The impact of optimal dating on the assessment of fetal growth.

BACKGROUND: The impact of using the Intergrowth (IG) dating formulae in comparison to the commonly used Robinson dating on the evaluation of biometrics and estimated fetal weight (EFW) has not been evaluated. METHODS: Nationwide cross-sectional study of routine fetal ultrasound biometry in low-risk pregnant women whose gestational age (GA) had been previously assessed by a first trimester CRL measurement. We compared the CRL-based GA according to the Robinson formula and the IG formula. We evaluated the fetal biometric measurements as well as the EFW taken later in pregnancy depending on the dating formula used. Mean and standard deviation of the Z scores as well as the number and percentage of cases classified as <3rd, < 10th, >90th and > 97th percentile were compared. RESULTS: Three thousand five hundred twenty-two low-risk women with scans carried out after 18 weeks were included. There were differences of zero, one and 2 days in 642 (18.2%), 2700 (76.7%) and 180 (5%) when GA was estimated based on the Robinson or the IG formula, respectively. The biometry Z scores assessed later in pregnancy were all statistically significantly lower when the Intergrowth-based dating formula was used (p < 10- 4). Likewise, the number and percentage of foetuses classified as <3rd, < 10th, >90th and > 97th percentile demonstrated significant differences. As an example, the proportion of SGA foetuses varied from 3.46 to 4.57% (p = 0.02) and that of LGA foetuses from 17.86 to 13.4% (p < 10- 4). CONCLUSION: The dating formula used has a quite significant impact on the subsequent evaluation of biometry and EFW. We suggest that the combined and homogeneous use of a recent dating standard, together with prescriptive growth standards established on the same low-risk pregnancies, allows an optimal assessment of fetal growth.

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.

[Feticide procedures in second and third trimesters terminations of pregnancy]. / Geste d'arrêt de vie fœtale : techniques pour les interruptions médicales de grossesse des deuxième et troisième trimestres.

Performing a feticide as part of termination of late pregnancy is recommended in many countries. Feticide avoids a live birth of a severely affected premature newborn and prevents fetal pain. There are limited data on feticide procedures since only a few countries in the world authorize late termination of pregnancy. The objective of this review was to assess the most appropriate feticide procedure based on published data during the last thirty years. Administration of an initial fetal analgesia followed by a lethal lidocaine injection through the umbilical cord, under ultrasound guidance, appears to be the most effective, safe and ethical way to perform feticide. According to the current knowledge regarding the risk of fetal pain and survival of extremely preterm infants, a feticide should be discussed as early as 20-22 weeks of gestation.

[Prenatal diagnosis and postnatal outcome of isolated intra-abdominal calcifications: A 10-year experience from a referral fetal medicine center]. / Diagnostic prénatal et issue néonatale des calcifications intra-abdominales isolées : étude rétrospective sur 10 ans.

INTRODUCTION: Intra-abdominal calcifications (iAC) detected during fetal ultrasound examinations are characterized by their isolated or associated nature, as well as their location. Our objective was to describe all cases of isolated iAC along with their etiological investigations and neonatal outcome, during a 10-year practice in a referral center. METHODS: We conducted a retrospective descriptive monocentric study on neonates diagnosed with isolated iAC after antenatal expert ultrasound scan and referred to the Multidisciplinary Center for Prenatal Diagnosis at Trousseau Hospital and born between January 1st, 2008 and June 30th, 2018. The exclusion criteria were: retroperitoneal calcifications, iAC associated with other digestive abnormalities or with congenital malformations. RESULTS: The 32 isolated iAC cases accounted for 46% of all iAC. Nine cases were excluded for missing neonatal data. Among the 23 remaining isolated iAC cases, we observed 15 intra-hepatic calcifications, 5 peri-hepatic and two peritoneal calcifications. One fetus had both intra- and peri-hepatic calcifications. The majority of iAC remained stable throughout pregnancy. No cases of aneuploidy, fetal infection, or cystic fibrosis were detected. The neonatal outcome was favorable in all cases. CONCLUSIONS: In case of isolated and stable iAC after expert ultrasound scan, after having ruled out infectious diseases of the fetus and looked for the most frequent mutations of cystic fibrosis in the parents, the prognosis is favorable. Fetal karyotyping is recommended when additional structural anomalies are present.

Evaluation of septal insertion of atrioventricular valves in fetuses by postmortem 4.7 Tesla cardiac MRI: A feasibility study.

