Modelling Isolated Spina Bifida Screening Performance Using Axial and Sagittal Views of the Brain and Spine Anatomy at the 11-13-Week Scan

wjpmr, 2017,3(1), 74-82. SJIF Impact Factor: 3.535 Research Article Tudorache et al. WORLD JOURNAL OF World PHARMACEUTICAL Journal of Pharmaceutical and Medical Research AND MEDICAL RESEARCH ISSN 2455-3301 www.wjpmr.com WJPMR

MODELLING ISOLATED SPINA BIFIDA SCREENING PERFORMANCE USING AXIAL AND SAGITTAL VIEWS OF THE BRAIN AND SPINE ANATOMY AT THE 11-13-WEEK SCAN

1Maria Florea, 2*Dominic Gabriel Iliescu, 3Roxana Dragusin, 4Alex Stepan, 5Lucian Zorila, 6Stefania Tudorache

1University of Medicine and Pharmacy, Obstetrics and Gynecology Craiova, Romania. 2University of Medicine and Pharmacy of Craiova, Obstetrics and Gynecology, Prenatal Diagnostic Unit, University 3Emergency Hospital, Craiova, Dolj, Romania. 4University Emergency Hospital, Pathology Department, Craiova, Dolj, Romania. 5University of Medicine and Pharmacy, Obstetrics and Gynecology Craiova, Romania. 6University of Medicine and Pharmacy Craiova, Obstetrics and Gynecology, Prenatal Diagnostic Unit, University Emergency Hospital, Craiova, Dolj, Romania.

*Corresponding Author: Dominic Gabriel Iliescu, MD, PhD, MPH

Senior Lecturer, University of Medicine and Pharmacy Craiova Petuniilor, nr. 50, Craiova, Romania, 20041.

Article Received on 15/11/2016 Article Revised on 04/12/2016 Article Accepted on 25/12/2016

ABSTRACT

Objectives: The aim of this research is to evaluate the modeled predictive value of different features of the fetal anatomy in the detection of isolated open spina bifida, at first-trimester scan. Methods: We retrospectively assessed audited randomized two-dimensional and three- dimensional datasets from 6 cases of open spina bifida and 60 normal fetuses, with no structural or chromosomal associated anomalies, scanned at the same age (12 weeks +4 days). We analyzed direct and indirect signs, using both continuous and categorical variables. Effects were quantified using multiple logistic regression analysis to develop a mathematical model. The performance of screening was determined by Receiver Operating Characteristics (ROC) curve analysis. Results: We found many significant markers’ differences between the two groups. We determined the optimum set of features and their effect on OSB diagnosis. The intracranial subjective markers obtained in axial planes (the dry brain phenomenon, position of the Sylvius aqueduct and the crush sign) had the highest potential on improving OSB diagnostic accuracy. Conclusions: Application of intracranial markers performs better than the direct spine assessment. Application of cranial axial views based screening model (the lateral third-ventricle view and the transthalamic view, used for fetal head biometry) resulted in the highest predicted detection rates, thus a better screening performance than using sagittal views. Following a complete protocol in the FT might be the only efficient way to screen for isolated spina bifida at the 11–13-week scan. The findings should be confirmed in population-based prospective studies.

KEYWORDS: Open spina bifida, first trimester scan, screening.

INTRODUCTION preserved, offering an early diagnosis will be a tool enhancing the autonomy of the pregnant women. The Open spina bifida (OSB) often leads to severe disability, standard approach for the FT scan is in many countries being considered one of the most devastating nonlethal transabdominal, due to superior convenience. The direct congenital anomalies. Recent data suggest that affected visualization of the spine defects remained difficult, thus fetuses may already have an impaired cerebral cortex at indirect intracranial morphological markers were 11-15 weeks of gestation.[1] proposed.

