Prevalence of COL4A1 and COL4A2 mutations in severe fetal multifocal hemorrhagic and/or ischemic cerebral lesions.

OBJECTIVE: To establish the prevalence of COL4A1 and COL4A2 gene mutations in fetuses presenting with a phenotype suggestive of cerebral injury. METHODS: This was a single-center retrospective analysis of all cases of fetal cerebral anomalies suggestive of COL4A1 or COL4A2 gene mutation over the period 2009-2018. Inclusion criteria were: (1) severe and/or multifocal hemorrhagic cerebral lesions; (2) multifocal ischemic-hemorrhagic cerebral lesions. These anomalies could be of different ages and associated with schizencephaly or porencephaly. Between fetuses with and those without a mutation, we compared gestational age at the time of diagnosis, parity and fetal gender. RESULTS: Among the 956 cases of cerebral anomaly diagnosed in our center during the 10-year study period, 18 fetuses were identified for inclusion. A pathogenic COL4A1 gene mutation was found in five of these cases, among which four were de-novo mutations. A variant of unknown significance was found in four fetuses: in the COL4A1 gene in one case and in the COL4A2 gene in three cases. No COL4A1 or COL4A2 mutation was found in the remaining nine fetuses. The median (interquartile range) gestational age at diagnosis was significantly lower in cases with a mutation (24 (22-26) weeks) than in cases without a mutation (32 (29.5-34.5) weeks) (P = 0.03). CONCLUSIONS: A phenotype suggestive of cerebral injury was found in 18 of the 956 (1.9%) cases in our population, in 28% of which there was an associated COL4A1 or COL4A2 mutation. COL4A1 and COL4A2 gene mutations should be sought systematically in cases of severe and/or multifocal hemorrhagic or ischemic-hemorrhagic cerebral lesions, with or without schizencephaly or porencephaly. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

New insights in cerebral findings associated with fetal myelomeningocele: a retrospective cohort study in a single tertiary centre.

OBJECTIVE: To investigate cerebral anomalies other than Chiari type 2 malformation in fetuses with myelomeningocele (MMC). DESIGN: A retrospective cohort study in a single tertiary centre. SETTING: A review of associated cerebral anomalies in cases with prenatal diagnosis of myelomeningocele. POPULATION: Seventy cases of fetal myelomeningocele. METHODS: Ultrasound and MRI images were blindly reviewed. Postnatal imaging and results of the postmortem results were also reviewed. The association between cerebral anomalies and the following ultrasound findings was measured: level of the defect, ventriculomegaly, microcephaly and fetal talipes. MAIN OUTCOME MEASURES: A microcephaly was observed in 32/70 cases (46%) and a ventriculomegaly was observed in 39/70 cases (56%). Other cerebral anomalies were diagnosed in 47/70 (67%). RESULTS: Other cerebral anomalies were represented by 42/70 cases with abnormal CC (60%), 8/70 cases with perinodular heterotopia (PNH; 11%), 2/70 cases with abnormal gyration (3%). MRI performed only in fetal surgery cases confirmed the ulltrasound findings in all cases and provided additional findings in two cases (PNH). Risk ratios of fetal cerebral anomalies associated with MMC did not reach significance for microcephaly, ventriculomegaly, talipes or the level of the defect There was an overall good correlation between pre- and postnatal findings with a Kappa value of 0.79 [95% CI 0.57-1] and 82% agreement. CONCLUSION: Fetal brain anomalies other than Chiari type 2 malformation are frequently observed in fetuses with myelomeningocele, predominantly represented by CC anomalies. Whether these associated cerebral anomalies have an impact on selecting cases eligible for fetal surgery needs further evaluation. TWEETABLE ABSTRACT: Fetal cerebral anomalies other than Chiari type 2 malformation, microcephaly, and ventriculomegaly may be associated with MMC in up to 67% of the cases.

[Preliminary results from the French study on prenatal repair for fetal myelomeningoceles (the PRIUM study)]. / Résultats préliminaires de l'étude PRIUM : programme de réparation in utero des myéloméningocèles.

OBJECTIVES: To present the preliminary results of the PRIUM study, a French pilot study of prenatal repair for myelomeningoceles (MMC). MATERIAL AND METHODS: The fetal surgery for MMC is offered in cases of patients that did not opt for termination of pregnancy. RESULTS: Thirty-six patients were referred in an 18-month period. Eight patients were not eligible for prenatal repair. Another type of dysraphism was made in 6 cases (one spina-lipoma, 5 cases of limited dorsal myeloschisis). Twenty-two patients were eligible to fetal surgery. A prenatal repair was performed in three cases (14%). Four patients opted for a conventional postnatal treatment. Fifteen patients opted for termination of the pregnancy. CONCLUSION: The establishment of a prenatal repair of MMC protocol in France was justified. The experience of the first 18months of this study however suggests that only a limited number of couples will choose this procedure after specialized counseling in a reference center.

