CMV-infected Fetuses Research Articles

Neonatal and short-term outcome after late vertical transmission in congenital CMV-infected fetuses following primary first-trimester maternal seroconversion

ObjectiveTo document the course of neonatal and short-term outcomes in pregnancies after first trimester CMV (cytomegalovirus) seroconversion and negative amniotic fluid (AF) CMV PCR.MethodsWe included 375 patients with a first-trimester...

Brain Metabolite Differences in Fetuses With Cytomegalovirus Infection: A Magnetic Resonance Spectroscopy Study.

Cytomegalovirus (CMV) is the most common intrauterine infection and may be associated with unfavorable outcomes. While some CMV-infected fetuses may show gross or subtle brain abnormalities on MRI, their clinical significance may be unclear. Conversely, normal development cannot be guaranteed in CMV-infected fetuses with normal MRI. To assess brain metabolite differences in CMV-infected fetuses using magnetic resonance spectroscopy (MRS). Retrospective. Out of a cohort of 149 cases, 44 with maternal CMV infection, amniocentesis results, and good-quality MRS were included. CMV-infected fetuses with positive polymerase chain reaction (PCR) (N = 35) were divided based on MRI results as follows: typical brain abnormalities (gross findings, N = 8), exclusive white matter hyperintense signal (WMHS) on T2-weighted images (subtle findings, N = 7), and normal MRI (N = 20). Uninfected fetuses (negative PCR) with normal MRI were included as controls (N = 9). 3 T, T2-weighted half Fourier single-shot turbo spin-echo (HASTE), T2-weighted true fast imaging with steady-state free precession (TrueFISP), T1- and T2*-weighted fast low angle shot (FLASH), and 1H-MRS single-voxel point resolved spectroscopy (PRESS) sequences. MRI findings were assessed by three radiologists, and metabolic ratios within the basal ganglia were calculated using LCModel. Analysis of covariance test with Bonferroni correction for multiple comparisons was used to compare metabolic ratios between groups while accounting for gestational age. A P-value <0.05 was deemed significant. MRS was successfully acquired in 63% of fetuses. Substantial agreement was observed between radiologists (Fleiss' kappa [k] = 0.8). Infected fetuses with gross MRI findings exhibited significantly reduced tNAA/tCr ratios (0.64 ± 0.08) compared with infected fetuses with subtle MRI findings (0.85 ± 0.19), infected fetuses with normal MRI (0.8 ± 0.14) and controls (0.81 ± 0.15). No other significant differences were detected (P ≥ 0.261). Reduced tNAA/tCr within the apparently normal brain tissue was detected in CMV-infected fetuses with gross brain abnormalities, suggesting extensive brain damage. In CMV-infected fetuses with isolated WMHS, no damage was detected by MRS. 3 TECHNICAL EFFICACY: Stage 3.

Congenital Cytomegalovirus Infection With Isolated “Minor” Lesions at Fetal Magnetic Resonance Imaging: Long-Term Neurological Outcome

BackgroundThe prognostic relevance of fetal/early postnatal magnetic resonance (MR) imaging (MRI) isolated “minor” lesions in congenital cytomegalovirus (CMV) infection is still unclear, because of the heterogeneity of previously reported case series. The aim of this study was to report the imaging and long-term clinical follow-up data on a relatively large cohort of infected fetuses. MethodsAmong 140 CMV-infected fetuses from a single-center 12-year-long fetal MRI database, cases that showed isolated “minor” lesions at MRI, mainly represented by polar temporal lesions, were selected. MRI features were described, and clinical follow-up information was collected through consultation of medical records and telephone interview to establish the auditory and neurological outcome of each patient. ResultsThirty-six cases were included in the study. The frequency of “minor” lesions increased progressively with ongoing gestational age in cases who underwent serial MR examination; 31% of cases were symptomatic at birth for unilateral altered auditory brainstem response. At long-term clinical follow-up, performed in 35 patients at a mean age of 64.5 months (range: 25 to 138), 43% of patients were asymptomatic and 57% presented with mild/moderate disability including hearing loss (34%), unilateral in all cases but one (therefore classified as severe), and/or minor cognitive and behavioral disorders (49%). ConclusionsDescriptive analysis of the type and modality of occurrence of “minor” lesions suggests performing serial fetal/postnatal MR examinations not to miss later-onset lesions. Follow-up data from the present cohort, combined with maternal/fetal factors and serologic-laboratory parameters may contribute to improve prenatal and neonatal period counselling skills.

