Symptomatic Congenital Infection Research Articles

Maternal Fever and Reduced Fetal Movement as Predictive Risk Factors for Adverse Neonatal Outcome in Cases of Congenital SARS-CoV-2 Infection: A Meta-Analysis of Individual Participant Data from Case Reports and Case Series

Objectives: To determine risk factors for primary and secondary adverse neonatal outcomes in newborns with congenital SARS-CoV-2 infection. Data sources: PubMed/MEDLINE and Google Scholar from January 2020 to January 2022. Study eligibility criteria: newborns delivered after 24 weeks of gestation with confirmed/possible congenital SARS-CoV-2 infection, according to standard classification criteria. Methods: Execution of the IPD analyses followed the PRISMA-IPD statement. Univariate non-parametric tests compared numerical data distributions. Fisher’s exact or Chi-square test determined categorical variables’ statistical significance. Multivariate logistic regression revealed risk factors for adverse neonatal outcome. Results: Maternal fever was associated with symptomatic congenital infection (OR: 4.55, 95% CI: 1.33–15.57). Two-thirds of women that reported decreased fetal movements were diagnosed with IUFD (p-value = 0.001). Reduced fetal movement increased the risk of intrauterine fetal death by 7.84 times (p-value = 0.016, 95% CI: 2.23–27.5). The risk of stillbirth decreased with gestational age at the time of maternal infection (p-value < 0.05, OR: 0.87, 95% CI: 0.79–0.97). Conclusions: Maternal fever and perception of reduced fetal movement may be predictive risk factors for adverse pregnancy outcome in cases with congenital SARS-CoV-2 infection.

On the classification of cytomegalovirus infection in newborn children

Relevance: Cytomegalovirus (CMV) infection is the most common infection that is most commonly found in sick newborns and may be the leading cause of their morbidity and mortality. Current research and clinical observations confirm the likelihood of contracting CMV infection not only in the antenatal period but also in the perinatal and postnatal periods. The study aimed to comment on the current understanding of neonatal CMV infection, its clinical manifestations depending on the time of infection, perinatal outcomes, and long-term consequences to develop a functional classification of CMV infection in newborns. Materials and methods: A systematic review and analysis of the literature sources published by scientists in neonatology and perinatology, healthcare practitioners, and professional associations was carried out. Literature searches were conducted in PubMed, Embase, Scopus, and Euro-Peristat over the past decade by the study keywords. A total of 30 sources were included in the analysis. Results: Delayed sequelae, symptomatic and asymptomatic congenital and perinatal infections have been identified. A review shows that, to date, the incidence of asymptomatic congenital CMV infection has not been established. There is no systematization of the clinical manifestations and outcomes of congenital, perinatal, and postnatal CMV infection in newborns. Conclusion: Based on the literature review, we have developed a functional classification of CMV infection in newborns by the time of infection. Thus, CMV infection can be congenital, perinatal, or postnatal. The classification presents manifestations of symptomatic forms of CMV infection, perinatal and distant outcomes. However, there are no clear diagnostic criteria for asymptomatic forms of CMV infection. There is no clear rationale for etiopathogenetic therapy, prognostic and preventive criteria for various forms of CMV infection. All of the above tasks require further prospective cohort studies.

Maternal-Fetal Infections (Cytomegalovirus, Toxoplasma, Syphilis): Short-Term and Long-Term Neurodevelopmental Outcomes in Children Infected and Uninfected at Birth.

