| Background and objectivesVentriculomegaly (VM) is a descriptive term, indicating the presence of an excess of fluid, usually cerebrospinal fluid (CSF), in the lateral ventricles of the developing brain. It is defined as the width of one or both ventricles, measured at the level of the glomus of the choroid plexus (atrium), is≥10mm. Some authors define VM as mild when the width of one or both ventricles is10-14.9mm and severe when>15mm (the ’true’hydrocephalus), whereas others define mild VM as between10-12mm and moderate VM as between12.1-14.9mm. Based on the evidence of additional abnormalities, VM is defined as isolated and non-isolated.VM can result from different processes including the abnormal turnover of CSF, anomalies of the periventricular brain structures and other disorders. An abnormal turnover of CSF may be a consequence of forking formation, septum, gliosis secondary to infections and blood clots secondary to intraventricular haemorrhage, Chiari Ⅱ malformation and cerebello-medullary cistern. Anomalies of the periventricular brain structures include corpus callosum agenesis, neuronal migration and proliferation disorders and disorders of fetal development. Other disorders include tumors and vascular anomalies.The first step of etiologic analysis of fetal ventriculomegaly is to make sure whether there are associated neural or extraneural malformations. Ultrasound imaging is widely used as a routine referral examination in prenatal screening, however the sensitivity of ultrasound in screening of VM is controversial, especially when there are subtle malformations and abnormalities in gyration. Many studies have indicated that magnetic resonance imaging (MRI) adds important information to that obtained by ultrasound imaging with a higher resolution and a possibility of multi-plane imaging. MRI image is least affected by obesity of the mother, amniotic fluid, low position of fetal head or calcification of fetal cranium. Fetal CNS anomalies that were better seen on MRI compared to ultrasound include:porenceohaly, cortical gyral abnormalities, partial or complete hypoplasia, vermian cysts, hemorrhage, cortical cleft, mid-brain dysgenesis, partial or complete agenesis of the septi pellucid, and subependymal and cortical tubers. However, MRI hasn’t been widely used in prenatal diagnosis, especially in the etiological analysis of fetal ventriculomegaly.Chromosomal anomalies can also cause fetal ventriculomegaly. It has been shown that about2.8%isolated VM is associated with chromosomal abnormalities-mainly trisomy21-in a large number of studies. Recent studies addressing the issue of the risk of trisomy21in idiopathic mild VM highlighted that this finding is present in0.15%of euploid fetuses and in1.4%of trisomy21fetuses, providing a likelihood ratio of9for the risk aneuploidy. Along with the development of biochemistry and molecular biology, several research groups have been using microarray to detect microdeletions and microduplications in corpus callosum agenesis patients, and abnormalities locate at8q23,1p36,1q42-43and6qter have been identified. Although karyotyping is still the standard method in prenatal diagnosis of fetal ventroculomegaly, molecular biological methods are necessarily used in addition to routine cytogenetic analysis.Congenital infection may cause VM as a consequence of gliosis of the white matter surrounding the aqueduct and subsequent obliteration. Possible pathogens include Toxoplasma, cytomegalovirus (CMV) and rubella. The incidence of CMV as a cause of mild VM varies from0-5%with a poor prognosis.Factors that influence the prognosis of fetuses with ventriculomegaly include the size of ventricles, the in-utero progression of ventricular dilatation, the association with other abnormalities and the presence of chromosomal anomalies. A measurement of10-12mm is generally associated with a lower incidence of neurodevelopmental delay (11.8%) than12.1-14.9mm (17.1%). The in-utero variation of ventricular dilatation is one of the most important prognostic factors in fetal VM and the possible variations include regression and progression of the ventricular dilatation. Stable and regressive ventriculomegaly is with a good prognosis, while progressive ventricular dilatation often gives a poor prognosis. The prognosis of isolated VM (IVM) is controversial. Some authors pointed out that85%IVM (10-15.0mm) fetuses could be lively born without neurological abnormalities, while others found11.5%IVM fetuses will suffer from neurological disorders.Here in our study, an MRI test was performed after the routine ultrasound imaging, and a standard karyotype examination combined with of microdeletion microduplication detection was conducted to find out the correlations between chromosomal abnormalities and fetal VM. Once VM had been diagnosed, monthly ultrasound scans were performed and parents were contacted and invited to participate in postnatal follow-up. Maternal age, gestational age at initial diagnosis, fetal sex, size of ventricles and symmetry of the ventricular system was analyzed to identify factors correlated with the outcome of VM on postnatal neurological development.Methods and Materials Patients234pregnancies confirmed of ventriculomegaly, from Nanfang Hospital, General Hospital of Guangzhou Military Command of PLA and Shenzhen Maternal and Child Hospital during March2010to December2012, were recruited after the medical informed consent.30normal fetuses were recruited as the control.MethodsA cohort study was conducted on ventriculomegaly fetuses diagnosed by ultrasound