The impact of prenatal diagnosis on the occurrence of chromosome abnormalities

From the public health point of view, several formal attempts have been made to measure the impact of prenatal diagnosis (PND) on the incidence of Down's Syndrome (DS), but the results have varied widely. The impact of PND (reduction in the birth rate of chromosomally abnormal neonates) is related to utilization rates but quantitative estimates of this have not been established. In a three-year (1981–1983) total population study from Queensland, Australia, we present results to measure the impact of a voluntary PND programme on the birth incidence of DS, and also other chromosomally abnormal births. Utilization rates for the PND service were 15·5 per cent in that population of mothers 35 years and over. Numbers and rates of all cases of chromosomal abnormalities are presented, subclassified by type of diagnosis–-either by PND or by clinical diagnosis after birth. For the total population, 7·3 per cent of cases of DS were detected prenatally, and 15·4 per cent of all chromosome abnormalities. (A method for measuring the impact of PND is described.) Using this in conjunction with our demographic data, we estimate that with a 15 per cent utilization rate of PND by older mothers, 14 per cent of DS births can be prevented in this age group, or a 5 per cent overall reduction can be achieved if mothers of all ages are considered. One index–-the ratio of the percentage of DS births which are preventable compared with the population utilization rates of PND–-has potential for widespread use. Queensland data for this ratio is 0·34, a figure consistent with that from other studies. Thus a 3·5 per cent drop in the overall DS birth rate may be expected for each 10 per cent increase in the utilization rates of PND for mothers of 35 years and over. A diagram is presented which may serve as a model for improved data collection and better impact estimates in the future.     

The prenatal diagnosis of joubert's syndrome of familial agenesis of the cerebellar vermis

The prenatal diagnosis by ultrasound examination of Joubert's syndrome of familial agenesis of the cerebellar vermis is described allowing termination of pregnancy ai 26 weeks gestation. The diagnosis was made by a comparison of the prenatal ultrasound examination with computerized axial tomography obtained from the siblings with the same condition.     

Pericentric inversion of the Y chromosome and prenatal diagnosis

Pericentric inversion of the human Y chromosome has been estimated to occur with a frequency of 1–2 per thousand in various populations, and the results of this study, derived from over 12 000 prenatal diagnosis cases, is 1.15 per 1000. In these cases, it was concluded that there was no clinical significance because the fathers and male fetuses had the same pericentric inversion. Chromosome analysis of the father is advisable to determine whether or not the inversion is familial in order to be able to provide genetic counselling.     

Improved performance in a prenatal screening programme for Down's syndrome incorporating serum-free hCG subunit analyses

A prenatal screening programme for Down's syndrome potentially detecting 76 per cent of affected pregnancies in the South Australian general population at an amniocentesis rate of 3.9 per cent was designed following analysis of mid-trimester serum samples from 57 women who carried an affected fetus. This equates to one affected pregnancy being detected for 41 chromosomal analyses performed. For the experimental series, 75.4 per cent of affected pregnancies were detected, while 4.1 per cent of control specimens produced estimated risk odds consistent with further action. A maternal risk odds of birth of a Down's syndrome fetus of 1:420 was taken as the decision value, which is the prevalence of Down's syndrome births to 35-year-old mothers in South Australia. This screening performance was achieved by investigating combinations of serum analytes not previously reported and by refining the calculation of maternal risk odds to include selective weighting of indicator analytes. Combination of the measurements of free α-subunits and β-subunits of chorionic gonadotrophin, α-fetoprotein, unconjugated oestriol, and placental lactogen was found to be most effective in indicating Down's syndrome fetuses. In all combinations of analytes tested, replacing the measurements of free α-subunits and free β-subunits of chorionic gonadotrophin with the measurement of intact chorionic gonadotropin produced a less effective screen.     

The outcome of pregnancy and prenatal chromosomal diagnosis of fetuses in couples including a translocation carrier

In order to evaluate the relation between chromosomal translocation and the outcome of pregnancy, 50 couples were examined. Subjects consisted of 35 couples that included a reciprocal translocation carrier; 13 included a Robertsonian translocation carrier and 2 included a carrier of a mosaic reciprocal translocation. The reasons for performing chromosomal examinations were mainly infertility and abnormality of neonates. The rates of miscarriages and neonatal abnormalities in prior pregnancies were significantly higher than the birth rate of morphologically normal newborns. The presence of a translocation is closely related to reproductive failure because of the chromosomal imbalance. However, prenatal chromosomal examination after the 15th gestational week in subsequent pregnancies revealed that almost half of the fetuses showed normal karyotypes and only 12.8 per cent of the fetuses showed a chromosomal imbalance. Many chromosomally imbalanced fetuses are spontaneously aborted before amniocentesis. The risk of chromosomal imbalance is relatively low in prenatal diagnosis, but partial trisomies of small rearrangements tend to be preserved.     

