Publications by authors named "Ritsuko K Pooh"

31 Publications

Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population.

Am J Obstet Gynecol 2019 12 4;221(6):650.e1-650.e16. Epub 2019 Oct 4.

Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address:

Background: The administration of aspirin <16 weeks gestation to women who are at high risk for preeclampsia has been shown to reduce the rate of preterm preeclampsia by 65%. The traditional approach to identify such women who are at risk is based on risk factors from maternal characteristics, obstetrics, and medical history as recommended by the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. An alternative approach to screening for preeclampsia has been developed by the Fetal Medicine Foundation. This approach allows the estimation of patient-specific risks of preeclampsia that requires delivery before a specified gestational age with the use of Bayes theorem-based model.

Objective: The purpose of this study was to examine the diagnostic accuracy of the Fetal Medicine Foundation Bayes theorem-based model, the American College of Obstetricians and Gynecologists, and the National Institute for Health and Care Excellence recommendations for the prediction of preterm preeclampsia at 11-13 weeks gestation in a large Asian population STUDY DESIGN: This was a prospective, nonintervention, multicenter study in 10,935 singleton pregnancies at 11-13 weeks gestation in 11 recruiting centers across 7 regions in Asia between December 2016 and June 2018. Maternal characteristics and medical, obstetric, and drug history were recorded. Mean arterial pressure and uterine artery pulsatility indices were measured according to standardized protocols. Maternal serum placental growth factor concentrations were measured by automated analyzers. The measured values of mean arterial pressure, uterine artery pulsatility index, and placental growth factor were converted into multiples of the median. The Fetal Medicine Foundation Bayes theorem-based model was used for the calculation of patient-specific risk of preeclampsia at <37 weeks gestation (preterm preeclampsia) and at any gestation (all preeclampsia) in each participant. The performance of screening for preterm preeclampsia and all preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and placental growth factor (triple test) was evaluated with the adjustment of aspirin use. We examined the predictive performance of the model by the use of receiver operating characteristic curve and calibration by measurements of calibration slope and calibration in the large. The detection rate of screening by the Fetal Medicine Foundation Bayes theorem-based model was compared with the model that was derived from the application of American College of Obstetricians and Gynecologists and National Institute for Health and Care Excellence recommendations.

Results: There were 224 women (2.05%) who experienced preeclampsia, which included 73 cases (0.67%) of preterm preeclampsia. In pregnancies with preterm preeclampsia, the mean multiples of the median values of mean arterial pressure and uterine artery pulsatility index were significantly higher (mean arterial pressure, 1.099 vs 1.008 [P<.001]; uterine artery pulsatility index, 1.188 vs 1.063[P=.006]), and the mean placental growth factor multiples of the median was significantly lower (0.760 vs 1.100 [P<.001]) than in women without preeclampsia. The Fetal Medicine Foundation triple test achieved detection rates of 48.2%, 64.0%, 71.8%, and 75.8% at 5%, 10%, 15%, and 20% fixed false-positive rates, respectively, for the prediction of preterm preeclampsia. These were comparable with those of previously published data from the Fetal Medicine Foundation study. Screening that used the American College of Obstetricians and Gynecologists recommendations achieved detection rate of 54.6% at 20.4% false-positive rate. The detection rate with the use of National Institute for Health and Care Excellence guideline was 26.3% at 5.5% false-positive rate.

Conclusion: Based on a large number of women, this study has demonstrated that the Fetal Medicine Foundation Bayes theorem-based model is effective in the prediction of preterm preeclampsia in an Asian population and that this method of screening is superior to the approach recommended by American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. We have also shown that the Fetal Medicine Foundation prediction model can be implemented as part of routine prenatal care through the use of the existing infrastructure of routine prenatal care.
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http://dx.doi.org/10.1016/j.ajog.2019.09.041DOI Listing
December 2019

Generation of Induced Pluripotent Stem Cells and Neural Stem/Progenitor Cells from Newborns with Spina Bifida Aperta.

Asian Spine J 2017 Dec 7;11(6):870-879. Epub 2017 Dec 7.

Department of Pediatric Neurosurgery, Takatsuki General Hospital, Takatsuki, Japan.

Study Design: We established induced pluripotent stem cells (iPSCs) and neural stem/progenitor cells (NSPCs) from three newborns with spina bifida aperta (SBa) using clinically practical methods.

Purpose: We aimed to develop stem cell lines derived from newborns with SBa for future therapeutic use.

Overview Of Literature: SBa is a common congenital spinal cord abnormality that causes defects in neurological and urological functions. Stem cell transplantation therapies are predicted to provide beneficial effects for patients with SBa. However, the availability of appropriate cell sources is inadequate for clinical use because of their limited accessibility and expandability, as well as ethical issues.

