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Andrea Dall’Asta, Noortje van Oostrum, Sheikh Nigel Basheer, Gowrishankar Paramasivam, Tullio Ghi, Letizia Galli, Irene AL Groenenberg, Amanda Tangi, Patrizia Accorsi, Monica Echevarria, et al. With compliments of Georg Thieme Verlag

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Etiology and Prognosis of Severe Ventriculomegaly Diagnosed at Late Gestation

DOI http://dx.doi.org/10.1055/a0627-7173 For personal use only. No commercial use, no depositing in repositories.

Publisher and Copyright © 2018 by Georg Thieme Verlag KG Rüdigerstraße 14 70469 Stuttgart ISSN 0172-4614 Reprint with the permission by the publisher only

Original Article

b

Etiology and Prognosis of Severe Ventriculomegaly Diagnosed at Late Gestation

Ätiologie und Prognose einer schweren Ventrikulomegalie bei Diagnose in der Spätschwangerschaft

Authors Andrea Dall’Asta1, 2, Noortje HM van Oostrum3, Sheikh Nigel Basheer1, 4, Gowrishankar Paramasivam1, Tullio Ghi2, Letizia Galli2, Irene AL Groenenberg3, Amanda Tangi5, Patrizia Accorsi6, Monica Echevarria7, Maria Angeles Rodríguez Perez7, Gerard Albaiges Baiget7, Federico Prefumo5, Tiziana Frusca2, Attie TJI Go3, Christoph C Lees1, 8, 9

Affiliations 1 Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom 2 Obstetrics and Gynaecology Unit, University of Parma, Parma, Italy 3 Department of Obstetrics, Gynaecology and Prenatal Diagnosis, Erasmus Medical Centre, Rotterdam, the Netherlands 4 Department of Paediatrics and Neonatal Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom 5 Department of Obstetrics and Gynaecology, University of Brescia, Brescia, Italy 6 Department of Child Neurology and Psychiatry, ASST Spedali Civili, Brescia, Italy 7 Fetal Medicine Section, Department of Obstetrics, Gynecology and Reproductive Medicine, University Hospital Quiron Dexeus, Barcelona, Spain 8 Department of Surgery and Cancer, Imperial College London, United Kingdom 9 Department of Development and Regeneration, KU Leuven, Leuven, Belgium Key words fetal neurosonography, central nervous system, antenatal ultrasound, third-trimester scan received 11.09.2017 accepted 16.04.2018

Bibliography DOI https://doi.org/10.1055/a-0627-7173 Published online: July 5, 2018 Ultraschall in Med © Georg Thieme Verlag KG, Stuttgart · New York ISSN 0172-4614

Correspondence Dr Christoph C. Lees, MD, MRCOG Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS, United Kingdom [email protected]

Dall’Asta A et al. Etiology and Prognosis… Ultraschall in Med

ABSTR AC T

Objectives We sought to assess the causes and outcomes of

severe VM diagnosed de novo after 24 weeks of gestation where a mid-trimester anomaly scan was described as normal. Methods Multicenter retrospective study of five European fetal medicine centers. The inclusion criteria were normal anatomy at the mid-trimester scan, uni/bilateral finding of posterior ventricle measuring ≥ 15 mm after 24 weeks with neonatal and postnatal pediatric and/or neurological assessment data. Results Of 74 potentially eligible cases, 10 underwent termination, the outcome was missing in 19 cases and there was 1 neonatal death. Therefore, 44 formed the study cohort with a median gestation at diagnosis of 32 + 0 weeks (25 + 6 – 40 + 5). VM was unilateral in five cases. Agenesis of the corpus callosum (ACC) and grade III/IV intraventricular hemorrhage (IVH) accounted for 14 cases each. ACC was isolated in 9 fetuses. Obstructive abnormalities included 5 arachnoid and 1 cavum velum interpositum cyst. Four fetuses had an associated suspected or confirmed genetic condition, 2 congenital infections, 1 abnormal cortical development and the etiology was unknown in 3/44. Postnatal assessment at median 20 months (3 – 96) showed 22/44 (50 %) normal, 7 (16 %) mildly abnormal and 15 (34 %) severely abnormal neurodevelopmental outcomes. Conclusion One half of babies with severe VM diagnosed after 24 weeks have normal infant outcome with ACC and IVH representing the most common causes. Etiology is the most important factor affecting the prognosis of fetuses with severe VM diagnosed at late gestation. Z US A M M E N FA SS U N G

Ziel Bestimmung der Ursachen und Folgen einer schweren Ventrikulomegalie (VM) mit de-novo Diagnose nach 24 Schwangerschaftswochen (SSW) bei unauffälligem Basisultraschall im 2. Trimenon. Methoden Multizentrische retrospektive Studie in 5 europäischen Pränatalzentren. Die Einschlusskriterien waren eine normale Fetoanatomie beim Screening im 2. Trimenon, ein nach der 24. SSW auftretender uni-/bilateraler Befund im Hinterhorn von > 15 mm sowie neonatale und postnatale pädiatrische und / oder neurologische Befunde.

Original Article

b

Ergebnisse Von 74 potentiell geeigneten Fällen wurde bei 10

die Schwangerschaft beendet, in 19 Fällen fehlte der Ausgang und in einem Fall verstarb das Neugeborene. Folglich bildeten 44 Fälle die Studienkohorte, die bei Diagnosestellung eine mediane SSW von 32 + 0 (25 + 6 bis 40 + 5) aufwies. In 5 Fällen war die VM einseitig. Eine Agenesie des Corpus Callosum (ACC) sowie eine intraventrikuläre Hämorrhagie (IVH) Grad III / IV bestand bei jeweils 14 Fällen. Eine isolierte ACC wurde bei 9 Feten festgestellt. Zu den obstruktiven Anomalien gehörten 5 arachnoidale Zysten und 1 Zyste des Cavum velum interpositum. Bei vier Feten war dies mit einer vermuteten oder bestätigten Erbkrankheit assoziiert, zwei hatten kongenitale