(1) Background: Infections in pregnancy can lead to miscarriage, premature birth, infections in newborns, and developmental disabilities in babies. Infected infants, symptomatic at birth, can have long-term sequelae, and asymptomatic babies are also at increased risk of developing long-term sensorineural outcomes. Targeted therapy of the pregnant mother can reduce fetal and neonatal harm. (2) Aim of the study: To explore the association between symptoms and time of onset of long-term sequelae in infected children born from mothers who contracted an infection during pregnancy, by a long-term multidisciplinary follow-up. (3) Methods: For up to 2-4 years, we evaluated cognitive, motor, audiological, visual, and language outcomes in infants with symptomatic and asymptomatic congenital infections and in uninfected infants. (4) Results: 186 infants born from women who acquired Cytomegalovirus infection (n = 103), Toxoplasma infection (n = 50), and Syphilis (n = 33) during pregnancy were observed. Among them, 119 infants acquired the infection in utero. Infected infants, symptomatic at birth, obtained lower scores on the Cognitive and Motor Scale on Bayley-III compared to asymptomatic and uninfected infants (p = 0.026; p = 0.049). Many severe or moderate sequelae rose up within the first year of life. At 24 months, we observed sequelae in 24.6% (14/57) of infected children classified as asymptomatic at birth, compared to 68.6% (24/35) of symptomatic ones (χ2 = 15.56; p < 0.001); (5) Conclusions: Infected babies symptomatic at birth have a worse prognosis than asymptomatic ones. Long-term sequelae may occur in infected children asymptomatic at birth after the first year of life. Multidisciplinary follow-up until 4-6 years of age should be performed in all infected children, regardless of the presence of symptoms at birth.

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...

A Newborn with an Incidental Finding on Cranial Ultrasonography.