Fetal two-dimensional doppler echocardiography (colour flow mapping) and its place in prenatal diagnosis

One hundred and fifty fetuses between 16 and 38 weeks of gestation were studied by fetal echocardiography using colour-coded two-dimensional Doppler echocardiography. Two-dimensional, M-mode, and Doppler spectral analyses were also performed. In 14 fetuses, structural and/or functional abnormalities were detected. Abnormalities were correctly ruled out in all the other fetuses. The advantages of two-dimensional Doppler echocardiography are (1) rapid screening for flow abnormalities in the fetal heart, and thus shortening of the Doppler examination time; (2) rapid diagnosis of valvular regurgitation, valvular stenosis, and abnormal shunting of blood across the interatrial and interventricular septa; and (3) facilitation of the diagnosis of complex congenital heart defects which in certain cases is possible only by using two-dimensional Doppler echocardiography.     

Residual risk for cytogenetic abnormalities after prenatal diagnosis by interphase fluorescence in situ hybridization (FISH)

Results from conventional cytogenetic studies on 21 609 amniotic fluid specimens were analyzed retrospectively to determine the residual risk for a cytogenetic abnormality if interphase FISH, capable of only detecting aneuploidy for chromosomes 13, 18, 21, X and Y, was performed and did not reveal an abnormality. Detection rates (the probability of detecting a cytogenetic abnormality when an abnormality is present) and residual risks (the likelihood of a cytogenetic abnormality, in view of normal interphase FISH results) were calculated for the four major clinical indications for prenatal diagnosis (advanced maternal age, abnormal maternal serum screen indicating increased risk for trisomy 18 or trisomy 21, abnormal maternal serum screen indicating increased risk for neural tube defects and ultrasound abnormality). Differences in detection rates were observed to depend on clinical indication and presence or absence of ultrasound abnormalities. The detection rate ranged from 18.2 to 82.6% depending on the clinical indication. The detection rates of abnormalities significant to the pregnancy being evaluated (i.e. abnormalities excluding familial balanced rearrangements and familial markers) were between 28.6 and 86.4%. The presence of ultrasound abnormalities increased the detection rate from 72.2 to 92.5% for advanced maternal age and from 78.6 to 91.3% for abnormal maternal serum screen, indicating increased risk for trisomy 18 or trisomy 21. With regard to residual risk, the risk for a clinically significant abnormality decreased from 0.9–10.1%, prior to the interphase FISH assay, to a residual risk of 0.6–1.5% following a normal interphase FISH result in the 4 groups studied. Providing patients with detection rates and residual risks, most relevant to their situation (clinical indication and presence or absence of ultrasound abnormality) during counseling, could help them better understand the advantages and limitations of interphase FISH in their prenatal diagnostic evaluation. Copyright © 2003 John Wiley & Sons, Ltd.     

A collaborative study of the segregation of inherited chromosome structural rearrangements in 1356 prenatal diagnoses

A collaborative study involving 71 European prenatal diagnosis centres has collected 1356 observations on the karyotype of fetal cells in diagnoses performed in couples in which a parent had a balanced structural rearrangement. The segregations of the inherited chromosome structural rearrangement were analysed in relation to the types of rearrangement, to the sex of the carrier parent, the methods of ascertainment of the anomaly in the family, the chromosomes involved and the potential imbalance of the anomaly. Wide differences in the incidence of unbalanced fetuses were observed in relation to these criteria, and these results can be used in counselling parents with balanced rearrange- ments. Distortions in segregation of normal versus balanced karyotypes were observed in some types of anomalies.     

