Prenatal evaluation and postnatal early outcomes of

fetal ventriculomegaly

Official Journal of the European Paediatric Neurology Society

a b s t r a c t

• Objective: This study aims to determine the incidence, etiology, diagnostic criteria and early outcomes of prenatally diagnosed fetal ventriculomegaly (VM).

• Methods: Diagnostic criteria for the fetal VM was atrial diameter of lateral ventricle measuring 10 mm, independent from gestational age.

• Results of our patients from ultrasonography (USG), karyotyping, congenital infections, and associated abnormalities were noted.

• Progress during pregnancy, postnatal USG results and neurobehavioral outcomes were recorded.

• Results: In our study, 40 subjects of fetal VM were recorded. 16 and 24 of those were bilateral (40%) and unilateral (60%) respectively. Female to male fetus ratio was 19/21 (0.9). Median gestational age at the diagnosis was 22 weeks (ranging between 16 and 34 weeks). While 21 VM subjects were isolated (52.5%) only 19 of the total were shown associated structural abnormalities in (47.5%) in addition to VM.

• Toxoplasmosis were diagnosed only in one subject (2.5%). Nineteen subjects had amniocentesis (47.5%) and 2 of them were showed abnormalities (10.5%) as follows; “inversion and duplication 8 (p11.2p23)” and “deletion 3”. VM got back in to normal size during pregnancy in 24 subjects (24/40, 60%). Eight pregnancies were terminated (8/40) (20%). Five babies passed away during neonatal and post- neonatal period. Some other structural abnormalities were diagnosed after the birth at six babies who classified as mild “isolated” VM.

Conclusions: • Our study revealed that amongst mild VM

subjects, incidence of associated abnormalities and termination rates were higher. Although most of mild VM subjects are thought to be benign, associated abnormalities should be carefully evaluated and determined pre- and postnatally.

Introduction

• Fetal ventriculomegaly is an USG diagnosis that refers to dilatation of lateral ventricles of the brain. When atrial diameter of lateral ventricle is greater than 10 mm, it is considered as VM.

• American College of Obstetricians and Gynecologists (ACOG) recommends routine prenatal USG screening which includes the evaluation of fetus intracranial anatomy as well as fetal ventricular size.

Contd..

• Previously, some authors used the definition of mild (10-12 mm), moderate (13-15 mm), and severe (>16 mm) to distinguish the severities of vetriculomegaly.

• There is no argument about the definition of the severe VM that, if the size of lateral ventricle diameter is over 15, it is assumed as severe VM.

• But many researchers and clinicians recently started to use the term “mild VM” to define lateral venticle diameter between 10 and 15 mm.

• Melchiorre et al. showed with their meta-analysis that isolated mild VM of 12 mm do not have significant better neurologic prognosis compared with those of 12-15 mm.

• The incidence of VM is between 0.3 and 2 per 1000 pregnancies.

• There are many causes of fetal VM among which are obstruction (leading to hydrocephalus), focal or generalized loss of brain volume, and CNS malformations.

• At the same time, some of the subjects have no known cause of VM in prenatal and postnatal period.

• Ventriculomegaly is generally bilateral. Unilateral VM incidence and its clinical significance is still unclear.

• Some reports show that if there are not any associated malformations and chromosomal abnormalities, mild VMs have favorable neurologic outcomes.

Contd..• Severe VM is associated with an increased risk of

prenatal and neonatal neurodevelopmental problems and death.

• The prognosis and management of severe forms primarily depends on whether the severity is complicated by additional intracranial or extracranial abnormalities.

• Detailed imaging, which consists of fetal neurosonography and fetal magnetic resonance imaging (MRI), gives physicians highly accurate information to redefine extra and intracranial abnormalities of fetus.

• If there are not any intracranial or extracranial abnormalities, it is termed as “isolated”severe VM.

• The aim of this retrospective study is to review the information regarding the background and progress of the VM subjects, whose mothers had received well prenatal care, were born in Baskent University, Ankara Hospital.

• We tried to figure out and attract attention to the role of prenatal diagnosis, at the same time, to understand different etiologic factors and early outcomes of isolated and associated VM.

Material and method

• Forty subjects of fetal VM were identified from the records of Department of Perinatology, Baskent University Ankara Hospital, between January 2006 and June 2013.

• Cross validation with genetics and pediatric cardiology databases allowed us maximal subject ascertainment.

• Standardization guidelines of Department of Perinatology, Baskent University Ankara Hospital for the management of fetal VM subjects (atrium measurement of 10 mm or greater) were agreed and VM records were carefully noted.

• The subjects were examined according to their ventricle size (mild and severe) and if they had associate abnormalities (isolated and associated).

• To determine possible etiologies, karyological records, whether performed by amniocentesis or chorionic villus sampling (CVS), were noted.

• Any related structural (intracranial or extracranial) abnormalities and syndromes were examined and noted.

• Serological evaluation of Toxoplasma, Rubella, Cytomegalovirus and Herpes Simplex Virus (TORCH) infections in maternal blood was also routinely investigated.