imaging and MRI. The etiological analysis was conducted by standard karyotype examination and maternal serologic investigation (TORCH). The postnatal neurological development was evaluated by assessment of infants’ general cognitive and motor skills. Based on the ventricular size of the initial diagnosis, patients were divided into3groups:mild ventriculomegaly group with ventricular dilatation to10-12mm; moderate ventriculomegaly group with ventricular dilatation to12.1-14.9mm and severe ventriculomegaly group with ventricular dilatation to more than15mm. Informations including maternal age, gestational age at initial diagnosis and associated abnormalities were collected and analyzed. The correlation of genetic anomalies and congenital infection to ventriculomagaly was studied. On-going pregnancies were followed up till childbirth. The in-utero alteration of ventricular dilatation was recorded and followed up till1year after birth.Summary statistics was performed using SPSS statistical software version13.0for Windows. Statistics for continuous variables were presented using the mean and standard deviation. Categorical and class variables were described by frequency, constituent ratio and crosstab. Two samples were detected by t-test and categorical variable were examined by x2test. Single-factor used Pearson/Spearman correlation coefficient, t-test and x2test. Two class variables were examined by Mann-Whitney and multi-samples detected by Kruskal-Wallis test. All the statistical tests were double-side test and data were deemed to be significantly different when P^0.05.Results and discussionIn our study, the affected males were1.5times more than females diagnosed by ultrasound imaging and MRI examination. Among all the ventriculomegaly cases,63.2%(148/234) were non-isolated VM. A lower incidence of non-isolated VM and bilateral VM was seen in mild ventriculomegaly (10-12mm) cases, which was55.1%(65/118)(X2=8.605, P=0.014<0.05) and38.1%(45/118) respectively (P=0.001<0.05).62/234fetuses underwent MRI examination, which is better at detecting partial agenesis of corpus callosum and hemorrhage etc, added important information to19.4%(12/62) ultrasound imaging results. Ultrasound results showed that51fetuses were with two or more additional abnormalities and the total number of abnormal cases was220. CNS abnormalities were with the highest incidence (37.3%,83/220), and intracranial cysts (19.2%,16/83) as well as corpus callosum agenesis (16.9%,14/83) were mostly seen. Extraneural abnormalities included abnormalities in ultrasound soft markers (11.8%), mild dilatation of posterior fossa (23.6%) and cardiovascular anomalies (5.9%).69.6%of severe VM (≥15mm) fetuses were complicated with neurodevelopmental delay, which is higher than mild and moderate VM (x2=41.420, P=0.000). However, the incidence of abnormalities in ultrasound soft markers is higher in mild VM fetuses (73.1%,38/52, x2=8.226, P=0.000).Karyotype examination showed12(5.1%) chromosomal abnormalities in VM fetuses, including10(83.3%) numerical abnormalities, and trisomy21was the most common prenatally detected chromosomal anomaly (50%,5/10). Multiplex ligation-dependent probe amplification (MLPA) was performed in88fetuses with normal karyotype and a Ip36microdeletion was identified in one case, which increased the diagnostic rate by1.1%. The factors that may be correlated to chromosomal abnormalities are advanced maternal age, bilateral VM and high risk of congenital infection.Among the173on-going pregnancies, the in-utero outcomes of mild VM (10-12mm) were better than moderate VM (12.1-14.9mm). About72.9%(78/109) mild VM spontaneously regressed (x2=15.769, P=0.000). IVM fetuses had better prognosis than VM ones, and the regression rate was74.6%(59/79) vs.52.1%(49/94)(X2=10.222, P=0.006). The in-utero outcomes of symmetrical VM were better than asymmetrical VM, and the regression rate was66.7%(44/66) vs.1/9(11.1%)(P=0.001). These indicated that the in-utero outcomes of mild (10-12mm) IVM fetuses were better.NBNA score of VM infants was lower than the normal ones (P=0.016). A follow-up visit was paid6months after birth.27cases lost to follow-up (16.5%,27/164). Neurodevelopmental assessment was by BSID Scales at the follow-up visit. There was a significant difference in PDI score between VM infants and normal ones (P=0.0148), and between IVM and VM (Z=-2.835, P=0.005). Infants with different in-utero outcomes had a significant difference in PDI and MDI score (P=0.000; P=0.018). Conclusion1.63.2%VM fetuses were complicated with neural or extraneural abnormalities. Fetuses with ventricular dilatation to12.1-14.9mm or more were with a higher incidence of CNS anomalies.2. MRI image is least affected by obesity of the mother, amniotic fluid, low position of fetal head or calcification of fetal cranium. Subtle abnormalities can be detected by MRI which added important information to19.4%(12/62) VM cases.3. Chromosomal abnormalities were detected in5.2%(12/234) VM fetuses, and Trisomy21was most common (38.5%,5/13). Advanced maternal age, bilateral VM were prone to a higher risk of chromosomal abnormalities. MLPA, microarray combined with standard cytogenetic technology can increase the diagnostic rate of microdeletion and microduplication by1.1%.4. Mild IVM (10-12mm) fetuses have better in-utero outcomes. Infant NBNA score of prenatal VM fetuses was lower than normal ones. Additional abnormalities and the in-utero outcomes were associated with neurodevelopment and psychomotor development. |
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