The Auditory Pathway in Congenitally Cytomegalovirus-Infected Human Fetuses.

Congenital cytomegalovirus (CMV) infection is the main cause of non-hereditary sensorineural hearing loss (SNHL). In order to shed light on SNHL pathophysiology, we examined the auditory pathway in CMV-infected fetuses; the temporal lobe, in particular the auditory cortex, and the inner ear. We investigated both inner ears and temporal lobes of 20 human CMV-infected fetuses at 21 weeks of gestation. As a negative group, five fetuses from spontaneous miscarriages without CMV infection were studied. Inner ears and temporal lobes were histologically examined, immunohistochemistry for CMV and CMV-PCR were performed. On the auditory cortex, we evaluated the local microglial reaction to the infection. CMV-positive cells were found in 14/20 brains and the damage was classified as severe, moderate, or mild, according to histological features. Fetuses with severe brain damage had a statistically higher temporal lobe viral load and a higher number of activated microglial cells in the auditory cortex compared to fetuses with mild brain damage (p: 0.01; p: 0.01). In the inner ears, the marginal cells of the stria vascularis were the most CMV positive. In our study, CMV affected the auditory pathway, suggesting a tropism for this route. In addition, in the auditory cortex, microglial activation may favor further tissue damage contributing to hearing loss.

Halo sign in fetal cytomegalovirus infection: cerebral imaging abnormalities and postmortem histopathology in 35 infected fetuses.

To evaluate the correlation of periventricular echogenic halo (halo sign) with histopathological findings and its association with other brain imaging abnormalities in fetuses with cytomegalovirus (CMV) infection. This was a retrospective study of fetuses diagnosed with severe CMV infection based on central nervous system (CNS) abnormalities seen on ultrasound, which had termination of pregnancy (TOP) or fetal demise at a single center from 2006 to 2021. All included cases had been evaluated by conventional complete fetal autopsy. A maternal-fetal medicine expert reanalyzed the images from the transabdominal and transvaginal neurosonography scans, blinded to the histological findings. The halo sign was defined as the presence of homogeneous periventricular echogenicity observed in all three fetal brain orthogonal planes (axial, parasagittal and coronal). Cases were classified according to whether the halo sign was the only CNS finding (isolated halo sign) or concomitant CNS anomalies were present (non-isolated halo sign). An expert fetal radiologist reanalyzed magnetic resonance imaging (MRI) examinations when available, blinded to the ultrasound and histological results. Hematoxylin-eosin-stained histologic slides were reviewed independently by two experienced pathologists blinded to the neuroimaging results. Ventriculitis was classified into four grades (Grades 0-3) according to the presence and extent of inflammation. Brain damage was categorized into two stages (Stage I, mild; Stage II, severe) according to the histopathological severity and progression of brain lesions. Thirty-five CMV-infected fetuses were included in the study, of which 25 were diagnosed in the second and 10 in the third trimester. One fetus underwent intrauterine demise and TOP was carried out in 34 cases. The halo sign was detected on ultrasound in 32 (91%) fetuses (23 in the second trimester and nine in the third), and it was an isolated sonographic finding in six of these cases, all in the second trimester. The median gestational age at ultrasound diagnosis of the halo sign was similar between fetuses in which this was an isolated and those in which it was a non-isolated CNS finding (22.6 vs 24.4 weeks; P = 0.10). In fetuses with a non-isolated halo sign, the severity of additional ultrasound findings was not associated with the trimester at diagnosis, except for microencephaly, which was more frequent in the second compared with the third trimester (10/18 (56%) vs 1/8 (13%); P = 0.04). With respect to histopathological findings, ventriculitis was observed in all fetuses with an isolated halo sign, but this was mild (Grade 1) in the majority of cases (4/6 (67%)). Extensive ventriculitis (Grade 2 or 3) was more frequent in fetuses with a non-isolated halo sign (21/26 (81%)) and those without a periventricular echogenic halo (2/3 (67%); P = 0.032). All fetuses with an isolated halo sign were classified as histopathological Stage I with no signs of brain calcifications, white-matter necrosis or cortical injury. On the other hand, 25/26 fetuses with a non-isolated halo sign and all three fetuses without a periventricular echogenic halo showed severe brain lesions and were categorized as histopathological Stage II. Among fetuses with a non-isolated halo, histological brain lesions did not progress with gestational age, although white-matter necrosis was more frequent, albeit non-significantly, in fetuses diagnosed in the second vs the third trimester (10/15 (67%) vs 3/11 (27%); P = 0.06). In CMV-infected fetuses, an isolated periventricular echogenic halo was observed only in the second trimester and was associated with mild ventriculitis without signs of white-matter calcifications or necrosis. When considering pregnancy continuation, detailed neurosonographic follow-up complemented by MRI examination in the early third trimester is indicated. The prognostic significance of the halo sign as an isolated finding is still to be determined. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Brain cortical maturation assessed by magnetic resonance imaging in unaffected or mildly affected fetuses with cytomegalovirus infection.