• Gestational age of VM subjects were noted after birth. Multiple USG examinations were performed every 2-4 weeks until the end of progress. The progress and outcomes of each pregnancy was followed up closely. Cranial USG and MRI results were collected.

• We also examined the postnatal USG or MRI results, and their postnatal progresses were noted via telephone interview if the babies did not come to follow-up appointment at our outpatient clinic.

• We asked whether any mortality or morbidity occurred due to his/her VM and related structural abnormalities in his/her 6 month.

• Mild and severe categories were not used in the analysis due to discrepancy of the numbers of the subjects in to each groups.

• Descriptive statistics were used in reporting ultrasonography and follow-up characteristics for all VM subjects.

Prenatal USG findings N

Corpus callosum agenesis þ colpocephaly (Severe VM) 1

Cerebeller vermis agenesis (Severe VM) 1

Galen vein aneurysm (Severe VM) 1

Galen vein aneurisym þ cystic hygroma þ ventricular septal defect, þ aorta hypoplasia 1

Ascites 1

Hyperechogenic intestine 1Bilateral 5th phalanxes with hypoplasia 1

Hydroureteronephrosis 1

Skeletal dysplasia 1

Choroid plexus cyst 2

Lemon shaped head, cleft lip & palate (Goldenhar syndrome) 1

Meningomyelocele, skeletal dysplasia (lemon shaped head, banana sign) 1

Meningomyelocele þ spina bifida occulta 1

Pericardial effusion þ nasal bone hypoplasia þ tricuspit regurgitaion (3') þ invdup 1Pulmonary stenosis 1

Syndactili 1

Facial abnormatilty þ syndactili 1

Cleft palate 1

Results

• Forty subjects of mild-to-severe form of VM were identified from perinatology records between January 2006 and June 2013 among 4152 pregnancies. Of those, median age of mothers was 29 (mean: 28.58 ± 5.349), median gestational age was 22 weeks (ranging between 16 and 34 weeks). Sixty-five % of the total was diagnosed before 24th gestational age.

• Nineteen of subjects were female (47.5%) and female to male ratio was (19/21) 90%. Twenty-three subjects were nulliparous while only 1 VM subject was the 4th gravidity of mother (2.5%). Three subjects got pregnant via in vitro fertil- ization (3/40, 7.5%). Multiple pregnancy rate was 2.5% (1/40). Only one of twins was affected. At the time of VM was detected, median of nuchal translucency of the fetuses was 1.4 mm (mean: 1.908 ± 1.396).

• Median atrium width of lateral ventricles was 10.5 mm ranging between 10 and 27 mm (mean: 11.58 ± 3.727). Twenty- four of the 40 VM subjects were unilateral (60%), while 16 of them were bilateral (40%).

• Twenty-one VM subjects were isolated (21/40, 52.5%) while there were associated structural abnormalities in 19 subjects (47.5%). Thirty-seven of the 40 VM subjects were identified as mild VM (92.5%) and 3 of them were classified as severe VM form (7.5%).

• Sixteen of 37 mild VM subjects had at least one associated abnormalities (43.3%) and 21 of 37 mild VM subjects were classified as “isolated” form (56.7%). All of the three severe VM subjects had associated abnormalities (100%).

• All subjects were screened for “TORCH” infections, and only one was resulted positive for toxoplasmosis in mild VM group (2.5%).

• Nineteen subjects had amniocentesis (40%) and 2 of them showed abnormalities (10.5%). First one was “inversion and duplication chromosome 8 (p11.2p23)”, who had mild, associated VM and was terminated at 26 weeks of pregnancy. The second one was “deletion chromosome 3” who had mild VM and after birth, MRI revealed “galen vein aneurysm” and “cystic hygroma”. She passed away on her 2nd postnatal day.

• All of the isolated mild VM subjects (n ¼ 21) and 3 of the 16 non-isolated mild VM subjects were improved and their ventricle sizes returned to normal during pregnancy (<10 mm) (Total n ¼ 24). Four of 16 associated VM subjects had stable ventricle sizes (25%) while ventricle size of 1 of the 16 mild associated VM subjects increased during pregnancy (6.2%). The ventricle sizes of all severe VM subjects increased during pregnancy (3/3, 100%).

• One of the severe VM subject was born on 39th gestational weeks. MRI showed “Cerebellar Vermis Agenesis” and he underwent neurosurgical intervention in postneonatal period. The other severe VM subject was born on 41st gestational age. MRI showed “Colpocephaly þ Corpus Callosum Agenesis”.

• She was reported dead when she was 8th months old. The last severe VM subject was born on 32nd gestational age and MRI confirmed “Galen vein aneurysm”.

• She passed away on her2nd postnatal day. None of the severe VM subjects were found to be isolated. None of the severe VM subjects went under termination. The ventricle sizes of all severe VM subjects were increased during pregnancy (3/3, 100%).

• Eight subjects were terminated due to fetal abnormalities (20%) and 32 babies born alive (80%). Terminations were performed between 16 and 28 weeks of gestation (median: 22 weeks). All of the terminated fetus' were in associated and mild VM group. Six of the 8 terminated fetuses underwent postnatal autopsy (75%).