Most cases of isolated OSB are still detected during the Since 1997, when the lemon sign was found at 10-14 second trimester anomaly ultrasound (US) scan.[2] weeks of amenorrhea[9], the US of the fetal head holds Although still debated[3], a screening test available in the promise for the OSB diagnosis at the end of the FT, first trimester (FT) would be desirable. Despite the fact instead of the fetal spine. The retraction of the frontal that significant progress has been made in the bones (”acorn-shaped head”) was described in the prevention[4], diagnosis[5] and treatment[6,7,8], and the transthalamic axial view, the cerebral peduncles intellectual potential in affected children is usually appearing parallel to each other.[10] www.wjpmr.com 74

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More recently the sagittal plane used for the nuchal FT diagnosed cases of isolated OSB that were scanned at translucency thickness (NT) measurement was 12 weeks of amenorrhea (WA) +4 days (crown-rump advocated: compression of the fourth ventricle, leading length CRL = 58.4 – 64.6 mm). We matched them with to decrease or disappearance of the normal intracranial 60 cases of normal fetuses, scanned at the same translucency (IT)[11,12,13], altered ranges of the brain gestational age (GA). Inclusion criteria for all cases stem[14], non-visualization of the cisterna magna[15,16,17], were: the mentioned CRL value, singleton pregnancy, decreased frontomaxillary facial (FMF) angle.[18] absence of any (other) structural anomalies, absence of any US markers for chromosomal anomalies, informed In axial views, the third-ventricle plane offers the consent, audited images, whole extended protocol measurements of the lateral ventricle area, the diameter achieved and stored in the database, known pregnancy of the roof of the third ventricle and the transthalamic outcome. plane - the diameter of the aqueduct of Sylvius, significantly decreased, all demonstrating the alteration For each case a number of 7 frozen images or videoclips of intracranial collection of cerebrospinal fluid.[19] These and two 3D static volumes, stored in the database were alterations were described as the ”dried-up brain reassessed, after anonymization and randomization. The phenomenon”. Abnormal midbrain position[20] and the planes were: the sagittal plane used for CRL posterior-caudal displacement of the mesencephalon measurement, the third-ventricle plane, the transthalamic (“crash sign”)[21] were described. plane, the fourth-ventricle view plane, the transversal abdominal plane, the sagittal plane used for the nuchal Moreover, it was demonstrated that fetuses with OSB NT measurement, the longitudinal plane of the spine in a have smaller heads[22,23,24], thus having altered intrafetal posterior insonation of fetus. Additionally, the observer ratios.[25] (a FMF-certified experienced member of the PDU) had the two 3D static volumes available: the fetal head, We aimed to evaluate the contribution of each specific acquired from the sagittal anterior plane and the trunk, fetal anatomical feature to the early OSB detection. acquired from the posterior insonation. We used as standard tests second trimester scan, pathological METHODS specimens and neonatal features.

The retrospective study was conducted in the University For the purposes of this study, the outcomes of interest Hospital Craiova, Romania. In the Prenatal Diagnostic were to determine the most significant screening marker Unit (PDU) a transabdominal FT extended protocol[26] at associated with spina bifida and to evaluate the the nuchal scan is used on a daily basis. The institutional diagnostic performance (sensitivity and specificity) of ethics committee (Ethical Committee of the University of examination of each (intracranial and spine) marker for Medicine and Pharmacy of Craiova) approved to the detection of OSB. prospectively collect all the FT data. All women scanned