Methods: Fibroblast cultures were established from small fragments of skin obtained from newborns with SBa during SBa repair surgery. The cultured cells were transfected with episomal plasmid vectors encoding reprogramming factors necessary for generating iPSCs. These cells were then differentiated into NSPCs by chemical compound treatment, and NSPCs were expanded using neurosphere technology.

Results: We successfully generated iPSC lines from the neonatal dermal fibroblasts of three newborns with SBa. We confirmed that these lines exhibited the characteristics of human pluripotent stem cells. We successfully generated NSPCs from all SBa newborn-derived iPSCs with a combination of neural induction and neurosphere technology.

Conclusions: We successfully generated iPSCs and iPSC-NSPCs from surgical samples obtained from newborns with SBa with the goal of future clinical use in patients with SBa.
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http://dx.doi.org/10.4184/asj.2017.11.6.870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738307PMC
December 2017

In vitro characterization of neurite extension using induced pluripotent stem cells derived from lissencephaly patients with TUBA1A missense mutations.

Mol Brain 2016 07 19;9(1):70. Epub 2016 Jul 19.

Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Lissencephaly, or smooth brain, is a severe congenital brain malformation that is thought to be associated with impaired neuronal migration during corticogenesis. However, the exact etiology of lissencephaly in humans remains unknown. Research on congenital diseases is limited by the shortage of clinically derived resources, especially for rare pediatric diseases. The research on lissencephaly is further limited because gyration in humans is more evolved than that in model animals such as mice. To overcome these limitations, we generated induced pluripotent stem cells (iPSCs) from the umbilical cord and peripheral blood of two lissencephaly patients with different clinical severities carrying alpha tubulin (TUBA1A) missense mutations (Patient A, p.N329S; Patient B, p.R264C).

Results: Neural progenitor cells were generated from these iPSCs (iPSC-NPCs) using SMAD signaling inhibitors. These iPSC-NPCs expressed TUBA1A at much higher levels than undifferentiated iPSCs and, like fetal NPCs, readily differentiated into neurons. Using these lissencephaly iPSC-NPCs, we showed that the neurons derived from the iPSCs obtained from Patient A but not those obtained from Patient B showed abnormal neurite extension, which correlated with the pathological severity in the brains of the patients.

Conclusion: We established iPSCs derived from lissencephaly patients and successfully modeled one aspect of the pathogenesis of lissencephaly in vitro using iPSC-NPCs and iPSC-derived neurons. The iPSCs from patients with brain malformation diseases helped us understand the mechanism underlying rare diseases and human corticogenesis without the use of postmortem brains.
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http://dx.doi.org/10.1186/s13041-016-0246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950778PMC
July 2016

Current topics on ultrasound in perinatology.

Authors:
Ritsuko K Pooh

J Perinat Med 2016 Mar;44(2):117-8

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http://dx.doi.org/10.1515/jpm-2016-0017DOI Listing
March 2016

3D/4D sonography - any safety problem.

J Perinat Med 2016 Mar;44(2):125-9

Gray-scale image data are processed in 3D ultrasound by repeated scans of multiple planes within a few seconds to achieve one surface rendering image and three perpendicular plane images. The 4D image is achieved by repeating 3D images in short intervals, i.e. 3D and 4D ultrasound are based on simple B-mode images. During 3D/4D acquisition, a fetus in utero is exposed by ultrasound beam for only a few seconds, and it is as short as real-time B-mode scanning. Therefore, simple 3D imaging is as safe as a simple B-mode scan. The 4D ultrasound is also as safe as a simple B-mode scan, but the ultrasound exposure should be shorter than 30 min. The thermal index (TI) and mechanical index (MI) should both be lower than 1.0, and the ultrasound study is regulated by the Doppler ultrasound if it is combined with simple 3D or 4D ultrasound. Recently, some articles have reported the functional changes of animal fetal brain neuronal cells and liver cell apoptosis with Doppler ultrasound. We discuss cell apoptosis by ultrasound in this report. Diagnostic ultrasound safety is achieved by controlling the output pulse and continuous ultrasound waves using thermal and mechanical indices, which should be <1.0 in abdominal and transvaginal scan, pulsed Doppler, as well as 3D and 4D ultrasound. The lowest spatial peak temporal average (SPTA) intensity of the ultrasound to suppress cultured cell growth is 240 mW/cm2, below which no ultrasound effect has been reported. An ultrasound user must be trained to recognize the ultrasound bioeffects; thermal and mechanical indices, and how to reduce these when they are higher than 1.0 on the monitor display; and guide the proper use of the ultrasound under the ALARA principle, because the user is responsible for ensuring ultrasound safety.
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http://dx.doi.org/10.1515/jpm-2015-0225DOI Listing
March 2016

Diagnosis of a case of Dandy-Walker malformation aided by measurement of the brainstem-vermis angle at 14 weeks gestation.

J Obstet Gynaecol Res 2015 May 10;41(5):790-3. Epub 2014 Dec 10.

