The ultrasonographic features correlated with the morphopathological aspects in open spina bifida

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on fetal neocortex development, we analyzed human fetuses of both sexes diagnosed with OSB between 11 and 15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB fetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early fetal therapy (i.e., in the first trimester of pregnancy).SIGNIFICANCE STATEMENT Open spina bifida (OSB) is one of the most prevalent congenital malformations of the CNS. This study provides novel data on neocortex development of human OSB fetuses. Our data indicate that neocortex development in OSB fetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB fetuses. Our findings support the need for an early fetal therapy and expand our understanding of the pathophysiology of OSB.

Periurethral carriage rates of enterobacteria have been studied in 20 normal women, 34 patients between episodes of bacteriuria, 34 patients with the "urethral syndrome," and 15 asymptomatic abacteriuric patients with a previous history of frequency and dysuria.Over a six-week period no difference in the Escherichia coli carriage rate was shown between these four groups. The carriage of all enterobacteria was slightly but significantly (P <0.05) lower in normal women compared with the patient groups but no difference was observed between the latter. There was no difference in the recovery rate and carriage of individual E. coli serotypes between the four groups.It is concluded that the presence of enterobacteria or E. coli on the periurethral area is not the principal determinant factor in the pathogenesis of recurrent urinary tract infection or the urethral syndrome and that definition of carriage status is of little practical value in management.

It is now clear that the vast majority of major fetal abnormalities can be diagnosed prenatally by ultrasound, that most of these abnormalities can be detected in the first trimester of pregnancy and that women want firsttrimester rather than later diagnosis. It is also clear that effective diagnosis of fetal abnormalities often necessitates the identification of easily recognizable markers which direct the attention of the sonographer to the specific abnormality. Good examples of such markers are the scalloping of the frontal bones (the ‘lemon’ sign) and caudal displacement of the cerebellum (the ‘banana’ sign), observed in the second trimester in most fetuses with open spina bifida, and increased nuchal translucency thickness (NT) which identifies in the first trimester the majority of fetuses with major aneuploidies, lethal skeletal dysplasias and a high proportion of major cardiac defects. It is now widely accepted that increased NT at 11–13 weeks is the single most effective marker of trisomy 21 and all other major aneuploidies. First-trimester screening by a combination of maternal age, fetal NT, nasal bone, Doppler assessment of blood flow in the ductus venosus and across the tricuspid valve together with maternal serum free β-hCG and PAPP-A can identify more than 95% of all major aneuploidies for a screen-positive rate of less than 3%. A major remaining challenge in first-trimester ultrasonography has been the diagnosis of open spina bifida. This challenge, however, may now have been resolved by the realization that open spina bifida can be suspected by an easily detectable marker within the brain in the same mid-sagittal plane of the fetal face as for measurement of NT and assessment of the nasal bone. In normal fetuses the fourth cerebral ventricle presents as an intracranial translucency (IT) parallel to the NT, while in fetuses with open spina bifida there may be absence of the IT 1 .

To evaluate whether in fetuses with open spina bifida (OSB) the tentorium can be seen to be displaced downwards and vertically oriented by the time of the 11-13-week scan and whether this is reflected in an alteration of the brainstem-tentorium (BST) angle. The study population was recruited between 2015 and 2020 from three fetal medicine referral centers and comprised a control group and a study group of pregnancies with OSB. The control group was recruited prospectively and included singleton pregnancies with a normal sonographic examination after first-trimester combined screening for chromosomal abnormalities and normal outcome. The study group was selected retrospectively and included all cases with OSB between 2015 and 2020. All cases underwent detailed ultrasound assessment at 11 + 0 to 13 + 6 weeks' gestation. The position of the torcular Herophili (TH) was identified in the midsagittal view of the fetal brain with the use of color Doppler and was considered as a proxy for the insertion of the tentorium on the fetal skull. The BST angle was calculated in the same view and was compared between the two groups. Sixty normal fetuses were included in the control group and 22 fetuses with OSB in the study group. In both groups, the BST angle was found to be independent of gestational age or crown-rump length (P = 0.8815, R2 = 0.0003861 in the controls, and P = 0.2665, R2 = 0.00978 in the OSB group). The mean BST angle was 48.7 ± 7.8° in controls and 88.1 ± 1.18°, i.e. close to 90°, in fetuses with OSB. Comparison of BST-angle measurements between the control group and cases with OSB showed a statistically significant difference (P = 0.0153). In all fetuses with OSB, the downward displacement of the TH and tentorium was clearly visible at the 11-13-week scan. In fetuses with OSB, the BST angle is significantly larger than in normal controls, with the tentorium being almost perpendicular to the brainstem. This sign confirms the inferior displacement of the tentorium cerebelli with respect to its normal insertion on the occipital clivus as early as the first trimester of pregnancy and is useful in the diagnosis of Chiari-II malformation at this early stage. In fetuses with OSB, the low position of the tentorium and TH is clearly visible, even subjectively, at the 11-13-week scan. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

