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Ultrasound Imaging of Early Embryonic and Fetal Development
Abstract
The early first trimester, from 5 to 11 week's gestation is investigated. A step-by-step comparison is made between embryonic development according to the Carnegie stages and ultrasound imaging. High-quality early embryonic-fetal imaging is provided together with anatomical detials obtained from CT-scan reconstruction of human embryos.
... The lower contrast resolution in three-dimensional ultrasound may lead to difficulties in interpreting the image at gray-scale boundaries. The quality of obtained images is directly related to the precision of the morphometric data [24][25][26]. The sensitivity of ultrasound examination in the diagnosis of skeletal abnormalities is limited and ranges between 40% and 60% [27]. ...
Detailed numerical data about the development of primary ossification centers in human fetuses may influence both better evaluation and early detection of skeletal dysplasias, which are associated with delayed development and mineralization of ossification centers. To the best of our knowledge, this is the first report in the medical literature to morphometrically analyze the primary ossification center of the squamous part of temporal bone in human fetuses based on computed tomography imaging. The present study offers a precise quantitative foundation for ossification of the squamous part of temporal bone that may contribute to enhanced prenatal care and improved outcomes for fetuses with inherited cranial defects and skeletodysplasias. The examinations were carried out on 37 human fetuses of both sexes (16 males and 21 females) aged 18–30 weeks of gestation, which had been preserved in 10% neutral formalin solution. Using CT, digital image analysis software, 3D reconstruction and statistical methods, the size of the primary ossification center of the squamous part of temporal bone was evaluated. With neither sex nor laterality differences, the best-fit growth patterns for the primary ossification center of the squamous part of temporal bone was modelled by the linear function: y = −0.7270 + 0.7682 × age ± 1.256 for its vertical diameter, and the four-degree polynomial functions: y = 5.434 + 0.000019 × (age) ⁴ ± 1.617 for its sagittal diameter, y = −4.086 + 0.00029 × (age) ⁴ ± 2.230 for its projection surface area and y = −25.213 + 0.0004 × (age) ⁴ ± 3.563 for its volume. The CT-based numerical data and growth patterns of the primary ossification center of the squamous part of temporal bone may serve as age-specific normative intervals of relevance for gynecologists, obstetricians, pediatricians and radiologists during screening ultrasound scans of fetuses. Our findings for the growing primary ossification center of the squamous part of temporal bone may be conducive in daily clinical practice, while ultrasonically monitoring normal fetal growth and screening for inherited cranial faults and skeletodysplasias.
Background:
Prenatal diagnosis of several major congenital anomalies can be achieved in the first trimester of pregnancy.
Objective:
This study investigates the timing of diagnosis and pregnancy outcome of foetuses and neonates with selected structural anomalies in the Northern Netherlands over a 10-year period when the prenatal screening programme changed significantly, but no first-trimester anatomical screening was implemented.
Methods:
We performed a population-based retrospective cohort study with data from the EUROCAT Northern Netherlands database on pregnancies with delivery or termination of pregnancy for fetal anomaly (TOPFA) date between 2010 and 2019. The analysis was restricted to anomalies potentially detectable in the first trimester of pregnancy in at least 50% of cases, based on previously published data. These included: anencephaly, encephalocele, spina bifida, holoprosencephaly, tricuspid/pulmonary valve atresia, hypoplastic left heart, abdominal wall and limb reduction defects, lethal skeletal dysplasia, megacystis, multiple congenital anomalies. The primary outcome was the timing of diagnosis of each structural anomaly. Information on additional investigations, genetic testing and pregnancy outcome (live birth, TOPFA and foetal/neonatal death) was also collected.
Results:
A total of 478 foetuses were included; 95.0% (n = 454) of anomalies were detected prenatally and 5.0% (n = 24) postpartum. Among the prenatally detected cases, 31% (n = 141) were diagnosed before 14 weeks of gestation, 65.6% (n = 298) between 14-22 weeks and 3.3% (n = 15) after 22 weeks. Prenatal genetic testing was performed in 80.4% (n = 365) of cases with prenatally diagnosed anomalies, and the results were abnormal in 26% (n = 95). Twenty-one% (n = 102) of pregnancies resulted in live births and 62.8% (n = 300) in TOPFA. Spontaneous death occurred in 15.9% (n = 76) of cases: in-utero (6.1%, n = 29), at delivery (7.7%, n = 37) or in neonatal life (2.1%, n = 10).
Conclusion:
Major structural anomalies amenable to early diagnosis in the first trimester of pregnancy are mostly diagnosed during the second trimester in the absence of a regulated first-trimester anatomical screening programme in the Netherlands and are associated with TOPFA and spontaneous death, especially in cases with underlying genetic anomalies.
Objectives
The aim of this study is to share our experience in the prenatal diagnosis of omphalocele by karyotyping, chromosomal microarray analysis (CMA) and whole exome sequencing (WES).
Methods
In this retrospective study, 81 cases of omphalocele were identified from 2015 to 2020. Associated anomalies and prenatal diagnosis based on karyotyping, CMA and WES were analysed.
Results
Fifty-eight (71.6%) of the 81 foetuses had other ultrasound anomalies. Giant omphalocele was present in 11 cases (13.6%) and small omphalocele was present in 70 cases (86.4%). Chromosomal abnormalities were found in 24 foetuses (29.6%, 24/81), the most common of which were trisomy 18 (58.8%, 11/24) and trisomy 13 (29.2%, 7/24). Compared to isolated omphalocele, non-isolated omphalocele was accompanied by an increased prevalence of chromosomal abnormalities (4.3% (1/23) vs. 39.7% (23/58), χ² = 8.226, p = .004). All chromosomal abnormalities were found in small omphalocele. Aside from aneuploidy, CMA showed one pathogenic copy number variants (CNVs) for a detection rate of 1.2%, one variants of unknown significance (VOUS) and one instance of loss of heterozygosity (LOH). WES was performed on 3 non-isolated cases, and one was found to have pathogenic variants.
