Evaluation of prenatal diagnosis by a registry of congenital anomalies

Prenatal diagnosis performed by fetal karyotype and ultrasound scan is now a routine part of antenatal care in many countries. How many fetal anomalies are actually detected by these procedures? We have used our registry of congenital malformations to answer this question. In our region, prenatal diagnosis was performed in 23.1 per cent of fetuses with a chromosomal aberration and in 20.1 per cent of fetuses with non-chromosomal anomalies. Only 6.9 per cent of the pregnancies with fetuses with non-chromosomal anomalies were terminated. The sensitivity of prenatal diagnosis by ultrasonographic examination was much lower for isolated malformations (fetuses with only one anomaly) than for multiple malformed children, 15.3 and 48.3 per cent respectively, chromosomal anomalies excluded.     

Chromosomal and subchromosomal anomalies associated to small for gestational age fetuses with no additional structural anomalies

Objectives: To assess the chromosomal and subchromosomal anomalies in small for gestational age (SGA) fetuses with no additional structural anomalies and their clinical outcomes. Methods: This study retrospectively reviewed the 128 SGA fetuses with no additional anomalies and underwent genetic testing with karyotyping and chromosomal microarray analysis (CMA). Stratified analysis was performed according to the existence of maternal risk factors for SGA (yes or no), gestational age at onset (before or after 32 weeks), presence of oligohydraminos (yes or no), and umbilical artery Doppler flow (normal or abnormal). Results: Chromosomal anomalies were identified in 6 (4.7%) SGA fetuses and pathogenic subchromosomal anomalies in 4 (3.1%) by microarray analysis. Chromosomal and subchromosomal anomalies were more frequently observed in cases with oligohydraminos (P = .017) and with early-onset SGA (P = .042). No differences were observed in relation to the existence of maternal risk factors and abnormal umbilical artery Doppler flow. Overall survival rate was 75.0% with different rates in the early and the late onset group (P < .001). Conclusions: There is a 3.3% incremental yield of subchromosomal anomalies in CMA above karyotyping in SGA fetuses. Chromosomal microarray analysis is recommended in SGA fetuses with no additional structural anomalies, especially coexisting with oligohydraminos and being early onset.     

Evaluation of routine prenatal diagnosis by a registry of congenital anomalies

Prenatal diagnosis performed by ultrasound scan is now a routine part of prenatal care in many countries. How many fetal anomalies are actually detected by these procedures? We have used our registry of congenital malformations to answer this question. In a previous study (Prenat. Diagn., 12 , 263–270, 1992), considering the period 1979–1988, we have shown that prenatal diagnosis was performed in 23.1 per cent of fetuses with a chromosomal aberration and in 20.1 per cent of fetuses with non-chromosomal anomalies. In 1991 and 1992, the percentatge of termination for Down syndrome was 44.4 and 41.9 per cent, respectively. From 1989 to 1992, the detection rate and the specificity of prenatal diagnosis by ultrasonographic examination were improved. The detection rate for isolated malformations (fetuses with only one anomaly) and for multiple malformed children was 26.2 and 66.0 per cent, respectively. The detection rate of congenital anomalies by ultrasonography was variable for the different categories of malformation. A high detection rate was observed for anencephaly (100 per cent) and urinary tract malformation. A low detection rate was seen for cleft lip (17.5 per cent) and limb reduction defects (18.2 per cent).     

Prenatal karyotyping in malformed fetuses

Experience with prenatal karyotyping of 237 fetuses with sonographic evidence of malformation is reported. Abnormal karyotype was found in 40 cases (16-8 per cent): chromosomal aberrations were found in 19 of the 178 fetuses with an isolated structural anomaly (10-6 per cent) and in 21 of the 59 fetuses with multiple malformations (35-6 per cent). Detailed cytogenetic and morphological information concerning fetuses affected by omphalocele, duodenal atresia, hydrocephalus, multicystic kidney, unilateral hydronephrosis and cystic hygroma is reported. The need for a very careful ultrasound evaluation of fetal anatomy in these pregnancies is stressed, as the risk of a chromosomal anomaly depends mainly on the existence of more than one ultrasonically diagnosed structural defect.     