To ascertain the reported association between reduced biparietal diameter (BPD) at 11-13 weeks' gestation and open spina bifida and to investigate its predictive value in a single-center study. This was a retrospective study of fetuses in which BPD was measured at 11-13 weeks' gestation, including 27 fetuses with isolated open spina bifida subsequently diagnosed at 16-24 weeks and 7775 unaffected controls. BPD values were converted into multiples of the expected median (MoM) after adjustment for crown-rump length and maternal characteristics. Multivariable logistic regression analysis was used to determine the maternal characteristics significantly associated with spina bifida. The performance of screening was determined by receiver-operating characteristics curve analysis. BPD values at 11-13 weeks' gestation were compared with those measured in the second trimester using Z-scores. BPD values at 11-13 weeks' gestation were below the 5(th) centile in 44.4% of cases of open spina bifida. In these fetuses, the median BPD MoM value was significantly smaller than that in the control group (0.930 vs 0.998 MoM; P < 0.0001). Multivariable logistic regression analysis showed a significant contribution from maternal age (P = 0.008) and BMI (P = 0.028) to the association between BPD MoM and spina bifida. The detection rate using BPD measurements in the first trimester was 55.6% with a false-positive rate of 11.6%. In fetuses with open spina bifida, the BPD Z-scores were significantly lower at 16-24 weeks compared to those recorded at 11-13 weeks (median, -1.71 (range, -3.98 to -0.20) vs -1.30 (-3.75 to 2.61); P = 0.006). Fetuses with open spina bifida have a smaller BPD in the first trimester. This observation may be useful in early screening. It is likely that a combination of maternal characteristics such as age and BMI, fetal BPD and maternal serum alpha-fetoprotein measured in the first trimester would provide a clinically useful screening test for open spina bifida.

First-trimester ultrasound of the cerebral lateral ventricles in fetuses with open spina bifida: a retrospective cohort study

To evaluate diagnostic performance of intracranial translucency (IT) for detection of open spina bifida and interobserver agreement for visualization of IT during the 11-13-week scan. A retrospective study was undertaken in a tertiary referral center. Two hundred 11-13-week scans for nuchal translucency, performed by sonographers certified by The Fetal Medicine Foundation, U.K., were reviewed independently for IT by two expert observers. When IT was not seen, the observers determined whether this was due to poor IT image quality or the presence of spina bifida. Discordant cases were reviewed by a third observer and the majority decision was used for analysis. All observers were blinded to individual pregnancy outcome and the number of cases with spina bifida. There were 191 normal fetuses, eight fetuses with open spina bifida and one with closed spina bifida (this case was excluded from analysis). IT was seen in 150 fetuses and all were normal. In six of the 49 cases in which IT was not seen, IT non-visibility was attributed to open spina bifida; among these cases, four fetuses had open spina bifida and two were normal. In the remaining 43 cases (including 39 normal fetuses), IT non-visibility was attributed to inadequate image quality. Sensitivity was 50% (4/8) and specificity was 99% (150/152). Concordance between the two observers concerning IT visibility was 79%, (κ = 0.47, representing moderate agreement). There was moderate interobserver agreement for visualization of IT on images obtained for nuchal translucency measurement at 11-13 weeks. When IT was confidently seen, open spina bifida could be excluded. However, non-visibility of IT correctly diagnosed only 50% of fetuses with open spina bifida.

To assess whether, at 11-13-week and mid-trimester ultrasound examinations, the biparietal diameter (BPD) in fetuses with open spina bifida is smaller than the reference range. In a multicenter retrospective analysis of data from 23 fetuses with open spina bifida diagnosed at 16-24 weeks, BPD at diagnosis was compared with that measured at 11-13 weeks, before diagnosis. Z-scores were calculated for comparison of BPD deviations from the reference range within the groups at 11-13 weeks and 16-24 weeks, and between these two time intervals. BPD Z-scores at 11-13 weeks and 16-24 weeks were significantly lower (P < 0.0001) in fetuses with open spina bifida when compared to the reference range, with mean values of - 1.29 and - 2.14, respectively, corresponding to the 10(th) and 1.5(th) centiles, respectively. At 11-13 weeks only six of the 23 (26%) fetuses with open spina bifida had BPD below the 5(th) centile, in comparison to 16 (69%) at mid-gestation. This was confirmed by paired t-test comparing the first-trimester with the second-trimester BPD measurements, which showed significantly slower growth of the BPD in fetuses with spina bifida. In fetuses with open spina bifida, BPD is smaller not only in the second trimester, as previously reported, but also in the first trimester. This is most likely due to loss of cerebrospinal fluid. We suggest that a BPD value < 10(th) centile in an otherwise normally grown fetus at 11-13 weeks' gestation should be considered as a potential subtle early marker for open spina bifida.

