Evaluation of screening performance of first-trimester competing-risks prediction model for small-for-gestational age in Asian population.

OBJECTIVE: To examine the external validity of the Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at 11-14 weeks' gestation in an Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 120 women with a singleton pregnancy undergoing routine assessment at 11-14 weeks' gestation. We applied the FMF competing-risks model for the first-trimester prediction of SGA, combining maternal characteristics and medical history with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) concentration. We calculated risks for different cut-offs of birth-weight percentile (< 10th , < 5th or < 3rd percentile) and gestational age at delivery (< 37 weeks (preterm SGA) or SGA at any gestational age). Predictive performance was examined in terms of discrimination and calibration. RESULTS: The predictive performance of the competing-risks model for SGA was similar to that reported in the original FMF study. Specifically, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA with birth weight < 10th percentile (SGA < 10th ) and preterm SGA with birth weight < 5th percentile (SGA < 5th ), with areas under the receiver-operating-characteristics curve (AUCs) of 0.765 (95% CI, 0.720-0.809) and 0.789 (95% CI, 0.736-0.841), respectively. Combining maternal factors with MAP and PlGF yielded the best model for predicting preterm SGA with birth weight < 3rd percentile (SGA < 3rd ) (AUC, 0.797 (95% CI, 0.744-0.850)). After excluding cases with pre-eclampsia, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA < 10th and preterm SGA < 5th , with AUCs of 0.743 (95% CI, 0.691-0.795) and 0.762 (95% CI, 0.700-0.824), respectively. However, the best model for predicting preterm SGA < 3rd without pre-eclampsia was the combination of maternal factors and PlGF (AUC, 0.786 (95% CI, 0.723-0.849)). The FMF competing-risks model including maternal factors, MAP, UtA-PI and PlGF achieved detection rates of 42.2%, 47.3% and 48.1%, at a fixed false-positive rate of 10%, for the prediction of preterm SGA < 10th , preterm SGA < 5th and preterm SGA < 3rd , respectively. The calibration of the model was satisfactory. CONCLUSION: The screening performance of the FMF first-trimester competing-risks model for SGA in a large, independent cohort of Asian women is comparable with that reported in the original FMF study in a mixed European population. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

First-trimester pre-eclampsia biomarker profiles in Asian population: multicenter cohort study.

OBJECTIVES: To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. METHODS: This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. RESULTS: In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. CONCLUSIONS: Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Increased Sylvian fissure angle as early sonographic sign of malformation of cortical development.

OBJECTIVE: To evaluate Sylvian fissure development by assessing Sylvian fissure angles in fetuses with malformation of cortical development (MCD). METHODS: This was a retrospective study of 22 fetuses with MCD. Cases with a stored three-dimensional (3D) brain volume acquired at 18 + 0 to 30 + 6 weeks of gestation at an ultrasound-based research clinic between January 2010 and December 2017 were identified through a database. Of the 22 fetuses, seven had an extracranial abnormality, such as cardiac, renal, gastrointestinal and/or digital anomalies, and five had a minor abnormality such as micrognathia, low-set ears and/or single umbilical artery. To confirm the final clinical diagnosis of brain abnormality, postmortem histological findings or prenatal or postnatal magnetic resonance images were used. For measurement of Sylvian fissure angle, an anterior coronal plane of the fetal brain on transvaginal 3D volume multiplanar imaging was visualized as a single image from the three orthogonal views. The right and left Sylvian fissure angles were measured between a horizontal reference line (0°) and a line drawn along the upper side of the respective Sylvian fissure. The Sylvian fissure angle on both sides was plotted on the graphs of the reference ranges for gestational age in weeks. RESULTS: In 21 (95.5%; 95% CI, 86.8-100.0%) of 22 fetuses with MCD, the Sylvian fissure angle on one or both sides was larger than the 90th percentile of the normal reference. There was one case with apparent focal MCD in the parietal lobe, but the Sylvian fissure angles were normal. A case with apparent unilateral cortical dysplasia and one with apparent unilateral schizencephaly had conspicuous discrepancies between the left and right Sylvian fissure angles. Abnormal genetic test results were obtained in six cases, including four cases with a mutation in a single gene. CONCLUSIONS: This study has shown that the Sylvian fissures, as defined by the Sylvian fissure angle, have delayed development in most MCD cases prior to the diagnosis of the condition. The Sylvian fissure angle may potentially be a strong indicator for the subsequent development of cortical malformation, before the time point at which the gyri and sulci become obvious on the fetal brain surface. Further research is required to validate these findings. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Transvaginal three-dimensional ultrasound assessment of Sylvian fissures at 18-30 weeks' gestation.