Introduction

Fetal cerebral ventriculomegaly (VM) is defined by the enlargement of the posterior horns (atria) of the lateral ventricles and accounts for approximately 0.1 – 1 % of all antenatally detected abnormalities [1]. VM has been considered a sign of abnormal development of the fetal central nervous system (CNS), but its prognosis varies depending upon the underlying condition, including structural and obstructive pathologies, infections, intracranial bleeding and genetic syndromes [2]. Severe VM is defined by measurement of the posterior horns of the lateral ventricles at or above 15 mm. This is reported to be suggestive of major brain abnormalities, associated with a high likelihood of progression of the ventricular enlargement and coexistence of additional CNS structural abnormalities [3]. In the largest reported case series of antenatally diagnosed severe VM, approximately 45 % had additional abnormalities [4] with higher proportions reported in other cohorts [3, 5, 6]. Although limited data are available regarding postnatal outcomes in survivors, very poor neurodevelopmental and motor prognosis and a high risk of neonatal death is reported even in cases where the severe VM is isolated. As a consequence, a high rate of termination of pregnancy (TOP) has been associated with the antenatal diagnosis of severe VM [4, 7, 8]. However, in most studies fetal outcomes have been aggregated irrespective of gestational age at diagnosis, which is usually performed at the second-trimester anomaly scan [3 – 5]. For this study we collected the data of a predefined cohort of fetuses diagnosed with severe VM after 24 weeks and with known postnatal follow-up aiming to evaluate whether late gestational age at the time of VM detection may influence the prognosis and to investigate outcomes where severe VM is detected after a midtrimester scan was described as normal.

Methods

This was a retrospective multicenter study involving five tertiary referral centers in Europe (Queen Charlotte’s and Chelsea Hospital, London, United Kingdom; University Hospitals of Parma and Brescia, Italy; Erasmus Medical Centre, Rotterdam, the Netherlands; University Hospital Quiron Dexeus, Barcelona, Spain). Since

Infektionen, bei einem lag eine abnormale Entwicklung des Cortex vor und in 3/44 Fällen war die Ätiologie nicht bekannt. Die postnatale Bewertung nach median 20 Monaten (3 – 96) ergab bei 22/44 (50 %) eine normale, in 7 (16 %) eine leicht auffällige und in 15 (34 %) schwer auffällige neurologische Entwicklung. Schlussfolgerung Die Hälfte der Babys mit einer nach 24 SSW diagnostizierten schweren VM hatte ein normales pädiatrisches Outcome, wobei ACC und IVH die häufigsten Ursachen waren. Die Ätiologie ist der wichtigste Einflussfaktor auf die Prognose von Feten mit Diagnose einer schweren VM in der Spätschwangerschaft.

2007 in all of these countries, a mid-trimester anomaly scan has been routinely offered to all pregnant women in accordance with national screening programmes. Cases of severe VM were identified by searching fetal medicine databases (Astraia GmbH, Munich, Germany), Viewpoint (GE Healthcare GmbH, Solingen, Germany) and a non-proprietary Electronic Database for the terms VM and hydrocephalus. Obstetric notes and scan reports and images were then reviewed. The criteria for inclusion of cases were a routine mid-trimester anomaly scan with normal findings performed according to relevant national or international standards [9 – 13] before 24 weeks and ultrasound (US) findings of either unilateral or bilateral severe VM, defined by measurement of the posterior horn of the lateral ventricle of 15 mm or greater on a standard transventricular axial plane as described by Cardoza et al. [14] at or after 24 weeks of gestation. We excluded cases in which an additional major structural anomaly which should have been diagnosed according to the National and/or International Guidelines, such as spina bifida or encephalocele, was identified at the time of the diagnosis of severe VM. In all cases full US overview of the fetal anatomy was performed, including two-dimensional neurosonography with or without three-dimensional mutiplanar imaging, and the diagnosis of severe VM was made or confirmed by fetal medicine experts from the centers involved in the study. Once severe VM was confirmed, detailed US inspection of the fetus for other structural anomalies was also performed. Additional investigations such as karyotype, SNP-array or CGH-array, “TORCH” (Toxoplasma, Rubella, Cytomegalovirus (CMV) and Parvovirus B19) and, where hemorrhage was noted, feto-neonatal alloimmune thrombocytopenia (FNAIT) screen were undertaken. We defined the severity of intraventricular hemorrhage (IVH) based on the classification proposed by Volpe [15]. In all cases the option of karyotyping or array testing was discussed antenatally and performed either antenatally or postnatally. COL4A1/2 testing was not performed antenatally but only postnatally at the discretion of the physician in cases of suspected IVH. In all cases the option of fetal magnetic resonance imaging (MRI) was discussed antenatally and performed either antenatally or postnatally in all surviving children.


b

Collected antenatal data included information on antenatal US findings, gestational age at diagnosis, width of the largest ventricle and mean ventricular width, laterality of the severe VM (unilateral vs. bilateral), MRI findings, results of the additional tests performed and delivery outcomes. Hydrocephalus was defined as VM and head circumference measurement on or above the 95th percentile for gestation. Details of the perinatal and postnatal outcome and subsequent follow-up were obtained and included US or MRI imaging, need for further treatment (ventriculo-peritoneal shunting or other surgery), final diagnosis and age of the children up to November 30, 2016. TOP after 24 weeks is legally precluded in Italy (L. 22 Maggio 1978, n. 194), permitted under specified circumstances in the United Kingdom (Clause E [Section l (l)(d)] of the 1967 UK Abortion Act, on the basis of “a substantial risk of severe handicap” if the babies were to be born alive) and in Spain (Ley Orgánica 2/ 2010, de salud sexual y reproductiva y de la interrupción voluntaria del embarazo), only on the basis of severe malformations incompatible with life or with expected severe sequelae, while in the Netherlands (Wet Afbreking Zwangerschap) TOP can only be performed on the basis of severe malformations incompatible with life after consultation. Surviving infants were referred to pediatric neurology clinics for further follow-up and outcomes were collected to the latest examination. No common neurodevelopmental scoring system was used. Neurodevelopmental outcome was defined as normal, mildly abnormal and severely abnormal. Mildly abnormal outcome comprised conditions not impacting the motor, mental and cognitive functions such as visual impairment, muscular stiffness or reduced tone, mild cerebral palsy or motor asymmetry, whereas severely abnormal outcomes included any condition where mental or motor dysfunction was impacting ability such as motor or developmental delay and cerebral palsy. All cases with unknown outcome were excluded from the analysis. Due to the design of this retrospective study and the inclusion of fully anonymized clinical data where no intervention was undertaken, it did not fulfill the criteria for requiring ethical committee consideration in any centers. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) v. 19.0 (IBM Inc., Armonk, NY, USA). Data were shown as median (range) or as number (percentage). The Chi-square test was used to compare categorical variables and p-values < 0.05 were considered statistically significant. This case series was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [16].

