UOG Journal Club: April 2017 Perinatal and long-term outcomes in fetuses diagnosed with isolated unilateral ventriculomegaly: systemic review and meta-analysis C. Scala, A. Familiari, A. Pinas, A.T. Papageorghiou, A. Bhide, B. Thilaganathan, A. Khalil Volume 49, Issue 4, Date: April (pages 450–459) Journal club slides prepared by Dr Yael Raz (UOG Editor for Trainees)

Introduction - Fetal ventriculomegaly Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Introduction - Fetal ventriculomegaly Definition: atrial width >10 mm, measured at the level of the glomus of the choroid plexus, perpendicular to the ventricular cavity and positioning the calipers inside the echoes generated by the lateral walls. Can be symmetrical, affecting both lateral ventricles (bilateral), or unilateral. Prevalence: 0.3 and 1.5 per 1000 births, depending on the gestational age at examination, the technique of measurement and whether one or both ventricles is/are evaluated.

Introduction - Fetal ventriculomegaly Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Introduction - Fetal ventriculomegaly Etiology: normal variation, aneuploidy, genetic syndromes, primary brain abnormalities, congenital infections, cerebrovascular accidents and intracranial hemorrhage. Fetal ventriculomegaly is a common sonographic feature and has been associated with a poor outcome. Even when fetal ventriculomegaly is isolated, there may be an associated risk of abnormal neurodevelopmental outcome. Most relevant studies have assessed the outcomes of bilateral fetal ventriculomegaly.

Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Aim of the study To quantify, via systematic review and meta-analysis, the perinatal and long-term outcomes in fetuses diagnosed with isolated unilateral ventriculomegaly during the second- or third-trimester ultrasound examination

Methods – study selection, data collection Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Methods – study selection, data collection Studies reporting data on the perinatal outcome of fetuses with isolated unilateral ventriculomegaly (atrial width >10 mm) detected during the second or third trimester of pregnancy were included. ‘Apparently isolated ventriculomegaly’ – no additional brain or extracerebral ultrasound abnormalities detected at the time of diagnosis. ‘Truly isolated ventriculomegaly’ - no additional brain or extracerebral abnormalities, chromosomal abnormality or congenital infection were detected pre- or postnatally. Ventriculomegaly was further classified into mild/moderate (atrial width 10–15 mm) and severe (atrial width ≥ 15 mm).

Results – Included studies Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Results – Included studies CDSR, The Cochrane Database of Systematic Reviews; CENTRAL, The Cochrane Central Register of Controlled Trials; DARE, Database of Abstracts of Reviews of Effects.

Results – Apparently isolated unilateral ventriculomegaly (108 cases) Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Results – Apparently isolated unilateral ventriculomegaly (108 cases) No case of abnormal karyotype Prevalence of congenital infection (n=7: 5 CMV, 2 parvovirus): 8.2% Prevalence in fetuses with apparently isolated unilateral ventriculomegaly with atrial width <15mm (101/108, 93.5%) were similar. Prevalence of associated extracerebral abnormalities detected on US: 6.8% *size of the boxes is proportional to study sample size

Results – Apparently isolated unilateral ventriculomegaly (108 cases) Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Results – Apparently isolated unilateral ventriculomegaly (108 cases) Prevalence of associated brain abnormalities detected by prenatal MRI: 5.1% Prevalence in fetuses with apparently isolated unilateral ventriculomegaly with atrial width <15mm (101/108, 93.5%) were similar. Prevalence of progression of ventriculomegaly during pregnancy: 5.4% *size of the boxes is proportional to study sample size

Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Results – Neurodevelopmental delay – apparently isolated unilateral ventriculomegaly (108 cases) Median age at neurological assessment: 30.3 (range, 24.2–36.5) months. Incidence of associated neurodevelopmental delay: 8.0% (atrial width <15mm: 5.9%) Incidence of associated mild neurodevelopmental delay (a): 2.1% and severe neurodevelopmental delay (b): 4.1% *size of the boxes is proportional to study sample size

Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Results – Neurodevelopmental delay – truly isolated unilateral ventriculomegaly (213 cases) 198/213 (93.0%) cases had postnatal neurodevelopmental assessment. Median age at neurological assessment: 38.0 (range, 27.0–49.8) months. Incidence of associated neurodevelopmental delay: 7% (in all cases, atrial width was <15mm) *size of the boxes is proportional to study sample size

Discussion - apparently isolated unilateral ventriculomegaly Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Discussion - apparently isolated unilateral ventriculomegaly In cases with apparently isolated unilateral ventriculomegaly detected on prenatal ultrasound, additional brain abnormalities can be detected on fetal MRI (pre- or postnatally) MRI should remain an important diagnostic tool in such cases. The same applies to screening for congenital infections and follow-up scans to look for progression of the ventriculomegaly.

Discussion - truly isolated unilateral ventriculomegaly Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Discussion - truly isolated unilateral ventriculomegaly Fetuses with truly isolated unilateral ventriculomegaly suffered from a low incidence of neurodevelopmental impairment postnatally. The incidence of neurodevelopmental impairment is similar to that reported in the general population.

Discussion - Unilateral vs bilateral ventriculomegaly Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Discussion - Unilateral vs bilateral ventriculomegaly In cases of mild apparently isolated unilateral ventriculomegaly the prevalence of congenital infection is similar to that in fetuses with bilateral ventriculomegaly. The observed prevalence of chromosomal abnormality (0%), risk of ventriculomegaly progression (5%) and associated brain abnormalities detected on fetal brain MRI (5%) seem to be lower than those for fetuses with bilateral ventriculomegaly.

Discussion - strengths and weaknesses Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Discussion - strengths and weaknesses Strengths Comprehensive search strategy Inclusion of a number of key outcomes identified in only isolated unilateral ventriculomegaly cases. Previous data is limited, findings of this meta-analysis could be valuable in parental counseling. Weaknesses Publication bias (small number of cases in current literature) Study heterogeneity: Gestational age at time of diagnosis Diagnostic interpretation of US and MRI images is difficult to standardize Method and period of follow-up used in assessing neurodevelopmental outcome. Age at neurodevelopmental assessment may be too early for some neurodevelopmental delays to be apparent (but less confounding factors)

Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Conclusions The prevalence of aneuploidy, congenital infection and progression of ventriculomegaly in fetuses with a prenatal diagnosis of apparently isolated unilateral ventriculomegaly is low. The incidence of neurodevelopmental delay in cases of both apparently and truly isolated unilateral ventriculomegaly with an atrial width <15mm is likely to be similar to that reported in cases of isolated bilateral ventriculomegaly and to that reported in the general population.

Outcomes in fetuses with isolated unilateral ventriculomegaly Scala et al, 2017 Future perspectives Large multicenter prospective studies are needed to ascertain the risk of neurodevelopmental delay and the possible risk factors that might influence postnatal prognosis. Points for discussion Should karyotype assessment be offered to women with apparently isolated unilateral ventriculomegaly? Does gestational age at diagnosis correlate with the chance for neurodevelopmental delay?