PURPOSE: The purpose of this study was to compare non-invasive high-spatial-resolution postmortem cardiac magnetic resonance imaging (MRI) and autopsy findings for evaluating the septal insertion of atrioventricular valves in fetuses. MATERIALS AND METHODS: Five fetal heart specimens including two normal hearts, one heart with complete atrioventricular septal defect (AVSD) and two hearts with linear insertion of atrioventricular valves (LIAVV; gestational age 17 to 34 weeks) were studied with cardiac MRI using a 4.7 T MRI scanner without sample preparation. Three (3D) and two-dimensional (2D) turbo-RARE (rapid imaging with refocused echoes) sequences in four-chamber and left-ventricular long-axis planes were obtained with a minimal isotropic/in-plane resolution of 156µm. Nonparametric tests were performed to compare the distance between insertions of medial leaflets of the atrioventricular valves and the inlet/outlet distance ratio between MRI and autopsy findings in normal, complete AVSD and with linear insertion of atrioventricular valves (LIAVV) fetal hearts. RESULTS: Despite apparent differences between LIAVV/normal hearts, no significant differences were found between differential insertion of medial leaflets and inlet/outlet distance ratios with both techniques. Very good to excellent reliability between both techniques was found for differential insertion (ICC: 87.2%; 95% CI: -21.7%, 99.1%) (P=0.963) and inlet/outlet distance ratio (ICC 98.3%; 95%CI: 85.2%, 99.8%) (P=0.537) measurements. CONCLUSION: Postmortem cardiac MRI could replace autopsy for assessing normal or abnormal septal insertion of atrioventricular valves in fetuses without requiring specific preparation of the heart.

Knowledge Representation and Management, It's Time to Integrate!

Objectives: To select, present, and summarize the best papers published in 2016 in the field of Knowledge Representation and Management (KRM). Methods: A comprehensive and standardized review of the medical informatics literature was performed based on a PubMed query. Results: Among the 1,421 retrieved papers, the review process resulted in the selection of four best papers focused on the integration of heterogeneous data via the development and the alignment of terminological resources. In the first article, the authors provide a curated and standardized version of the publicly available US FDA Adverse Event Reporting System. Such a resource will improve the quality of the underlying data, and enable standardized analyses using common vocabularies. The second article describes a project developed in order to facilitate heterogeneous data integration in the i2b2 framework. The originality is to allow users integrate the data described in different terminologies and to build a new repository, with a unique model able to support the representation of the various data. The third paper is dedicated to model the association between multiple phenotypic traits described within the Human Phenotype Ontology (HPO) and the corresponding genotype in the specific context of rare diseases (rare variants). Finally, the fourth paper presents solutions to annotation-ontology mapping in genome-scale data. Of particular interest in this work is the Experimental Factor Ontology (EFO) and its generic association model, the Ontology of Biomedical AssociatioN (OBAN). Conclusion: Ontologies have started to show their efficiency to integrate medical data for various tasks in medical informatics: electronic health records data management, clinical research, and knowledge-based systems development.

Towards ontology-based decision support systems for complex ultrasound diagnosis in obstetrics and gynecology.

INTRODUCTION: We have developed a new knowledge base intelligent system for obstetrics and gynecology ultrasound imaging, based on an ontology and a reference image collection. This study evaluates the new system to support accurate annotations of ultrasound images. We have used the early ultrasound diagnosis of ectopic pregnancies as a model clinical issue. MATERIAL AND METHODS: The ectopic pregnancy ontology was derived from medical texts (4260 ultrasound reports of ectopic pregnancy from a specialist center in the UK and 2795 Pubmed abstracts indexed with the MeSH term "Pregnancy, Ectopic") and the reference image collection was built on a selection from 106 publications. We conducted a retrospective analysis of the signs in 35 scans of ectopic pregnancy by six observers using the new system. RESULTS: The resulting ectopic pregnancy ontology consisted of 1395 terms, and 80 images were collected for the reference collection. The observers used the knowledge base intelligent system to provide a total of 1486 sign annotations. The precision, recall and F-measure for the annotations were 0.83, 0.62 and 0.71, respectively. The global proportion of agreement was 40.35% 95% CI [38.64-42.05]. DISCUSSION: The ontology-based intelligent system provides accurate annotations of ultrasound images and suggests that it may benefit non-expert operators. The precision rate is appropriate for accurate input of a computer-based clinical decision support and could be used to support medical imaging diagnosis of complex conditions in obstetrics and gynecology.

[Ultrasound screening for birth defects: A medico-economic review]. / Aspects médico-économiques du dépistage échographique des malformations fœtales : revue de la littérature.

OBJECTIVES: The systematic use of ultrasound during pregnancy aims at birth defect detection. Our objective was to assess the economic efficiency of prenatal ultrasound screening for fetal malformations. METHODS: We carried out a literature review on Medline via PubMed between 1985 and 2015, from the economic perspective of the prenatal ultrasound screening for fetal malformations. RESULTS: The literature on this subject was sparse and we selected only twelve articles presenting relevant economic data, of which only eight were proper medico-economic studies. We found arguments for the economic effectiveness of ultrasound screening for fetal malformation detection, which is largely linked to the terminations of pregnancies and to the cost of the handicaps "avoided". However, none of the reviewed articles could reach medico-economic conclusions. Additionally, we highlighted various elements making economic analyses more complex in this field: the choice of the method, the uncertainty around two essential parameters (the efficiency of ultrasound and the costs of procedures) and the difficulties to compare or to generalize results. We also noticed important methodological heterogeneity among the studies and the absence of French study. CONCLUSIONS: Previously published data are insufficient to assess the economic efficiency of prenatal ultrasound screening for fetal malformations.