To assess the trophism of the lower limbs of fetuses with open spina bifida using fractional thigh volume (TVOL) of three-dimensional (3D) ultrasound. A prospective cross-sectional study was carried out with normal fetuses and with open spina bifida (myelomeningocele and rachischisis) at 26 weeks' gestation. The TVOL (delimitation of five cross-sectional areas of the middle portion of the limb) was evaluated, as well as the subjective assessment of hypotrophy and lower limb movement. Thirty-one fetuses with open spina bifida, 21 with myelomeningocele and 10 with rachischisis, and 51 normal fetuses were included. There were no significant differences in the TVOL between normal and spina bifida fetuses (p=0.623), as well as between normal fetuses, with myelomeningocele and with rachischisis (p=0.148). There was no significant difference in the TVOL of fetuses with spina bifida with or without lower limb hypotrophy (p=0.148). Fetuses with spina bifida and with lower limb movement had higher TVOL values than fetuses without lower limb movement (p=0.002). There were no significant differences in the TVOL measurement of normal and spina bifida fetuses (rachischisis and myelomeningocele). Fetuses with spina bifida without spontaneous movement of the lower limbs had lower TVOL values.

Diagnostic accuracy of fetal choroid plexus length to head biometry ratio at 11 to 13 weeks for open spina bifida

To investigate the posterior fossa of normal fetuses and fetuses with open spina bifida in stored three-dimensional (3D) volumes and to describe signs that might allow early detection of this defect. A prospective study of 3D volumes of the fetal brain obtained from 10 normal fetuses and three fetuses with open spina bifida was undertaken. Measurements of the anteroposterior diameters of the cisterna magna and fourth ventricle were taken in the tilted axial view. In the mid-sagittal plane the brainstem (BS) diameter and the brainstem-occipital bone (BSOB) distance were measured. The BS/BSOB ratio was calculated. All measurements were expressed as Z-scores. Structural analysis of the differences in the posterior fossa between normal fetuses and fetuses with open spina bifida was undertaken. In normal fetuses all measurements were within ±2.5 Z-scores. In three fetuses with open spina bifida the BS Z-scores were 2.7, 2.8 and 2.8; the BSOB scores were -3.4, -2.8 and -2.9; the cisterna magna scores were -5.6, -3.7 and -4.2; and the BS/BSOB ratio scores were 4.1, 9.7 and 8.9. In normal fetuses the cisterna magna was posterior to the fourth ventricle and extended along its entire length. In fetuses with open spina bifida the cisterna magna was partially or completely obliterated. Assessment of the cranial posterior fossa is feasible at 11-13 weeks' gestation. There are distinct signs in fetuses with open spina bifida which can be evaluated by ultrasonography.

Until recently, most developed countries either hadadopted the first-trimester combined test as the standardapproach to antenatal screening for Down syndromeor were in the process of doing so. Some had evenintroduced sequential protocols such as the contingenttest, which builds on the combined-test markers andoffers second-trimester serum markers and/or furtherultrasound examination to a large subgroup of women,selected according to their estimated risk. Others haveextended the combined test by incorporating routinelysimultaneous determination of additional ultrasoundmarkers. However, the situation has changed radicallywith the introduction of non-invasive prenatal testingusing maternal plasma cell-free (cf) DNA.Inresponsetotheencouragingpublishedresultsofearlystudies, professional bodies cautiously recommended theuse of cfDNA only as a secondary test in those patientsalready regarded as being at high risk. This approachrestricted testing to women with positive conventionalscreening tests and, in some localities, to women withadvanced maternal age, a family history of aneuploidyor ultrasound markers of aneuploidy. Since then, furtherconfirmatory studies have been published, particularlyin unselected populations, and now there can be nodoubt that primary cfDNA screening could achieve vastlysuperiorperformanceforthedetectionofDownsyndromecompared with any of the conventional protocols orsecondary cfDNA screening. However, this approachis currently impractical in most public-health settingsbecause of the high cost of cfDNA testing and the factthat, in many localities, the tests are available only byshipping samples to commercial laboratories in the USAand China.To overcome the problem of cost, a compromisehas been suggested: the contingent cfDNA test

