Fetal Structural Abnormalities Research Articles

A de novo duplication of chromosome 21q22.11 → qter associated with Down syndrome: Prenatal diagnosis, molecular cytogenetic characterization and fetal ultrasound findings

Objectives To present prenatal diagnosis and molecular cytogenetic characterization of de novo partial partial trisomy 21q (21q22.11 → qter) associated with clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus on prenatal ultrasound. Materials, Methods, and Results A 34-year-old gravida 2, para 1 woman underwent amniocentesis at 20 weeks of gestation because of fetal structural abnormalities on prenatal ultrasound. A level II ultrasound at 20 weeks of gestation showed polyhydramnios, clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus. Amniocentesis revealed an aberrant derivative chromosome 9, or der(9). Parental karyotypes were normal. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that the der(9) contained a segment of chromosome 21 distal to chromosome 9q, and FISH analysis additionally showed that the distal subtelomeric region of 9q was not deleted. Array comparative genomic hybridization (aCGH) demonstrated a 14.8-Mb duplication of distal 21q encompassing the Down syndrome critical region (DSCR) but no genomic imbalance in the distal euchromatic region of chromosome 9. The karyotype was 46,XX,der(9)t(9;21) (q34.3;q22.11)dn. Polymorphic DNA marker analysis revealed the maternal origin of the aberrant chromosome. The pregnancy was subsequently terminated. A malformed female fetus was delivered with a characteristic phenotype of Down syndrome. Conclusion SKY, FISH and aCGH are useful in prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 21q encompassing the DSCR may present characteristic Down syndrome features on prenatal ultrasound.

Diagnosis, etiology, and outcome of fetal ascites in a South African hospital

Objective To analyze the etiology and outcome of fetal ascites in a hospital in a low-resource country. Method Data were reviewed for patients with fetal ascites who attended Groote Schuur Hospital, Cape Town, South Africa, from 1 January, 2006, to 31 December, 2009. Results There were 50 cases of fetal ascites. Prenatal investigations included detailed ultrasonography, Doppler studies, TORCH screening and chromosome analysis if amniocentesis was accepted by the patient. The underlying cause was diagnosed prenatally for 41 (82%) cases. The following etiologies were documented: secondary to a genetic cause (n = 10); structural fetal abnormality (n = 20); congenital syphilis (n = 4) or other infection (n = 3); fetal environment (n = 3); placenta (n = 3); and unknown origin (n = 7). The perinatal mortality was 72%. Factors predicting a poor prognosis included multiple abnormalities (100% fetal loss), cardiac anomalies (91% loss), hydrops fetalis (80% loss), and infection (71% loss). Ascites of unknown origin and ascites secondary to renal causes had the best prognosis (perinatal loss of 17% and 25%, respectively). Conclusion The cause, and therefore the prognosis, was identified in 82% of cases of fetal ascites. The prognosis for prenatally diagnosed ascites was poor; however, a few patients did well, which has important implications for genetic counseling.

BOOK REVIEW

Alan Cameron, Janet Brennand, Lena Crichton . Fetal Medicine for the MRCOG and Beyond, 2nd edn. 214 pages . RCOG press, London, UK, 2011. ISBN 978-1-906985-36-3. Price ∼60 €. The MRCOG and Beyond series is a collection of comprehensive guides on a range of the subspecialties in obstetrics and gynecology. Each guide gives a clear explanation of the foundations of the subject. The books are essential reading for all MRCOG trainees, but can be relevant for trainees and others elsewhere in the world. The second edition of Fetal Medicine for the MRCOG and Beyond has been updated to reflect the current clinical practice in an expanding and developing field of medicine. This updated edition provides a well-structured and easy-to-read 10 chapter overview written to assist not only MRCOG candidates for the Part Two examination, but also anyone working in fetal medicine who wants to update their knowledge at any stage in their career, including consultants, trainees and midwives. The first chapter gives a fairly comprehensive overview of the principal methods and programmes of chromosomal abnormality screening. In the second chapter, the invasive prenatal diagnostic techniques are well described, including a look into the future with the promising developments of non-invasive prenatal testing by the use of fetal cells isolated from the maternal circulation. Chapters 3 and 4 are devoted to the ultrasound examinations; the routine anomaly scan and a more detailed description of the scanning procedures for fetal structural abnormalities, including tables of risk factors and so on. The ultrasound images and photographs are generally of high quality, including the text and labelling. Chapter 5 is a well-updated chapter describing the current standards and future possibilities of invasive fetal therapy. This chapter briefly deals with complexity of decision making and ethical considerations. The later chapters of the book describe principles of fetal surveillance in intrauterine growth restriction and twin pregnancy, including Doppler evaluation of fetal blood flow patterns and laser therapy of twin–twin transfusion syndrome. I enjoyed the last part of the book, a comprehensive overview of intrauterine fetal infections, including the pitfalls of serology testing and the updated recommendations for treatment and mode of delivery of women with HIV. This book gives the reader a brief, up-to-date overview of the most fundamental areas of fetal medicine and is in no way to be regarded as an in-depth textbook covering all areas of the field. For the trainee, the book would be useful not only for the theoretical content, but also for the practical. For the specialist, the book gives an up-to-date review in the field of fetal medicine and the opportunity to discover how much he or she did not know.