Mosaic-activating FGFR2 mutation in two fetuses with papillomatous pedunculated sebaceous naevus.

Papillomatous pedunculated sebaceous naevus (PPSN) has been described as a subtype of sebaceous naevus (SN), typically affecting the scalp and face. In contrast with Schimmelpenning syndrome, no cerebral, ocular or skeletal anomalies have hitherto been reported. We report two unrelated fetuses with PPSN, one with large pink exophytic tumours, the other with minor features but similar microscopic findings. We performed whole-exome sequencing in affected skin tissue from fetus 1, which identified a postzygotic de novo FGFR2 c.1144T>C (p.Cys382Arg) mutation in 34·6% of reads which was absent in the parents' blood. Targeted deep sequencing of FGFR2 confirmed its mosaic status in additional affected skin from fetus 1, and identified the same substitution in 26% of reads in affected skin from fetus 2. FGFR2 p.Cys382Arg is a known somatic driver mutation in human cancer, previously reported to result in activation of RAS signalling. A similar paralogous missense mutation in the transmembrane domain of FGFR3 (p.Gly380Arg) has been reported in keratinocytic epidermal naevi. Our findings define a distinct clinical and molecular subgroup of SN, beside HRAS or KRAS-related SN, and expand the spectrum of mosaic skin conditions associated with receptor tyrosine kinase mutations.

Searching for rare diseases in PubMed: a blind comparison of Orphanet expert query and query based on terminological knowledge.

BACKGROUND: Despite international initiatives like Orphanet, it remains difficult to find up-to-date information about rare diseases. The aim of this study is to propose an exhaustive set of queries for PubMed based on terminological knowledge and to evaluate it versus the queries based on expertise provided by the most frequently used resource in Europe: Orphanet. METHODS: Four rare disease terminologies (MeSH, OMIM, HPO and HRDO) were manually mapped to each other permitting the automatic creation of expended terminological queries for rare diseases. For 30 rare diseases, 30 citations retrieved by Orphanet expert query and/or query based on terminological knowledge were assessed for relevance by two independent reviewers unaware of the query's origin. An adjudication procedure was used to resolve any discrepancy. Precision, relative recall and F-measure were all computed. RESULTS: For each Orphanet rare disease (n = 8982), there was a corresponding terminological query, in contrast with only 2284 queries provided by Orphanet. Only 553 citations were evaluated due to queries with 0 or only a few hits. There were no significant differences between the Orpha query and terminological query in terms of precision, respectively 0.61 vs 0.52 (p = 0.13). Nevertheless, terminological queries retrieved more citations more often than Orpha queries (0.57 vs. 0.33; p = 0.01). Interestingly, Orpha queries seemed to retrieve older citations than terminological queries (p < 0.0001). CONCLUSION: The terminological queries proposed in this study are now currently available for all rare diseases. They may be a useful tool for both precision or recall oriented literature search.

[How to assess the neutral position of the fetus for the crown-rump length measurement at the nuchal translucency scan]. / Comment évaluer la flexion de l'embryon lors de la mesure de la longueur cranio-caudale.

OBJECTIVES: The objective of this study was to establish a simple and reproducible method for the assessment of the fetal head position when measuring crown-rump length (CRL) at the nuchal translucency scan. METHODS: Two observers conducted a retrospective analysis of a consecutive series of 570 images of CRL collected by the French College of Fetal Echography (CFEF) national practice assessment program for the first-trimester scan. The images were deemed hyper-flexed if no fluid was visible between the chin and the chest of the fetus. The images were deemed hyper-extended if the angle between the palate and the CRL line was 90° or more. The images were deemed neutral if no hyper-extension nor hyper-flexion was observed. RESULTS: The proportion of agreement for a non-neutral position of the fetal head was 91.3% (kappa=0.80, 95% CI [0.75 to 0.86]). Images with a non-neutral position corresponded to poor CRL quality images according to the CFEF score (relative risk=4.2, 95% CI [2.9 to 6.1] for one observer and 4.9, 95% CI [3.3 to 7.2] for the other observer). Proportions of agreement for the hyper-flexion and for the hyper-extension were 94.6% (kappa=0.80, 95% CI [0.72 to 0.87]) and 96.8% (kappa=0.81, 95% CI [0.72 to 0.90]), respectively. No additional lines were drawn on the ultrasound images during the evaluation process. CONCLUSIONS: The proposed method for evaluating the extent to which the fetal head has a non-neutral position at measurement of the CRL appears both simple and reproducible.