To assess by magnetic resonance imaging (MRI) the cortical maturation pattern in fetuses with cytomegalovirus (CMV) infection with mild or no abnormalities on ultrasound (US) and MRI, and to establish possible differences compared with healthy controls. This was a retrospective case-control study of consecutive pregnancies with a CMV-infected fetus undergoing prenatal MRI as a complementary diagnostic tool in two centers, and a control group of singleton low-risk pregnancies without fetal structural abnormalities, with normal fetal growth and with healthy newborns. CMV infection was confirmed by extraction of CMV-DNA from fetal and neonatal samples. Only fetuses with mild (mildly affected) or no (unaffected) neuroimaging abnormalities on US and MRI were included. MRI measurements of fetal parieto-occipital sulcus, cingulate sulcus and calcarine sulcus depth, Sylvian fissure depth and Sylvian fissure angles were performed and cortical development grading of specific cortical areas and sulci were assessed by one operator who was blinded to CMV infection status. Data were compared between controls and fetuses with CMV infection, using linear regression and non-parametric trend analysis. Twenty-four CMV-infected fetuses (seven unaffected and 17 mildly affected) and 24 healthy controls that underwent fetal MRI between 27 and 36 weeks' gestation were included. Compared with controls, CMV-infected fetuses showed significantly larger median lateral ventricular width (right side, 7.8 (interquartile range (IQR), 5.9-9.9) mm vs 3.9 (IQR, 2.6-5.3) mm; left side, 7.5 (IQR, 6.0-10.9) mm vs 4.2 (IQR, 3.2-5.3) mm), significantly decreased parieto-occipital sulcus depth (right side, 12.6 (IQR, 11.3-13.5) mm vs 15.9 (IQR, 13.5-17.3) mm; left side, 12.3 (IQR, 10.6-13.5) mm vs 16.0 (IQR, 13.3-17.5) mm) and calcarine sulcus depth (right side, 15.4 (IQR, 14.4-16.3) mm vs 17.5 (IQR, 16.1-18.7) mm; left side, 14.6 (IQR, 14.1-15.6) mm vs 16.7 (IQR, 15.6-18.9) mm) (P < 0.001 for all). Compared with controls, CMV-infected fetuses also had significantly smaller upper (right side, 42.8° (IQR, 35.8-45.8°) vs 48.9° (IQR, 38.4-64.7°); left side, 40.9° (IQR, 34.2-45.8°) vs 48.2° (IQR, 41.9-60.7°)) and lower (right side, 41.6° (IQR, 34.4-49.2°) vs 48.9° (IQR, 40.6-60.9°); left side, 42.2° (IQR, 38.8-46.9°) vs 48.9° (IQR, 39.5-57.5°)) Sylvian fissure angles (P < 0.05 for all). In addition, the mildly affected CMV-infected fetuses had a significantly lower cortical development grading in the temporal and parietal areas, and the parieto-occipital and calcarine sulci compared with healthy fetuses (P < 0.05). These differences persisted when adjusting for gestational age, ipsilateral atrium width, fetal gender and when considering small-for-gestational age as a confounding factor. Unaffected and mildly affected CMV-infected fetuses showed delayed cortical maturation compared with healthy controls. These results suggest that congenital CMV infection, even in non-severely affected fetuses that are typically considered of good prognosis, could be associated with altered brain cortical structure. Further research is warranted to better elucidate the correlation of these findings with neurodevelopmental outcomes. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Fetal Ultrasound and Magnetic Resonance Imaging Abnormalities in Congenital Cytomegalovirus Infection Associated with and without Fetal Growth Restriction.