[Fetal abdominal cysts at the first trimester scan]. / Images kystiques abdominales fœtales du premier trimestre.

OBJECTIVES: Abdominal cysts are seldom detected at the first trimester scan. The aim of this study is to ascertain their outcome, which is currently not established. METHODS: The French College of Fetal Ultrasound conducted a prospective observational study of 24months, collecting all cases of abdominal cysts discovered during the first trimester ultrasound. Cases of megacystis were excluded from the study. Ultrasound images, prenatal diagnosis expert reports and pregnancy outcomes were collected by sonographers after patient consent. RESULTS: Ten cases of abdominal cysts were collected. The cysts had a mean diameter of 15mm. They were anechoic in 5 cases, hyperechoic in 2 cases and mixed in 3 cases. In 6 of 10 cases, complete resolution was observed at 18WG with a good post-natal outcome; the five cases with anechoic images were associated with normal pediatric examination at birth and in the case of the resolved hyperechoic image, an isolated imperforate anus was observed. In the four cases of hyperechoic or mixed images that had not resolved, the outcome was poor with four termination of pregnancies, including two cases of cloacal dysgenesis. CONCLUSIONS: Abdominal cysts are rare at the first trimester scan. They resolve in two thirds of cases and are then associated with good outcome. When they do not resolve or when they are not strictly anechoic, they require a referral ultrasound examination at 18 and 22WG.

Limits of the surgically induced model of myelomeningocele in the fetal sheep.

PURPOSE: The prevention of Chiari type II malformation (CM) is commonly used as a primary outcome for the evaluation of techniques of fetal myelomeningocele (MMC) surgery in the fetal lamb. The aim of our study was to investigate the frequency of the associated CM in the MMC fetal sheep model and to investigate the contribution of prenatal ultrasound evaluation of CM at the time of prenatal repair. METHODS: A MMC-like lesion was surgically created at 75 days of gestation in 21 fetuses performing a L1-L5 laminectomy followed by an excision of the exposed dura and a midline myelotomy. At a 90-day gestation, among the 19 alived fetuses, a conventional repair of the MMC-like lesion was performed in seven, four of whom underwent cerebral ultrasound (US) examination before the repair. Twelve fetuses remained untreated (control group). All fetuses underwent post-mortem examination (PM) at 138 days. RESULTS: At a 90-day gestation, CM was demonstrated by US examination in all four evaluated fetuses. At birth, CM was found in 3/6 control whether CM was absent in all alived fetuses in the prenatal repair group (n = 4). CONCLUSIONS: Creation of a MMC-like lesion with an additional myelotomy does not always lead to hindbrain herniation. Our study suggests that CM should be assessed by ultrasound examination at the time of the prenatal repair to demonstrate the effectiveness of new techniques for the prenatal repair of MMC.

Screening for fetal spina bifida at the 11-13-week scan using three anatomical features of the posterior brain.

OBJECTIVE: To evaluate the contribution of examination of specific anatomical features of the fetal posterior brain on mid-sagittal first-trimester ultrasound examination to the early detection of open spina bifida. METHODS: Four independent observers reviewed a series of 260 mid-sagittal first-trimester ultrasound images from 52 cases of open spina bifida and 208 normal fetuses. The following analysis was performed by each reviewer for each image: Herman score calculation, intracranial translucency score (CFEF-IT) calculation and determination of presence or absence of three anatomical criteria: intracranial translucency (IT), caudal displacement of the brainstem and cisterna magna. The sensitivity and the false-positive rate for spina bifida detection were calculated for each of the latter three criteria. A secondary analysis was performed on the subset of images achieving a Herman score ≥ 7. RESULTS: The highest detection rate for spina bifida was achieved by non-visualization of the cisterna magna, with associated sensitivity of 50-73% and 39-76%, respectively, for all images and for the subset of images achieving a Herman score ≥ 7. Posterior shift of the brainstem achieved the highest detection rate (86%), but for a single reviewer only. The level of variation in performance between observers was also greatest for this sign. Absence of IT was associated with a lower detection rate for all observers. Overall, an abnormal posterior brain presenting at least one of these three criteria was associated with a detection rate ranging from 50 to 90%. CONCLUSION: In the detection of spina bifida, non-visualization of the cisterna magna achieved the best screening performance. Both non-visualization of the IT and posterior shift of the brainstem were associated with acceptable but lower detection rates. A prospective evaluation of changes in the posterior brain is needed to allow assessment of the most pertinent criteria for first-trimester screening for spina bifida.