Conclusions
The most common genetic cause of omphalocele is aneuploidy and the prevalence of chromosomal abnormalities is increased with non-isolated and small omphalocele. CMA and WES can be useful for providing further genetic information to assist in prenatal counselling and pregnancy management.
Background:
Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure.
Methods:
A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute's ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls.
Results:
Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96-9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04-16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84-8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11-11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94-12.31).
Conclusions:
Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.
The study presents a pictorial essay of acrania-exencephaly-anencephaly sequence using two-(2D) and three-dimensional (3D) ultrasonography, documenting the different phenotypic characterization of this rare disease. Normal and abnormal fetuses were evaluated during the first trimester scan. The International Society of Ultrasound in Obstetrics and Gynecology practice guidelines were adopted to standardize first trimester anatomical ultrasound screening. The guidelines outline the importance of systematic fetal head and brain examination including the formation of cranial bones, choroid-plexus and ventricles. Acrania-exencephaly-anencephaly sequence and/or other neural tube defects, such as meningoencephalocele, may be identified during a routine 11-14 week scan. Early first trimester detection of acrania-exencephaly-anencephaly sequence with the characterization of different related phenotypes, 2D and 3D ultrasound imaging as well as differential diagnosis are also presented in this pictorial essay. The main diagnostic ultrasound features of the disease may be characterized by findings of acrania with increased amniotic fluid echogenicity; "Mickey-Mouse" bi-lobular face, cystic, elongated, irregular and overhanging head morphology. Lightening techniques have also been added to 3D ultrasound to enhance anatomical details. Moreover, discordant amniotic fluid echotexture in the setting of twin pregnancies may be the first sign of acrania-exencephaly-anencephaly sequence. Extracranial malformations, aneuploidy and genetic syndromes associated with acrania-exencephaly-anencephaly sequence are also reported and described. First trimester neuroscan by an expert sonographer with appropriate training together with the application of standardized protocol are essential for a high detection rate of this rare type of neural tube defect malformation during a scan performed at 11 and 13 weeks and 6 days.
Objective:
This study assessed the percentage and type of congenital anomalies diagnosed at first-trimester ultrasound (US) scan in a primary care setting without following a standardized protocol for fetal anatomical assessment.
Materials and methods:
US scans performed between 11+0 and 13+6 weeks of gestation in pregnancies with estimated date of delivery between January 1, 2012 and January 1, 2016 were searched. Data were supplemented with results of 20-week scans and pregnancy outcome.
Results:
Of all scans, 38.6% were dating scans and 61.4% were part of first-trimester screening. Anomalies were diagnosed prenatally in 200 (1.8%) fetuses; 81 (0.7%) were chromosomal and 119 (1.1%) were structural. Of all prenatally detected anomalies, 27% (n = 32) were detected at first-trimester scan, with a false-positive rate of 0.04%. All cases of anencephaly (n = 4), encephalocele (n = 2), exomphalos (n = 9), megacystis (n = 4), and limb reduction (n = 1) were diagnosed. First-trimester detection of gastroschisis and congenital heart defects was 67 and 19%, respectively.
Conclusion:
In a primary care setting, global fetal anatomical assessment at first-trimester scan without following a standardized protocol detects about 30% of all structural anomalies and most of the severe anomalies, with an extremely low false-positive rate. We hypothesize that additional training and use of a systematic protocol would improve early detection of structural anomalies.
Objective:
Megacystis represents a challenge in terms of counseling and management due to its various etiology and evolution. The aim of this study is to present a comprehensive overview of the underlying etiologies and structural anomalies associated with fetal megacystis.
Methods:
This was a retrospective multicenter study carried out at the Fetal Medicine Units (FMUs) of the eight Academic Hospitals in the Netherlands. For each case referred to one of these centers due to fetal megacystis, data and measurements of fetal urinary tract and associated structural anomalies were collected. All available postmortem examinations and postnatal investigations were reviewed in order to establish the final diagnosis. In the first trimester, fetal megacystis was defined as a bladder with a longitudinal diameter (LBD) ≥ 7 mm, and in the 2nd and 3rd trimester as an enlarged bladder failing to empty during an extended US examination lasting at least 40 minutes.
Results:
Out of 541 megacystis, megacystis was isolated (or merely accompanied by other signs of LUTO) in 360 cases (66%); and associated with other abnormal ultrasound findings in 181 cases (34%). The most common associated anomaly was an increased nuchal translucency (NT22%), followed by SUA and cardiac defects (10%). A final diagnosis was established in 418 cases, including 222 cases with isolated LUTO (53%) and 60 infants (14%) with normal micturition or isolated urological anomalies. In the remaining 136 cases (33%), a genetic syndrome, developmental or chromosomal abnormality was diagnosed. In total, 40 chromosomal abnormalities were diagnosed, including: Trisomy 18 (n = 24), Trisomy 21 (n = 5), Turner syndrome (n = 5), Trisomy 13 (n = 3) and deletion 22q11 (n = 3). Thirty-two cases presented with Ano-Rectal Malformations involving anus, rectum and urogenital tract. In cases with confirmed urethral and anal atresia, megacystis occurred early in pregnancy and the bladder appeared severely distended (the longitudinal diameter was equal or greater than twice the gestational age). Fetal macrosomia was detected in 6 cases and an overgrowth syndrome was detected in other 4 cases: 2 infants with Beckwith-Wiedemann and 2 infants with Sotos syndrome. Megacystis-microcolon-intestinal hypoperistalsis syndrome was diagnosed in five cases (1%) and prenatally suspected only in one case.
Conclusions:
Although the main cause of megacystis is LUTO, an enlarged fetal bladder can also be present as corollary finding of miscellaneous genetic syndromes, developmental disturbances and chromosomal abnormalities. This study provides an overview of the structural anomalies and congenital disorders associated with megacystis and proposes a flowchart for the differential diagnosis of genetic syndromes, chromosomal and developmental abnormalities, focusing on the morphological examination of the fetus. This article is protected by copyright. All rights reserved.