Results

Over the study period, 74 cases were identified with severe VM first diagnosed after 24 weeks. Among these, 10 underwent termination of pregnancy due to suspected genetic syndrome (1 case), grade 3 IVH (3 cases), grade 4 IVH (3 cases), agenesis of the corpus callosum (ACC) (2 cases) and severe fetal anemia secondary to anti-D antibodies (1 case). Postmortem examination was performed in all of these fetuses and in all cases the antenatal diagnosis was confirmed. Of live-born fetuses, 1 died neonatally


▶ Fig. 1 Flow chart (according to STROBE guidelines) [16] for inclusion of cases. TOP: termination of pregnancy; NND: neonatal death. *Mildly abnormal outcome included conditions not impacting motor, mental and cognitive functions such as visual impairment, muscular stiffness or reduced tone, mild cerebral palsy or motor asymmetry. #Severely abnormal outcomes included any condition in which mental or motor dysfunction was impacting ability such as motor or developmental delay, and cerebral palsy.

(IVH secondary to COL4A1/2 mutation – HANAC Syndrome) and 19 infants had an unknown outcome, leaving 44 fetuses eligible for analysis (▶ Fig. 1). The antenatal characteristics of the included cases are summarized in ▶ Table 1. Severe VM was diagnosed at a median gestational age of 32 + 0 weeks (25 + 6 –40 + 5 ). At diagnosis, the mean width of the wider ventricle was 22.6 + 7.9 mm. Severe VM was bilateral in 39 fetuses and progressive in 20 out of the 39 fetuses who had at least two serial scans (51.3 %), while hydrocephalus was concomitant in 15 cases. Male gender was recorded in 26 of the 44 included cases (60.5 %).

b


case N

gestation at diagnosis of severe VM

Vp worst

Vp mean

progressive ventricular enlargement

hydrocephalus

antenatal US/MRI diagnosis

final postnatal diagnosis

case 1

33 + 4

22

17

Y

N

ACC, bilateral severe VM with colpocephaly

ACC

case 2

33 + 2

18

15

1 scan

N

ACC, bilateral severe VM

ACC

case 3

33 + 6

18

18

N

N


ACC

case 4

40 + 5

49

48

1 scan

Y

bilateral severe VM with hydrocephalus, posterior fossa cyst, distal aqueduct stenosis, hydrocephalus

congenital posterior fossa cyst with aqueduct stenosis and hydrocephalus

case 5

33 + 2

15

15

N

N


ACC

case 6

35 + 3

20

16.5

N

N

ACC, interhemispheric cyst

ACC, interhemispheric cyst

case 7

34 + 0

22

21

Y

Y

bilateral severe VM with hydrocephalus, dilated 3 rd ventricle, cavum velum interpositum cyst

cavum velum interpositum cyst

case 8

34 + 2

30

28

Y

Y

bilateral severe VM with hydrocephalus, grade IV IVH and ventriculitis

grade IV IVH and post-hemorrhagic hydrocephalus

case 9

25 + 6

18

13.7

N

N

left unilateral severe ventriculomegaly of unknown cause

unilateral severe VM, unknown etiology

case 10

36 + 6

15.8

12.4

Y

N

left unilateral severe VM, right unilateral moderate VM

unilateral severe VM, unknown etiology

case 11

29 + 1

16

15

Y

N

right unilateral severe VM, grade 3 IVH with ventriculitis

grade III IVH

case 12

37

21

19

1 scan

N

bilateral severe VM with enlarged 3 rd ventricle, grade III IVH

bilateral severe VM, grade III IVH

case 13

38 + 6

31.9

–

Y

Y

bilateral severe VM with progressive hydrocephalus secondary to Grade IV IVH

grade IV IVH and post-hemorrhagic hydrocephalus

case 14

35 + 4

36

29.5

Y

Y

grade IV IVH, porencephalic cyst

grade IV IVH and post-hemorrhagic hydrocephalus, porencephalic cyst

case 15

36 + 3

20

18.5

Y

N

bilateral severe VM, ACC, IUGR

ACC

case 16

32 + 4

17.7

–

Y

N

bilateral severe VM, ACC

ACC, 17q21.31 microdeletion (Koolen-de Vries syndrome)

case 17

35 + 1

27.7

28.3

1 scan

N


ACC, porencephalic cyst

case 18

31 + 0

24.5

23.9

Y

N

bilateral severe VM, dilated 3 rd ventricle, suspected aqueductal stenosis

grade III IVH

case 19

31 + 2

17.7

17.5

N

N


bilateral severe VM, ACC, Pierre-Robin sequence, suspected genetic etiology but testing declined by the parents

Original Article

▶ Table 1 Features of the included cases: antenatal findings and final postnatal diagnosis.

(Continuation)

b


▶ Table 1 case N

gestation at diagnosis of severe VM

Vp worst

Vp mean


hydrocephalus



case 20

35 + 6

45

40

Y

Y

bilateral severe VM, hydrocephalus, congenital toxoplasmosis

congenital toxoplasmosis

case 21

31 + 5

21.5

20.7

1 scan

N

bilateral severe VM; partial ACC

partial ACC

case 22

31 + 6

17.7

16.8

Y

Y

bilateral severe VM, ACC, hydrocephalus

bilateral severe VM, ACC, hydrocephalus

case 23

31 + 3

15.3

15.1

N

N

right unilateral severe VM, left unilateral moderate VM, ACC

bilateral VM, ACC, dysmorphic features, Mowat-Wilson Syndrome

case 24

34 + 3

17

17

Y

Y

bilateral severe VM, posterior fossa arachnoid cyst

bilateral VM, posterior fossa arachnoid cyst, hypoplastic cerebellum

case 25

30 + 6

28

23.5

Y

Y

bilateral severe VM, dilated 3 rd ventricle, ventriculitis, grade III IVH

bilateral IVH and post-hemorrhagic hydrocephalus

case 26

37 + 5

36

–

Y

Y

aqueduct stenosis of unknown cause, hydrocephalus

aqueduct stenosis secondary to IVH, and post-hemorrhagic hydrocephalus

case 27

31 + 1

31

29.5

Y

Y

bilateral severe VM, dilated 3 rd ventricle, ACC, hydrocephalus, grade III/IV IVH grade