Congenital cytomegalovirus infection (cCMV) can cause fetal growth restriction (FGR) and severe sequelae in affected infants. Clinicians generally suspect cCMV based on multiple ultrasound (US) findings associated with cCMV. However, no studies have assessed the diagnostic accuracy of fetal US for cCMV-associated abnormalities in FGR. Eight FGR and 10 non-FGR fetuses prenatally diagnosed with cCMV were examined by undergoing periodic detailed US examinations, as well as postnatal physical and imaging examinations. The diagnostic accuracy of prenatal US for cCMV-associated abnormalities was compared between FGR and non-FGR fetuses with cCMV. The diagnostic sensitivity rates of fetal US for cCMV-related abnormalities in FGR vs. non-FGR fetuses were as follows: ventriculomegaly, 66.7% vs. 88.9%; intracranial calcification, 20.0% vs. 20.0%; cysts and pseudocysts in the brain, 0% vs. 0%; ascites, 100.0% vs. 100.0%; hepatomegaly, 40.0% vs. 100.0%; splenomegaly, 0% vs. 0%. The diagnostic sensitivity of fetal US for hepatomegaly and ventriculomegaly in FGR fetuses with cCMV was lower than that in non-FGR fetuses with cCMV. The prevalence of severe long-term sequelae (e.g., bilateral hearing impairment, epilepsy, cerebral palsy, and severe developmental delay) in the CMV-infected fetuses with FGR was higher, albeit non-significantly. Clinicians should keep in mind the possibility of overlooking the symptoms of cCMV in assessing fetuses with FGR.

Anatomical and diffusion-weighted imaging of brain abnormalities in third-trimester fetuses with cytomegalovirus infection.