in the PDU had provided informed consent for the use of In order to find the most robust screening marker for US images for research purposes. The extended protocol OSB the following data were retrospectively assessed: includes transverse planes of cranium, for assessing the continuous variable (CRL, head circumference - HC, contour and shape, the choroid plexus and cerebral occipital-frontal diameter - OFD, biparietal diameter - peduncles planes, and also sagittal planes, with BPD, the abdominal circumference AC, the ratio measurement of nuchal translucency thickness - NT and BPD/AC, the choroid plexus area, the lateral ventricle - frontomaxillary facial angle - FMF angle, and LV area, both measured by the tracing method, the ratio intracranial translucency - IT. Complete posterior brain choroid plexux/LV area, the aqueduct of Sylvius to morphometry (brainstem- diameter BS and brainstem to occiput distance (AOD), the IT measurement, BS brainstem–occipital bone distance ratio-BS/BSOB) is diameter, BSOB diameter, the BS/BSOB ratio, the FMF performed in cases with abnormal IT. The spine angle, the cisterna magna measurement) and categorical assessment includes longitudinal planes (preferably using variables (the acorn-shaped head, the parallel cerebral posterior insonation of fetus), confirming the regularity peduncles, the dry brain, the crush sign, the subjective of spine and the continuity of the underlying skin caudal displacement of the brainstem, 2D spine layer.[26] Whenever possible, we acquire and store at least assessment, 3D spine assessment). Of note, we decided a three-dimensional (3D) static volume of the fetal head to interpret the ratio BPD/AC instead of the reported (the acquisition plane - the sagittal anterior plane) and a BPD/TAD[25] ratio, because we hypothesized a lower 3D volume of the trunk (the acquisition plane - the operator dependency and interobserver variability of AC sagittal posterior plane). We use a Voluson Expert 750 if compared to TAD, and due to the availability of the and an E8 (GE Medical Systems, Zipf, Austria) machine, measurement. The operator was allowed to obtain the equipped with 4-8-MHz curvilinear transducer. data either from the available images and videoclips, or by post processing the 3D volumes. The forms were From our database, we selected only cases (normal and subsequently filled in. OSB) that had neither structural associated anomalies nor

chromosomal anomalies, and were scanned at the same age. For the purpose of this study, we selected 6 cases of www.wjpmr.com 75

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We chose patients from the two groups so that the CRL curve analysis for every most significant marker for measurement was not statistically different. The mean of spina bifida previously obtained. CRL delta values in the control fetuses group (mean, 63; 95%CI, 62.53-63.46) was not statistically different A p-value of <0.05 was considered statistically (p=0.123>0.05) from the ones in the OSB group (mean, significant. The analysis was performed using the 61.70; 95%CI, 59.45-63.95). statistical software packages SPSS 19.0.

Categorical data (presented as %) were compared RESULTS between the two groups (Normal group vs. Spina bifida We found significant differences between the two groups group) using Chi-square test. Continuous data (presented for the values of: HC, BPD, BPD/AC, BSOB diameter, as mean (95% Confidence Interval)) were compared BS/BSOB, Cisterna magna, AOD, Choroid plexus area, between the two groups using Independent-Samples t- Ratio Choroid plexus/LV, FMF angle (p<0.05 - see Test for normal distribution and the Mann-Whitney test Table 1). for not normally distributed data. The Kolmogorov-

Smirnov test, mean vs. median, the analyses of The following subjective markers, used as categorical skewness, kurtosis and histograms for each variables: dry brain(subjective large choroid plexus), the characteristics demonstrated that for AC, Choroid plexus crush sign, caudal displacement of the brainstem, parallel area, AOD, BS diameter, BSOB diameter and FMF cerebral peduncles and images obtained after the angle, the distribution of values was normal in both postprocessing 3D static volumes of the spine showed Control and Spina bifida groups. So, for these features statistically significant differences between the two the Independent-Samples t-Test was used to determine groups (p<0.05). the significance of differences in the mean delta values

between the two groups. Significance was assessed at a Thus, these 15 features should be considered as potent p-value of less than 0.05. markers for the OSB early diagnosis. Correlation

analysis shows the most potent features that influence the We subsequently analyzed the correlation between true positive OSB case diagnosis. The most important having OSB and these markers. The correlation falls features positively influencing the diagnosis are: the dry- between −1 and +1. Independence between the variables up brain phenomenon and the crush sign, the subjective implies that the Pearson coefficient r equals zero. The caudal displacement of the brainstem and BS/BSOB (see larger the correlation is in absolute value, the farther the Table 2). In fetuses with OSB the assessment of BSOB data fall from independence in the linear dimension. diameter, Cisterna magna (not visible), AOD, BPD/AC,