A 4-day-old male newborn has an incidental head ultrasound finding.Born to a 22-year-old gravida 2, para 1 White womanAntenatal serologic testing unremarkableNormal prenatal ultrasound scansNo history of consanguinityEstimated gestational age 36 weeksSpontaneous vaginal delivery, rupture of membranes 1 hour before deliveryApgar score: 9 and 10 at 1 and 5 minutes, respectivelyA male newborn is admitted to the NICU on day 2 after birth due to respiratory distress and was noted to have a sparse petechial rash; these symptoms resolved within 24 hours. A sepsis evaluation was completed and was negative. He remained hospitalized for 12 days due to feeding difficulties that improved over time.Heart rate: 152 beats/minRespiratory rate: 34 breaths/minBlood pressure: 75/56 mm Hg (mean 63 mm Hg)Oxygen saturation: 100% (in room air)Temperature: 98°F (36.6°C)Birthweight 2,635 kg (42nd percentile), length 46.5 cm (39th percentile), head circumference 33.0 cm (59th percentile)Weight 2,420 kgHead: Normocephalic; normal, open, flat fontanelles; symmetric facies; patent nares; intact palate; no neck mass or crepitus; nondysmorphicOral cavity: Pink mucosae, intact palate, no lymphadenopathy, normal suck and rooting reflexLungs: Clear, equal breath sounds; no respiratory distressCardiovascular: Normal S1, S2; regular rate and rhythm; no murmurs or gallopsAbdomen: Not distended; no organomegaly; no apparent discomfort on abdominal palpationGenitourinary: Normal male genitalia; patent anusSkeletal: Spine appears normalSkin: No icterus, birthmarks, or other rashesNeurologic: Symmetric Moro reflex, normal strength and toneComplete blood cell count with differential: NormalC-reactive protein: <0.29 mg/dL (<2.9 mg/L)Blood culture: SterileAt 4 days of age, head ultrasonography was performed in accordance with unit protocol for late preterm infants (Fig 1A and 1B).For a 4-day old late preterm newborn with an incidental finding on cranial ultrasonography, differential diagnostic considerations include: Hypoxic-ischemic encephalopathyCongenital infection (cytomegalovirus [CMV], toxoplasmosis, HIV, syphilis, rubella)Intracranial hemorrhageStrokeCongenital CMV infection.The ultrasound findings consist of thick hyperechogenic linear streaks in the thalami and basal ganglia (Figs 2A and 2B), without any signs of hemorrhage or stroke. These are consistent with stage 3 lenticulostriate vasculopathy (LSV). Antenatal serologic tests were reviewed: the mother was not tested for CMV during pregnancy. A CMV polymerase chain reaction (PCR) urinary screen was performed on day 8, with positive result.The infant had a normal hearing screen. Liver enzymes, bilirubin concentration, and renal function were also normal. He was discharged from the hospital at 12 days of age with a recommendation for follow-up in the neonatology outpatient clinic. He is currently 4 months old, has remained asymptomatic, and his neurodevelopment, vision, and hearing are all normal. Currently, he is not receiving any therapy.Given the risk of sensorineural deafness and ophthalmologic, neurologic, and neurodevelopmental disorders associated with CMV, this child will follow up with a multidisciplinary team with periodic developmental assessments.LSV is an ultrasonographic finding that is characterized by increased echogenicity in the lenticulostriate arteries at the basal ganglia and/or thalamus. The pathogenesis is unclear. (1) The diagnosis of LSV is operator-dependent; to reduce interrater variability, Sisman et al proposed a classification system that categorizes LSV into 4 stages, according to vessel thickness and hyperechogenicity (2): Stage 0: Lenticulostriate vessels are not visibleStage 1: Lenticulostriate vessels are thin and faintly seenStage 2: Lenticulostriate vessels are thin, but hyperechogenicStage 3: Lenticulostriate vessels are thick and hyperechogenic (echogenicity similar to sylvian fissure)LSV can be associated with many conditions, infectious and noninfectious, including Toxoplasma gondii, other agents, rubella, CMV, and herpes simplex virus (TORCH) infections, chromosomal disorders, and asphyxia. LSV can also be a nonspecific finding in 19% of cases and it is most commonly associated with hypoxic-ischemic conditions. (3) It is detected in 0.4% to 5.8% of head ultrasound scans obtained in neonates. (4) A more accurate classification by stages and the assessment of progression may be useful in the future to reduce the range of differential diagnoses. (2)The most common congenital infection associated with LSV is CMV; the greater the severity of the LSV, the more likely the infant has CMV. (5) In addition, when LSV is associated with other structural abnormalities in the brain, CMV infection is even more likely and associated with worse outcomes. (5) Routine CMV assessment in the presence of isolated LSV is controversial; in this scenario, it is reasonable to perform urine CMV PCR screening, keeping in mind that this is an inexpensive and noninvasive test. (1)(6) Amir et al suggest that LSV is a possible marker of high risk for sensorineural loss in both symptomatic and asymptomatic CMV congenital infection. (4) The prognostic value of LSV has been challenged by other authors who believe that more extensive neuroimaging anomalies have greater prognostic value. (7) The clinical significance of asymptomatic LSV on long-term neurodevelopmental outcome is not clear. (1)Several cranial ultrasound signs are suggestive of congenital infections; these include ventriculomegaly; calcifications; subependymal, periventricular, or germinolytic cysts; and brain atrophy. (7)(8) Maternal serologies can help to exclude HIV, syphilis, and rubella.Hypoxic-ischemic encephalopathy in the newborn may also present with focal brain injury in the thalamic and basal ganglia regions. Ultrasound findings include focal or diffuse hyperechogenicity in the thalamus, basal ganglia, and perirolandic cortex, and signs of cerebral edema, such as loss of grey-white matter differentiation and obliteration of the cerebrospinal fluid–containing spaces. (8) Magnetic resonance imaging is more specific and sensitive than ultrasonography to diagnose hypoxic-ischemic encephalopathy. In the case presented, this etiology was less likely because there was no prenatal sentinel event, there were no signs of fetal distress or need for resuscitation, the infant’s Apgar scores were normal, and the infant had normal neurologic findings.A thalamic stroke or hemorrhage can also present with hyperechogenicity on cranial ultrasonography. However, it usually has a curved well-delineated configuration as opposed to the linear streaks in LSV and is mostly unilateral. The clinical signs associated with these conditions include seizures, apnea, and hypotonia, among other neurologic deficits.LSV is often a nonspecific ultrasonographic finding but it can be associated with congenital infections or other etiologies.Although controversial, if LSV stage 3 is identified on head ultrasonography, testing for CMV should be considered.Early detection can have an impact on prognosis because of the possibility of close follow-up and initiation of potential therapies in cases of LSV that are associated with congenital CMV.

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.

Identification of Biomarkers for Diagnosis and Prognosis of Congenital and Acute Toxoplasmosis.