[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.

[A simple self-assessment tool for the first-trimester ultrasound images]. / Une auto-évaluation simplifiée des images échographiques du premier trimestre.

OBJECTIVES: The objective of this study was to establish a minimum subset of simple criteria for the self-assessment of the quality of first-trimester ultrasound images of nuchal translucency (NT) and crown-rump length (CRL). METHODS: We designed 162 simplified image-scoring methods (ISM) based on 1, 2, 3 or 4 binary criteria derived from the 8 criteria of the original image scoring method of the French College of Fetal Ultrasound (CFEF). These ISM were assessed on 68,250 consecutive scans of the French national audit conducted by the CFEF on NT and CRL images. The ISM associated with the best precision to identify excellent/reasonable quality scans were selected. RESULTS: Simplified ISM based on 1, 2, 3 and 4 criteria showed maximum positive predictive values of 95.3% (95.11-95.50) 98.0% (97.87-98.14), 99.3% (99.17-99.35) and 99.7% (99.68-99.79), respectively, to identify excellent/reasonable quality scans. The proportion of excellent/reasonable scans was 2.8 to 16.7% when three criteria among the 8 were insufficient, and 0.17 to 3.95% when four criteria were insufficient. CONCLUSIONS: The best performing ISM was based on the following four quality criteria: (i) sagittal plane of the NT, (ii) calipers placement for measuring the NT, (iii) image magnification of NT images and (iv) CRL measurement. This score might be the most relevant in clinical practice in the first-trimester screening.

[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.

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.

Rare diseases knowledge management: the contribution of proximity measurements in OntoOrpha and OMIM.

In this paper, we introduce an application of Proxima and define a new measure of proximity between two concepts present in an ontology. The approach is based on the three dimensions of a conceptualization: intention with relations between concepts, expression with terms denoting concepts, and extension with instances of concepts. This preliminary work, in the field of rare diseases, involved the Orphanet Ontology of Rare Diseases (OntoOrpha) and corpus of texts extracted from Online Inheritance in Man (OMIM). The proximity measurements are consistent with an appropriate representation of groups of diseases in the ontology, which are derived from the Orphanet classifications of rare diseases. Other semantic relations are explored and new perspectives in medical knowledge curation are proposed.

[Interest of CA 125 level in management of ovarian cancer]. / Intérêt du dosage du CA 125 dans la prise en charge du cancer de l'ovaire.

CA 125 is the most sensitive and the most used marker in the management of ovarian cancer at various stages of the disease. CA 125 is used at the time of diagnosis of the disease, to evaluate the possibility of complete resection during surgery, to estimate sensibility for adjuvant or neo-adjuvant chemotherapy and for diagnosis of recurrences. CA 125 has a diagnostic and therapeutic value and could be of help during therapeutic evaluation. CA 125 has been the topic of many studies for optimizing the management of epithelial ovarian cancers. Mandatory before any ovarian surgery, serum CA 125 levels is a help for the determination of the appropriate surgery. It appears to be a help in choosing therapeutic strategy, to predict optimal surgery and also global and progression-free survival. Low preoperative rates, half-life and fast normalization of CA 125 during the adjuvant chemotherapy are correlated with an optimal surgery and a better global and progression-free survival. The normal range of CA 125 is a strong predictive factor for disease recurrence even if its role in survival has not yet been determined. The dosage of CA 125 and its dynamic interpretation is an indispensable approach to the diagnosis, therapeutics and follow-up of ovarian cancer. Simple serum CA 125 concentration is a very important prognostic and predictive factor for a personalized care.

Prenatal ultrasonographic diagnosis of polymicrogyria.

We report a rare case of polymicrogyria diagnosed at 27 weeks' gestation on ultrasound examination and associated with cytomegalovirus (CMV) infection. The ultrasound finding suggesting this diagnosis was the direct visibility of the overfolded cortical ribbon. The cerebral surface was clearly visible because of a markedly enlarged pericerebral space associated with micrencephaly secondary to CMV infection. Bilateral opercular dysplasia was also present. Very few sonographic markers of infectious fetopathy were observed other than periventricular cysts located behind both ventricular horns. Magnetic resonance imaging (MRI) of the fetal brain confirmed the ultrasound findings and also showed the presence of marked micrencephaly, whereas cephalic measurements acquired on ultrasound examination (biparietal diameter and head circumference) were within the normal range. This case emphasizes the complementary roles of sonography and MRI in the prenatal diagnosis of cerebral abnormalities. Moreover, it illustrates the fact that polymicrogyria is easier to diagnose on ultrasound examination during the second trimester, before the development of secondary sulci.