Objective: Brain stem depth/brain stem occipital bone distance (BS/BSOB ratio) and the four-line view, in images obtained for nuchal translucency (NT) screening in fetuses with open spina bifida (OSB). Methods: Single center, retrospective study based on the assessment of NT screening images of fetuses with OSB. A ratio between the BS depth and the BSOB distance was calculated (BS/BSOB ratio) and the four-line view observed, and the sensitivity for a BS/BSOB ratio superior/equal to 1, and for the lack of detection of the four-line view were calculated. Results: There were 17 cases of prenatal diagnosis OSB. In six cases, the suspicion on OSB was raised during NT screening, in six cases, the diagnosis was made before 20 weeks and in five cases during anomaly scan. The BS/BSOB ratio was superior/equal to 1 in all 17 cases, and three lines, were visualized in 15/17 images of the OSB cases, being the sensitivity 100% (95% CI, 81 to 100%) and 88% (95% CI, 65 to 96%). Conclusion: Assessment of BS/BSOB ratio and four-line view in NT images is feasible detecting affected by OSB with high sensitivity. The presence of associated anomalies or of an enlarged NT enhances the early detection.

Purpose To develop a deep learning algorithm to automatically assess the posterior fossa on first-trimester US screening scans and identify open spina bifida (OSB) and cystic posterior fossa (CPF) anomalies. Materials and Methods This was the retrospective part of an international study involving 10 fetal medicine centers. Normal and abnormal (OSB, CPF anomaly) midsagittal fetal brain US images acquired between 11 and 14 weeks of gestation (July 2009-January 2024) with confirmed diagnosis at follow-up were evaluated. Images were manually annotated to delineate the posterior fossa. The dataset was split into a training/validation set (70%) and internal test set (30%). Three convolutional neural networks were trained via threefold cross-validation on the training/validation set, with predictions on the internal test set obtained by ensemble averaging across folds. Model performance in detecting OSB and CPF anomalies was evaluated for the whole cohort and for fetuses with OSB or CPF anomalies separately. Results Images from 251 fetuses were analyzed (mean gestational age [±SD], 12.7 weeks ± 0.65; 150 normal and 101 abnormal [43 OSB and 58 CPF anomalies] images). On the internal test, the MobileNetV3 Large Weights achieved the best performance: area under the receiver operating characteristic curve, 0.94 (95% CI: 0.88, 0.99); accuracy, 88% (67 of 76); recall, 81% (25 of 31); specificity, 93% (42 of 45); precision, 89% (25 of 28); negative predictive value, 88% (42 of 48); and F1 score, 0.85. OSB was classified more accurately (93% [52 of 56] vs 88% [57 of 65]; P = .38) and with higher recall (91% [10 of 11] vs 75% [15 of 20]), although the difference was not significant (P = .38). Conclusion MobileNetV3 Large Weights accurately assessed the fetal posterior fossa between 11 and 14 weeks of gestation, distinguishing normal images from those showing OSB or CPF anomalies. Clinical trial registration no. NCT0579047 Keywords: Artificial Intelligence, First Trimester Ultrasound Screening, Fetal Brain Anomalies, Deep Learning Supplemental material is available for this article. © RSNA, 2026 See also commentary by Rafful in this issue.

To compare two different methods in the ultrasound screening of OSB at 11–13 weeks. Single centre prospective study, including all fetuses with OSB diagnosed over a period of three years and a non-consecutive series of normal fetuses as controls. Only cases with available images of the 11-13-week scan were included. In all fetuses an evaluation of the posterior cranial fossa (PCF) structures was performed measuring the ratio between brainstem and brainstem-to-occipital-bone distance (BS/BSOB) on the midsagittal plane, and the aqueduct-to-occipital bone space (AOS) on the axial one. BS/BSOB and AOS were converted in multiple of the medians obtained from the published charts and compared between cases and controls. Overall, 26 fetuses were recruited for the study purposes, including 5 with OSB and 21 as controls. BS/BSOB was significantly increased (p < 0.001) and AOS significantly reduced (p < 0.01) in OSB group. Both parameters were predictive for OSB, with an area under the receiver operating characteristic curve of 0.990 for BS/BSOB and 0.89 for AOS. The quantitative evaluation of PCF structures at the 11-13 weeks scan has been confirmed to perform extremely well in detecting the OSB. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.