grade IV IVH, confirmed COL4A1 mutation

case 28

39 + 0

18

16.5

N

Y

bilateral severe VM, posterior fossa arachnoid cyst

posterior fossa arachnoid cyst

case 29

29 + 4

32

32

Y

Y

bilateral severe VM, arachnoid cyst, non-communicating hydrocephalus

Arachnoid cyst

case 30

32 + 6

22

20

N

N


grade III IVH, Chiari 1 malformation

case 31

27 + 4

18

16.3

N

N


post-hemorrhagic ventriculomegaly

case 32

36 + 0

20

14

Y

Y


post-hemorrhagic hydrocephalus

case 33

36 + 0

16

16

N

N

bilateral severe VM, partial ACC

partial ACC

case 34

30 + 1

15.5

15

N

N

undetermined encephalopathy

CMV encephalopathy

case 35

32 + 0

20

18

N

N

bilateral severe VM, abnormal cortical development

bilateral severe VM, abnormal cortical development

case 36

35 + 0

18

17

N

N


grade III IVH

case 37

31 + 0

23.6

22.3

N

N

bilateral severe VM, suspected callosal hypoplasia

post-hemorrhagic ventriculomegaly (grade III IVH)

case 38

31 + 0

30

26.5

Y

Y

post-hemorrhagic hydrocephalus, periventricular leukomalacia, vein of Galen aneurysm

grade IV IVH, and post-hemorrhagic hydrocephalus, and vein of Galen aneurysm

case 39

26 + 4

16.5

13.2

N

N

right unilateral severe VM

right unilateral severe VM, unknown etiology

Original Article

HC = head circumference; IVH = intraventricular hemorrhage; VM = ventriculomegaly; TCD = transcerebellar diameter; ACC = agenesis of the corpus callosum; CC = corpus callosum; CSP = cavum septum pellucidum.

ACC bilateral severe VM, ACC N N 16 34 case 44

16

ACC bilateral severe VM, ACC N N 17 31 + 4 case 43

17

arachnoid cyst

ACC bilateral severe VM, ACC

bilateral asymmetrical ventriculomegaly, suspect intraventricular cyst near Monro foramen N

N N

N 19.5

18

31 case 42

21

33 + 0 case 41

19

bilateral severe VM, callosal hypoplasia, vermian hypoplasia bilateral severe VM, thin corpus callosum N Y 18 33 + 2 case 40

21

gestation at diagnosis of severe VM case N

▶ Table 1

(Continuation)

Vp worst

Vp mean


hydrocephalus



b

Antenatal MRI was performed in 38/44 cases, yielding additional information compared to expert neurosonography in 4 (9.1 %); all cases underwent postnatal MRI. TORCH screening was performed in all cases and was positive in 2. FNAIT screening was performed in all women and a positive result for anti-platelet alloimmune antibodies was found in 1. All cases had either antenatal or postnatal karyotyping with or without CGH-array and infants were assessed by a geneticist whenever a genetic syndrome was either suspected or confirmed. IVH and ACC represented the most common diagnosis, accounting for 14 cases (31.8 %) each. Specifically, there were 9 cases classified as grade 3 IVH and 5 cases as grade 4 IVH. Isolated complete and partial ACC accounted for 9 and 2 cases, respectively; additionally, there was 1 case of partial agenesis of the ACC associated with vermian hypoplasia of the cerebellum and 2 cases of complete ACC associated with interhemispheric cyst and porencephalic cyst, respectively. Intracranial cysts leading to an obstructive pathology were diagnosed in 6 cases: 5 arachnoid cysts, of which 3 were infratentorial, and 1 cavum velum interpositum cyst. Genetic abnormalities responsible for VM were either diagnosed or suspected in 4 fetuses. Among these, intracranial bleeding related to COL4A1/2 mutation was confirmed in one case. Other genetic conditions were Koolen de-Vires and Mowat-Wilson Syndromes, while in one fetuses a genetic etiology appeared highly likely but could not be confirmed (case 19). Congenital infections were diagnosed in two fetuses (one each of Toxoplasma and CMV), while in 1 case VM was associated with abnormal cortical development. In the remaining 3 fetuses, no apparent cause for the severe VM was identified. The perinatal and postnatal outcomes are shown in ▶ Table 2. The 44 fetuses were delivered at a median gestation of 38 + 0 (33+ 1–41+ 2) weeks. Caesarean section was scheduled in 10 of the 15 fetuses diagnosed with severe VM and hydrocephalus (67 %) and in 10/29 fetuses (35 %) with normal head size. Pediatric neurology assessment was performed at a median age of 20 months (3 – 96). Normal neurodevelopmental and cognitive outcome at the last evaluation by a pediatric neurologist was recorded in 22 of the 44 surviving children (50 %). A mildly abnormal outcome was reported in 7 cases (16 %). 15 children (34 %) showed severe abnormalities in neurodevelopment and/or in motor functions, with or without epilepsy. The poorest postnatal outcomes were reported in the 4 children suspected or diagnosed with a genetic syndrome or COL4A1/2 mutation, in all but one case of grade IV IVH and two cases of grade III IVH, in one case each of isolated complete and partial ACC, in one case with ACC associated with porencephalic cyst, in one case of posterior fossa arachnoid cyst (case 4) and in both cases of congenital infection. Ventriculo-peritoneal shunting was required in 13 infants; in 8/14 cases of IVH, in 4/6 cases of VM secondary to an obstructive pathology and in the only case of congenital toxoplasmosis. Normal neurodevelopmental outcome was noted in only 4/13 fetuses (31 %) who underwent shunting procedures, including 1/4 (25 %) with obstructive etiology and 2/8 (25 %) with IVH. Normal outcome was reported in 9/14 cases of ACC (6 cases of isolated complete ACC, 1 case of isolated partial ACC, 1 of complete ACC associated with interhemispheric cyst and 1 of partial


b


▶ Table 2 Perinatal and long-term outcomes. The included cases are re-ordered non-consecutively so that they are grouped as “normal”, “mildly abnormal” and “severely abnormal” outcome. case N

gestation at delivery

mode of delivery

birth weight

gender

neonatal outcome

early neurological observations and examination

postnatal imaging (US/MRI)

shunt

age (months) at last neurological follow-up

postnatal outcome

case 2

40 + 5

SVD

3000

male

normal outcome

normal neonatal condition

MRI: ACC, radial orientation of the cingulate gyrus, bilateral VM with colpocephaly, opened 4th ventricle, Rathke cleft cyst