Molecular karyotyping using massively parallel sequencing – a next generation approach to prenatal diagnosis?

Underlying chromosomal copy number variation is responsible for 10–15% of fetal structural abnormalities, but even in the presence of a normal karyotype neonatal outcome can be poor. Current whole genome...

Fetal oromandibular limb hypogenesis syndrome following uterine curettage in early pregnancy

Fetal structural abnormalities, particularly limb reduction defects, have been reported after early hypoxic injury, such as chorionic villus sampling (CVS) before 66 day's gestation. We present a case of uterine curettage in early pregnancy associated with the subsequent prenatal diagnosis of fetal oromandibular limb hypogenesis syndrome. This case is consistent with previous hypotheses concerning the role of hypoxic trauma in inducing fetal structural defects in early pregnancy.

Unbalanced reciprocal translocations at amniocentesis

Objective To present perinatal findings, modes of ascertainments, and modes of segregation in unbalanced reciprocal translocations detected at amniocentesis. Materials and Methods Between January 1987 and July 2010, 40 cases with unbalanced reciprocal translocations were diagnosed by amniocentesis at Mackay Memorial Hospital, Taipei, Taiwan. The 40 cases originated from 29 families; 21 families with one case, 7 families with two cases, and 1 family with five cases. Results Of 40 cases, 33 (82.5%) presented fetal ultrasound abnormalities and 7 (17.5%) presented no ultrasound abnormalities. Of 40 cases, 36 (90%) had a segregation mode of adjacent-1 2:2 segregation, 3 (7.5%) had a segregation mode of 3:1 segregation with tertiary trisomy, and 1 (2.5%) had a segregation mode of 3:1 segregation with tertiary monosomy. Of 29 families, 7 (24.1%) had de novo translocations and 22 (75.9%) had inherited translocations. In seven de novo cases, the main modes of ascertainments included abnormal ultrasound findings ( n = 5) and advanced maternal age ( n = 2). In 22 inherited families, the main modes of first ascertainment included abnormal ultrasound findings ( n = 8), a previous aneuploid child ( n = 8), advanced maternal age ( n = 4), parental carrier status ( n = 1), and abnormal maternal serum screening results ( n = 1). Among 22 inherited families, 9 (40.9%) had a known parental carrier status, but 13 (59.1%) were unaware of parental carrier status at amniocentesis. Conclusion Unbalanced reciprocal translocations detected at amniocentesis are frequently associated with abnormal ultrasound findings. Prenatal diagnosis of an unbalanced translocation may incidentally detect a balanced translocation in the family. Prenatal diagnosis of fetal structural abnormalities should alert structural chromosome rearrangements and prompt cytogenetic analysis of the fetus and parents if necessary.

Is a Routine Ultrasound in the Third Trimester Justified? – Additional Fetal Anomalies Diagnosed After Two Previous Unremarkable Ultrasound Examinations

The detection of fetal structural abnormalities is a routine part of antenatal care. Ultrasound examination policies vary among European countries. An additional ultrasound for fetal structural anomalies in the 3 rd trimester seems important for many reasons. Some abnormalities develop or first become apparent later in pregnancy. The aim of the study was to analyze the rate of previously undetected structural abnormalities in the 3 rd trimester. 8074 fetuses were examined in this prospective study between 1998 and 2008. All received an examination at 11 - 14 weeks and 79 % (6378 / 8074) of these fetuses also received an ultrasound at 20 - 24 weeks. If both of the examinations did not detect structural abnormalities, the fetuses were included in the study group and received an ultrasound at 28 - 32 weeks (n = 5044). New structural abnormalities in the 3 rd trimester were analyzed. The outcome was available in 96 % of the cases. The overall incidence of fetal malformations was 3.6 % (n = 289), of which 40 % (116 / 289) were diagnosed at 11 - 14 weeks. The following 2nd trimester scan revealed 102 (35 %) new fetal malformations. An additional 44 (15 %) structural abnormalities were found in the 3 rd trimester. These were mainly abnormalities of the urogenital system (n = 18). There were also anomalies of the cardiovascular system (n = 9), the gastrointestinal system (n = 6) and the central nervous system (n = 4). One of the cases had a previously undiagnosed abnormal karyotype. The ultrasound examination in the 3 rd trimester is of additional benefit and can detect previously unknown structural abnormalities. These findings are relevant for perinatal management and postnatal follow-up.