Objective. Conjoined twin is a rarely seen congenital anomaly together with severe mortality and morbidity. The more common types of conjoined twins include the thoracopagus type, where the fusion is anterior, at the chest, and involves the heart. We are reporting one case of conjoined thoracopagus twins diagnosed by ultrasonography at 11 weeks. Case Report. In a multigravid pregnant woman who has been admitted to our clinic with a diagnosis of conjoined twins, thoracopagus, by ultrasonography at an 11-week gestation, termination of the pregnancy was performed. Conclusion. Making an early diagnosis with ultrasonographic examination gives the parents a chance to elect pregnancy termination.
Due to advancements in ultrasound techniques, the focus of antenatal ultrasound screening is moving towards the first trimester of pregnancy. The early first trimester however remains in part, a ‘black box’, due to the size of the developing embryo and the limitations of contemporary scanning techniques. Therefore there is a need for images of early anatomical developmental to improve our understanding of this area. By using new imaging techniques, we can not only obtain better images to further our knowledge of early embryonic development, but clear images of embryonic and fetal development can also be used in training for e.g. sonographers and fetal surgeons, or to educate parents expecting a child with a fetal anomaly.
The aim of this review is to provide an overview of the past, present and future techniques used to capture images of the developing human embryo and fetus and provide the reader newest insights in upcoming and promising imaging techniques. The reader is taken from the earliest drawings of da Vinci, along the advancements in the fields of in utero ultrasound and MR imaging techniques towards high-resolution ex utero imaging using Micro-CT and ultra-high field MRI. Finally, a future perspective is given about the use of artificial intelligence in ultrasound and new potential imaging techniques such as synchrotron radiation-based CT to increase our knowledge regarding human development.
Objectives
Antenatal detection of acrania-exencephaly-anencephaly (AEA) sequence beyond 10 completed weeks of gestation is usually straight-forward. An earlier detection and classification of the causative conditions prior to disaggregation of exposed dysplastic brain tissue remains challenging.
Case presentation
We present two- and three-dimensional ultrasound correlated with fetoscopic findings of an unusual type of neural tube defect at 11 gestational weeks caused by an amniotic constriction ring resulting in cystic degeneration of the developing skull.
Conclusions
By giving further illustrative insights into early defective brain development, this report confirms recent findings of an unusual subtype of acrania-exencephaly-anencephaly sequence suggesting early disruption of the developing brain, following an amniotic entrapment of the skull.
Objectives:
Rationale for prenatal therapy in lower urinary tract obstruction (LUTO) is debated. The aim of this study was to identify favorable renal histology in early severe LUTO and determine timing and selection criteria for prenatal surgery.
Methods:
This multicentric retrospective study included male fetuses with severe LUTO deceased before 24 weeks of gestation (January 2000-December 2018). Age-paired controls were used as standard for renal histology. Prenatal ultrasound features, fetal serum and/or urine β2microglobulin and kidney slides (Hematein-Eosin-Safran, α-smooth-muscle actin (αSMA) immunostaining) were reviewed. αSMA positive staining of the blastema relates to its aberrant differentiation into myofibroblastic cells. Cases were sorted into histopathologic groups (favorable or unfavorable) according to blastema's morphology and αSMA labelling.
Results:
Seventy-four fetuses were included at a median gestational age of 17.6 weeks' [13-23.5]. Parenchymal organization was preserved in 48% of the kidneys. Although blastema was present in 90% of them, it was morphologically normal in only 9% and αSMA negative in only 1% of them. Most fetuses had an unfavorable prognosis (82%), including early renal lesions (≤ 18 weeks') in 36% of them. Fetuses with an early gestational age were associated with a favorable renal prognosis (p=0.001). LUTO fetuses had a significant reduction in mature glomeruli (p<0.001) compared to controls. However, no significant reduction in glomeruli generations was found between the early unfavorable prognosis group (≤ 18 weeks') and the favorable one (p=0.19). Comparison of prenatal ultrasound features and biochemical markers between groups could not identify any prenatal selection criteria.
Conclusions:
Before 18 weeks', around 30% of fetuses with severe LUTO still have potential for kidney development. Prenatal therapeutic strategy could therefore have a better impact if they could identify these cases. This article is protected by copyright. All rights reserved.
Objectives:
The acrania-anencephaly sequence is a lethal condition with a high detection rate in experienced hands after 10 weeks' gestation. However, earlier in gestation, many cases remain undetected. Different phenotypic appearances have been described and might help increase the detection rate in less experienced hands and also earlier in gestation. The purpose of this study was to assess interobserver reliability in classifying cases of the acrania-anencephaly sequence during first trimester in 6 different subtypes according to their ultrasound appearances.
Methods:
This was a retrospective descriptive cohort study at 3 centers for fetal imaging. Each case was classified according to its phenotypic appearance by 2 independent operators as "bilobular," "cystic," "elongated," "irregular," "foreshortened," or "overhanging." Frequencies of each type are described, and interoperator agreement was assessed with the intraclass correlation coefficient.
Results:
From the 88 included cases, the frequencies of the different subtypes classified as overhanging, elongated, bilobular, cystic, foreshortened, and irregular were 31%, 25%, 19%, 11%, 8%, and 6%, respectively. The interoperator reliability was good, with an intraclass correlation coefficient of 0.903 (95% confidence interval, 0.853-0.937; P < .001).
Conclusions:
Using different subtypes may improve the detection of the acrania-anencephaly sequence. An accurate early diagnosis could lead to timely, less traumatic, and safer management of affected pregnancies.
A previously unrecognized first‐trimester presentation of the acrania‐anencephaly sequence is described. Ultrasound features included a constriction ring around the external base of the developing skull and an enlarged globular head, resembling a Turkish turban, with large cystic spaces replacing the brain. This constellation of findings was noted in 3 first‐trimester fetuses. In 2 of them, it was possible to identify the amniotic membrane attached to the constriction ring. One case presented with anencephaly and fetal demise at 16 weeks. The other 2 women terminated the pregnancies and aborted anencephalic fetuses. This subtype of the acrania‐anencephaly sequence could represent an earlier segmental rupture of the amnion, which subsequently entraps the developing fetal skull.