Department of Obstetrics and Gynecology, Showa University Northern Yokohama Hospital, Yokohama, Japan.

Reported is a fetal Dandy-Walker malformation that was strongly suspected in the first trimester through measurement of the brainstem-vermis (B-V) angle, which was found to be 119° on transvaginal ultrasound examination at 14 weeks and 2 days gestation. Definitive diagnosis of the Dandy-Walker malformation was made by magnetic resonance imaging following stillbirth. Ultrasound measurement of the B-V angle may be a useful index for prenatal diagnosis of Dandy-Walker anomalies during early pregnancy.
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http://dx.doi.org/10.1111/jog.12623DOI Listing
May 2015

Recurrent structural malformations identified among Mowat-Wilson syndrome fetuses.

Prenat Diagn 2014 Mar 23;34(3):296-8. Epub 2013 Dec 23.

Department of Obstetrics and Gynaecology, Wuhan Medical Care Center for Women and Children, Wuhan, China; Fetal Medicine Unit, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.

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http://dx.doi.org/10.1002/pd.4292DOI Listing
March 2014

Diagnosis, treatment, and long-term outcomes of fetal hydrocephalus.

Semin Fetal Neonatal Med 2012 Dec 23;17(6):330-5. Epub 2012 Oct 23.

Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.

This study analyzed 156 cases of fetal hydrocephalus treated at Osaka National Hospital from 1992 to 2011 to review current methods for diagnosing and treating fetal hydrocephalus, and for estimating its clinical outcome. This was a retrospective study of a single institute (Osaka National Hospital). Of 156 cases in total, 37% were diagnosed as isolated ventriculomegaly, 50% as another type of malformation (36 cases of myelomeningocele, six of holoprosencephaly, three of Dandy-Walker syndrome, one case of Joubert syndrome, 12 of arachnoid cyst, nine of encephalocele, three of atresia of Monro and eight of corpus callosum agenesis, and 13% as secondary hydrocephalus. Diagnoses were made between 13 and 40 weeks of gestation (average 27 weeks). Diagnosis was made before 21 weeks of gestation in 24% of cases, from the first day of 22 weeks to the sixth day of 27 weeks in 27%, and after the first day of 28 weeks in 49%. With the exclusion of 17 aborted cases and 40 cases in which the patients were too young to evaluate or lost during follow-up, the final outcome was analyzed for 90 cases. Of these, 17% of the patients died, 21% showed severe retardation, 13% moderate retardation, 26% mild retardation, and 23% showed a good outcome. The long-term outcome was mostly influenced by the basic disease and accompanying anomaly. The time of diagnosis showed no correlation with outcome. Hydrocephalus associated with arachnoid cyst, atresia of Monro, and corpus callosum agenesis, and hydrocephalus due to fetal intracranial hemorrhage, resulted in good outcomes. By contrast, holoprosencephaly, hydrocephalus associated with encephalocele, syndromic hydrocephalus, and hydrocephalus due to fetal virus infection led to poor outcomes. For accurate diagnosis and proper counseling, established protocols are important for the diagnosis and treatment of fetal hydrocephalus, including not only fetal sonography, fetal magnetic resonance imaging, and TORCH (toxoplasma, rubella, cytomegalovirus, herpes simplex) screening test, but also chromosomal and gene testing.
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http://dx.doi.org/10.1016/j.siny.2012.07.004DOI Listing
December 2012

Imaging diagnosis of congenital brain anomalies and injuries.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Dec 29;17(6):360-76. Epub 2012 Aug 29.

CRIFM Clinical Research Institute of Fetal Medicine PMC, 7-3-7, Uehommachi, Tennoji, Osaka 543-0001, Japan.

Fetal brain is rapidly developing and changing its appearance week by week during pregnancy. The brain is the most important organ but it is quite hard to observe detailed structure of this organ by conventional transabdominal sonography. Transvaginal high-resolution ultrasound and three-dimensional (3D) ultrasound has been a great diagnostic tool for evaluation of three-dimensional structure of fetal central nervous system (CNS). This method has contributed to the prenatal assessment of congenital CNS anomalies, intracranial vascular anomalies and acquired brain damage in utero. It is possible to observe the whole brain structure by magnetic resonance imaging in the post half of pregnancy but transvaginal high-resolution 3D ultrasound is certainly powerful modality as well for understanding brain anatomy. Longitudinally and carefully evaluation of neurological short- or long-term prognosis should be required according to precise prenatal diagnosis, for proper counseling and management based on precise evidence.
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http://dx.doi.org/10.1016/j.siny.2012.08.001DOI Listing
December 2012

Sonogenetics in fetal neurology.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Dec 22;17(6):353-9. Epub 2012 Aug 22.

CRIFM Clinical Research Institute of Fetal Medicine PMC, 7-3-7, Uehommachi, Tennoji, Osaka #543-0001, Japan.