Ancillary benefits of prenatal maternal serum screening achieved in the California program

To evaluate the extent of fetal structural abnormalities, other than neural tube and abdominal wall defects (AWDs), identified by California's Prenatal Screening Program. The Quad Marker Prenatal Screening records of 516,172 women were examined for screening interpretation and the diagnosis of structural abnormalities detected via follow-up. Women who were screen-positive for trisomy 21, trisomy 18, neural tube defects (NTDs) or Smith-Lemli-Opitz syndrome (SLOS) received follow-up services at state-approved Prenatal Diagnosis Centers (PDCs). Detailed reports of services and diagnostic information were linked in a database to the original screening results. A total of 26 323 women received follow-up ultrasound services at the PDCs in the study time period. Of these women, 1085 (4.1%) were identified as having fetuses with significant structural abnormalities, other than NTDs (n = 207) or AWDs (n = 254). In addition to the structural abnormalities, 225 cases of fetal demise, 4 molar pregnancies, 15 cases of twin-to-twin transfusion, and 92 cases with placental abnormalities were identified. While Prenatal Screening Programs do not explicitly screen for structural abnormalities other than NTDs and AWDs, clearly many other structural abnormalities may be associated with a screen-positive status. Thus, the detection of these additional structural defects can be considered an ancillary program benefit.

A New System for Determining the Causes of Stillbirth

To describe the methods for assigning the cause of death for stillbirths enrolled in the Stillbirth Collaborative Research Network (SCRN). A complete evaluation, including postmortem examination, placental pathology, medical record abstraction, and maternal interview was available on 512 stillbirths among 500 women. These 512 stillbirths were evaluated for cause of death using the definitions outlined in this report. Using the best available evidence, SCRN investigators developed a new methodology to assign the cause of death of stillbirths using clinical, postmortem, and placental pathology data. This new tool, designated the Initial Causes of Fetal Death, incorporates known causes of death and assigns them as possible or probable based on strict diagnostic criteria, derived from published references and pathophysiologic sequences that lead to stillbirth. Six broad categories of causes of death are accounted for, including maternal medical conditions; obstetric complications; maternal or fetal hematologic conditions; fetal genetic, structural, and karyotypic abnormalities; placental infection, fetal infection, or both; and placental pathologic findings. Isolated histologic chorioamnionitis and small for gestational age were not considered causes of death. A new system, Initial Causes of Fetal Death, to assign cause of death in stillbirths was developed by the SCRN investigators for use in this study but has broader applicability. Initial Causes of Fetal Death is a standardized method to assign probable and possible causes of death of stillbirths based on information routinely collected during prenatal care and the clinical evaluation of fetal death.

Isolated and unexplained polyhydramnios: an independent risk factor for fetal congenital abnormalities

ObjectivesTo examine the incidence of fetal congenital abnormalities in cases of isolated polyhydramnious after exclusion of the common causes of polyhydramnious.MethodsRetrospective analysis of all cases of polyhydramnious over a 7-year...

Genetic sonography: the historical and clinical role of fetal echocardiography

The association of congenital heart defects with trisomy 21 was reported over 50 years ago and heart defects remain one of the most common and lethal abnormalities present postnatally in individuals affected by Down syndrome1–4. The purpose of this Editorial is to review the use of second-trimester fetal echocardiography as an adjunct to the genetic sonogram from a clinical perspective, based on my experience over the past 20 years5–13. The following topics are discussed as they relate to trisomy 21: (1) the incorporation of ultrasound evaluation of the fetal heart as part of the genetic sonogram and comparison of it with other screening modalities from a historical perspective; (2) the postnatal incidence of congenital heart defects; (3) the prenatal incidence of structural and functional heart abnormalities; (4) the relative risk for various cardiac findings; and (5) the suggested use of fetal echocardiography as part of the genetic sonogram given current screening technologies.