Omphalocele (exomphalos) is one of the most common abdominal wall defects. The size of the defect and the severity of the associated anomalies determine the overall morbidity and mortality. Routine prenatal screening and diagnosis of the abdominal wall defect and concurrent anomalies is important as it allows for effective prenatal counseling and optimal perinatal management. The purpose of this article is to discuss the approach to prenatal diagnosis and management of omphalocele.
Introduction:
Ablation of the acardiac twin umbilical cord in the TRAP protects the normal donor twin.
Materials and methods:
Two case descriptions, one of interstitial laser photocoagulation and one of laser umbilical cord occlusion (L-UCO) of the acardiac twin in monochorionic monoamniotic pregnancies are reported.
Results:
L-UCO in two pregnancies with TRAP syndrome in the second trimester resulted in intrauterine fetal death in both cases after 1 month. Case 1 had no detectable cause of fetal death. Case 2 had rupture of the amniotic sac causing anhydramnios and acute chorioamnionitis. A groove on the umbilical cord of the normal twin indicated a cord stricture due to cord entanglement.
Conclusion:
Our experience confirms that the best timing and optimal treatment of MC/MA twins complicated by TRAP sequence still remains a controversial clinical issue. Cord entanglement may continue be a potential clinical risk factor for adverse perinatal outcome even after ablation therapy.
Holoprosencephaly (HPE) is partial or complete failure of the forebrain to divide into hemispheres and can be an isolated finding or associated with a syndrome. Most cases of HPE are associated with a syndrome and roughly 40%–60% of fetuses with HPE have trisomy 13 which is the most common etiology of HPE. Other syndromes associated with HPE include additional aneuploidies like trisomy 18 and single gene disorders such as Smith–Lemli–Opitz syndrome. There are a number of syndromes such as pseudotrisomy 13 which do not have a known molecular etiology; therefore, this review has two parts: syndromes with a molecular diagnosis and syndromes where the etiology is yet to be found. As most HPE is syndromic, this review provides a comprehensive list and description of syndromes associated with HPE that may be used as a differential diagnosis and starting point for evaluating individuals with HPE.
Holoprosencephaly (HPE) is a structural brain anomaly characterized by failure of the forebrain to separate during early embryogenesis. Both genetic and environmental etiologies of HPE have been discovered over the last three decades. Traditionally, the genetic workup for HPE has been a karyotype, chromosomal microarray, and/or Sanger sequencing of select genes. The recent increased availability of next‐generation sequencing has changed the molecular diagnostic landscape for HPE, associating new genes with this disorder such as FGFR1. We conducted a systematic review of the medical literature for the molecular testing of HPE for studies published in the last 20 years. We also queried known commercial diagnostic laboratories and used information on their websites to construct a list of available commercial testing. Our group released its first recommendations in 2010 and this update incorporates the technology shifts and gene discoveries over the last decade. These recommendations provide a guide for genetic diagnosis of HPE, which is paramount for patients and their families for prognosis, treatment, and genetic counseling.
The objective of this paper was to determine if prenatal sonographic findings can accurately differentiate between the causes of bladder distention and pyelectasis in the male fetus. Twenty-one cases were evaluated for the presence of oligohydramnios, posterior urethral dilation, bladder wall thickening, urachal patency, cortical thinning, cortical cysts, and increased renal echogenicity. Postnatal diagnosis included posterior urethral valves (10 cases), prune belly syndrome (four cases), vesicoureteral reflux (four cases), left ureterovesical junction obstruction (one case), and nonrefluxing, nonobstructive megacystis-megaureter (two cases). Oligohydramnios was present in eight of 10 cases of posterior urethral valves and in one of four cases of prune belly syndrome. A dilated posterior urethra was noted in seven of 10 cases of posterior urethral valves and transiently in two of four cases of prune belly syndrome. Bladder wall thickening developed in all cases of posterior urethral valves and was noted in two of four patients with prune belly syndrome. A patent urachus likewise was identified in two of four cases of prune belly syndrome. The presence of oligohydramnios, progressive bladder wall thickening, and dilated posterior urethra was most suggestive of posterior urethral valves, whereas the presence of a patent urachus was most suggestive of prune belly syndrome. The presence of pyelectasis and megacystis without additional amniotic fluid, bladder, urethral, or renal abnormalities was most suggestive of vesicoureteral reflux, ureterovesical junction obstruction, or nonrefluxing, nonobstructive megacystis-megaureter. Owing to the overlap and evolution of these findings, close follow-up evaluation is recommended.
Digital reconstruction of human development
The detailed morphology of human development has intrigued scientists and the medical field alike. However, the scarcity of specimens hampers detailed mapping of tissue architecture. Furthermore, inaccuracies in the description of human development have crept into textbooks from observations of animal models that are extrapolated to humans. By mapping normal developmental processes and patterns, such as the growth and relative placement of organs, congenital anomalies can be better understood. de Bakker et al. generated interactive three-dimensional digital reconstructions based on the Carnegie collection of histologically sectioned human embryos spanning the first 2 months of gestation. These interactive models will serve as educational and scientific resources for normal and abnormal human development.
Science , this issue p. 10.1126/science.aag0053
Monochorionic diamniotic quadruplet pregnancy; Three-dimensional ultrasound; Magnetic resonance imaging; 3D physical models
The new edition of The Embryonic Human Brain: An Atlas of Developmental Stages represents the integration of analysis of the serial sections of human embryos in the Carnegie collection with results of the latest ultrasound studies. It provides summaries of the morphological status of the brain at each stage of development, covering both normal and anomalous conditions. Preceding the atlas are several chapters that present historical aspects, techniques, and prenatal measurements, as well as an introduction to embryonic staging, and terminology accompanied by over definitions of key terms. Now illustrated in full colour throughout Includes high quality photographs, photomicrographs, and diagrams Expands coverage of magnetic resonance imaging of the fetal and perinatal periods Highlights molecular and genetic aspects of normal and abnormal development of the brain Utilizes a set of standardized abbreviations Provides selected references to seminal studies Review for the Second Edition: "[A] really beautiful and wonderfully informative book that no embryologist, comparative anatomist, pediatric neurologist or neurosurgeon should be without. Putting aside the medical relevance of this atlas, it also provides the most captivating version of one of the most complex and fascinating embryological stories of all." BRAIN This atlas is an invaluable resource for neuroscientists, developmental biologists, comparative anatomists, neurologists, pathologists, radiologists, and neurosurgeons.