Fetal imaging technology has been advancing remarkably and prenatal detection and diagnoses have been moved forward from the second and third trimesters to the first trimester. Structural abnormalities detected by fetal imaging often lead to prenatal diagnoses of genetic disorders. However, there are still dilemmas in fetal diagnoses in normal karyotype cases with strong suspicion of congenital genetic disorders from sonographic findings. When fetal sonography reveals multiple minor abnormalities originating from various organs, counseling dilemmas and parental anxieties become greater than before karyotyping. Array-comparative genomic hybridization (aCGH) was developed as a high-resolution analysis of DNA copy number variations (CNVs). In seven cases presenting with abnormal brain structures by fetal imaging, abnormal CNVs were confirmed by aCGH but conventional karyotyping yielded normal results. Although careful patient selection is required in order to deal with microarray results and parental counseling, 'sonogenetics' - incorporating the idea of 'fetuses first' - will play an important role in the era of molecular genetics. Recent advances in non-invasive prenatal testing by using fetal cell-free DNA in maternal plasma has the potential to generate misleading prenatal diagnoses without the observation of fetuses. However, no fetal diagnoses should be made without observing fetuses and we must not forget 'the fetus as a patient'.
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http://dx.doi.org/10.1016/j.siny.2012.07.005DOI Listing
December 2012

Molecular genetics in fetal neurology.

Semin Fetal Neonatal Med 2012 Dec 19;17(6):341-6. Epub 2012 Aug 19.

Fetal Medicine Unit, Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR.

Brain malformations, particularly related to early brain development, are a clinically and genetically heterogeneous group of fetal neurological disorders. Fetal cerebral malformation, predominantly of impaired prosencephalic development namely agenesis of the corpus callosum and septo-optic dysplasia, is the main pathological feature in fetus, and causes prominent neurodevelopmental retardation, and associated with congenital facial anomalies and visual disorders. Differential diagnosis of brain malformations can be extremely difficult even through magnetic resonance imaging. Advances in genomic and molecular genetics technologies have led to the identification of the sonic hedgehog pathways and genes critical to the normal brain development. Molecular cytogenetic and genetic studies have identified numeric and structural chromosomal abnormalities as well as mutations in genes important for the etiology of fetal neurological disorders. In this review, we update the molecular genetics findings of three common fetal neurological abnormalities, holoprosencephaly, lissencephaly and agenesis of the corpus callosum, in an attempt to assist in perinatal and prenatal diagnosis.
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http://dx.doi.org/10.1016/j.siny.2012.07.007DOI Listing
December 2012

Fetal neurology: volume I.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Oct 2;17(5):251. Epub 2012 Aug 2.

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http://dx.doi.org/10.1016/j.siny.2012.07.003DOI Listing
October 2012

Fetal neurology: volume II.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Dec 1;17(6):309. Epub 2012 Aug 1.

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http://dx.doi.org/10.1016/j.siny.2012.07.006DOI Listing
December 2012

Non-invasive prenatal screening of fetal sex chromosomal abnormalities: perspective of pregnant women.

J Matern Fetal Neonatal Med 2012 Dec 10;25(12):2616-9. Epub 2012 Aug 10.

Fetal Medicine Centre, Paramount Clinic, Central, Hong Kong.

Objective: To study whether pregnant women would like to be informed if sex chromosomal abnormalities (SCA) were suspected with the non-invasive prenatal diagnosis of fetal Down syndrome (the NIFTY) test.

Methods: Two hundred and one patients carried a singleton pregnancy requesting the NIFTY test were invited to give their preferences if there was suspicion of SCA by the NIFTY test.

Results: Over 93.5% were ethnic Chinese, with a mean age of 36. Prior Down screening was positive in 66 (32.8%). Over 50% of subjects considered SCA to be better in terms of disability compared to Down syndrome, and only 5.2% considered SCA to be worse. Yet, the majority (198, 98.5%) indicated that they wanted to be informed if there was suspicion of SCA. Of whom 34.8% would have an amniocentesis for confirmation, while 57.1% were not certain, indicating the possibility of accepting these conditions.

Conclusion: Besides screening Down syndrome by NIFTY, most pregnant women would also like to be informed if there was suspicion of SCA. Those screened positive should be counseled by those with experience in genetics to avoid unnecessary pregnancy termination.
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http://dx.doi.org/10.3109/14767058.2012.712569DOI Listing
December 2012

Normal anatomy by three-dimensional ultrasound in the second and third trimesters.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Oct 19;17(5):269-77. Epub 2012 Jul 19.

CRIFM Clinical Research Institute of Fetal Medicine PMC, Tennoji, Osaka, Japan.