FMF angle were significantly decreased (p<0.01) when After we established the most significant markers for compared with normal fetuses. spina bifida (for p<0.05, noted in Table 2 with X , X , …, 1 2 X ), we examined the relationship between the 15 OSB diagnosis was predicted via a generalized linear dependent discrete variable with two possible outcomes model with a log link function. Multiple logistic (to have or not to have OSB, noted with Y) and these regression analysis of these characteristics identified a independent variables for Pearson coefficient │r│>0.5. model for the likelihood of OSB occurrence, with 9 most Multiple logistic regression[27] is the appropriate important predictors, as it follows. regression model to use when the dependent variable is a Logarithmic dichotomous outcome (pass or fail the test of having Units=6.37+32.44*X +32.44*X +12.05*X +11.16*X - OSB) and there are multiple explanatory variables. An 1 2 3 4 4.71*X +18.38*X +0.55*X +0.11*X -0.65*X advantage with logistic regression is that it does not 5 6 7 8 9 (Eq. 2) require the assumption of normality or homogeneity of

variance (we have normal and not normal distribution of Raw Odds=exp(Logarithmic Units) data). The model for the log odds is. (Eq. 3) logit[P(Y=1)]=α+β X +β X +…+β X 1 1 2 2 9 9 (Eq.1) Probability of OSB=Raw Odds/(1+Raw Odds)

(Eq. 4) We calculated the regression coefficients β that refer to i the effect of X on the log odds when Y=1 (the fetus has i The equation from the mathematical model (Eq. 2) also OSB), where i is from 1 to 9 – the first nine variables indicates the order of significance levels of positive from Table 2 for which there is positive or negative (Pearson coefficient r>0) and negative (Pearson predictable relationship and │r│>0.5. coefficient r<0) effects of the pregnancy characteristics.

The characteristics that influence more the early Multiple regression analysis was used to determine the diagnosis of OSB are the following, listed in descending power of significant predictors of OSB. order: the dry brain, the crush sign, the subjective caudal

displacement of the brainstem, the ratio BS/BSOB, In order to evaluate the performance of screening we BSOB diameter, the cisterna magna, AOD, the ratio determined Receiver Operating Characteristics (ROC) BPD/AC, the FMF angle, the BPD, the HC, the ratio www.wjpmr.com 76

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Choroid plexus/LV, the 3D spine post processed images, Figure 1. subjective parallel cerebral peduncles and the choroid Ultrasound image correlations: first column (a,c,e) - first plexus area. trimester open spina bifida case, second column (b,d,f) – first trimester normal control case. The diagnostic accuracy is measured by the Receiver Operating Characteristic (ROC) curve or the sensitivity First line: the sagittal plane, used for sonographic vs. (1-specificity) plot. An area under the ROC curve of measurement of nuchal translucency (NT) thickness. 1 represents a perfect test. The area under the ROC curve Second line: the transthalamic view plane, used for fetal was 1 for Dry brain, Crush sign (axial views) and head biometry (measurement of the biparietal diameter BS/BSOB, BSOB diameter (sagittal views). The area and head circumference). under the ROC curve for other significant marker alone Third line: the lateral third-ventricle view plane, used for in predicting open spina bifida (>0.9 for an excellent choroid plexus assessment. test) was: 0.994 (AOD), 0.992 (FMF angle), 0.986 (BPD/AC), 0.971 (Cisterna magna), 0.917 (Ratio Figure 2. Choroid plexus/LV). The area under the ROC curve for Open spina bifida case, 12 weeks +4 days of other significant marker alone in predicting open spina amenorrhea: bifida (>0.8, <0.9 for a good test) was: 0.888 (BPD), a. sagittal face view abnormal: IT measurement = 2.3 0.868 (HC), 0.833 (Caudal displacement of the mm, BS diameter = 3.6 mm, BSOB diameter = 3.9 brainstem). mm, BS/BSOB ratio 0.932, the FMF angle = 68.61, the cisterna magna not visible, subjective caudal This study reports a very good relationship between the displacement of the brainstem present. detection rate (DR) and the false-positive rate (FPR) for b. On-line spine assessment, static 3D surface render 7 markers (Dry brain, Crush sign, BS/BSOB ratio, BSOB mode – negative test. diameter, AOD, FMF angle, BPD/AC). The calculated c. Off-line spine assessment, postprocessing revealed screening performance using the subjective Dry brain the spine defect – positive test. and Crush sign from axial views and numeric BS/BSOB d. Medical method used for first trimester termination ratio and BSOB diameter from sagittal views is excelent: of pregnancy: pathologic specimen (13+2 WA) – 100% DR at any given FPR. The calculated screening positive postmortem confirmation. performance is also very high using AOD (DR is 98% at a given 5% FPR), FMF angle (DR is 93% at a given 5% Figure 3. FPR) or BPD/AC (DR is 84% at a given 5% FPR). Open spina bifida case, with hemivertebrae: a. Off-line spine assessment, postprocessing failure to Legends demonstrate the overlying skin defect the spine Table 1. Markers' comparison between the control group defect – negative test. and the OSB group. Markers are categorical data b. Medical method used for early second trimester (presented as %) and continuous data (presented as mean termination of pregnancy: pathologic specimen (95% Confidence Interval). (16+2 WA) – positive postmortem confirmation.