Unusual case of a fetus with congenital cystic adenomatoid malformation of the lung associated with trisomy 13

Congenital cystic adenomatoid malformation of the lung can be detected with antenatal ultrasound as hyperechogenic areas in the fetal chest. Associated extrapulmonary malformations as well as chromosomal aberrations are described as very rare. We present a case report of a fetus in the 23rd week of gestation who showed in the course of a routine ultrasound screening a large number of malformations: holoprosencephaly, arrhinencephaly, cleft palate, CCAM type III of the right inferior pulmonary lobe, ventricular septal defect and bilateral clubfeet. Chromosome analysis confirmed the suspicion of trisomy 13. The present case shows how important it is—even with malformations that are rarely accompanied by associated anomalies and which have a very good prognosis—to carry out a directed diagnosis including a fetal karyotyping. Copyright © 2003 John Wiley & Sons, Ltd.     

Ultrasound diagnosis of fetal abnormalities and cytogenetic evaluation

Over a 65½ year period, in 288 pregnancies a variety of fetal malformations were detected by ultrasound. Two hundred and ten fetuses (73 per cent) were karyotyped. Gestational age at detection ranged from 11 to 38 weeks. The incidence of an abnormal karyotype in the total series was 14 per cent and 14.7 per cent in the 210 pregnancies in which a karyotype was performed. Single structural anomalies were found in 149 cytogenetically investigated fetuses, of which 25 had a chromosomal abnormality (17 per cent). Multiple structural malformations were present in 61 fetuses, of which 16 had an abnormal karyotype (26 per cent). Trisomy 18 was the most frequent finding. The most constant ultrasound finding in cases of an abnormal karyotype was polyhydramnios and severe IUGR in combination with structural defects. There is a need for extensive detailed ultrasound examination in high-risk pregnancies.     

Karyotype abnormalities in fetuses diagnosed as abnormal on ultrasound before 20 weeks' gestational age

This study examined rates of karyotype abnormalities in fetuses diagnosed by ultrasound as abnormal before 20 weeks' gestational age and which prompted a follow-up amniocentesis or chorionic villus sampling. Those diagnosed before 20 weeks were compared with those diagnosed at or after 20 weeks. A retrospective study identified ultrasonographically abnormal fetuses in whom karyotyping had been undertaken, 306 fetuses before 20 weeks' gestational age and 241 after. Isolated malformations before 20 weeks had, on average, an 18 per cent risk of karyotype abnormality, compared with 20 per cent later. Specific rates were calculated; for example, heart abnormality was associated with karyotype abnormality in 7 per cent of cases before 20 weeks and in 14 per cent later. Multiple malformations and karyotype abnormalities were found together in 28 per cent of fetuses prior to 20 weeks and in 33 per cent of the older fetuses. Specific associations included nuchal oedema and trisomy 21 in 21 per cent of fetuses before 20 weeks. No karyotype abnormalities were found in fetuses diagnosed with choroid plexus cysts. An overview of trisomies in Victoria, in 1991, showed that 50 per cent of trisomy 18, 42 per cent of trisomy 13, and 9·5 per cent of trisomy 21 cases were identified by ultrasound in women less than 37 years of age. Another 28·6 per cent of trisomy 21 fetuses were detected in women of advanced maternal age who underwent amniocentesis or chorionic villus sampling, making a total of 38·1 per cent of trisomy 21 that were detected prenatally. The importance of early karyotyping specifically relates to the ongoing management of the pregnancy if the chromosomes are normal, and facilitates decision-making regarding termination of pregnancy if the chromosomes are abnormal.     

Transvaginal sonography—detection of findings suggestive of fetal chromosomal anomalies in the first and early second trimesters

Over a 4-year period, 14 dyskaryotic fetuses were diagnosed by amniocentesis, performed after early detection of malformations using transvaginal sonography (TVS). These 14 dyskaryotic fetuses were detected out of 4878 sonographic screenings performed by TVS between 9 and 16 weeks' gestation. Twenty-eight per cent of the referrals were at high risk and 72 per cent were at low risk for fetal malformations. Two hundred and twenty-nine fetuses (4.7 per cent) of the screened population had 265 anomalies, 39 per cent of them being transient. In 7 of the 14 dyskaryotic fetuses (50 per cent), the sonographically detected anomalies were transient, being undetected by follow-up sonographic screenings at later gestational ages (⩾18 weeks). Postponing the first sonographic scan aimed at malformation detection to a later gestational age may lead to transient anomalies and their associated dyskaryosis being missed.     