Fetal brain is rapidly developing and changing its appearance week by week during pregnancy. It is quite difficult to observe detailed structure of the brain by conventional transabdominal sonography. Transvaginal high-resolution ultrasound and three-dimensional (3D) ultrasound have been establishing sonoembryology in the first trimester as well as neurosonography. It is possible to observe the whole brain structure by magnetic resonance imaging in the latter half of pregnancy but transvaginal high-resolution 3D ultrasound is also a powerful modality for understanding brain anatomy. As for brain vascularization, main arteries and veins have been demonstrated and evaluated in various central nervous system conditions. Transvaginal high-resolution 3D ultrasound can demonstrate even cerebral fine vascular anatomy such as medullary vessels and it is greatly expected to estimate neurological prognosis in relation to vascular development during the fetal period.
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http://dx.doi.org/10.1016/j.siny.2012.06.003DOI Listing
October 2012

Neurosonoembryology by three-dimensional ultrasound.

Authors:
Ritsuko K Pooh

Semin Fetal Neonatal Med 2012 Oct 15;17(5):261-8. Epub 2012 Jul 15.

CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan.

High-resolution three-dimensional (3D) ultrasound has enabled the visualization of small embryos and fetuses, and embryology in vivo - '3D sonoembryology' - has been established based on conventional embryology. Recently developed imaging techniques allow the definition of in-vivo anatomy including visualization of the embryonic circulation and dynamic features that could not be characterized in fixed specimens. Three-dimensional ultrasound has facilitated increasingly accurate and objective prenatal diagnoses of cranium bifidum/spina bifida, holoprosencephaly and associated anomalies in the first trimester and may allow detection of pathologic central nervous system (CNS) development at an earlier gestational age. It may be no exaggeration to suggest that prenatal diagnoses of fetal abnormalities have shifted from second to first trimester. However, fetal brain develops rapidly in the second trimester, therefore early scanning covers only selected CNS anomalies described in this article and serial continuous observation in the second trimester will be required.
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http://dx.doi.org/10.1016/j.siny.2012.05.008DOI Listing
October 2012

Clinical utility of noninvasive fetal trisomy (NIFTY) test--early experience.

J Matern Fetal Neonatal Med 2012 Oct 28;25(10):1856-9. Epub 2012 Apr 28.

Fetal Medicine Centre, Paramount Clinic, Hong Kong.

Objective: To report the initial experience of noninvasive prenatal diagnosis of fetal Down syndrome (The NIFTY test) in a clinical setting.

Methods: The NIFTY test was offered as a screening test for fetal Down syndrome to pregnant women with a singleton pregnancy at 12 weeks of gestation or beyond. A satisfaction questionnaire was sent to the first 400 patients.

Results: During a 6-month period, 567 NIFTY tests were performed. Over 90% of those studied were ethnic Chinese, and the mean age of the women studied was 36 years. The test was performed at 12-13 weeks of gestation in 49.21%. The median reporting time was 9 days. The test was positive for trisomy 21 in eight cases, and for trisomy 18 in 1 case; all were confirmed by fetal karyotyping. There was no false-positive result. Of the questionnaires, 182 completed responses were received. Over 95% had complete or almost complete resolution of anxiety. Except for one, all were satisfied with the NIFTY test, and all indicated that they would recommend the test to their friends.

Conclusion: The NIFTY test was a highly specific test. Unnecessary invasive tests and associated fetal losses could be avoided in almost all women who have a normal fetus.
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http://dx.doi.org/10.3109/14767058.2012.678442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483059PMC
October 2012

3D/4D sonography moved prenatal diagnosis of fetal anomalies from the second to the first trimester of pregnancy.

J Matern Fetal Neonatal Med 2012 May 13;25(5):433-55. Epub 2011 Dec 13.

The introduction of 3D/4D sonography with high frequency transvaginal transducer has resulted in remarkable progress in ultrasonographic visualization of early embryos and fetuses and development of new fields of 3D sonoembryology. With the proper use of this new diagnostic modality and with experienced examiner, both structural and functional development in the first trimester of gestation can be assessed more objectively and reliable. Indeed new technology moved embryology from postmortem studies to the in vivo environment. Furthermore, there are good reasons to believe that 3D/4D sonography moved prenatal diagnosis of fetal abnormalities from the second to the first trimester of pregnancy. We will try to illustrate it with the number of convincing slides.
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http://dx.doi.org/10.3109/14767058.2011.636107DOI Listing
May 2012

Noninvasive prenatal diagnosis of common fetal chromosomal aneuploidies by maternal plasma DNA sequencing.

J Matern Fetal Neonatal Med 2012 Aug 24;25(8):1370-4. Epub 2012 Feb 24.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong.

Objective: To develop a new bioinformatic method in the noninvasive prenatal identification of common fetal aneuploidies using massively parallel sequencing on maternal plasma.

Methods: Massively parallel sequencing was performed on plasma DNA samples from 108 pregnant women (median gestation: 12(+5) week) immediately before chorionic villus sampling (CVS) or amniocentesis. Data were analysed using a novel z-score method with internal reference chromosome. The diagnostic accuracies of the fetal karyotyping status were compared against two previously reported z-score methods--one without adjustment and the other with GC correction.