N

12

normal neurodevelopmental and neurological examination

NORMAL

case 3

39 + 3

SVD

2900

male

normal outcome


confirmed antenatal findings

N

32


NORMAL

case 5

–

SVD

unknown

female

normal outcome

normal early outcome


N

4


NORMAL

case 6

41 + 1

SVD

5013

male

normal outcome

normal early outcome


N

30


NORMAL

case 7

–

ElLSCS

unknown

male

normal outcome

macrocephaly (HC 99th percentile), asymptomatic


N

8

normal neurodevelopmental and neurological examination; under neurosurgical surveillance but no surgery indicated at this time

NORMAL

case 9

34 + 6

SVD

2160

male

spontaneous preterm delivery

normal examination, HC on 50th percentile

neonatal cranial ultrasound scan shows left-sided ventriculomegaly (left ventricular index > 97th percentile)

N

10

asymptomatic macrocephaly (head circumference > 99th percentile), normal neurodevelopmental and neurological examination

NORMAL

case 10

–

SVD

unknown

female


normal examination

neonatal cranial US scan normal; mild asymmetry of ventricle (left more prominent), normal bilateral ventricular index (50 – 75th percentiles)

N

3

normal neurodevelopmental and neurological examination, no further follow-up arranged

NORMAL

(Continuation)

b


case N


mode of delivery

birth weight

gender

neonatal outcome



shunt


postnatal outcome

case 12

–

SVD

unknown

male


normal examination

neonatal cranial US: bilateral ventriculomegaly (bilateral ventricular index > 97th percentile, dilated 3 rd ventricle), right IVH

N

22

normal neurological examination and neurodevelopment using Bayley Scales of Infant DevelopmentIII; normal motor and non-motor parameters including communication

NORMAL

case 15

37 + 4

SVD

2050

male


normal examination


N

24


NORMAL

case 18

39 + 5

SVD

3840

male


normal examination

bilateral severe VM, normal CC, features suggesting grade III IVH

N

18


NORMAL

case 25

37 + 0

ElLSCS

2970

male


normal examination

cranial US: grade III IVH, hydrocephalus confirmed

N

13


NORMAL

case 28

39 + 6

ElLSCS

3200

male

normal outcome, transfer to NICU for observation

normal examination

confirmed antenatal US findings

Y

59

surgery for cyst resection; normal neurodevelopmental and neurological examination

NORMAL

case 29

37 + 0

ElLSCS

2780

female

normal early outcome, transfer to NICU for observation

normal examination

confirmed antenatal US findings

Y

36

endoscopic fenestration of the cyst and VP shunt at 1 month; repeated shunt at 17 months; normal neurodevelopmental and neurological examination

NORMAL

case 31

37 + 4

CS

3270

female


normal examination


N

4


NORMAL

case 32

36 + 5

SVD

2300

female


suction difficulties

post-hemorrhagic triventricular non-communicating hydrocephalus

Y

24


NORMAL

case 33

39 + 1

CS

3650

male


normal examination

partial ACC

N

57

normal neurodevelopment; febrile convulsions

NORMAL

Original Article

▶ Table 2

(Continuation)

b


▶ Table 2 case N


mode of delivery

birth weight

gender

neonatal outcome



shunt


postnatal outcome

case 36

37 + 0

CS

–

female


normal examination


N

39


NORMAL

case 37

37 + 5

CS

2970

male


normal examination


Y

32


NORMAL

case 40

39 + 0

SVD

3350

female


normal examination

bilateral severe VM, callosal hypoplasia, vermian hypoplasia

N

–


NORMAL

case 42

33 + 1

SVD

2790

male


normal examination

left ventricular obstructive hydrocephalus due to arachnoid cyst

N

19

surgery for septostomy and marsupialization of the arachnoid cyst; normal neurodevelopmental and neurological examination

NORMAL

case 43

40 + 6

OVD

3200

female


normal examination

bilateral severe VM, ACC, colpocephaly, acute left frontal intraparenchymal hematoma

N

50


NORMAL

case 44

40 + 0

SVD

3240

male


normal examination

bilateral severe VM, colpocephaly, ACC

N

38


NORMAL

case 1

41 + 2

SVD

3550

male

normal outcome


MRI declined by parents because of need for sedation

N

12

seen by ophthalmologist: bilateral optic nerve hypoplasia; no other abnormal neurological findings

MILDLY ABNORMAL

case 22

38 + 2

SVD

2740

male


mild left hemiparesis

severe VM and ACC confirmed

N

16

mild left unilateral cerebral palsy

MILDLY ABNORMAL

case 24

38 + 4

vacuum delivery (FTP)

2800

female

normal neonatal outcome, transfer to NICU until shunting

normal examination

MRI: bilateral VM, big arachnoid cyst behind cerebellum, hypoplastic cerebellum, prominent choroid plexus cyst

Y

11

normal neurodevelopment, mild bilateral cerebral palsy

MILDLY ABNORMAL

(Continuation)

b


case N


mode of delivery

birth weight

gender

neonatal outcome



shunt


postnatal outcome

case 26

38 + 6

EmLSCS (FTP)

3100

female

normal neonatal outcome, transfer to NICU for observation

mild left hemiparesis

hydrocephalus, IVH

Y

3

left unilateral mild hemiparesis

MILDLY ABNORMAL

case 35

39 + 2

SVD

3660

male

Transient tachypnea

normal examination

unknown cause

N

3

mild left ocular strabismus, mild reduction of muscle tone

MILDLY ABNORMAL

case 38

38 + 0

CS

3580

female

prolonged intubation, embolization of vein of Galen aneurysm at 40 days

upper limb motor asymmetry

triventricular hydrocephalus, vein of Galen aneurysm, right hemisphere malacic lesions, right ponto-mesencephalic atrophy

N

5

upper limb motor asymmetry

MILDLY ABNORMAL

case 39

34 + 0

SVD

1943

male

transient tachypnea

normal examination

mild ventricular enlargement (right>left), colpocephaly, small right subependymal cyst

N

28

alternating divergent strabismus (right>left)

MILDLY ABNORMAL

case 4

41 + 1

ElLSCS

4600

male

normal outcome

severe ventriculomegaly and macrocephaly (HC > 99th percentile); asymptomatic

MRI: posterior fossa arachnoid cyst, distortion of the brainstem with superior transtentorial herniation, aqueduct stenosis with hydrocephalus, bilateral PCA infarcts

Y

16

substantial speech and language delay

SEVERLY ABNORMAL

case 8

37 + 1

ElLSCS

unknown

female


severe ventriculomegaly, and macrocephaly (HC > 99th percentile), asymptomatic

MRI: bilateral post-hemorrhagic hydrocephalus, right thalamic injury

Y (required revisions)