In this study of cytomegalovirus (CMV)-infected fetuses with first-trimester seroconversion, we aimed to evaluate the detection of brain abnormalities using magnetic resonance imaging (MRI) and neurosonography (NSG) in the third trimester, and compare the grading systems of the two modalities. We also evaluated the feasibility of routine use of diffusion-weighted imaging (DWI) fetal MRI and compared the regional apparent diffusion coefficient (ADC) values between CMV-infected fetuses and presumed normal, non-infected fetuses in the third trimester. This was a retrospective review of MRI and NSG scans in fetuses with confirmed first-trimester CMV infection performed between September 2015 and August 2019. Brain abnormalities were recorded and graded using fetal MRI and NSG grading systems to compare the two modalities. To investigate feasibility of DWI, a four-point rating scale (poor, suboptimal, good, excellent) was applied to assess the quality of the images. Quantitative assessment was performed by placing a freehand drawn region of interest in the white matter of the frontal, parietal, temporal and occipital lobes and the basal ganglia, pons and cerebellum to calculate ADC values. Regional ADC measurements were obtained similarly in a control group of fetuses with negative maternal CMV serology in the first trimester, normal brain findings on fetal MRI and normal genetic testing. Fifty-three MRI examinations of 46 fetuses with confirmed first-trimester CMV infection were included. NSG detected 24 of 27 temporal cysts seen on MRI scans, with a sensitivity of 78% and an accuracy of 83%. NSG did not detect abnormal gyration visible on two (4%) MRI scans. Periventricular calcifications were detected on two MRI scans compared with 10 NSG scans. While lenticulostriate vasculopathy was detected on 11 (21%) NSG scans, no fetus demonstrated this finding on MRI. MRI grading correlated significantly with NSG grading of brain abnormalities (P < 0.0001). Eight (15%) of the DWI scans in the CMV cohort were excluded from further analysis because of insufficient quality. The ADC values of CMV-infected fetuses were significantly increased in the frontal (both sides, P < 0.0001), temporal (both sides, P < 0.0001), parietal (left side, P = 0.0378 and right side, P = 0.0014) and occipital (left side, P = 0.0002 and right side, P < 0.0001) lobes and decreased in the pons (P = 0.0085) when compared with non-infected fetuses. The ADC values in the basal ganglia and the cerebellum were not significantly different in CMV-infected fetuses compared with normal controls (all P > 0.05). Temporal and frontal ADC values were higher in CMV-infected fetuses with more severe brain abnormalities compared to fetuses with mild abnormalities. Ultrasound and MRI are complementary during the third trimester in the assessment of brain abnormalities in CMV-infected fetuses, with a significant correlation between the grading systems of the two modalities. On DWI in the third trimester, the ADC values in several brain regions are abnormal in CMV-infected fetuses compared with normal controls. Furthermore, they seem to correlate in the temporal area and, to a lesser extent, frontal area with the severity of brain abnormalities associated with CMV infection. Larger prospective studies are needed for further investigation of the microscopic nature of diffusion abnormalities and correlation of different imaging findings with postnatal outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Amniotic fluid biomarkers predict the severity of congenital cytomegalovirus infection.

BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins — the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3–binding protein (Gal-3BP) — were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%–93.8% positive predictive value, and 92.9%–92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund – Hadassah Medical Organization.

Fetal Liver Volume Assessment Using Magnetic Resonance Imaging in Fetuses With Cytomegalovirus Infection†.

ObjectiveTo assess fetal liver volume (FLV) by magnetic resonance imaging (MRI) in cytomegalovirus (CMV)-infected fetuses compared to a group of healthy fetuses.MethodMost infected cases were diagnosed by the evidence of ultrasound abnormalities during routine scans and in some after maternal CMV screening. CMV-infected fetuses were considered severely or mildly affected according to prenatal brain lesions identified by ultrasound (US)/MRI. We assessed FLV, the FLV to abdominal circumference (AC) ratio (FLV/AC-ratio), and the FLV to fetal body volume (FBV) ratio (FLV/FBV-ratio). As controls, we included 33 healthy fetuses. Hepatomegaly was evaluated post-mortem in 11 cases of congenital CMV infection. Parametric trend and intraclass correlation analyses were performed.ResultsThere were no significant differences in FLV between infected (n = 32) and healthy fetuses. On correcting the FLV for AC and FBV, we observed a significantly higher FLV in CMV-infected fetuses. There were no significant differences in the FLV, or the FLV/AC or FLV/FBV-ratios according to the severity of brain abnormalities. There was excellent concordance between the fetal liver weight estimated by MRI and liver weight obtained post-mortem. Hepatomegaly was not detected in any CMV-infected fetus.ConclusionIn CMV-infected fetuses, FLV corrected for AC and FBV was higher compared to healthy controls, indicating relative hepatomegaly. These parameters could potentially be used as surrogate markers of liver enlargement.