Results: A total of 32 cases with fetal aneuploidy were confirmed by conventional karyotyping, including 11 cases of Trisomy 21, 10 cases of Trisomy 18, 2 cases of Trisomy 13, 8 cases of Turner syndrome (45, XO) and one case of Klinefelter syndrome (47, XXY). Using the z-score method without reference adjustment, the detection rate for Trisomy 21, Trisomy 18, Trisomy 13, Turner syndrome, and Klinefelter's syndrome is 100%, 40%, 0%, 88% and 0% respectively. Using the z-score method with GC correction, the detection rate increased to 100% for Trisomy 21, 90% for Trisomy 18, 100% for Trisomy 13. By using the z-score method with internal reference, the detection rate increased to 100% for all aneuploidies. The false positive rate was 0% for all three methods.

Conclusion: This massively parallel sequencing-based approach, combined with the improved z-score test methodology, enables the prenatal diagnosis of most common aneuploidies with a high degree of accuracy, even in the first trimester of pregnancy.
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http://dx.doi.org/10.3109/14767058.2011.635730DOI Listing
August 2012

Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus).

J Neurosurg Pediatr 2011 Oct;8(4):411-6

Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka City, Japan.

Object: The aim of this study was to evaluate the feasibility of prenatal L1CAM gene testing for X-linked hydrocephalus (XLH).

Methods: In a nationwide study conducted in Japan between 1999 and 2009, the authors identified 51 different L1CAM gene mutations in 56 families with XLH. Of these 56 families, 9 obligate carriers requested prenatal gene mutation analysis for the fetal L1CAM gene in 14 pregnancies.

Results: In 2004, new clinical guidelines for genetic testing were established by 10 Japanese genetic medicine-related societies. These guidelines stated that the genetic testing of carriers should be done only with their consent and with genetic counseling. Therefore, because females are carriers, since 2004, L1CAM gene analysis has not been performed for female fetuses. The authors report on 7 fetal genetic analyses that were performed at the request of families carrying L1CAM mutations, involving 3 female (prior to 2004) and 4 male fetuses. Of the 7 fetuses, 3 (1 male and 2 female) carried L1CAM mutations. Of these 3, 1 pregnancy (the male fetus) was terminated; in the other cases, the pregnancies continued, and 3 female and 3 male babies without the XLH phenotype were born.

Conclusions: Prenatal L1CAM gene testing combined with genetic counseling was beneficial for families carrying L1CAM mutations.
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http://dx.doi.org/10.3171/2011.7.PEDS10531DOI Listing
October 2011

3D and 4D sonography and magnetic resonance in the assessment of normal and abnormal CNS development: alternative or complementary.

J Perinat Med 2011 01 27;39(1):3-13. Epub 2010 Oct 27.

CRIFM Clinical Research Institute of Fetal Medicine PMC, Osaka, Japan.

Advanced transvaginal neurosonography has revealed normal and abnormal intracranial morphology. Transvaginal three-dimensional (3D) sonography demonstrates bony structure, multiplanar analysis of inside detailed morphology, tomographic ultrasound imaging in any cutting sections, 3D sonoangiography and volume calculation of ventricles and/or intracranial lesions. Longitudinal assessment of normal and abnormal central nervous system (CNS) development is done by serial scanning. However, the transvaginal high-frequency approach has several limitations due to lack of penetration and cranial bone ossification with advanced gestational age. Magnetic resonance neuroimaging enabled observation of the whole intracranial cavity, brainstem and cortical gyral/sulcal development. On the other hand, neuro-sonography has advantages in detecting intracranial calcification, vascular abnormalities, intratumoral vascularity and bone dysplasia. Moreover, 3D ultrasound demonstrates extra CNS abnormalities, strongly associated with CNS abnormalities. Any less-invasive modalities can be used for a CNS anomaly screening scan and ultrasound is no doubt the first choice. Once CNS abnormality is suspected, it is suggested to use the different technologies according to what is looked for in each abnormal CNS case. Of course, MR and 3D ultrasound imaging should be complementary as well as alternative.
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http://dx.doi.org/10.1515/jpm.2010.118DOI Listing
January 2011

Imaging of the human embryo with magnetic resonance imaging microscopy and high-resolution transvaginal 3-dimensional sonography: human embryology in the 21st century.

Am J Obstet Gynecol 2011 Jan 25;204(1):77.e1-16. Epub 2010 Oct 25.

Clinical Research Institute of Fetal Medicine Pooh Maternity Clinic, Osaka, Japan.

Objective: This article illustrates early human development, demonstrated by magnetic resonance (MR) microscopy and computer graphics on human embryo specimens, and advanced 3-dimensional (3D) sonography in clinical obstetrics.