9

developmental delay and cerebral impairment

SEVERELY ABNORMAL

Original Article

▶ Table 2

(Continuation)

b


▶ Table 2 case N


mode of delivery

birth weight

gender

neonatal outcome



shunt


postnatal outcome

case 11

37 + 2

ElLSCS

3570

female

neonatal hypotonia and transient need for nasal oxygen and NG tube feeding

asymptomatic, macrocephaly (HC on 99th percentile)

MRI: residual evidence of a right germinal matrix hemorrhage, right thalamic abnormality, bilateral ventriculomegaly with some reduction in the periventricular white matter volume

N

11

developmental delay, severely delayed cognitive skills and significant cerebral visual impairment with abnormal visual evoked

SEVERELY ABNORMAL

case 13

38 + 6

ElLSCS

4135

female


asymptomatic, macrocephaly

MRI: right frontal cerebral infarction, hydrocephalus

Y

84

triventricular hydrocephalus; left unilateral cerebral palsy, spastic due to cerebral infarction right frontal and hydrocephalus due to prenatal intraventricular bleeding

SEVERELY ABNORMAL

case 14

36 + 4

SVD

2830

female


early information not available

porencephalic cyst, severe VM, most likely secondary to IVH

Y

72

cerebral palsy, spastic unilateral right side, refractory epilepsy

SEVERELY ABNORMAL

case 16

40 + 4

EmLSCS (obstruction)

3040

male


abnormal sucking and swallowing


N

48

delayed neurodevelopment, dysmorphic features diagnosis of Koolen-de Vries syndrome

SEVERELY ABNORMAL

case 17

39 + 3

SVD

4470

male


normal physical and neurological examination

postnatal US: right hemisphere porencephalic cyst (not seen antenatally), bilateral severe VM

N

54

right unilateral cerebral palsy, epilepsy, delayed neurodevelopment, IQ55

SEVERELY ABNORMAL

case 19

41 + 1

SVD

3260

male


normal examination

ACC

N

14

delayed neurodevelopment, Pierre-Robin sequence suspected genetic cause but genetic testing declined by the parents

SEVERELY ABNORMAL

(Continuation)

b


case N


mode of delivery

birth weight

gender

neonatal outcome



shunt


postnatal outcome

case 20

37 + 4

SVD

3100

female

Normal neonatal condition

normal examination, left-sided microphthalmia

MRI: hydrocephalus confirmed, microphthalmia left eye

Y

24

delayed motor development and language, hydrocephalus, microphthalmia

SEVERELY ABNORMAL

case 21

36 + 1

EmLSCS (abruption)

1900

male


normal examination

–

21

delayed neurodevelopment, bilateral cerebral palsy; PHVD after IVH, suspicion of brain atrophy

SEVERELY ABNORMAL

case 23

37 + 6

SVD

3815

male


neonatal seizures

US and MRI confirmed antenatal US findings

N

15

delayed neurodevelopment, epilepsy; diagnosis of Mowat-Wilson syndrome

SEVERELY ABNORMAL

case 27

35 + 1

EmLSCS (FTP)

2920

female

normal outcome, transfer to NICU for observation

CNS infection after drain

grade III/IV IVH, hydrocephalus

Y (repeated)

4

first drain infected after few days, CNS infection, second drain cerebral palsy COL4A1 mutation confirmed

SEVERELY ABNORMAL

case 30

38

CS

3380

male

transfer to NICU, intubated

respiratory depression, suction difficulties

Chiari 1 malformation, choroid plexus hemorrhage, ventriculomegaly,

Y

96

delayed neurodevelopment

SEVERELY ABNORMAL

case 34

36 + 0

CS

1850

male


normal suction and swallowing

CMV encephalopathy: diffuse leukomalacia, ventriculomegaly, abnormal cortical development, bilateral germinolytic cysts

N

–


SEVERELY ABNORMAL

case 41

39 + 4

CS

2810

male


reduced spontaneous motility, upper limb tremors


N

40


SEVERELY ABNORMAL

HC = head circumference; IVH = intraventricular hemorrhage; VM = ventriculomegaly; TCD = transcerebellar diameter; ACC = agenesis of the corpus callosum; CC = corpus callosum; PHVD = posthemorrhagic ventricular dilatation; PCA = posterior cerebral artery; FTP = failure to progress.

Original Article

▶ Table 2

b

ACC associated with vermian hypoplasia), in 7/14 cases of IVH (all were grade 3), in 4/6 cases in which an obstructive cause was considered responsible for the severe VM and in 2 cases in which the etiology was unknown. There was no relationship between postnatal outcome and progression of the ventricular enlargement (abnormal outcome in 12/19, 63.2 %, vs. 8/20, 40 %, p 0.15) and fetal gender (abnormal outcome in 12/26 male fetuses, 46.2 %, vs. 9/17 female fetuses, 52.9 %, p 0.66). Regarding the relationship between etiology and outcome, good prognosis was noted in cases of isolated partial or complete ACC (6/7 cases, 86 %), grade 3 IVH (6/9 cases, 67 %), obstruction of the ventricular system (4/6 cases, 67 %) and idiopathic causes (2/3 cases, 67 %). On the other hand, grade 4 IVH and genetic causes were invariably associated with a severely abnormal outcome.

Discussion

To our knowledge this is the first study specifically focused on severe ventriculomegaly diagnosed de novo after 24 weeks. We show considerably better infant neurodevelopmental and motor outcome among live-born fetuses compared to formerly reported data [3 – 6]. Within our cohort, half of fetuses survived with no impairment and those remaining with either a mildly or severely abnormal outcome. There was one neonatal death. Former data on severe VM reported the pathology and the outcomes associated with severe VM regardless of the gestational age at diagnosis. In the largest case series published to date [4], antenatally diagnosed severe VM was concomitant with structural or genetic abnormalities or other complications in nearly twothirds of all cases (100/157, 64 %), among whom CNS malformations (65/100, 65 %) and particularly neural tube defects represented the most common diagnosis (29/100, 29 %). Such findings are consistent with those reported in other case series [3, 5, 6]. It is important to note, however, that in all but one study [6] the median gestational age at diagnosis was lower than we report [3 – 5]. Furthermore, only one study [5] provides information on the neurodevelopmental outcome of the surviving 8 fetuses with severe VM. Otherwise, outcomes are described only in relation to intrauterine death (IUD) or TOP, live births and neonatal deaths [3, 4, 6]. Our data show that the most frequent pathologies in late onset severe VM were complete or partial ACC and IVH, accounting for over half of the cases. One-third of the fetuses diagnosed with late onset severe VM after a mid-trimester anomaly scan was described as normal had major structural intracranial abnormalities. Although these were potentially diagnosable at an earlier scan, it is important to note that the degree of detail of CNS examination on ultrasound varies considerably with the setting of the ultrasound scan and the experience of the operator. Isolated ACC, either complete or partial, is more likely to be associated with normal neurodevelopmental outcome [17, 18]. Severe disability has been reported in 10 % and 30 % of complete and partial ACC, respectively [19]. With expert neurosonographic examination, ACC should be diagnosed earlier in most cases. However, in many national and international guidelines [9 – 13], visualization of the corpus callosum is not required at the routine mid-trimester anomaly scan. In such cases, ACC may be suspected