Fetal cholecystomegaly: A prenatal marker of aneuploidy

The fetal gall bladder can now be easily identified during the second and third trimesters using high-resolution ultrasonography. In this report we present eight fetuses with an enlarged gall bladder detected on prenatal ultrasonography at a mean gestational age of 24.6 weeks (range 19–31 weeks). Additional ultrasonographic findings were present in four cases: fetal anomalies and intrauterine growth retardation in three and polyhydramnios in one. Of those cases associated with fetal anomalies, one woman underwent amniocentesis at 21 weeks revealing trisomy 18. The other two declined prenatal karyotyping; neonatal karyotyping revealed trisomy 13 in one and trisomy 18 in the other. Although an enlarged fetal gall bladder can be a normal variant in the second and third trimesters, the prenatal detection of cholecystomegaly should prompt a search for associated anomalies and other markers of aneuploidy. If found, prenatal karyotyping should be considered.     

Diagnostic yield of exome sequencing in isolated fetal growth restriction: Systematic review and meta-analysis

The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with isolated fetal growth restriction (FGR). This was a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies included those with (a) only fetuses with FGR in the absence of fetal structural anomalies and (b) negative CMA or karyotyping results. Only positive variants classified as likely pathogenic or pathogenic determined as causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Eight studies with data on ES diagnostic yield, including 146 fetuses with isolated FGR, were identified. Overall, a pathogenic variant determined as potentially causative of the fetal phenotype was found in 17 cases, resulting in a 12% (95% CI: 7%–18%) incremental performance pool of ES. The vast majority were studied before 32 weeks'gestation. In conclusion, a monogenic disorder was prenatally found in association with apparently isolated FGR in 12% of these fetuses.     

Single umbilical artery: Prenatal findings

In 450 patients with pregnancy at high risk for fetal malformation and/or intrauterine growth retardation, the umbilical cord was investigated sonographically for the presence of a single umbilical artery. A single umbilical artery was diagnosed in four fetuses between 23 and 33 weeks of gestation and suspected in two. Three cases were overlooked at sonography. All seven surviving fetuses had growth retardation at delivery and four also showed severe malformations. Whenever a single umbilical artery is found at sonography, further work-up is required to rule out associated anomalies, intrauterine growth retardation, or chromosomal abnormality.     

Evaluation of prenatal diagnosis of congenital heart disease

Prenatal diagnosis performed by fetal ultrasound scan is now a routine part of antenatal care in many countries. That an increasing number of fetal anomalies may be detected on prenatal ultrasound is beyond doubt. What is possible is not, however, always practical, especially when congenital heart diseases (CHDs) are concerned and when whole antenatal populations are screened rather than high-risk groups. Thanks to our registry of congenital anomalies, a retrospective study was undertaken to evaluate the prenatal detection of CHDs by ultrasound scan in 131 760 consecutive pregnancies of known outcome from 1979 to 1988. Only 84 out of 912 malformed fetuses with CHDs without chromosomal anomalies were detected (9.2 per cent). The sensitivity of detection varied from around 38 per cent for malformations such as hypoplastic left heart and single ventricle to around 5 per cent for ventricular and atrial septal defects. The effectiveness of the detection of some forms of major congenital heart disease has increased dramatically since 1987 by including routine examination of the four-chamber view and of the inflow and outflow tracts of the fetal heart. Our results stress the need to obtain a definite clear four-chamber view, to perform scans at ⩾ 18 weeks of gestation, and to train sonographers in order to improve the prenatal detection of CHDs.     

A new report of mesomelic camptomelia,polydactyly and Dandy–Walker complex in siblings

Two male siblings with several malformations are reported. The anomalies detected in both fetuses were mesomelic camptomelia, postaxial hexadactyly and Dandy–Walker complex. There was only one similar previous report in the literature. This combination could represent a specific pattern of malformation or a new syndrome, with different variants. The parents' consanguinity and the recurrence in a subsequent pregnancy suggest an autosomal recessive inheritance pattern. Copyright © 2003 John Wiley & Sons, Ltd.     