Study Design: Fixed human embryo specimens were imaged by MR microscopy coupled with computer graphics technology. Transvaginal 3D sonography was used to examine embryos in ongoing gestations and compare embryological findings.

Results: Advances in MR microscopy allowed detailed visualization of embryo specimens. Computational techniques allowed reconstruction of tomographic images to render them as 3D structures. High-resolution transvaginal 3D sonography produced images that demonstrated the neural tube from week 6; brain anatomy and vasculature from week 8; and craniofacial morphology and other structures from week 11.

Conclusion: MR microscopy is a novel technique that enables nondestructive, high-resolution imaging of embryo specimens. On the other hand, 3D sonoembryology allows detailed anatomical visualization in vivo and is the basis for the assessment of anomalies as well as human development.
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http://dx.doi.org/10.1016/j.ajog.2010.07.028DOI Listing
January 2011

Classification of pathogenic or benign status of CNVs detected by microarray analysis.

Expert Rev Mol Diagn 2010 Sep;10(6):717-21

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR.

Multiple lines of evidence indicated that microarray analysis has a better diagnostic yield of clinically significant genetic changes than do conventional methods in patients with constitutional abnormalities. However, interpretation of microarray data is complicated by the presence of both novel and recurrent copy number variants (CNVs) of unknown significance. To address this issue, Hehir-Kwa et al. described a new computational method for determining the pathogenicity between benign and mental retardation (MR)-associated CNVs among patients with MR. This study demonstrated the value of objectively prioritizing MR-associated CNVs using structural and functional genomic features in diagnostics. In this regard, we discuss an evidence-based summary of how to classify pathogenic or benign status of a CNV in clinical genetics and advocate that there is a need for algorithmic adjustment between constitutional cytogenetic and prenatal diagnosis settings.
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http://dx.doi.org/10.1586/erm.10.68DOI Listing
September 2010

The potential of 4D sonography in the assessment of fetal neurobehavior--multicentric study in high-risk pregnancies.

J Perinat Med 2010 ;38(1):77-82

Department of Obstetrics and Gynecology, Medical School University of Zagreb, Sveti Duh Hospital, Zagreb, Croatia.

Objective: An evolving challenge for obstetrician is to better define normal and abnormal fetal neurological function in utero in order to better predict antenatally which fetuses are at risk for adverse neurological outcome.

Patients And Methods: Prenatal neurological assessment in high-risk fetuses using four-dimensional ultrasound applying the recently developed Kurjak antenatal neurodevelopmental test (KANET). Postnatal neurological assessment was performed using Amiel Tison's neurological assessment at term (ATNAT) for all live-borns and general movement (GM) assessment for those with borderline and abnormal ATNAT.

Results: Inclusion criteria were met by 288 pregnant women in four centers of whom 266 gave birth to a live-born baby. It was revealed that 234 fetuses were neurologically normal, 7 abnormal and 25 borderline. Out of 7 abnormal fetuses ATNAT was borderline in 5 and abnormal in 2, whereas GM assessment was abnormal in 5 and definitely abnormal in 2. Out of 25 KANET borderline fetuses, ATNAT was normal in 7, borderline in 17 and abnormal in 1, whereas the GM assessment was as follows: normal optimal in 4, normal suboptimal in 20, and abnormal in 1. In summary, out of 32 borderline and abnormal fetuses ATNAT was normal in 7, borderline in 22 and abnormal in 3; GM assessment was normal optimal in 4, normal suboptimal in 20, abnormal in 6 and definitely abnormal in 2.

Conclusion: The sonographic test requires further studies before being recommended for wider clinical practice.
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http://dx.doi.org/10.1515/jpm.2010.012DOI Listing
April 2010

Detailed multigrade evaluation of fetal disorders with the quantified actocardiogram.

J Perinat Med 2009 ;37(4):392-6

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.

Aims: To evaluate fetal disorders using detailed quantitative values from the actocardiogram (ACG) involving simultaneous tracing of ultrasonic Doppler fetal movement bursts and fetal heart rate (FHR).

Methods: Duration of FHR accelerations and fetal movement bursts were measured manually in 20 common fetal disorders. The severity of the fetal disorder was estimated using the FHR acceleration duration to movement burst ratio (A/B ratio) and 10-0 clinical severity ranks derived from the A/B ratio. The correlation of the A/B ratio and 1 and 5 min Apgar scores, as well as numerically expressed long-term outcomes were studied.

Results: A/B ratios were significantly correlated with the 1 and 5 min Apgar scores and the numerically evaluated long-term outcomes. Controversial cases of FHR pattern were more easily understood using the A/B ratio. The 10-0 severity derived from the A/B ratio was useful in clinical fetal studies.