The diagnosis of congenital toxoplasmosis can be inconclusive in many cases. Despite the several serological tests developed, the literature on biomarkers that can assist in the diagnosis of congenital an acute toxoplasmosis is limited. The objective of this study was to analyze the immunoreactive profile of Toxoplasma gondii protein bands with the potential to be biomarkers for diagnosis and prognosis of congenital and acute toxoplasmosis. Peripheral blood samples from women of childbearing age and/or pregnant women diagnosed with acquired toxoplasmosis as well as from congenitally infected children were selected and submitted to immunoblotting for analysis of the immunoreactive bands profile by immunoglobulin G (IgG) antibodies. When comparing the immunoreactive bands profile for antibodies present in samples from different groups and subgroups, the 150, 18.5, and 16.96-kDa bands were more immunoreactive with the antibodies present in serum samples from the acquired infection group. The 343, 189, 150, 75, and 42-kDa bands showed more chance to be detected by the symptomatic congenital infection subgroup samples, while the 61, 50, and 16.96-kDa bands were significantly immunoreactive with the acute infection subgroup samples. The identification of these potential biomarkers can assist in early diagnosis and treatment of congenital toxoplasmosis.

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.

Keypoints for management of neonatal cytomegalovirus infection

Congenital infection of cytomegalovirus (CMV) of neonates and perinatal infection in preterm infants could be hazardous, especially for very low birth weight (VLBW) infants.Some permanent sequelae might occur in most symptomatic congenital infection and severe perinatal infection cases.However, most of the CMV infection in neonates is subclinical.It is still important to take appropriate measures to deal with different neonatal CMV infection situations.This article was focused on the epidemiology of neonatal CMV infection, clinical characteristics after infection, diagnosis of the pathogen, indications for treatment and the methods for processing the breast milk with virus. Key words: Cytomegalovirus; Infant, newborn; Very low birth weight infant; Treatment

Recurrent maternal CMV infection associated with symptomatic congenital infection: results from a questionnaire study in Portugal

ObjectiveHuman cytomegalovirus (CMV) is the most widespread agent of congenital infection in humans and is still a challenging issue. Despite lower rates of vertical transmission being associated with recurrent infection...

Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children

IntroductionZika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs)...

Diagnostic anténatal des infections virales materno-fœtales

Viruses that can be transmitted from mother to fetus during pregnancy are mainly rubella virus, cytomegalovirus, varicella zoster virus, parvovirus B19 and Zika virus. Congenital infections may lead to severe damage of the fetus or the newborn depending on the infectious agent and the term of pregnancy where the infection occurred. Symptomatic congenital infections more likely occur in case of maternal primary infection in the first half of pregnancy. Prenatal diagnosis mainly relies on PCR on amniotic fluid, and is usually very reliable. The aim of this article is to describe biological tools available for prenatal diagnosis, and management of congenital viral infections.

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.

Maternal and neonatal screening methods for congenital cytomegalovirus infection.

Human cytomegalovirus (CMV) is a common cause of congenital infection that may lead to severe long-term sequelae. Because there are no established vaccines, fetal interventions or neonatal treatments, neither maternal nor neonatal screening is recommended. However, recent studies have indicated that early antiviral treatment may improve neurological outcomes in symptomatic infants with congenital infection. Therefore, prenatal detection may be important in newborns at high risk of such infection. Polymerase chain reaction for CMV DNA in the amniotic fluid is considered the gold standard for diagnosis of intrauterine infection, but its use is limited because amniocentesis is an invasive procedure. In a prospective cohort study, we have reported that the presence of CMV DNA in secretions of the maternal uterine cervix were predictive of congenital infection in groups at high risk. However, we also recently demonstrated that maternal serological screening for primary CMV infection using specific immunoglobulin G, the immunoglobulin G avidity index or specific immunoglobulin M can overlook many cases. Previous research has indicated that the combination of early detection by universal neonatal screening of urinary CMV DNA combined with early antiviral therapy can improve outcomes in infants with symptomatic congenital infection. In this article, we review the current state of maternal and neonatal screening for congenital CMV infection.

OC21.06: Ultrasound prediction of symptomatic congenital Zika virus infection

OC21.06: Ultrasound prediction of symptomatic congenital Zika virus infection

Infections virales chez le nouveau-né

Neonatal infections can occur in the prenatal period (congenital infection) or in the first days of life. Congenital infections may lead to severe damage of the fetus or the newborn depending on the infectious agent and the term of pregnancy where the infection occurred. Symptomatic congenital infections more likely occur in case of maternal primary infection in the first half of pregnancy (cytomegalovirus, rubella virus, varicella-zoster virus). In the post-natal period, the virus’ involved are usually herpes simplex virus’, enterovirus, and varicella-zoster virus’. The aim of this article is to describe clinical consequences, biological tools available for diagnosis, and management of viral infections in the neonate.