P11.05: Fetal aneuploidy and structural abnormalities by a 11-14-week routine ultrasound scan in an unselected Serbian population

A prospective observational cohort study of unselected pregnant women attending an 3D/4D abdominal and vaginal ultrasound examination in 11–14 weeks' gestation. Prenasal thickness, NT and jugular lymphatic sacs (JLS) as markers for aneuploidy. Morphological data revealed that nuchal edema is associated with jugular lymphatic distension. We used the multiplanar mode to obtain the exact mid-sagittal plane and measured the prenasal thickness as the shortest distance between the anterior edge of the lowest part of the frontal bone and the skin anteriorly. Out of 2824 pregnant women, 56 (2.0%) were found to have a missed abortion at the time of the ultrasound scan and 36 (1.3%) were diagnosed as twins. One case was occasionally diagnosed as a mola. 24 major structural abnormalities were detected, 2 cases of holoprosencephaly with hypothelorisam (one case also had a spina bifida), 1 case with hydranencephaly, 2 hydrocephalic fetuses, 2 cases with gastroschisis, 2 case with a bilateral hydronephrosis, 2 unilat. kidney agenesis, 1 megacistis, 2 osteogenesis imperfecta, 2 transposition of great vessels, 2 hypoplastic left ventricle, 1 stenosis A. pulmonalis with ASD, 4 case with a generalized hydrops and 1 fetus with multiple malformations. An additional number of 6 structural defects were detected at birth, including 2 polydactily and 4 non operative VSD. The antenatal ultrasound detection rate was 80% (24/30). Ten patients had a nuchal translucency greater than 3 mm; three of them had chromosomal abnormalities (trisomy 21, trisomy 18). Fetal structural abnormalities at a routine 11–14 weeks ultrasound scan for dating, in an unselected pregnant population, were detected in 80% of the cases. Three out of ten fetuses with a nuchal translucency greater than 3mm. and prenasal thickness and JLS was above the 95th centile had a chromosomal abnormality.

OP03.02: Diagnostic sensitivity and clinical value of prenatal ultrasound, post-mortem magnetic resonance imaging and conventional autopsy in structural fetal abnormality

OP03.02: Diagnostic sensitivity and clinical value of prenatal ultrasound, post-mortem magnetic resonance imaging and conventional autopsy in structural fetal abnormality

P16.05: Diagnosis of fetal structural abnormalities at the 11-14 week scan

P16.05: Diagnosis of fetal structural abnormalities at the 11-14 week scan

Ultrasound screening for fetal structural abnormalities performed by trained midwives in the second trimester in a low‐risk population – an appraisal

To determine the performance of trained midwives in second trimester ultrasound screening for fetal structural abnormalities in a low-risk population. Retrospective study. University Department of Obstetrics and Gynecology. About 13,882 women with singleton pregnancies. The findings of routine second trimester anomaly scan performed by midwives were reviewed. Reasons for referral to maternal fetal medicine (MFM) specialists for further assessment were analyzed. The detection, false positive and false alarm rates for fetal anomalies. One hundred and eighty-nine pregnancies with unknown outcome were excluded from the final analysis. Overall, 617 (4.51%) women were referred to MFM specialists for further assessment, of which 470 (70.2%) were for soft markers alone and 147 (23.8%) for suspected fetal structural abnormalities. In these 13,693 fetuses with known outcome, malformed fetuses were present in 185, a prevalence of 1.35%. Of these, 115 were detected during the second trimester scan and two were detected in the third trimester. The remaining 68 malformed fetuses, most of which had minor anomalies, were identified after birth. The detection rate for a malformed fetus in second trimester scan was 62.2% (115/185) (95% CI 55.2-69.2). There were four cases of false positives and 33 cases of false alarm. Experienced midwives with proper training can detect the majority of major structural abnormalities. Continuous audit and quality control plays a significant role in optimizing the fetal structural examination.

Anomalias e prognóstico fetal associados à translucência nucal aumentada e cariótipo anormal

This study aimed to evaluate the incidence of chromosomal abnormalities in fetuses with increased nuchal translucency (NT) measurement. Incidence of structural abnormalities and pregnancy outcome was also described in fetuses with increased NT and abnormal karyotype.This was a retrospective study involving 246 fetuses with increased NT and known karyotype followed at the Fetal Medicine Unit, Hospital das Clínicas, São Paulo University Medical School.Fetal karyotype was abnormal in 14.2% of the cases. Ultrasound anomaly scan and specialized echocardiographic studies in these cases showed fetal structural abnormalities in 80.8% and cardiac defects were found in 61.5% of the fetuses. Pregnancy outcome was abnormal in 76.5% of these women.Increased NT measurement at 11 to 13 weeks and 6 days is an important marker for fetal chromosomal and structural abnormalities, mainly fetal cardiac defects. This finding also indicates increased risk of spontaneous fetal and neonatal death.