OBJECTIVE: To (1) evaluate the normal development of the Sylvian fissures in the anterior coronal view of the fetal brain at 18-30 weeks' gestation by transvaginal three-dimensional (3D) ultrasound, (2) develop reference ranges of measurements of the right and left Sylvian fissure angles during normal pregnancy at 18-30 weeks' gestation, and (3) examine intra- and interobserver repeatability of measurements of the right and left Sylvian fissure angles. METHODS: This was a prospective cross-sectional study of 422 women with a singleton pregnancy attending an ultrasound-based research clinic between March and December 2017. The entry criteria for the study were appropriately grown live fetus with no suspected structural and/or chromosomal defects between 18 + 0 and 30 + 6 weeks' gestation. Normal development of the Sylvian fissures was assessed in the anterior coronal plane of the fetal brain using transvaginal 3D volume multiplanar imaging. The coronal view was visualized as a single image from the three orthogonal views. Subsequently, the right and left Sylvian fissure angles were measured between a horizontal reference line (0°) and a line drawn along the upper side of the respective Sylvian fissure. Intra- and interobserver repeatability of the Sylvian fissure angle measurements was assessed by Bland-Altman plots. Reference equations were constructed for right and left Sylvian fissure angles for gestational age (GA) and head circumference (HC) using the Generalized Additive Models for Location Scale and Shape package. RESULTS: In the anterior coronal view of the fetal brain, an inward rotation of the upper portion of the Sylvian fissures was observed during the second and third trimesters of pregnancy. There was a significant negative polynomial association between the Sylvian fissure angles and GA and HC. Both Sylvian fissure angles crossed the reference line (zero), going from positive to negative, at around 25 weeks' gestation or at HC of 22 cm. Z-score difference between the smoothed percentiles of the right and left Sylvian fissure angles indicated that median, 10th and 90th smoothed percentiles were closest and almost the same for the GA-based references between 18 and 28 weeks and for the HC-based references between 14 and 24 cm. The intraclass correlation coefficient of the right and left Sylvian fissure angle measurements between the two sonographers was excellent at 0.993 (95% CI, 0.988-0.996) and 0.991 (95% CI, 0.985-0.995), respectively. On Bland-Altman analysis, the mean difference between the two sonographers in right Sylvian fissure angle measurement was 0.4° (95% CI, -10.2 to 10.1°) and in left Sylvian fissure angle it was 1.0° (95% CI, -9.6 to 11.6°). CONCLUSIONS: Assessment of the Sylvian fissure angles is highly reproducible. Sylvian fissure angle reference charts can serve as a screening tool for malformations of cortical development, guiding subsequent follow-up and referral for fetal brain magnetic resonance imaging and/or assessment by an expert neurosonologist. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Transvaginal 3D and Doppler ultrasonography of the fetal brain.

Transvaginal sonographic approach to the fetal brain, which provides detailed information about the fetal intracranial morphology, opened a new field in medicine, "neurosonography." The clinical significance of 3D ultrasound for prenatal diagnosis has been discussed since three-dimensional ultrasound was introduced in obstetrics. Three-dimensional ultrasound has several functions: surface reconstruction, multiplanar image analysis, three-dimensional sono-angiography, and volume calculation. In this article, we introduce transvaginal three-dimensional ultrasound for the assessment of fetal head and brain. Surface mode shows not only fetal head abnormality such as acrania but also normal cranial bones and sutures in the first trimester. Rotation of the brain volume image and multiplanar analysis enable tomographic visualization as magnetic resonance imaging. Sono-angiography shows the brain circulation three-dimensionally and extracted volume images of target organ provide information on detailed intracranial conditions. The technology is easy, noninvasive, and reproducible methods, and produces comprehensible and objective information.