Table 2. Pearson's correlation coefficients for significant markers influencing OSB diagnosis.

Tables Table 1: Markers' comparison between the control group and the OSB group. Markers are categorical data (presented as %) and continuous data (presented as mean (95% Confidence Interval)).

Controls Spina bifida Parameter p (n=60) (n=6) HC 72.56 (71.73-73.39) 66.58 (61.67-71.50) 0.003 OFD 22.46 (22.09-22.83) 21.53 (19.61-23.45) 0.255 BPD 19.86 (19.60-20.11) 18.02 (16.74-19.29) 0.002 AC 58.11 (57.72-58.72) 59.67 (56.98-56.35) 0.287 BPD/AC 0.34 (0.34-0.35) 0.30 (0.29-0.32) <0.001 Acorn-shaped head 100% no 83.33% no 0.091 Parallel cerebral peduncles 95% no 50% no 0.008 Dry brain (subjective large choroid plexus) 100% no 0% no <0.001 Choroid plexus area (cm2) 1.33 (1.30-1.37) 1.50 (1.33-1.66) 0.040 LV area (cm2) 2.42 (2.36-2.46) 2.29 (2.00-2.59) 0.334 Ratio Choroid plexus/LV 0.55 (0.54-0.57) 0.65 (0.61-0.70) 0.001 AOD 4.49 (3.64-5.33) 1.97 (1.45-2.48 <0.001 Crush sign 100% negative 0% positive <0.001

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IT (fourth ventricle) 2.19 (2.09-2.28) 2.15 (1.98-2.32) 0.955 BS diameter 3.25 (3.16-3.34) 3.52 (3.16-3.88) 0.120 BSOB diameter 4.92 (4.83-5.01) 3.33 (2.93-3.74) <0.001 BS/BSOB 0.66 (0.64-0.69) 1.06 (0.98-1.14) <0.001 1.67% not visible 83.33% not visible Cisterna magna <0.001 1.41 (1.30-1.51) 0.15 (0.01-0.54) Subjective caudal displacement of the brainstem 100% no 33% no <0.001 FMF angle 81.99 (80.88-83.10) 71.85 (68.90-74.79) <0.001 2D Spine Assessment 100% negative 83.33% negative 0.091 3D Spine on-line assessment 100% negative 83.33% negative 0.091 3D Spine postprocessing 91.67% negative 33.33% negative 0.004

Comparison between Control group and Spina bifida or nonparametric Mann-Whitney U-test for continuous group was performed using Independent-Samples t-Test variable and chi-square test for categorical variables. p<0.05 statistical significant

Table 2: Pearson's correlation coefficients for significant markers influencing OSB diagnosis.