The Prevalence of Chronic Deciduitis in Cases of Preterm Labor without Clinical Chorioamnionitis

Preterm labor is a major cause of perinatal mortality and morbidity, and in approximately 30% of cases a clinical cause is not identified. Acute chorioamnionitis is found histologically in a significant percentage of placentas from preterm deliveries, and the mother is often asymptomatic. Although such subclinical acute chorioamnionitis is known to play a role in preterm labor, this study explores the hypothesis that chronic deciduitis with plasma cells is seen more frequently in cases of preterm labor than in control placentas. Thirty-nine singleton placentas from patients with idiopathic preterm labor were examined microscopically and compared in a blinded fashion with 39 gestational age-matched control placentas. Cases of clinical acute chorioamnionitis and known chronic maternal diseases were excluded. Thirty-nine control singleton placentas were obtained from patients undergoing induction of labor for fetal structural abnormalities, excluding aneuploidy. The presence or absence of acute chorioamnionitis, acute fetal inflammatory response, chronic deciduitis, chronic villitis, infarction, and decidual vasculopathy was noted. Immunohistochemical staining was undertaken to further define leukocyte subtypes. Forty-one percent of cases and 15% of controls showed chronic deciduitis (P = 0.022). Forty-six percent of cases and 18% of controls showed histologic acute chorioamnionitis (P = 0.015). There were 8 cases demonstrating acute fetal inflammatory response but only 1 control (P = 0.029). Little difference was seen in the distribution of lymphocyte subsets between cases and control placentas. Our findings suggest that chronic deciduitis plays a role in the etiology of some cases of preterm labor.

448: Ultrasound screening for major structural fetal abnormalities: Between 11 and 13 weeks of gestation

448: Ultrasound screening for major structural fetal abnormalities: Between 11 and 13 weeks of gestation

Application of transcervical hysterofetoscopy and cord blood collection at first trimester termination of pregnancy for fetal abnormalities

To examine the applicability of hysterofetoscopy and cord blood collection at first trimester termination of pregnancy for fetal abnormalities. From 2004 to 2007, transcervical hysterofetoscopy was performed in seven patients at the same operation setting of surgical termination of pregnancy. The findings were compared with prenatal diagnosis. Feasibility of cord blood collection was also examined. Out of these seven patients, six of them had prenatal ultrasound diagnosis of cystic hygroma. All of them had chromosomal abnormalities. Subcutaneous oedema was confirmed by hysterofetoscopy with good view. Another pregnancy was complicated by homozygous alpha thalassaemia and the diagnosis was confirmed by electrophoresis of fetal haemoglobin collected from umbilical cord vessel. Cord blood collection was also attempted in two other patients yielding fetal blood with minimal maternal contamination. Transcervical hysterofetoscopy is a feasible tool in confirming external fetal structural abnormalities before surgical termination of pregnancy. It can be performed under either general anaesthesia or conscious sedation. Umbilical cord blood collection can facilitate confirmation of genetic diseases. It may also allow the potential of isolating fetal mesenchymal stem cell in first trimester.

Suitability of Rapid Aneuploidy Detection for Prenatal Diagnosis

ObjectiveTo determine the suitability of replacing full karyotype analysis with molecular genetic rapid aneuploidy detection (RAD) methods, in particular quantitative fluorescence polymerase chain reaction (QF-PCR), for prenatal diagnosis in amniotic fluid samples obtained by amniocentesis. MethodsWe reviewed all fetal karyotypes done at our centre between August 29, 2000, and February 28, 2006. Outcome measures included (1) the proportion of prenatal samples with abnormal karyotypes that would not have been detected by RAD, as a whole and for each indication, and (2) pregnancy outcome for each chromosome abnormality that was predicted to be clinically significant or of uncertain significance and would not have been detected by RAD. ResultsOf the 6411 karyotypes reported in the study period, 70 (1.09%) were abnormal karyotypes which would not have been detected by RAD alone. These included 32 cases (0.50%) predicted to confer no increased risk to the fetus, 17 (0.27%) predicted to have a low risk of fetal abnormality, and 21 (0.33%) with an uncertain or high risk of fetal abnormality. If full karyotype was added for nuchal translucency greater than 3.5 mm, structural fetal abnormality on ultrasound, or parental balanced chromosome rearrangement, only five uncertain or high risk cases (0.08%) would not have been detected by RAD alone. ConclusionThese results suggest that if the policy of offering full karyotype analysis to all women were to be changed to a policy of offering RAD alone to women without other risk factors such as fetal abnormalities on ultrasound, increased nuchal translucency, or history of chromosome abnormality, this would mean that a chromosome abnormality with a substantial risk of clinically significant fetal abnormality would be missed in fewer than 1/1000 amniocenteses. Our results are similar to others previously reported.