To review prognostic parameters reported recently in the evaluation of abdominal wall defects in the first trimester.
Evaluation of abdominal wall defects in the first trimester is based principally on associated structural or chromosomal anomalies. In the case of gastroschisis, which is rarely associated with other anomalies, evaluation of prenatal or postnatal outcome is based mainly on the course of pregnancy. In the case of isolated omphalocele in the first trimester, recent studies have evaluated parameters that could help predict prenatal or postnatal outcome.
We review recent studies using new parameters to diagnose abdominal wall defects in the first trimester and to provide early prenatal counselling to parents regarding prenatal and postnatal prognosis.
Objective:
To evaluate the initial experience at our centre in the treatment of monochorionic twin pregnancies complicated by twin reversed arterial perfusion sequence (TRAP), using radiofrequency ablation (RFA) with expandable needles, and to review the existing literature on the subject.
Study design:
Between July 2007 and October 2010, 11 monochorionic twin pregnancies complicated by TRAP were referred to our centre. Seven patients underwent intrafetal ablation of the acardiac twin with RFA using LeVeen™ expandable needle electrodes. Data on the procedures and the obstetric outcome were reviewed, and subsequently we performed a review of the literature on the use of RFA in TRAP.
Results:
Median gestational age at the intervention was 17(+3) weeks (range 14(+1)-23(+1) weeks). Technical success was obtained in all cases. Preterm premature rupture of membranes (PPROMs) occurred in 4/7 (57%) patients. Intrauterine death of the pump twin occurred in one patient at 21(+5) weeks, and one patient opted for termination of pregnancy because of PPROM at 21(+4) weeks. Five fetuses were delivered alive at a median gestational age of 33(+0) weeks (range 31(+0)-39(+5) weeks). All five infants (71%) were alive and had a normal examination at 6 months of age. The review identified 6 studies, for a total of 78 pregnancies (either monochorionc twins or triplets with a monochorionic component). Including our data, overall neonatal survival was 75/88 (85%).
Conclusion:
RFA appears to be a relatively safe and reliable technique in the treatment of TRAP sequence pregnancies. Further research is needed to define the best timing of the procedure.
Objective:
To determine the prevalence and outcome of lower urinary tract obstruction (LUTO), including the sensitivity of antenatal diagnosis.
Design:
A retrospective population-based study.
Setting:
Regional population-based congenital anomalies register (WMCAR).
Population:
Fetuses affected by LUTO delivered between 1995 and 2007 to women resident in the West Midlands.
Methods:
Cases were selected from the WMCAR using codes and keyword terms from the International Classification of Diseases, tenth revision (ICD10). Diagnoses were validated using additional data sets from Regional Fetal Medicine, Perinatal Pathology and Paediatric services.
Main outcome measures:
Rates of prevalence, prenatal diagnosis and mortality, with trends.
Results:
There were 284 LUTO cases in 851 419 births during the study period, representing a total prevalence of 3.34 (2.95-3.72) per 10 000 births, and this prevalence did not change significantly over time. The prevalence of LUTO was significantly higher in Black and minority ethnic groups when compared with white Europeans (OR 2.38; 95% CI 1.87-3.03), and are associated with area-based deprivation measures (P < 0.01). Of all LUTO cases, 221 (77.8%) were isolated, and the remainder were associated with other structural or chromosomal anomalies. The most common subtype was posterior urethral valves (PUVs; n = 179, 63%). In total there were 211 (74.3%) cases of isolated, non-female, singleton fetuses that fitted the referral criteria for in utero vesico-amniotic shunting, giving a prevalence of 2.48 (2.14-2.81) per 10 000 live births. Within this group, the prenatal diagnosis rate was 46.9% (99/211).
Conclusion:
This is the largest population-based study of LUTO that has been performed to date, and provides accurate estimates for prevalence. The low prevalence and relatively low rate of antenatal detection limit the number of cases amenable to prenatal surgical intervention.
Twenty‐five fetuses with limb body wall complex (LBW complex) were evaluated. The diagnosis was based on two out of three of the following: exencephaly/ encephalocele with facial clefts; thoraco‐ and/or abdominoschisis; and limb defect. Ninety‐five percent (24/25) of the fetuses had associated internal structural de‐fects. In 72% (18/25) the internal defects have been recognized as being secondary to vascular disruption. Concordance was not found between the side and location of the body wall defect versus the limb, internal, and cranial defects. In 85% there was evidence for persistence of the extraembryonic coelom by examination of the placenta. In this same group (85%) there was persistence of the ectodermal‐amnion margin, with the amnion being continuous with the skin of the body wall defect. In 40% (10/25) there were tags and amniotic adhesions at other sites. There was no difference in the types or incidence of internal defects between those with and those without amniotic bands.
The abnormalities in this collection and experimental animal models support vascular disruption during 4‐6 weeks' gestation as an etiology for LBW complex. There is disruption and loss of existing tissues, persistence of embryonic structures, and secondary malformations. Persistence of the extraembryonic coelom may lead to the typical amniotic tags, ring constrictions, and adhesions seen in some specimens.
A review of over 1,800 publications concerning the embryology and pathologic anatomy of conjoined twins provides convincing evidence that they all result from the secondary union of two originally separate monovular embryonic discs. This “fusion” theory seems to be confirmed by the adjustments to union and the pattern and incidence of specific anomalies at the proposed sites of conjunction in more than 1,200 cases, all of which can be arranged in two uninterrupted series of cases, the one united dorsally (in the neural tube) and the other, ventrally (over a shared a yolk sac). No theoretical “fission” of the vertebrate embryo at any stage of development, in any plane, in any direction can explain (1) the selection of the observed sites of fusion, (2) the details of the union, or (3) the limitation to the specific areas in which the twins are found to be joined. Part I of this disquisition deals with the pertinent normal and theoretical embryology, the adjustments to union, and the parasitic cases, as well as conjoined triplets and quadruplets, and a comparison of oviparous and viviparous embryos. Part II (in a subsequent issue of this journal) will compare and correlate the abnormalities of the various organ systems involved in 1,200 cases. Clin. Anat. 13:36–53, 2000. © 2000 Wiley-Liss, Inc.
