Publications by authors named "Ritsuko Pooh"

42 Publications

Fetal Megalencephaly with Cortical Dysplasia at 18 Gestational Weeks Related to Paternal UPD Mosaicism with Mutation.

Genes (Basel) 2021 Mar 2;12(3). Epub 2021 Mar 2.

Fetal Diagnostic Center, CRIFM Clinical Research Institute of Fetal Medicine, Osaka 543-0001, Japan.

The phosphatase and tensin homolog () gene is a tumor-suppressor gene located on 10q22-23. Since the introduction of molecular genetics in prenatal diagnostics, various birth defects associated with gene mutations have been diagnosed. However, no reports on fetal cases related to mutation have been found, so far. We encountered a rare case of fetal mutation. Fetal macrocephaly was noted at 16 weeks. At 18 and 20 weeks, neurosonography revealed megalencephaly with an asymmetrical structure and multifocal polygyria. The head circumference (HC) was +6.2 SD at 18 weeks and +8.1 SD at 20 weeks. The parents opted for pregnancy termination, and the male fetus was delivered at 21 weeks, with HC +9.3 SD. Single-nucleotide polymorphism (SNP) array for amniotic cells showed paternal uniparental disomy (UPD) 10q mosaicism, and the mosaic ratio was calculated as 56% from B-allele frequency. Exome sequencing revealed the pathogenic mutation with mosaicism. The heterozygous mutation may not cause early manifestations from the fetal period, and an abnormal phenotype may appear after birth. This may be the reason why fetal defects associated with mutation are not detected. Since this case had homozygous and heterozygous mutations, survival was possible, exhibiting an incredibly huge head with cortical dysplasia from early pregnancy.
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http://dx.doi.org/10.3390/genes12030358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999901PMC
March 2021

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

HDlive Flow Silhouette Mode for Diagnosis of Ectopia Cordis With a Left Ventricular Diverticulum at 15 Weeks' Gestation.

J Ultrasound Med 2018 Oct 12;37(10):2465-2467. Epub 2018 Mar 12.

Department of Pediatrics, Kindai University Faculty of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1002/jum.14583DOI Listing
October 2018

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

Three-dimensional neurosonography - a novel field in fetal medicine.

Ginekol Pol 2017 ;88(4):215-221

Neurosonography is a promising technique for prenatal diagnosis, combining features of ultrasound imaging with fetal neurology. The brain is a three-dimensional structure, therefore observing brain structure in the three basic planes (sagittal, coronal and axial) is mandatory. The anterior fontanelle and sagittal suture may serve as acoustic ultrasound windows in the transvaginal brain scan, allowing to obtain high-resolution neuroimages of the intracranial structures. Furthermore, three-dimensional (3D) ultrasound combined with the transvaginal brain approach provides detailed and sophisticated neuroimages. Three orthogonal planes of the brain, tomographic ultrasound imaging (TUI) and other off-line approaches (e.g. volume contrast imaging (VCI) or HDlive silhouette imaging) may be obtained from a single 3D dataset. 3D Doppler ultrasound enables visualization of the intracerebral vascularity, allowing to obtain more precise information on cerebral perfusion. Various abnormal brain conditions, including ventriculomegaly, agenesis of the corpus callosum, posterior fossa abnormalities and others, can be well-demonstrated. Due to high rates of the associated anomalies and uncertain prognosis, any suspicion of CNS abnormalities shall imply detailed ultrasonographic evaluation of the fetal anatomy to exclude the associated anomalies. Despite a growing number of neuroimaging modalities, prenatal counselling remains a challenge as prediction of brain functionality and the neurological prognosis often remain uncertain. New investigations on the relations between various migration disorders and gene mutations, as well as recent clinical research on the relations between neuroimaging detection of local migration disorders using sophisticated imaging technologies and the postnatal neurological prognosis will contribute to the development of maternal-fetal medicine as well as pediatric neurology.
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http://dx.doi.org/10.5603/GP.a2017.0041DOI Listing
July 2018

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

Fetal magnetic resonance imaging and ultrasound.

J Perinat Med 2016 Jul;44(5):533-42

Magnetic resonance imaging (MRI) has been increasingly adopted in obstetrics practice in the past three decades. MRI aids prenatal ultrasound and improves diagnostic accuracy for selected maternal and fetal conditions. However, it should be considered only when high-quality ultrasound cannot provide certain information that affects the counseling, prenatal intervention, pregnancy course, and delivery plan. Major indications of fetal MRI include, but are not restricted to, morbidly adherent placenta, selected cases of fetal brain anomalies, thoracic lesions (especially in severe congenital diaphragmatic hernia), and soft tissue tumors at head and neck regions of the fetus. For fetal anatomy assessment, a 1.5-Tesla machine with a fast T2-weighted single-shot technique is recommended for image requisition of common fetal abnormalities. Individual judgment needs to be applied when considering usage of a 3-Tesla machine. Gadolinium MRI contrast is not recommended during pregnancy. MRI should be avoided in the first half of pregnancy due to small fetal structures and motion artifacts. Assessment of fetal cerebral cortex can be achieved with MRI in the third trimester. MRI is a viable research tool for noninvasive interrogation of the fetus and the placenta.
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http://dx.doi.org/10.1515/jpm-2015-0226DOI Listing
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

Controversial ultrasound findings in mid trimester pregnancy. Evidence based approach.