Pearson Characteristic Variables p Correlation (r) Dry brain (subjective large choroid plexux) X1 1 <0.001 Crush sign X2 1 <0.001 Subjective caudal displacement of the brainstem X3 0.803 <0.001 BS/BSOB X4 0.796 <0.001 BSOB diameter X5 -0.791 <0.001 Cisterna magna X6 -0.668 <0.001 AOD X7 -0.667 <0.001 BPD/AC X8 -0.647 <0.001 FMF angle X9 -0.576 <0.001 BPD X10 -0.469 <0.001 HC X11 -0.461 <0.001 Ratio Choroid plexus/LV X12 0.46 <0.001 3D Spine postprocessing X13 0.454 <0.001 Parallel cerebral peduncles X14 0.450 <0.001 Choroid plexus area X15 0.327 0.007

Correlation is significant at the 0.05 level of p and the Pearson coefficient closer to -1 or 1.

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Figure 1.

Figure 2.

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DISCUSSION the operator’s experience. Contrary, the measurement of the BS/BSOB ratio at 11-13 weeks is simple and could Nowadays the FT scan should target all isolated major be easily incorporated into the routine FT scan. As structural anomalies.[28] When the technical and available reported before[32,33], in our study the IT measurement expertise issues will be overcome, the offer of an early did not reach significant differences between the two diagnosis of OSB will provide important information, groups, although the following most accurate markers enhancing the couples’ autonomy. In the second were obtained in the same plane: BS/BSOB ratio and trimester, OSB is an extremely easy US diagnosis, the BSOB diameter. striking markers being (beside the typical ”lemon” and

”banana” signs, and usually an easy to see dysraphic In terms of the spine study, neither 2D US nor defect of the spine) the excess of intracranial fluids: the volumetric (online and post processed images) US did ”hanging” choroid plexuses in the dilated lateral not reach statistical significance, although in 3 cases the ventricles. On the contrary, in the FT, most US signs are operator was able to obtain suggestive information off- centered on the alteration of intracranial collection, with line (figure 2). Although 3D reconstruction surface less cerebrospinal fluid. rendering is usually instrumental in raising the operator’s

confidence in spine normality, this approach performed The most important advantage of searching markers in poorer than intracerebral US signs. The area under the the sagittal planes, despite the subtle changes reported, is ROC curve for 3D spine postprocessing alone in their widely use in screening for chromosomal predicting open spina bifida was 0.783 and would be anomalies[29] (figure 1a, 1b). The most important considered a “fair” test, but not good enough. Multiple advantage of axial planes is the more striking regression analysis demonstrated, also, that 3D spine displacement of the structures[20,21](figure 1c-f). postprocessing has a small correlation with detecting

OSB (figure 3). In 1997, Sebire et al. reported that in 61 972 pregnancies

that had undergone NT screening at 10–14 weeks, all the The ratio choroid plexus/LV area, the numerical 29 cases of OSB were missed. A more recent review correspondent of the subjective marker known as the reported a 16% OSB DR.[30] Still, examples of extremely ”dried-up brain” phenomenon, reached statistical early diagnosis (9 weeks) are provided, through the significance, yet proved a lower performance when transvaginal approach. compared with the categorical data.

Today high DRs are reported, between 92.3%[21] and This research has its limitations, the most important one 100%3 in the FT. We have also picked up all of the being the retrospective design and the use of just presented cases after extending the FT protocol. The auditable datasets, highly skilled observers being PDU operators stated that the features raising the early involved in the acquiring and in interpreting the data. suspicion were the intracranial ones in all cases, and This could have led to the performance overestimation of moreover, all cases were in fact identified by subjective many markers, especially in regards to the subjective markers, without any measurements. These observations ones. The bias level implied will be clarified by an triggered the present research. The most important interobserver variability study, involving less finding of this study is the confirmation that, as other experimented observers. study groups reported[31], OSB can be diagnosed in the

FT by visual assessment alone, without using categorical The strengths of our study include adjustment for GA in variables. both study groups, of pathologic and unaffected

pregnancies. We also included only cases of isolated Our study showed that visualizing the myelomeningocele OSB, as the accuracy of the diagnosis is known to be was impossible in many cases in 2D US, by the affected by associated structural abnormalities or transabdominal approach. Moreover, although the direct aneuploidy markers. spinal signs of OSB were missing both in 2D and in 3D