A previous report in this journal (Spencer, 2000) discussed the probable embryologic etiology of conjoined twins, along with a system of classification based on the embryological structures postulated to be involved in the union. Part II correlates and compares the variations in the abnormal development of the individual organ systems in more than 1,200 actual cases, revealing details of embryogenesis not considered in previous publications. The site, incidence, and range of anomalies in the conjoined structures, as well as the associated malformations, follow a definite pattern as the union proceeds from one area to another; many can be explained in relation to the proposed embryologic adjustments to union, including both temporal and spatial influences. In addition, six currently inexplicable or unclassifiable cases are briefly described (including one with 12 feet), as well as two examples of early abnormal conjoined twins. Clin. Anat. 13:97–120, 2000. © 2000 Wiley-Liss, Inc.
The spread of chemicals, including insecticides, into the environment often raises public health concerns, as exemplified by a recent epidemiologic study associating in utero piperonyl butoxide (PBO) exposure with delayed mental development. The insecticide synergist PBO is listed among the top 10 chemicals detected in indoor dust; a systematic assessment of risks from PBO exposure, as for many toxicants unfortunately, may be underdeveloped when important biological targets that can cause toxicity are unknown. Hedgehog/Smoothened signaling is critical in neurological development. This study was designed to use novel high-throughput in vitro drug screening technology to identify modulators of Hedgehog signaling in environmental chemicals to assist the assessment of their potential risks. A directed library of 1408 environmental toxicants was screened for Hedgehog/Smoothened antagonist activity using a high-content assay that evaluated the interaction between Smoothened and βarrestin2 green fluorescent protein. PBO was identified as a Hedgehog/Smoothened antagonist capable of inhibiting Hedgehog signaling. We found that PBO bound Smoothened and blocked Smoothened overexpression-induced Gli-luciferase reporter activity but had no effect on Gli-1 downstream transcriptional factor-induced Gli activity. PBO inhibited Sonic Hedgehog ligand-induced Gli signaling and mouse cerebellar granular precursor cell proliferation. Moreover, PBO disrupted zebrafish development. Our findings demonstrate the value of high-throughput target-based screening strategies that can successfully evaluate large numbers of environmental toxicants and identify key targets and unknown biological activity that is helpful in properly assessing potential risks.
To compare the sex specific outcome of fetuses with prenatally detected urinary tract dilatation, with the exclusion of pyelectasia.
Included in the study were 709 cases of major dilatation of the fetal urinary tract, diagnosed at routine ultrasound scan. For each sex group, cases were divided into two subgroups depending on the level of dilatation. Final diagnosis was based on postnatal evaluation or on fetal autopsy. Postnatal renal function was evaluated using serum creatinine at two years of age.
Bilateral higher urinary tract dilatation was prenatally observed in 148 (20.8%) and lower urinary tract obstruction or bladder dilatation in 561 (79.1%) of the 709 cases (121 female and 588 male fetuses) (P <0.001). Bladder dilatation was less frequent in female fetuses (62%) than in males (82.6%) (P <0.001). At final diagnosis, associated malformations were observed in 53.7% of female fetuses versus 11% in males (P <0.001). The survival rate was 42.7%. Postnatal renal function, evaluated in 289/303 live infants, was impaired in 29.7% of cases and depended on the level of obstruction, but not on the sex.
Prenatally detected urinary tract dilatation has a poor prognosis both in male and female fetuses. Associated malformations are observed more frequently in female than in male fetuses.
Neural tube defects (NTDs), most commonly spina bifida and anencephaly, can be prevented with periconceptional intake of folic acid in about 70% of cases. Recurrence of NTDs despite supplementation of high dose of folic acid further suggests that a proportion of NTD cases might be resistant to folic acid. Moreover, heterogeneity of NTDs has been suggested in animal studies, indicating that only some sub-type of NTDs should be considered sensitive to folate intake. Inositol isomers (particularly myo- and chiro-inositol) can prevent folate-resistant NTDs in the curly-tail mutant mouse, suggesting that some cases of human NTDs might benefit from inositol supplementation. In humans, lower inositol blood concentration was found in pregnant women carrying NTD fetuses, whereas a periconceptional combination therapy with folic acid associated with inositol has been linked to normal live births, despite high NTD recurrence risk. Fifteen pregnancies from 12 Caucasian women from different parts of Italy with at least one previous NTD-affected pregnancy underwent periconceptional combined myo-inositol and folic acid supplementation. Maternal serum α-feto-protein levels were found in the normal range, and normal results on ultrasound examination were found in all the pregnancies that followed. No collateral effects or intense uterine contractions were demonstrated in this pilot study in any of the pregnancies after inositol supplementation, and seventeen babies were born without any type of NTD.
To report on a clinical antenatal management strategy based on integrating ultrasound (US) and magnetic resonance imaging (MRI) in the evaluation of herniated bowel following early prenatal diagnosis of gastroschisis.
Antenatal US and ultrafast single-shot spin-echo (SSSE) MRI.
Fetal gastroschisis was documented at 12 weeks at the time of first trimester screening for Down syndrome. Fetal karyotype was performed at 16 weeks and showed a 46,XY karyotype. Ultrasound scan at 20 weeks diagnosed gastroschisis as isolated finding. Follow-up scans were planned monthly, and antenatal ultrafast SSSE MRI was arranged at 35 weeks and demonstrated a right fetal abdominal wall defect measuring 2.4 mm on transverse diameter with an integrity of the intra-abdominal and extra-abdominal loops of small bowel. The colon was in situ as were the stomach, the liver, and the spleen.
The choice of integrating both the diagnostic procedures has shown to be clinically useful in planning the timing of delivery (Cesarean section) and in turn has been associated with an easy surgical repair and to a favorable postnatal outcome. The result of amniocentesis was crucial for the parent's decision-making process whether to continuing with the pregnancy. Moreover, amniotic fluid α-fetoprotein levels may be used as an index of small bowel damage when loops of small bowel lied uncovered within the amniotic cavity.