Conclusion: Common fetal disorders were evaluated quantitatively and in more detail using the A/B ratio from the actocardiogram than when using common binary good or bad evaluation. The A/B ratio was useful in outcome estimation, where the prognostic capability of the A/B ratio was confirmed by significant correlation with 1 and 5 min Apgar scores and long-term outcomes of fetal disorders.
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http://dx.doi.org/10.1515/JPM.2009.056DOI Listing
September 2009

Fetal behavior analyzed by ultrasonic actocardiogram in cases with central nervous system lesions.

J Perinat Med 2006 ;34(5):398-403

Department of Obstetrics and Gynecology Emeritus, Tottori University, Yonago, Japan.

Aims: This study examined whether analysis of fetal behavioral states by monitoring fetal heart rate and movement using an actocardiogram (ACG), could provide prognostic information related to fetal central nervous system (CNS) lesions.

Methods: The ACG simultaneously records fetal heart rate (FHR) and fetal movement bursts composed of spikes of ultrasonic Doppler signals. Durations of FHR accelerations and fetal movement bursts were measured manually. Five actocardiographic indices were studied in 12 fetuses with CNS lesions and in 14 normal pregnancies of 28-38 weeks.

Results: Severity of the fetal CNS lesions was estimated from the acceleration/burst (A/B) duration ratio, which correlated with the rank of the sonographic fetal functional test in cases with CNS lesions. Severity of a fetal lesion may also be estimated by the regression equation of the A/B duration ratio and behavioral ranking.

Conclusion: The severity of fetal CNS lesions may be estimated by quantitative analysis of ACG usings the measurement of A/B duration ratio to provide a prognosis. An ACG may demonstrate a loss of CNS control in cases with severe brain damage.
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http://dx.doi.org/10.1515/JPM.2006.079DOI Listing
February 2007

Structural and functional early human development assessed by three-dimensional and four-dimensional sonography.

Fertil Steril 2005 Nov;84(5):1285-99

Department of Obstetrics and Gynecology, Medical School, University of Zagreb, Sveti Duh Hospital, Zagreb, Croatia.

Objective: To summarize the role of three-dimensional and four-dimensional ultrasound in the assessment of early human development.

Design: Review of literature.

Setting: Ultrasound research center and obstetrics and gynecology department in a tertiary care facility.

Result(s): The introduction of high-frequency transvaginal tranducers has resulted in remarkable progress in ultrasonographic visualization of early embryos and fetuses and the development of sonoembryology. Furthermore, recent introduction of three-dimensional and four-dimensional ultrasounds combined with the transvaginal approach has produced more objective and accurate information on embryonal and early fetal development. For the first time parallel analyses of structural and functional parameters in the first 12 weeks of gestation become possible.

Conclusion(s): The anatomy and physiology of placental and embryonic development is a field where medicine exerts its greatest impact on early pregnancy at present time, and it opens fascinating aspects of embryonic differentiation. Clinical assessment of those stages of growth rely heavily on three-dimensional and four-dimensional sonography, one of the most promising forms of noninvasive diagnostics today and embryological phenomenon, once matters for textbooks are now routinely recorded with outstanding clarity.
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http://dx.doi.org/10.1016/j.fertnstert.2005.03.084DOI Listing
November 2005

B-flow and B-flow spatio-temporal image correlation in visualizing fetal cardiac blood flow.

Croat Med J 2005 Oct;46(5):808-11

Division of Maternal Fetal Medicine, Center for Maternal, Fetal and Neonatal Medicine, Kagawa National Children's Hospital, Zentsuji 2603, Zentsuji City Kagawa #765-8501, Japan.

Aim: To evaluate the clinical usefulness of two-dimensional B-flow imaging and four-dimensional (4D) B-flow spatio-temporal image correlation (STIC) as real-time three-dimensional technology in visualizing fetal cardiac blood flow.

Method: We examined 65 normal singleton fetuses between 21 and 39 weeks of gestation, using VOLUSON 730 Expert ultrasound device with transabdominal 3D/4D transducer. After visualizing fetal cardiac blood flow by two dimensional B-flow mode, B-flow STIC images were acquired .The acquisition angle was 40 degrees and acquisition time 15 s. The cardiac vascular system was analyzed off-line on multiplanar and reconstructed 3D/4D rendered images.

Results: In 38 out of 65 cases, all extracardiac vessels of aortic arch, descending aorta, inferior vena cava, ductus venosus and hepatic vein could be detected on reconstructed 3D/4D images. In all 65 cases, two or more pulmonary veins were easily depicted. On a cardiac back-front view created by rotating 4D reconstructed image, two pulmonary veins among a total of four were depicted in 34 cases (52.3%), three veins in 28 cases (43.1%) and all four pulmonary veins in three cases (4.6%).

Conclusion: B-flow and/or B-flow STIC allow visualization of fine small vessels with low velocity, such as pulmonary veins, and may have a great potential for detailed detection of an abnormality of small cardiac vessels, such as total anomalous pulmonary venous return.
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October 2005