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

BackgroundCitomegalovirus (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 presentationWe 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.ConclusionTo 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.

Pathophysiology of Hyperechogenic Bowel in Congenitally Human Cytomegalovirus Infected Fetuses.

Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach’s myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB.

Congenital Cytomegalovirus Infection: A Narrative Review of the Issues in Screening and Management From a Panel of European Experts.

Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education.

Blood parameters in fetuses infected with cytomegalovirus according to the severity of brain damage and trimester of pregnancy at cordocentesis

Background and objectiveCytomegalovirus (CMV) remains a major cause of congenital infection and disease. During pregnancy, symptomatic cases can be detected through ultrasound (US) features, nevertheless, prognostic assessment is difficult. The aim of this study was to assess the predictive value of specific blood parameters in CMV infected fetuses. Study designTwenty-eight CMV-infected fetuses in which a cordocentesis had been performed were included. Fetuses were considered severely or mildly affected according to prenatal US/MRI brain damage. Fetal blood parameters were assessed for the prediction of severe brain abnormalities, and compared according to the trimester of pregnancy. Logistic regression and receiver operating curve analysis were performed. ResultsThrombocytopenia (≤100,000/mm3; p:0.03) and high levels of gamma-glutamyl transpeptidase (GGT) (≥151 IU/L; p:0.02) signaled severity. For the prediction of brain damage, GGT levels ≥ 183 UI/l achieved 71% sensitivity, 83% specificity (AUC: 0.78), and OR of 2.05 (95% CI: 1.22–3.43) per 100 IU/l increase, adjusted for gestational age. However, thrombocytopenia (91% vs 50%; p: 0.04), β2 microglobulin >10.4 mg/l (60% vs 0% p: 0.03), CMV-DNA >50,000 copies/ml (80% vs 25%; p: 0.02), and positive IgM (70% vs 17%; p: 0.04) were observed significantly more often in severely damaged fetuses sampled ≤28 weeks than thereafter. ConclusionIn CMV infected fetuses, thrombocytopenia and high levels of GGT are associated with severe US/MRI brain abnormalities. Nevertheless, among severely affected fetuses, blood parameters, with exception of GGT, change according to gestational age. Fetal blood could be less predictive of brain damage in the third trimester.

456: MRI-based volumetric measurements of the brain in cytomegalovirus-infected fetuses with otherwise “normal” interpretation of brain MRI

To compare magnetic resonance imaging (MRI)-based volumetric measurements of the brains of apparently normally developed fetuses versus those of fetuses suspected of being infected by cytomegalovirus (CMV). Brain MRI data of 25 apparently normal fetuses (control group) and 22 fetuses suspected of being infected by CMV (study group), all between 30-37 weeks of gestation, were collected retrospectively and analyzed. All MRI examinations were originally interpreted as being “normal” by a single senior pediatric neuroradiologist. Indications for MRI in the control group were based upon obstetrical history or suspected pathology by US. Suspected fetal CMV infection was based upon maternal seroconversion or a positive PCR for CMV in an amniotic fluid sample. Data for volumetric measurements were acquired using a 3D Fast Imaging Employing STeady-state Acquisition (FIESTA) sequence of the fetal brain and body (TR/TE=3/1.3sec, Matrix=256x256, 4mm slice thickness). Manual segmentation of the whole brain and the ventricular system were performed using AnalyzeDirect software by two independent qualified readers and validated by a senior pediatric radiologist. Interobserver variability was evaluated. Figure 1 displays the correlations between gestational age and total brain volume, excluding ventricles and CSF, of both groups. Figure 2 provides the volumes of ventricles of both groups. Interobserver agreement was excellent. The mean gestational age was equivalent for the study and control groups (33.04±1.2 and 32.24±1.64 weeks respectively P>0.05). The mean brain volume was 171,946±41,670 mm3 for the study group and 184,947±36,019 for the control group (P=0.24) and the mean ventricular volume was 8,410±2,139 mm3 and 6,876±2,096, respectively (P=0.028). The volume of ventricles of fetuses infected by CMV as measured in MRI is significantly greater than that of apparently normally developed fetuses at the same gestational age,with no significant differences in total brain volumes. Notably, conventional interpretation of the MRIs of all the fetuses was normal. Further studies with larger sample sizes are needed in order to provide normal MRI reference volumetric data of the fetal brain of both healthy and CMV-infected fetuses, and to establish whether this parameter has clinical significance.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