Prevalence of congenital cytomegalovirus infection in symptomatic newborns under 3\xa0weeks in Tehran, Iran

BackgroundCytomegalovirus (CMV) is a common cause of congenital infection worldwide and infants with symptomatic congenital CMV (cCMV) infection are at significantly increased risk of developing adverse long-term outcomes. This study aimed to determine the prevalence of cCMV infections in symptomatic infants under 3 weeks in Tehran, IRAN and to evaluate the usefulness of serologic markers in these neonates.MethodsUrine and serum samples of 100 symptomatic infants, under 3 weeks old, with clinical signs referred to Tehran medical centers from June 2013 to December 2014, were collected and tested for CMV-DNA and IgG/IgM antibody titers by PCR and ELISA, respectively.ResultsCMV-DNA was detected in urine of 58 cases, whereas only 20 cases had detectable CMV-IgM titers. All CMV-IgM positive cases excreted CMV-DNA through their urine. Of the 100 patients, only 59 had CMV-IgG antibody and CMV-DNA was found in the urine of only 40 of them.ConclusionsWe conclude that CMV is an important etiologic agent of congenital infections in symptomatic infants in Tehran, IRAN (prevalence: 58%) and CMV-DNA detection immediately after delivery is recommended for early treatment and reduction of post infection problems. Furthermore, our study showed that the serologic markers are unreliable for diagnosis of cCMV infection in infants. This is the first report of cCMV prevalence in symptomatic congenital infections in Iran showing similarity with the world averages.

Perinatal Outcomes of Non-Primary Maternal Cytomegalovirus Infection: A 15-Year Experience

Objective: To evaluate perinatal outcomes in case of non-primary maternal cytomegalovirus (CMV) infection. Methods: We performed a retrospective cohort study of pregnant women with active CMV infection referred to our unit over a 15-year period (January 2000 to December 2014). Non-primary infection was diagnosed on the basis of the results of confirmatory serological and virological tests (avidity test, immunoblotting, real-time PCR-DNA). The vertical transmission rate and the percentage of symptomatic congenital infection were determined in this group of patients. Results: A total of 205 pregnant women were enrolled. Congenital infection occurred in 7 (3.4%) fetuses/neonates. Symptomatic disease was present at birth in 3 of the 7 congenitally infected neonates (1.5%). Two out of 3 symptomatic newborns presented a pathologic second-trimester ultrasound scan. Conclusion: Maternal immunity offers substantial protection against intrauterine transmission of CMV infection, but not against disease once the fetus is infected.

Primary versus non-primary maternal cytomegalovirus infection as a cause of symptomatic congenital infection – register-based study from Finland

Background: Both primary and non-primary maternal cytomegalovirus (CMV) infection during pregnancy can lead to vertical transmission. We evaluated the proportion of maternal primary/non-primary infections among 26 babies with symptomatic congenital CMV infection born in Finland from 2000 to 2012.Methods: We executed a database search on hospital records from all five university hospitals in Finland to identify infants with congenital CMV infection. The preserved maternal serum samples drawn at the end of the first trimester were analysed for CMV antibodies. Maternal infection was classified to be non-primary, if there was high avidity CMV immunoglobulin G (IgG) in the early pregnancy samples. Infection was considered primary in the case of either low avidity IgG (primary infection in the first trimester or near conception) or absent CMV IgG at the end of the first trimester (primary infection in the second or third trimester).Results: The majority of the symptomatic congenital CMV infections (54%) were due to maternal non-primary infection, 27% due to maternal primary infection in the first trimester or near conception, and 19% during the second or third trimester. Long-term sequelae occurred in 59% of patients: in 6/7 after primary infection in the first trimester, in 0/5 after primary infection in the second or third trimester, and in 9/14 after non-primary infection.Conclusions: In this register-based cohort, non-primary infections caused the majority of symptomatic congenital CMV infections, and resulted in significant morbidity.

Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta

Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from mid-gestation placentas formed foci of infection, and interferon-β production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-xL by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-xL, indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment.