased. However, despite intrauterine therapy and intensive neonatal care, the infant died soon after birth. The expression of CMV antigen in the nucleus of polymorphonuclear leukocytes in fetal cord blood indicated that the fetal hydrops was caused by CMV infection. When symptomatic CMV infection of a fetus is suspected from serological and ultrasound findings, further examinations should be performed for the diagnosis. Intrauterine immunoglobulin therapy could be one of the therapeutic options for the affected fetus.     

Fetal manifestations and poor outcomes of congenital cytomegalovirus infections: possible candidates for intrauterine antiviral treatments

AIM: This retrospective study was performed to reveal the natural history of cytomegalovirus (CMV) infected fetuses during the perinatal period and to find prenatal findings associated with poor outcomes. METHODS: 33 neonates with CMV infection, born after 30 weeks of gestation, were registered from a total of 12 414 infants between 1995 and 2003. Maternal and neonatal medical records were reviewed regarding fetal growth; abdominal signs including ascites and hepatosplenomegaly; cerebral signs including ventriculomegaly, microcephaly, and calcification; and fetal heart rate monitoring, for signs which may have been detected by the standard obstetric ultrasonography. Univariate and multivariate analyses were performed to test for any associations between these manifestations and poor outcomes such as death and neurological damages. RESULTS: Among the 33 infants, 6 died, 10 developed neurological damage including cerebral palsy (n = 8), epilepsy (n = 5), and hearing difficulties (n = 5), and the remaining 17 were normal. After adjusting for ganciclovir treatment and gender, death was 40-fold more likely associated with infants having abdominal signs (OR 40, 95%CI 4.6-930) than those without abdominal signs. Similarly, poor outcomes (death or neurological damage) were more likely associated with infants having either abdominal or cerebral signs (OR 39, 95%CI 3.8-1323). Fetal growth restriction and non-reassuring fetal heart rate patterns were not significantly associated with poor outcomes. CONCLUSION: The absence of abdominal signs guarantees the infant's survival. The presence of abdominal or cerebral signs is associated with poor outcomes, suggesting that these fetuses are possible candidates to receive in-utero therapy of congenital CMV infection.     

Congenital cytomegalovirus infection in Central Germany: an underestimated risk

Purpose

This is the first study to determine the cytomegalovirus (CMV) seronegativity rate for women of childbearing age in Saxony-Anhalt and to determine the prevalence of clinically relevant congenital CMV (cCMV) infection in Central Germany, because there are no valid data available.

Methods

The retrospective study was undertaken between January 2005 and December 2015. For the first time in Germany, the following seven data sources were used to analyze the prevalence of clinically relevant cCMV infection and the rate of CMV seronegative women of childbearing age: CMV Screening in maternity unit, University Women’s Hospital, Social Paediatrics Centre (SPC), Malformation Monitoring Centre (MMC), Newborn Hearing Screening (NHS), Neonatal Intensive Care Unit (NICU), and In-house Doctor Department. Key parameters were anti-CMV IgG and IgM, CMV PCR of urine, and clinically relevant symptoms caused by CMV.

Results

Between 46 and 52% of women of childbearing age were CMV seronegative. The prevalence of clinically relevant cCMV infection was between 0.008 and 0.04%.

Conclusions

The CMV seronegativity rate of women of childbearing age was confirmed to be in the middle range of estimated data from other sources in Germany. Data from the NICU, SPC, NHS, and MMC show the prevalence of clinically relevant cCMV infection. The risk of all cCMV infections is underestimated. Thus, the true prevalence of clinically relevant and subclinical cCMV infections is >0.04%.