Outcome of fetal echogenic bowel: A systematic review and meta-analysis

The main aim of this systematic review was to explore the outcome of fetuses with isolated echogenic bowel (EB) on antenatal ultrasound. Inclusion criteria were singleton pregnancies with isolated EB no associated major structural anomalies at the time of diagnosis. The outcomes observed were: chromosomal anomalies, cystic fibrosis (CF), associated structural anomalies detected only at follow-up scans and at birth, regression during pregnancy, congenital infections, intra-uterine (IUD), neonatal (NND) and perinatal (PND) death. Twenty-five studies (12 971 fetuses) were included. Chromosomal anomalies occurred in 3.3% of the fetuses, mainly Trisomy 21 and aneuploidies involving the sex chromosomes. Cystic fibrosis occurred in 2.2%. Congenital infections affected 2.2%, mainly congenital Cytomegalovirus (CMV) infection. The majority of fetuses with EB experienced regression or disappearance of the EB at follow-up scans. Associated anomalies were detected at a follow-up scan in 1.8%. Associated anomalies were detected at birth and missed at ultrasound in 2.1% of cases. IUD occurred in 3.2% of cases while the corresponding figures for NND and PND were 0.4% and 3.1%. Fetuses with EB are at increased risk of adverse perinatal outcome, highlighting the need for a thorough antenatal management and postnatal follow-up. Assessment during pregnancy and after birth should be performed in order to look for signs of fetal aneuploidy, congenital infections and associated structural anomalies.     

Agenesis of the corpus callosum: What to tell expecting parents?

Agenesis of the corpus callosum (ACC) is one of the most common brain malformations, with an incidence estimated to range from 0.5 to 70 in 10,000 among the general population. Prenatal diagnosis is made via ultrasound; however, fetal MRI is useful to confirm or exclude the presence of associated cerebral abnormalities–mostly cortical malformations–that may affect postnatal prognosis. When no additional central nervous system (CNS) or extra CNS anomalies are identified and no genetic cause is found, an isolated ACC is diagnosed. Overall, in cases of ACC, an underlying genetic cause can be identified in up to 12.5% with chromosomal microarray (CMA) and up to 47% with whole exome sequencing (WES). In cases where ACC is the only anomaly detected, the yield of WES is 30%. Postnatal outcomes are variable and depend on whether the condition is isolated or not. In truly isolated ACC, outcomes range from normal in 65% of cases through mild to severe neurodevelopmental impairments in 35% of cases. An interdisciplinary team of medical experts is key in guiding parents toward informed decision-making in pregnancies complicated by ACC. Considering current and expected advancements in genetic testing and imaging technologies in upcoming years, we herein summarize current recommendations for the management and prenatal counseling of expecting parents of fetuses with ACC. Our review pertains primarily to expecting parents of fetuses with complete ACC.     

Cardiac and extra-cardiac anomalies as indicators for trisomies 13 and 18: A prenatal ultrasound study

The purpose of the present study was to establish sonographic markers for prenatal diagnosis of trisomies 13 and 18. Retrospective analysis of sonographic morphology was therefore carried out in seven fetuses with trisomy 13, and 16 fetuses with trisomy 18. Gestational age ranged between 17 and 39 weeks (median 28 weeks). Polyhydramnios and symmetrical growth retardation were present in 14 of 23 fetuses. A cardiac anomaly was diagnosed in all 23 fetuses, the majority representing a ventricular septal defect (n = 8) or double outlet right ventricle (n = 8). Extra-cardiac anomalies were characterized by a high incidence of limb deformities (polydactyly, clenched hands, club feet; n = 15) and omphalocele (n = 7). We conclude that the combined appearance of cardiac and extra-cardiac anomalies should prompt fetal karyotyping. Cardiac anomalies in combination with fetal limb deformities and omphalocele are suspicious for trisomies 13 and 18.     