Clinical application of three-dimensional ultrasound in fetal brain assessment.

AIM: To clarify the usefulness of three-dimensional (3D) ultrasound in the assessment of the fetal head and brain, according to 3D ultrasound surface reconstruction, multiplanar image analysis, three-dimensional angiography, and volume calculation. METHODS: We examined 326 normal fetuses between 10 and 40 weeks of gestation using 3D ultrasound (Voluson, 530D, Medison, Seoul, Korea), mainly with transvaginal 3D transducer. Fetal head structures, such as the skull, brain structure, and brain circulation, were presented by surface mode, multiplanar imaging mode, and three-dimensional Doppler mode. After automatic volume acquisition of the fetal head, image analyses were performed off-line, and 3D View software was used for volume imaging of the lateral ventricle and choroid plexus in randomly selected 30 normal fetuses. Seven fetuses with intracranial abnormalities were evaluated by 3D ultrasound functions. RESULTS: Surface mode of 3D ultrasound objectively depicted in vivo development of the cranial bones and formation of the cranial sutures and fontanelles in normal fetuses. Multiplanar image analysis of the brain structure presented a fetal brain in more cutting sections than conventional 2D ultrasound. Transvaginal 3D angiography was successful in 13% of normal fetuses and rotation of 3D circulatory image allowed the analysis of the intracranial vessels. Volume imaging showed the intracranial structures, such as the lateral ventricle and choroid plexus. Intracranial abnormalities were longitudinally evaluated by 3D ultrasound and objective images helped in reaching prenatal diagnoses. CONCLUSION: Advanced 3D ultrasonography and software for volume analysis can provide additional objective information about the fetal skull formation, brain structure, and brain circulation.

Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome.

Apert syndrome is characterized by craniosynostosis, midfacial hypoplasia and bilateral syndactyly. We document in detail the intrauterine natural history of Apert syndrome by serial sonographic examination. Ultrasound examination of a 19-week fetus revealed an abnormal appearance of the skull. The subsequent examination including transvaginal brain scanning demonstrated a deformed occipital part of the cerebrum and lateral ventricles, frontal bossing, a low nasal bridge and an abnormal appearance of the fetal hands and feet. The distortion of the fetal profile became progressively worse with advancing gestation. Towards the end of pregnancy, anterior prominence of the cerebrum, ventricles and corpus callosum was demonstrated and mild non-progressive ventriculomegaly was seen. The female 3152-g newborn with the typical facial appearance of Apert syndrome, bilateral syndactyly of the fingers and toes and isolated cleft palate was delivered at 37 weeks. Postnatal three-dimensional computed tomography scan demonstrated the fusion of the coronal suture and a wide mid-line calvarial defect, and cranial magnetic resonance imaging confirmed the prenatal sonographic findings. Although the karyotype was normal, genomic DNA analysis of the fibroblast growth factor receptor 2 revealed Ser252Trp, which is specified in the mutational basis of Apert syndrome. The time course of the prenatal findings in this case may help increase understanding of the intrauterine natural history of Apert syndrome.

Transvaginal Doppler assessment of fetal intracranial venous flow.