Cephalothoracopagus is the less common type of conjoined twins (CTs) with an incidence estimated at one in three million births or one in 58 conjoined twins. Maternal gene Vg1, a member of the TGF-beta family of cell-signalling molecules which are implicated in dorsoanterior development, and specific actions of Hox and Pax genes that are implicated in very early embryogenesis may be identified as aetiologic factors.
A prenatal diagnosis of cephalothoracopagus CTs diagnosed at 17 weeks in a woman undergoing amniocentesis for advanced maternal age is reported.
Although first-trimester diagnosis of CTs is feasible and has been reported as early as 8 weeks's gestation, CTs may be misdiagnosed with monoamniotic twins, lymphangioma, teratoma, and/or neoplasm and may be undiagnosed until early second trimester. Three-dimensional and color Doppler ultrasound enabled precise prenatal visualization of the fusion site. Ultrafast MR imaging should be considered an adjunct to ultrasound for antenatal characterization of structural anomalies and for planning surgical separation in selected cases. Echocardiography is mandatory in all cases of CTs as congenital heart defects are seen in 20-30% and polyhydramnios in 50-75%. Neural tube and midline fusion defects, diaphragmatic hernia, and imperforate anus are the frequently associated abnormalities. Prognosis among survivors is usually poor (44% die in the neonatal period) and is dependent upon the type of conjunction, degree of involvement of the shared organs, and presence or absence of associated anomalies, with the worst prognosis in case of twins sharing liver and heart.
This study was carried out to determine the prognosis, and the clinical approach, in fetuses with umbilical cord cysts, during the second and third trimesters of gestation, according to our experience and data in the current literature.
We identified 10 fetuses with umbilical cord cysts that were diagnosed during the second and third trimesters of pregnancy at three referral centers. All underwent detailed ultrasound evaluation at the time of diagnosis and during follow-up. Prenatal karyotype testing was offered to all women. A MEDLINE review of the literature published from 1980 to 2009 was carried out to identify previous studies and case reports of fetuses with umbilical cord cysts.
In our series of 10 cases, significant additional abnormalities were observed in two during a detailed sonogram. In one case, trisomy 18 was diagnosed, leading to pregnancy termination, and in the other case a neonate with heart defects and a normal karyotype was born. These results differ from those reported in the literature, in which the association between second- and third-trimester umbilical cord cysts and fetal anomalies ranged from 38 to 100%.
In our study, as in other publications, an association was found between the presence of second- and third-trimester umbilical cord cysts and fetal anomalies. The strong association between second- and third-trimester umbilical cord cysts and aneuploidy in the literature seems to be biased, mainly because of the tendency to report abnormal cases. When these findings are accompanied by additional sonographic abnormalities, the association with aneuploidy is clear and should be an indication for fetal karyotype testing.
Conjoined twins are uncommon and refer to monozygotic, monoamniotic and monochorionic twins with varying degree and sites of fusion between the twins. In this report, we illustrate a case of thoracopagus twins highlighting the prenatal sonographic and magnetic resonance imaging appearance. Emphasis is laid on the role of appropriate imaging strategy in prognostic assessment and postnatal surgical treatment planning of these cases.
In the following review, the early development of the central nervous system (CNS), as described by embryologists and anatomists in modern embryological textbooks, is compared with sonoanatomic descriptions from two-dimensional (2D) and three-dimensional (3D) ultrasound studies, week by week in the first trimester. The anatomic descriptions are limited to details that are of interest for the understanding of ultrasound examinations. Further, the detection of main CNS anomalies including spina bifida during the first trimester are presented and discussed. Empty or enlarged brain cavities, or abnormal contours of the head and spine are important diagnostic markers for the detection of CNS anomalies in the very early pregnancy.
One hundred fifty embryos with holoprosencephaly were found among the total of 36,380 conceptuses obtained through induced abortion in the period from 1962 to 1974, giving an overall incidence of 0.4 percent. The occurrence was period from 1962 to 1974, giving an overall incidence of 0.4 percent. The occurrence was largely at random through time, and no "epidemic" was noted in particular years or months, but there appeared more cases derived from conceptions in winter than in summer months. The mean maternal age did not differ significantly from that of the general embryonic population, indicating that, although none of our cases were karyotyped, chromosome aberrations such as trisomies 13 and 18 that are closely associated with maternal age may not constitute a major part as causes of holoprosencephaly in human embryos. Materal age did not differ by the presence or absence of associated external anomalies. No association was found with paternal age, parental consanguinity nor with maternal medical history, including irregularity of menstrual cycles, and smoking and drinking habits. There was an indication that the mothers were prone to have repeated miscarriages, supporting the view that some kind of maternal predisposition is responsible for the causation of holoprosencephaly. Argument was made that, apart from various chromosome aberrations well documented as causes of this malformation, polygenic mechanism probably accounts for the majority of the cases with normal karyotype.
Extreme variants of anencephaly in two human embryos of the same stage, namely 22 (54 days), shed new light on problems such as craniocerebral interrelationships and the timing of developmental events. Embryo X had a chondrocranium that possessed features typical of a holoacranial anencephalic skull and an extremely well-preserved brain, in which some of the neural tracts were comparable to those in a normal control. On the other hand, embryo Y of the same stage had a completely degenerated brain, although the chondrocranium was more nearly normal and represented the precursor of a meroacranial skull. A comparison of the two cases seems to indicate a certain independence between skull and brain. Moreover, it appears possible that the disturbances are related primarily to the skeletal, and only secondarily to the nervous, component. Comparisons with experimental data allow the conclusion that the maldevelopment involves mostly paraxial mesenchyme and little or no disturbance of neural crest. The timing of the mesenchymal defect is probably as early as stages 8 and 9 (18-20 days). This is also the time at which mesenchymal defects can result in failure of the neural tube to close.