from indirect findings, including ventriculomegaly or failure to visualize the cavum septum pellucidum [20, 21]. Nevertheless, nonvisualization of the cavum septum pellucidum is not a reliable sign in the diagnosis of ACC [22]. Furthermore, ACC may coexist with additional CNS findings and with a variety of chromosomal abnormalities or genetic conditions [18] which may negatively impact the prognosis. In our cohort, ACC was diagnosed in 1 case of arachnoid cyst, 1 porencephalic cyst, 1 vermian hypoplasia and in the fetus that had a final diagnosis of Koolen-de Vries Syndrome. Although ventriculomegaly may reflect primary abnormality in neuronal migration and cerebral development such as cortical dysplasias, polymicrogyria, or lissencephaly [2, 23 – 25], there was only one case of abnormal cortical development in our cohort, which is in contrast with previous reports [3 – 6]. This leads us to speculate that complex abnormalities such as cortical dysplasias are unlikely to be overlooked at the mid-trimester scan, regardless of the presence or absence of the corpus callosum. Severe VM developing after 24 weeks seems more likely to represent the consequence of acquired conditions. Furthermore, given the number of cases of severe VM associated with ACC from our cohort not identified at the mid-trimester anomaly scan, the midsagittal view might usefully be included in the routine assessment of the fetal brain. IVH may cause ventriculomegaly which may be complicated by obstruction of the cerebrospinal fluid circulation, usually at the level of the aqueduct of Silvius, but possibly at the foramina of Monro [26]. In utero IVH has been linked to maternal trauma and fetal coagulation disorders [26]. IVH may represent a similar pathophysiological process as seen in preterm newborns of similar gestation, i. e. subependymal germinal matrix hemorrhage with spread within the ventricular system following a variety of possible insults including perfusion abnormalities [15]. Within our cohort, one woman out of 14 with IVH screened positive for alloimmune anti-platelet antibodies. A mutation of the COL4A1 gene was identified in 1 child. This has been reported in conjunction with intracranial bleeding thought to be related to abnormal collagen development and small vessel vasculopathy [27]. Previously reported data suggested a 50 % chance of poor neurodevelopmental outcome in fetuses with IVH associated with VM, high in utero and perinatal mortality rates and also high rates of termination of pregnancy [26]. Consistent with these observations, in our cohort neurodevelopmental outcome was normal in 50 % of the surviving fetuses. The involvement of the cerebral parenchyma, which defines grade IV IVH, was invariably associated with a severely abnormal outcome, while normal neurodevelopment was reported in most children with grade III IVH, i. e. without parenchymal injury. A very poor prognosis was also reported in the two cases of ventriculomegaly secondary to congenital infection, consistent with previous reports [28, 29]. Obstructive causes of VM other than IVH, represented predominantly by arachnoid cysts in our cohort, and idiopathic causes of severe VM were more often associated with a normal or a near-normal outcome. Features of obstructive pathology include increased head circumference, partial or complete destruction of the cavum septi pellucidi, decrease or absence of pericerebral spaces and, in some cases, if the obstruction is below the third ventricle, at the level of the Sylvian aqueduct, the presence of dilated third ventricle and suprapineal recess [2]. Depending on their position within the brain

Original Article

b

parenchyma, which can be infratentorial or supratentorial, intracranial cysts may be associated with abnormalities of the corpus callosum in addition to fetal ventriculomegaly. Postnatal neurology examination was normal in two-thirds of cases of intracranial cysts. Such figures are consistent with those recently reported for second and third trimester fetuses by Youssef et al. [30] and suggest that severe VM secondary to benign cystic lesions is not associated with a worse prognosis than that of intracranial cysts themselves. Similarly, normal neurodevelopment and motor function were noted in fetuses showing apparently isolated severe VM. According to our data, this diagnosis of exclusion after 24 weeks, though uncommon, is associated with a better outcome than reported, both in terms of survival and survival with intact neurodevelopment [3 – 6]. Strict inclusion criteria and completeness of the outcome data, particularly those concerning the postnatal neurodevelopment, are among the main strengths of our work. The retrospective design of the study and the lack of a standardized scale for neurodevelopmental evaluation are limitations. Nevertheless, in all cases the information regarding postnatal follow-up was complete and collected from case notes or correspondence from dedicated pediatric clinics even though the length of infant follow-up was variable. One half of the included cases had a follow-up of less than 24 months, and a quarter of less than 12 months. Finally, in the standard transventricular plane, only the hemisphere on the far side of the transducer is clearly visualized, as the hemisphere close to the transducer is usually obscured by a reverberation artifact, so we cannot exclude that some of our cases of unilateral VM were overlooked at screening ultrasound because of fetal position. In conclusion, we describe the pathologies responsible for severe VM diagnosed after 24 weeks and childhood neurodevelopment in a cohort of fetuses with normal assessment at the mid-trimester anomaly scan. Within a selected cohort of fetuses in which severe VM was diagnosed at late gestation, we find a higher rate of normal neurodevelopmental outcome than previously reported and no association with progression of ventricular enlargement and fetal gender. The detection of severe VM should prompt a careful examination of the fetal brain. Depending on the differential diagnosis of the potential causes of VM, additional investigations including genetic testing should be offered, as outcome is strongly dependent on the underlying etiology. These data can be useful in the counseling of the prospective parents.

AB BRE VI ATIONS

VM CNS TOP US CMV FNAIT MRI IVH ACC

ventriculomegaly central nervous system termination of pregnancy ultrasound cytomegalovirus feto-neonatal alloimmune thrombocytopenia magnetic resonance imaging intraventricular hemorrhage agenesis of the corpus callosum

Conflict of Interest

The authors declare that they have no conflict of interest.