J Perinat Med 2016 Mar;44(2):131-7

Mid trimester fetal anatomy scan is a fundamental part of routine antenatal care. Some U/S soft markers or controversial U/S signs are seen during the scan and create some confusion regarding their relation to fetal chromosomal abnormalities. Example of these signs: echogenic focus in the heart, echogenic bowel, renal pyelectasis, ventriculomegaly, polydactely, club foot, choroid plexus cyst, single umbilical artery. We are presenting an evidence based approach from the literature for management of these controversial U/S signs.
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http://dx.doi.org/10.1515/jpm-2015-0223DOI Listing
March 2016

Ultrasound in Africa: what can really be done?

J Perinat Med 2016 Mar;44(2):119-23

Today we are living in a globalized world in which information on what is happening in one part of the world is easily communicated to other parts of the world. This happens thanks to advancement in science and technology. One area where technology has made the greatest impact is heath care provision. Ultrasound technology is now playing a critical role in health care provision particularly in Obstetrics and Gynaecology. This has significantly assisted in provision of quality health care to pregnant women and their unborn infants and in reducing maternal and neonatal morbidity and mortality in the developed world. Africa the continent with greatest health care challenges and with the highest maternal and neonatal mortalities is yet to fully utilize this important technology. The need for this technology is great as the conditions requiring its application abound. The effective application of Ultrasound however faces serious challenges in Africa. To successfully entrench Ultrasound in quality Obstetrics and Gynaecology care various approaches must be adopted to overcome the challenges. The aim of this paper is to identify the benefits and the challenges inimical to the application Ultrasound in Obstetrics and Gynecology in Africa. It also examines what needs to be done to achieve better application of Ultrasound in Obstetrics and Gynecology.
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http://dx.doi.org/10.1515/jpm-2015-0224DOI 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

Is intrauterine surgery justified? Report from the working group on ultrasound in obstetrics of the World Association of Perinatal Medicine (WAPM).

J Perinat Med 2016 Oct;44(7):737-743

Fetal surgery involves a large number of heterogeneous interventions that vary from simple and settled procedures to very sophisticated or still-in-development approaches. The overarching goal of fetal interventions is clear: to improve the health of children by intervening before birth to correct or treat prenatally diagnosed abnormalities. This article provides an overview of fetal interventions, ethical approaches in fetal surgery, and benefits obtained from antenatal surgeries.
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http://dx.doi.org/10.1515/jpm-2015-0132DOI Listing
October 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

Novel application of three-dimensional HDlive imaging in prenatal diagnosis from the first trimester.

J Perinat Med 2015 Mar;43(2):147-58

Recent development of three-dimensional (3D) high definition (HD) ultrasound has resulted in remarkable progress in visualization of early embryos and fetuses in sonoembryology. The new technology of HDlive assesses both structural and functional developments in the first trimester with greater reliably than two-dimensional (2D) ultrasound. The ability to visualize not only fetal face, hands, fingers, feet, and toes, but also amniotic membranes, is better with volumetric ultrasound than 2D ultrasound. In this article, detailed and comprehensive structures of normal and abnormal fetuses depicted by 3D HDlive are presented, including various faces of Down's syndrome and holoprosencephaly, as well as low-set ear and finger/toe abnormalities from the first trimester. Three-dimensional HDlive further "humanizes" the fetus, enables detailed observation of the fetal face in the first trimester as shown in this article, and reveals that a small fetus is not more a fetus but a "person" from the first trimester. There has been an immense acceleration in understanding of early human development. The anatomy and physiology of embryonic development is a field where medicine exerts greatest impact on early pregnancy at present, and it opens fascinating aspects of embryonic differentiation. Clinical assessment of those stages of growth relies heavily on 3D/four-dimensional (4D) HDlive, one of the most promising forms of noninvasive diagnostics and embryological phenomena, once matters for textbooks are now routinely recorded with outstanding clarity. New advances deserve the adjective "breathtaking", including 4D parallel study of the structural and functional early human development.
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http://dx.doi.org/10.1515/jpm-2014-0157DOI Listing
March 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

Brain malformation with loss of normal FGFR3 expression in thanatophoric dysplasia type I.

Neuropathology 2013 Dec 1;33(6):663-6. Epub 2013 Apr 1.

Department of Pathology & Applied Neurobiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Sciences, Kyoto, Japan.

Thanatophoric dysplasia is a lethal form of chondrodysplastic dwarfism in which the cerebral cortex displays a unique and complex malformation. We report a female case of thanatophoric dysplasia type I (TD1) with FGFR3 mutation. In this case, fetal ultrasonography at the 18th week of gestation led to a prenatal diagnosis of TD1 with characteristic bone features. The subject was stillborn at the 21st week of gestation, showing marked shortening of the long bones, small thorax and curved short femurs, but without a cloverleaf skull. The temporal lobe was enlarged and hyperconvoluted, appearing as broad gyri and deep sulci, which were composed of focal polymicrogyria-like shallow sulci and heterotopic neuroblastic nests in the intermediate zone and marginal zone. Abundant precursor cells, immunoreactive for nestin and Ki-67 were observed with scattered mitoses in the thickened inner intermediate and subventricular zones of the temporal and occipital lobes. The cytoarchitecture from the entorhinal cortex to Ammon's horn was disorganized with leptomeningeal glioneuronal heterotopia, immunoreactive for doublecortin and nestin. The expression of FGFR3 was virtually not discernible in the temporal and occipital lobes or in the hippocampus. Genetic analysis revealed a point mutation at C8526T (R248C) in the exon 7 of FGFR3. This is the first report that demonstrates that overproduction of intermediate progenitor cells might be induced by FGFR3 mutation in a human TD1 case.
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http://dx.doi.org/10.1111/neup.12036DOI Listing
December 2013

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