First trimester gestations of 95 patients were studied by high-frequency transvaginal sonography, which permits the imaging of organs shortly after their development. This new technique has great potential for clinical implementation in such cases as accurate gestational dating and malformation workup.
The development of the human brain during the eighth embryonic week was studied in serial sections of 22 embryos, and graphic reconstructions were prepared. The cortical plate appears in stage 21 in the area of the future insula and is an excellent feature for staging. The internal capsule contains neocortical fibres. Its three main outlets begin to be present in stage 22 and lead to epithalamus, to dorsal thalamus, and to mesencephalon. At this time a well developed lateral olfactory tract can be seen. The anterior commissure appears in stage 23. A clear developmental relationship between claustrum and olfactory area is described for the first time in human embryos. The optic tract reaches the ventral area of the lateral geniculate body. Scattered fibres of the lateral lemniscus reach at least as far as the caudal mesencephalon, in which superior and inferior colliculi can be distinguished at stage 23; two caudalBlindsäcke containing ventricular recesses form in stage 23. The cerebellum is still present as a plate, but its internal bulge is considerably enlarged. It possesses radially- and tangentially-arranged cells; the latter form the external germinal layer. The dentate nucleus, as well as the inferior and superior cerebellar peduncles and some of the cerebellar commissures, are present. Compared with the highly developed and probably already functional remainder of the hindbrain, the cerebellar plate shows far less differentiation. Two caudal migratory streams (marginal and submarginal) are present and represent the corpus pontobulbare. The decussation of the pyramids appears in stage 23.
This article concludes the study of the developing human brain during the embryonic period, from stage 8 to stage 23. The series was based on 340 serially-sectioned embryos and graphic reconstructions from 89 brains. No comparable investigation of the fetal brain is available.
This morphological study, based on serial sections and graphic reconstructions at 4-8 postovulatory weeks (stages 11-23), is believed to be the first account of the ventricular system in staged human embryos. Closure of the caudal neuropore at stage 12 heralds the onset of the ventricular system and separates the ependymal from the amniotic fluid. After the appearance of the optic ventricle at stage 11, the cavity of the telencephalon medium is discernible at stage 13. At stage 14 the future cerebral hemispheres and lateral ventricles begin, and the rhomboid fossa becomes apparent. The medial and lateral ventricular eminences cause indentations in the lateral ventricle by stage 15. The hypothalamic sulcus is evident at stage 16. At stages 17-18 the interventricular foramina are becoming relatively smaller, and cellular accumulations indicate the future choroid villi of the fourth and lateral ventricles. The areae membranaceae rostralis and caudalis are visible in the roof of the fourth ventricle at stage 18, and the paraphysis is appearing. At stage 19 choroid villi are seen in the fourth ventricle, and a mesencephalic evagination (Blindsack) is detectable. Choroid villi are noticeable in the lateral ventricle at stage 20. An olfactory ventricle is present by stage 21. At about stages 21-23 the lateral ventricle has become C-shaped, so that anterior and inferior horns are visible. Several recesses, e.g., the optic, infundibular, and pineal, develop in the third ventricle during the embryonic period. Features of the ventricular system that do not become apparent until the fetal period include the posterior horn of the lateral ventricle, choroid plexus of the third ventricle, suprapineal recess, interthalamic adhesion, aqueduct, and apertures in the roof of the fourth ventricle.
This paper reports the ultrasound diagnosis at 16 weeks' gestation of thoracopagus conjoined twins. Ultrasound examination showed the two fetuses conjoined at the sternum, with a single heart and a single liver. After informing the couple of the extremely poor prognosis, medical termination of pregnancy was requested. Pathologic examination of the conjoined female fetuses revealed a single, non-duplicated heart, two livers connected at the right lobe, completely separate bile ducts and digestive tract, and a single placenta and umbilical cord containing two arteries and six veins. The karyotype was normal. Diagnostic ultrasound criteria for thoracopagus conjoined twins include: the relative position of the two fetuses facing each other, hyperextension of the cervical spine, continuity of the skin and mirror image body parts with limbs close together. The presence of a single heart, liver and umbilical cord, all of increased size, confirms the diagnosis. Various degrees of fetal fusion result from incomplete division of the inner cell mass 13 to 15 days after fertilization. Although the precise causes are unknown, many workers believe that the factors responsible for monozygosity may also play a role in conjoined twins. In Switzerland, 1% of all live births are twins with approximately 1/4 of these monozygotic. If incomplete division of the inner cell mass occurs in 1% of these cases, the estimated incidence of conjoined twins is 1/40000 births. Although thoracopagus twins are more frequent, omphalopagus twins are more commonly encountered at birth, due to lower fetal mortality. The overall prognosis depends on the degree of organ sharing between fetuses. Very few surgically separated thoracopagus conjoined twins have lived and those who did survive had separate hearts. Also, conjoined twins can cause dystocia with the risk of rupture of the uterus, and often require cesarean section which may have negative consequences for the obstetrical future of the mother. However, an early ultrasound diagnostic can modify prognosis and allow medical termination of pregnancy in the case of seriously malformed thoracopagus conjoined twins. The risk that the condition recurs in a subsequent pregnancy may be considered negligible.
Fetal omphalocele and gastroschisis are congenital defects of the abdominal wall that require prompt surgical management at the time of delivery. To evaluate the role of prenatal sonography in identifying factors that influence prognosis, 24 cases of abdominal-wall defect (16 omphalocele, eight gastroschisis) were reviewed. Sonograms were evaluated for location of umbilical cord insertion, contents of the ventral defect, presence or absence of a covering membrane, fetal ascites, bowel-wall thickening, and coexisting anomalies. Sonographic differentiation between omphalocele and gastroschisis was possible in 18 (75%) of 24 cases. Eighteen patients had congenital defects in addition to the abdominal-wall defect. Associated abnormalities were present in 14 (88%) of 16 fetuses with omphalocele and four (50%) of eight with gastroschisis. Overall survival rate was 50%, excluding six terminated pregnancies. Survival rate was 33% for neonates with omphalocele and 83% for those with gastroschisis. The better prognosis for neonates with gastroschisis appears to reflect the lower frequency of associated congenital anomalies.