The use of fetal neurosonography and brain MRI in cases of cytomegalovirus infection during pregnancy: A retrospective analysis with outcome correlation.

To analyze ultrasound (US) and magnetic resonance imaging (MRI) results and developmental outcome in cases of maternal primary cytomegalovirus (CMV) infection during pregnancy. We retrospectively reviewed the results of fetal neurosonography and brain MRI of CMV-infected fetuses (Group 1). Cases of maternal infection in which the fetal status was unknown, and subsequently had a negative CMV postnatal urine analysis, were independently analyzed (Group 2). Imaging results were classified as follows: positive, negative, or inconclusive. Developmental landmarks were followed up. Eighty-one women were included in the study: 48 (59.2%) in Group 1 and 33 (40.8%) in Group 2. In Group 1, termination of pregnancy was performed in 8 cases (16.7%) following the diagnosis of brain abnormalities. Among the remaining cases, concordance rate between US and MRI was 78%. False negative rates for US and MRI were 5.5% and 6.4%, respectively (hearing deficits). For MRI, we found 17.5% of false positive/inconclusive results, while for the US, we found 5% of inconclusive results. In Group 2, false positive rates for US and MRI were 6.5% and 12.9%, respectively. Adding MRI in CMV-infected cases with a normal neurosonographic follow-up should be weighed against a nonnegligible rate of false positive and inconclusive findings.

Region-specific reductions in brain apparent diffusion coefficient in cytomegalovirus-infected fetuses.

To evaluate the effects of cytomegalovirus (CMV) infection on apparent diffusion coefficient (ADC) values of the fetal brain in utero. In this retrospective analysis we compared 58 fetal head magnetic resonance imaging (fhMRI) scans of PCR-verified CMV-infected fetuses, obtained in 2008-2012, with those of a normal control group of 36 gestational age (GA)-matched uninfected fetuses scanned between 2006 and 2012. Estimated GA at infection ranged from 1 to 32 weeks, and fhMRI was performed at 24 to 38 weeks. The frontal, parietal, temporal and occipital lobes (mainly white matter), basal ganglia, thalamus, pons and cerebellum were analyzed by assessing ADC values. Two pregnancies were terminated and postmortem confirmation was available in these cases. ADC values of CMV-infected fetuses correlated significantly and negatively with GA in all brain regions except the basal ganglia. The cerebellum had the greatest reduction (r = -0.52, P < 0.0001). Maternal age correlated positively with ADC in the frontal lobe (P < 0.05). GA at infection and overt pathological changes did not affect ADC significantly. Compared with non-infected fetuses, ADC values of affected fetuses were significantly reduced in the frontal (P < 0.0001), parietal (P < 0.0001), occipital (P = 0.0005) and temporal (P = 0.001) lobes and thalamus (P = 0.006). CMV infection of the fetal brain results in a highly significant, region-dependent reduction of ADC values in the frontal, parietal, occipital and temporal lobes and thalamus, probably reflecting hypercellularity and inclusion bodies in damaged areas. Further studies are needed to determine if reduction in ADC values may serve as a prognostic factor in CMV-infected fetuses. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.