• Pathology reports demonstrated that one of the fetus had features of Goldenhar Syndrome with lemon head shape.

• In one subject, severe skeletal dysplasia with meningomyelocele was identified. In other subjects, autopsy findings were consistent with the prenatal imaging and provided no additional information.

• Three of the autopsy results were not identified because they were performed in different health care centres.

• There were 2 neonatal and 3 postneonatal deaths among all VM subjects (12.5%) (5/40) . Three of the deaths among a total of 5 neonatal and postneonatal deaths were classified in the mild associated group, while 2 were classified in the severe associated group (Table 4). The mortality rate of our associated VM subjects was found out to be 68.4% .

(13 (5 postnatal and 8 terminated)/19).

• Six of 21 live born babies (28.5%), who had previously detected to have mild isolated VM were consulted to pediatric neurology (n:3, Two had choroid plexus cysts and 1 had arachnoid cyst, all which were determined on 5th day with cranial USG), pediatric cardiology (n:2; one had atrial septal defect and the other one had ventricular septal defect, referred due to murmur), and with pediatric nephrology (n:1; one had Grade1-2 unilateral hydroureteronephrosis, referred due to oliguria after birth), in their postnatal period.

Discussion• In literature incidence of fetal VM is 0.3 to 2 per 1000

preg-nancies. • However our study showed incidence of VM in our

clinic is 9.6 per 1000 pregnancies. It's probably because our clinic is a tertiary referral centre. The European Surveillance of Congenital Abnormalities reported a incidence of severe fetal hyrdrocephalus and VM as 4.25 per 10,000 births.

• We confirmed 3 severe fetal VM among 4385 births, incidence of severe VM is 6.6 per 10,000 births in our clinic.

• In our series, the main gestational age at diagnosis was found 22 weeks (range: 16-31 weeks).

• Breeze et al. reported that median gestation at detection of severe VM was 28 weeks (range 16-36 weeks), while Kennelly et al. informed median gestation at referral was 26.9 weeks (range 19-40).

• The incidence of associated structural malformation was found 47.5% in our report. However Madazlı et al. reported a higher incidence of associated abnormalities with VM that 77.4% of their VM subjects had at least one associated structural abnormality.

• Same study reported a mortality rate of 86% among their associated VM subjects. The mortality rate of our VM subjects having associated malformations was 68.4% (13/19). This deaths were assumed to be due to the associated anomalies seen with ventriculomegaly, rather than the ventriculomegaly “group” itself.

• In our study, all severe VM were associated with at least one severe CNS malformation (100%) in accordance with the report by Gaglioti et al.

• Hannon T et al. reported that 49.7% of all severe fetal VM forms were associated with an abnormal-ity.

• Graham E et al. reported a high association between severity of VM and mortality.

• We found a mortality rate of 66.6% (2/3) among severe VM subjects, which was higher than the study of Levitsky et al. among severe VM subjects with a mortality rate of 26.6%.

• Vergani P. revealed that most of the mild isolated VM forms improve and have good outcomes.

• Lipitz et al. reported that almost all of their mild (both isolated or non-isolated) VM forms diagnosed at mid-gestation resolved or stable in the neonatal period.

• In concordant with these studies, ventricle sizes of all of “isolated mild” VM (21 subjects) were resolved during progress of pregnancy. But after birth, 28.5% of our “isolated mild” VM subjects were detected to have some ab-normalities when examined carefully (6/21).

• In our study; 19 of 40 VM subjects had karyotype analysis (47.5%) and chromosomal abnormality was detected in 2 of 19 subjects (2/19) (10.5%). Both of these subjects were mild VM forms which match well with previous reports confirming that chromosomal abnormalities are highly encountered in the mild form VMs.

• Congenital infections are considered as one of the etiologic causes of VM. In our report, only one VM subject was attrib-uted to congenital infection which was diagnosed positive for toxoplasmosis and terminated on 29th gestational age (1/40, 2.5%). In subjects of mild VM, the rate of congenital infections varies between 1 and 5%.

• The termination rate of VM determined pregnancies was 8/ 40 (20%). All of the terminated subjects were in the mild VM class and found to have at least one associated intracranial abnormality together with VM. Breeze et al. reported 50% of their fetal VM subjects underwent termination.

• Gaglioti et al. also reported a high termination rate when VM diagnosis was made before 24 weeks.

• The main limitation of this study is lack of imaging of VM subjects with intrauterine MR (iu MR). iuMR imaging is started to be used widely because of its high value in diagnostic pathway. Griffiths PD et al. showed that 17% of 147 singleton fetuses referred from sonography with a confident diagnosis of isolated VM, has shown to have brain abnormalities other than VM, when examined carefully with iuMR imaging.

• In conclusion; our report revealed that there were a high associated abnormality incidence and termination rate in mild VM subjects. Although most of mild VM subjects are thought to be benign, associated abnormalities must be carefully evaluated and determined pre and postnataly.