Prenatal ultrasonographic diagnosis of radial-ray reduction malformations

Radial-ray reduction malformations (RRRMs) may occur isolated or in association with other anomalies. The data of seven fetuses born with RRRMs were collected. Six fetuses had associated lethal abnormalities of the central nervous system, urogenital system, and/or heart, detected by ultrasound. In five cases, it was possible to establish the precise diagnosis, enabling an informed prognosis and subsequent genetic counselling. The diagnoses were: Edwards syndrome (n=3), VACTERL association (n=1), and Poland-Moebius-like complex (n= 1). In two cases, a complete diagnosis was not possible because of inadequate evaluation of these fetuses before and/or after birth. A proposal is given for the diagnostic approach for infants with RRRMs detected in the antenatal period by means of ultrasonography.     

Hyperechogenic fetal bowel and Down syndrome. Results of a French collaborative study based on 680 prospective cases

Hyperechogenic fetal bowel is prenatally detected by ultrasound during the second trimester of pregnancy in 0.1% to 1.8% of foetuses. It has been described as a normal variant and has often been associated with severe diseases, notably Down syndrome. The aim of the present study was to determine the risk of trisomy 21 in a prospective study of 680 fetuses with hyperechogenic foetal bowel. Karyotyping was performed on amniotic cells in 632 cases, and outcome was known in 655 cases. A 2.5% risk of Down syndrome and a 1% risk of other severe chromosomal anomalies were observed. Hyperechogenicity was isolated in 11/17 Down syndrome cases, and associated with other ultrasound anomalies in all seven cases of severe chromosomal anomalies. In conclusion, fetal bowel hyperechogenicity indicates a risk of chromosomal anomalies ten-fold higher than that expected on the basis of maternal age, therefore justifying invasive procedures. Copyright © 2002 John Wiley & Sons, Ltd.     

Prediction of an abnormal karyotype in fetuses with omphalocele

The aim of this study was to assess the value of ultrasonographic evaluation in predicting abnormal karyotypes in fetuses with omphalocele. Forty fetuses with antenatally diagnosed omphalocele and available karyotype results were reviewed. Ultrasound evaluation included herniation contents and size, and the detection of other anomalies. Nine of 40 consecutive fetuses had abnormal karyotypes: trisomy 18 (n = 5), trisomy 13 (n = 3), 47,XXX (n = 1). Only 1/25 with an extracorporeal liver versus 8/15 with an intracorporeal liver had abnormal chromosomes [P = 0·0006, RR = 0·14 (0·02 < RR <0·9)]. Small defects (<3 cm) were associated with abnormal karyotypes [P = 0·01, RR = 4·7 (1·4<RR <15·6)]. Finding concurrent malformations was highly associated with chromosomal anomalies [P = 0·00004, RR = 4·4 (2·3 < RR < 8·5)]. The presence of associated malformations, an intracorporeal liver, and a small herniation size are highly suggestive of an associated abnormal karyotype.     

Cytogenetic analysis of trophoblasts by comparative genomic hybridization in embryo-fetal development anomalies

Cytogenetic studies of spontaneous abortions or intrauterine fetal death depend on conventional tissue culturing and karyotyping. This technique has limitations such as culture failure and selective growth of maternal cells. Fluorescent in situ hybridization (FISH) using specific probes permits diagnosis of aneuploidies but is limited to one or a few chromosomal regions. Comparative genomic hybridization (CGH) provides an overview of chromosomal gains and losses in a single hybridization directly from DNA samples. In a prospective study, we analyzed by CGH trophoblast cells from 21 fetuses in cases of spontaneous abortions, intrauterine fetal death or polymalformed syndrome. Six numerical chromosomal abnormalities including one trisomy 7, one trisomy 10, three trisomies 18, one trisomy 21 and one monosomy X have been correctly identified by CGH. One structural abnormality of the long arm of chromosome 1 has been characterized by CGH. One triploidy and two balanced pericentromeric inversions of chromosome 9 have not been identified by CGH. Sexual chromosomal constitutions were concordant by both classical cytogenetic technique and CGH. Contribution of trophoblast analysis by CGH in embryo-fetal development anomalies is discussed. Copyright © 2001 John Wiley & Sons, Ltd.