Heart rate variability in humans infected with the cytomegalovirus (VIR1P.1145)

Abstract Humans infected with the cytomegalovirus (CMV+) have been shown to have a higher risk of cardio-vascular-disease (CVD) and mortality. Previous research supports a neuroimmunomodulatory reflex via vagally mediated t-cells in the splenic nerve end. Vagally-mediated heart rate variability (vmHRV) is a independent predictor of CVD mortality and associated with inflammatory processes. Existing studies investigated the association of CMV infection and HRV only in small samples of CMV infected infants or CMV-infected fetuses. The aim of the present study was to explore potential differences on vmHRV in individuals infected with CMV compared to their non-infected counterparts. 24-hour recordings of HRV were obtained by ECG holter monitoring and the high-frequency (HF) power was derived as index of vagal activity. CMV activity was determined by an enzyme-linked immunosorbent assay on plasma from fasted blood samples. Data from a total of 485 participants (10% females; mean age 46±10 years,) was available for analysis. Participants diagnosed as CMV+ (37%, n = 181) showed significantly (t(1.98) = 0.024, p = .024) lower vmHRV (HF 236±16.5 ms2) compared to individuals without CMV (CMV-, n = 304, HF 284±15.9 ms2).

OP16.03: Fetal brain ultrasound assessment by Texture Analysis in CMV infected fetuses with and without neurological damage

Objectives: To describe a cohort of fetuses with non visualization of fluid inside the cavum septi pellucidi without callosal agenesis. To discuss the significance of this finding regarding postnatal development. Methods: We reviewed all the files of patients referred because of suspected supratentorial midline anomalies searching for patients with a diagnosis of non-visualization or obliteration of the CSP. Results: From the initial cohort including 114 patients we identified 23 cases. They were referred at a mean gestational age of 24.5 ± 1.3 weeks; the referral diagnoses included: non visualization or an echogenic CSP (18), suspected callosal anomaly (5), other causes (5). The patients were examined for the first time at the FNC at a mean gestational age of 26.6 ± 3.1 weeks (range 22–34 weeks; median 27 weeks). In all the patients the zone where the fluid should have been observed was echogenic. In 17 this was an apparently isolated finding and in 6 it was associated with other findings but only one had associated malformations. Follow-up was available for 16 children at a mean age of 17.4 months (range 4–36 months, median 19.5 months). Fourteen children were developing normally. One had infantile hypotonia but normal developmental milestones; another had mild motor delay and language delay. These two children did not have associated anomalies. Conclusions: Non visualization of fluid inside the CSP is not always associated with ACC and when isolated may be considered a variation of normal development.

Inner ear lesions in congenital cytomegalovirus infection of human fetuses

Congenital cytomegalovirus (CMV) infection is the leading cause of non-hereditary congenital sensorineural hearing loss (SNHL). The natural course and the pathophysiology of inner ear lesions during human fetal CMV infection have not yet been reported. Inner ear lesions were investigated in six CMV-infected fetuses aged 19-35 postconceptional weeks and correlated with central nervous system (CNS) lesions. All the fetuses had high viral loads in the amniotic fluid and severe visceral and CNS lesions visible by ultrasound. Diffuse lesions consisting of both cytomegalic cells containing inclusion bodies and inflammation were found within all studied structures including the inner ear, brain, other organs, and placenta, suggesting hematogenous dissemination. Cochlear infection was consistently present and predominated in the stria vascularis (5/6), whereas the supporting cells in the organ of Corti were less often involved (2/6). Vestibular infection, found in 4/6 cases, was florid; the non-sensory epithelia, including the dark cells, were extensively infected. The endolymphatic sac was infected in 1 of 3 cases. The severity of inner ear infection was correlated with the CNS lesions, confirming the neurotropism of CMV. This study documenting infection of the structures involved in endolymph secretion and potassium homeostasis in fetuses with high amniotic fluid viral loads suggests that potassium dysregulation in the endolymphatic compartment of the inner ear may lead to secondary degeneration of the sensory structures. In addition, the occurrence of SNHL depends on the intensity and duration of the viral infection and inflammation.