References

[1] European Surveillance of Congenital Anomalies EUROCAT. Prevelance Tables for Nervous system anomalies (per 10000 births). EUROCAT Available via 2012 http://www.eurocat-network.eu/accessprevalencedata/prevalencetables. [29 November 2016] [2] Guibaud L, Lacalm A. Etiological diagnostic tools to elucidate “isolated” ventriculomegaly. Ultrasound Obstet Gynecol 2015; 46: 1 – 11

[3] Lam SJ, Kumar S. Evolution of fetal ventricular dilatation in relation to severity at first presentation. J Clin Ultrasound 2014; 42: 193 – 198

[4] Hannon T, Tennant PW, Rankin J et al. Epidemiology, natural history, progression, and postnatal outcome of severe fetal ventriculomegaly. Obstet Gynecol 2012; 120: 1345 – 1353 [5] Gaglioti P, Danelon D, Bontempo S et al. Fetal cerebral ventriculomegaly: outcome in 176 cases. Ultrasound Obstet Gynecol 2005; 25: 372 – 377 [6] Breeze AC, Alexander PM, Murdoch EM et al. Obstetric and neonatal outcomes in severe fetal ventriculomegaly. Prenat Diagn 2007; 27: 124 – 129

[7] Graham E, Duhl A, Ural S et al. The degree of antenatal ventriculomegaly is related to pediatric neurological morbidity. J Matern Fetal Med 2001; 10: 258 – 263 [8] Pilu G, Falco P, Gabrielli S et al. The clinical significance of fetal isolated cerebral borderline ventriculomegaly: report of 31 cases and review of the literature. Ultrasound Obstet Gynecol 1999; 14: 320 – 326 [9] International Society of Ultrasound in Obstetrics & Gynecology Education Committee. Sonographic examination of the fetal central nervous system: guidelines for performing the “basic examination” and the “fetal neurosonogram”. Ultrasound Obstet Gynecol 2007; 29: 109 – 116

[10] Italian Society of Ultrasound in Obstetrics and Gynecology (Società Italiana di Ecografia Ostetrico Ginecologica, SIEOG). SIEOG guidelines. 2015 http://www.sigo.it/wp-content/uploads/2015/12/LineeGuidaSieog_2015.pdf [11] Fetal anomaly screening programme: programme handbook June 2015. https://www.gov.uk/government/publications/fetal-anomaly-screening-programme-handbook [12] Spanish Society of Obstetrics and Gynecology (SEGO). Guidelines for antenatal ultrasound screening. http://www.gapsego.com/categoriaguia-asistencia/ecografia/ [13] Dutch Society of Obstetrics and Gynecology (Nederlandse Vereniging voor Obstetrie en Gynaecologie, NVOG). Structureel echoscopisch onderzoek (SEO) Versie 2.0. http://www.rivm.nl/dsresource?objectid=c05e9286-9198-47a4-88fc-99abfec96553&type=org&disposition=inline [14] Cardoza JD, Goldstein RB, Filly RA. Exclusion of fetal ventriculomegaly with a single measurement: the width of the lateral ventricular atrium. Radiology 1988; 169: 711 – 714 [15] Volpe JJ. Intracranial Hemorrhage: Germinal Matrix Intraventricular Hemorrhage of the Preterm Infant (Neuropathology and Pathogenesis). In: Volpe JJ, editor Neurology of the Newborn. Philadelphia: W.B. Saunders; 2001: 428 – 447 [16] von Elm E, Altman DG, Egger M et al. The strengthening the reporting of the observational studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370: 1453 – 1457

[17] D’Antonio F, Pagani G, Familiari A et al. Outcomes Associated With Isolated Agenesis of the Corpus Callosum: A Meta-analysis. Pediatrics 2016; 138: doi:10.1542/peds.2016-0445


b

[18] Santo S, D’Antonio F, Homfray T et al. Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet Gynecol 2012; 40: 513 – 521

[19] Sotiriadis A, Makrydimas G. Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Am J Obstet Gynecol 2012; 206: 337.e1 – 337.e5 [20] Barkovich AJ, Norman D. Absence of the septum pellucidum: a useful sign in the diagnosis of congenital brain malformations. Am J Roentgenol 1989; 152: 353 – 360

[21] Malinger G, Lev D, Kidron D et al. Differential diagnosis in fetuses with absent septum pellucidum. Ultrasound Obstet Gynecol 2005; 25: 42 – 49 [22] Ghi T, Carletti A, Contro E et al. Prenatal diagnosis and outcome of partial agenesis and hypoplasia of the corpus callosum. Ultrasound Obstet Gynecol 2010; 35: 35 – 41

[23] Malinger G, Lev D, Lerman-Sagie T. Abnormal sulcation as an early sign for migration disorders. Ultrasound Obstet Gynecol 2004; 24: 704 – 705 [24] Malinger G, Kidron D, Schreiber L et al. Prenatal diagnosis of malformations of cortical development by dedicated neurosonography. Ultrasound Obstet Gynecol 2007; 29: 178 – 191


[25] Guibaud L, Selleret L, Larroche JC et al. Abnormal Sylvian fissure development on prenatal cerebral imaging. Significance and correlation with neuropathological and postnatal data. Ultrasound Obstet Gynecol 2008; 32: 50 – 60 [26] Ghi T, Simonazzi G, Perolo A et al. Outcome of antenatally diagnosed intracranial hemorrhage: case series and review of the literature. Ultrasound Obstet Gynecol 2003; 22: 121 – 130 [27] Kutuk MS, Balta B, Kodera H et al. Is there relation between COL4A1 / A2 mutations and antenatally detected fetal intraventricular hemorrhage? Childs Nerv Syst 2014; 30: 419 – 424 [28] Malinger G, Lev D, Zahalka N et al. Fetal cytomegalovirus infection of the brain: the spectrum of sonographic findings. Am J Neuroradiol 2003; 24: 28 – 32 [29] Malinger G, Werner H, Rodriguez Leonel JC et al. Prenatal brain imaging in congenital toxoplasmosis. Prenat Diagn 2011; 31: 881 – 886 [30] Youssef A, D’Antonio F, Khalil A et al. Outcome of fetuses with supratentorial extra-axial intracranial cysts: a systematic review. Fetal Diagn Ther 2016; 40: 1 – 12