OBJECTIVE: To investigate physiologic blood-flow-velocity waveform patterns of the fetal cerebral venous system during normal pregnancies by transvaginal Doppler studies and to evaluate cases with abnormal venous-flow patterns. METHODS: Internal cerebral veins and the three dural sinuses, those of the superior sagittal sinus, vein of Galen, and straight sinus, were examined in normal cephalic-presenting fetuses of 20-40 weeks' gestation. For analysis, the venous index was defined as maximum minus minimum velocity divided by maximum velocity. Different cases with intracranial abnormalities were evaluated with emphasis on abnormal venous blood-flow patterns. RESULTS: Internal cerebral veins had pulsatile patterns with a venous index of 0.22 in 47.6% of fetuses, whereas all fetuses had pulsations in the dural sinuses. The vein of Galen had a significantly lower venous index (0.31) than the superior sagittal sinus (0.39) and the straight sinus (0.36), indicating that the amplitude of the intracranial venous pulsation might increase as the flow runs from the periphery toward the proximal portion. Significant regression lines of venous index were obtained, indicating the stability of the pulsation during pregnancy. A flat pattern of superior sagittal sinus flow was found in three cases of hydrocephalus and one of craniosynostosis. CONCLUSION: We showed the normal patterns of fetal cerebral venous blood-flow velocity and the abnormal patterns which might be associated with increased intracranial pressure. Doppler assessment of the intracranial venous system enabled us to evaluate intracranial abnormalities accompanied by increased intracranial pressure that might have prognostic clinical importance.

Transvaginal sonography of the fetal brain: detection of abnormal morphology and circulation.

AIM: To analyze the incidence, transvaginal detection age, sonographic appearance, clinical course, and outcomes of pregnancy in cases with abnormal fetal brain structure and/or circulation, and to evaluate the clinical significance of sonographic abnormalities. METHODS: Serial observation of the fetal brain and intracranial Doppler assessment by transvaginal approach at four-week intervals were performed in 306 singleton fetuses from the first trimester and 13 referral cases at our ultrasound units from January 1996 to December 1997. Detection of abnormalities was followed by subsequent serial scans every one or two weeks. RESULTS: Morphological abnormalities were found in 66 cases: open neural tube defect (9 cases), disorders of prosencephalic development (2), ventriculomegaly with cerebellar hypoplasia (1), hydrocephalus (1), craniosynostosis (1), unclassified brain anomaly (1), brain atrophy (1), isolated choroid plexus cysts (19), choroid plexus cysts with cerebellar hypoplasia (2), lateral ventricular asymmetry (26), and subependymal cyst (3). Chromosomal aberration was found in 4 cases. Artificial abortion was performed in 10 cases and fetal demise occurred in 2 cases. Isolated choroid plexus cysts, isolated ventricular asymmetry and subependymal cyst were not clinically significant. Two abnormal flow patterns of superior sagittal sinus, sharp doubled pulsatile pattern, and disappearance of normal pulsatile pattern were found in different situations. CONCLUSION: Serial transvaginal observation of the fetal brain provided evidence of hitherto unreported intracranial abnormalities: subependymal cyst, craniosynostosis, medullary kink in Chiari malformation, brain damage, and abnormal venous flows. Venous flow assessment may be of great potential in predicting fetal neurological well-being.

Transvaginal power Doppler angiography of the fetal brain.

Using transvaginal B-mode sonography combined with power Doppler flow mapping on a total of 65 fetuses between 12 and 30 weeks of gestation, fetal intracerebral arteries and veins and blood flow were demonstrated in the coronal and sagittal planes. Clear images of the fetal brain and intracerebral vascular flow were obtained in 36 of the 65 cases. Bilateral vertebral arteries, the basilar artery and posterior cerebral arteries were imaged in the coronal plane at 12 weeks of gestation. Bilateral carotid and middle cerebral arteries were also depicted in the coronal plane at 13 weeks of gestation. The middle cerebral arteries and their branches were depicted via the anterior fontanelle in the coronal plane at 20 weeks of gestation. The anterior cerebral artery and its branches were demonstrated in the sagittal plane at 26 weeks of gestation. The fetal cerebral venous systems of the superior sagittal sinus, internal cerebral vein, vein of Galen and straight sinus were clearly imaged in the mid-sagittal plane. Although we encountered several problems with this new technology of transvaginal power Doppler sonography, we were able to demonstrate its potential to assess fetal intracranial blood flow during pregnancy.