online methods, at least a marker showing the brain Our results suggest that using either axial or sagittal view structure alteration was accessible transabdominal in all of the brain will reach, at least in the near future, a better cases (figure 2). Thus, in terms of FT OSB screening, performance as a screening tool than using fetal spine despite the growing resolution of modern systems, it views. Following a complete protocol in the FT might be seems that we are in the same place where we were at the the only efficient way to screen for isolated spina bifida beginning, around 2002, when we were heading towards at the 11–13-week scan. Prospective studies with regards indirect signs.[10] to both axial and sagittal markers are needed for the

assessment of these markers’ accuracy in the FT Using both multiple logistic regression analysis and area screening for isolated OSB, as the majority of published under the ROC curve, we demonstrate that the subjective studies are retrospective. Unless we decide to incorporate Dry brain and Crush sign from axial views and numeric the assessment of a specific sign into screening BS/BSOB ratio and BSOB diameter from sagittal views protocols, it is difficult to establish to what extent a were significantly associated with the fetal risk of having specific marker could increase the early DR of OSB, OSB. Yet, subjective markers are crucially dependent on www.wjpmr.com 80

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allowing fewer cases referral to a fetal medicine expert. 7. Bebbington MW, Danzer E, Johnson MP, Adzick The present study aims to support in choosing the most NS. Open fetal surgery for myelomeningocele. valuable marker to be used in such prospective studies. Prenat Diagn., 2011; 31: 689-94. Local conditions and expertise in different centers may 8. Pedreira DA, Zanon N, de Sá RA, Acacio GL, affect the accuracy of the FT diagnosis, US being a Ogeda E, Belem TM, Chmait RH, Kontopoulos E, highly system-dependent and operator-dependent Quintero RA. Fetoscopic single-layer repair of open technique. Moreover, it must be highlighted again that spina bifida using a cellulose patch: preliminary the disorder prognosis is dependent mainly on the clinical experience. J Matern Fetal Neonatal Med., anatomic level of the lesion, more favorable if the lesion 2014; 27: 1613-9. is lower, and that intracerebral signs do not allow the 9. Sebire NJ, Noble PL, Thorpe-Beeston JG, Snijders prognosis assessment. Finally, because the FT scan RJ, Nicolaides KH. Presence of the 'lemon' sign in information may radically change the management of the fetuses with spina bifida at the 10-14-week scan. pregnancy, professionals involved in the prenatal Ultrasound Obstet Gynecol., 1997; 10: 403-5. diagnosis need to acknowledge and inform the parents 10. Buisson O, De Keersmaecker B, Senat MV, Bernard about the limits of the FT US scan. JP, Moscoso G, Ville Y. Sonographic diagnosis of spina bifida at 12 weeks: heading towards indirect ACKNOWLEDGEMENTS signs. Ultrasound Obstet Gynecol., 2002; 19: 290-2. 11. Chaoui R, Benoit B, Mitkowska-Wozniak H, Heling Research grant “Screening markers and early KS, Nicolaides KH. Assessment of intracranial management in detection of fetal chromosomal translucency (IT) in the detection of spina bifida at abnormalities” (SONOSEROSCREEN) financed by the 11-13-week scan. Ultrasound Obstet Gynecol., Romanian Ministry of Education and Research (PC41- 2009; 34: 249-52. 041- 2007/2010), offered funding for purchase of 12. Chaoui R, Nicolaides KH. Detecting open spina medical equipment, training, establishment of bifida at the 11-13-week scan by assessing international collaboration. The grant administrators intracranial translucency and the posterior brain were not involved in the study design, data collection, region: mid-sagittal or axial plane? Ultrasound data analysis, manuscript preparation and/or publication Obstet Gynecol., 2011; 38: 609-12. decisions. 13. Chaoui R, Benoit B, Heling KS, Kagan KO,

Pietzsch V, Sarut Lopez A, Tekesin I, Karl K. The authors would like to thank the researchers from Prospective detection of open spina bifida at 11-13 University Hospital of Craiova and Filantropia Hospital, weeks by assessing intracranial translucency and for their contribution in collecting the ultrasound data posterior brain. Ultrasound Obstet Gynecol., 2011; and the pregnancies outcome data. 38: 722-6.

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