Parental reaction and adaptability to the prenatal diagnosis of fetal defect or genetic disease leading to pregnancy interruption

The objective of the study was to evaluate the psychological reaction of two groups of parents to a pregnancy termination after they had undergone a prenatal diagnostic procedure. The analysis involved interviews with a study group of 76 patients who were at risk of giving birth to a child with a genetic disease or defect and a comparison group of 124 who had a pregnancy termination after a major anomaly had been detected by routine ultrasound and who were not at known risk for a genetic disease. Only patients in the study group had received counselling before the prenatal diagnosis and were aware that the fetus could be affected. The overall reaction of the comparison group was one of shock, denial of fetal abnormality, and guilt over ‘abandoning the fetus’. A feeling of guilt was expressed by patients in the comparison group (73 per cent versus 29 per cent) in the period immediately following the interruption. One-third of patients in both groups felt obliged to undergo a therapeutic abortion. More patients in the study group than in the comparison group expressed the need to see a psychiatrist at the time of the study (19 per cent versus 7 per cent) and viewed future pregnancies as a replacement for the lost pregnancy (63 per cent versus 19 per cent). The recommendations of the study focus on information sessions to personnel, nursing support, analgesia during the expulsion period, an atmosphere of respect that should be present at the time that the fetus is viewed, the anticipation of mourning, and the long-term follow-up of the couple to ensure that counselling for future pregnancies and psychological support are provided when needed.     

Dystrophin gene analysis and prenatal diagnosis of Duchenne muscular dystrophy in Russia

Of 126 families referred for counselling of Duchenne muscular dystrophy (DMD), DNA analysis has been suggested to 119 families with at least one affected child or with an affected close male relative of the woman at risk of being a DMD carrier. A large proportion (about 80 per cent) of the families were represented by sporadic cases (only one affected individual). By means of multiplex polymerase chain reactions with different sets of oligoprimers providing amplification of 10–11 different exons, altogether 49 dystrophin gene deletions were identified (41 per cent). Eighteen deletions clustered in the 5′ ‘hot spot’ region of DMD cDNA and 36 in the distal half of the central rod domain around exons 43–53. An unusually high frequency (18 per cent) of deletions involving exons 17–19 was discovered. Large deletions extending through both ‘hot spot’ regions and thus occupying over 30–40 exons were recorded in five cases (10 per cent). Seventy-six of 94 families were found to be informative by RFLP analysis for intragenic or extragenetic DNA probes. Carrier status was ascertained in 20 and rejected in 32 female relatives in 40 DMD families. Eight DMD-affected fetuses were diagnosed prenatally by direct deletion testing or by RFLP analysis. Feasible interpopulation variations in the dystrophin gene deletion pattern are discussed. The prospects for more effective prenatal diagnosis and carrier detection in high-risk DMD families in Russia are briefly outlined.     

Six years' experience with rapid karyotyping in prenatal diagnosis: Correlations between phenotype detected by ultrasound and fetal karyotype

From September 1985 to March 1992, 804 amniotic fluid samples from 64 different diagnostic centres of the Federal Republic of Germany were sent to our laboratory exclusively for rapid karyotyping. The average time needed for notification of the analysed karyotype was 4·65 days when the ‘pipette method’ was used for chromosome harvesting and 5·97 days when the ‘in situ’ technique was used. The overall incidence of chromosome aberrations was 15·3 per cent. Data are presented about the likelihood of abnormal ultrasound findings being caused by chromosome aberrations. These findings include polyhydramnios, oligohydramnios, growth retardation, fetal effusions, neural tube defects, craniofacial defects, heart defects, gastroschisis and omphalocele, gastrointestinal tract defects, urinogenital defects, and limb defects. In future, such data need to contain larger numbers of cases for each week of gestation. This will improve the risk evaluation for each case with abnormal ultrasound findings, which should lead to better management during pregnancy, delivery, and postnatal care for those who require rapid karyotyping.     

Decision making during the prenatal diagnostic procedure. A questionnaire and interview study of 211 women participating in prenatal diagnosis

Counselling in connection with prenatal diagnosis (PND) is a common task for the obstetrician and the midwife. However, the decision making processes of pregnant women are not completely known, for instance, the questions of women's autonomy, the decision on how to act in the case of an abnormal test, and the partner's participation in the decision. A questionnaire and interview study was carried out among 211 women undergoing PND by amniocentesis or chorionic villus biopsy. Most women in the sample indicated that PND was completely voluntary. However, at the same time almost every woman reported that it was difficult to decline from PND when offered. Even before the visit to register at the antenatal clinic, most of the women (83 per cent) had made up their minds to have PND. At the time of the test, many of the participants (62 per cent) had decided in favour of a legal abortion if the test indicated an abnormality in the fetus. At the same time, however, the data indicate a need for reflection and ambivalence, which the medical staff have to accept. In the questionnaire most of the women stated that they and their partners had similar attitudes towards PND, but when interviewed 38 per cent of the women admitted some differences between their own attitudes and their partners'. Although some women reported considerable deliberation and ambivalence, most of them said that they would undergo PND in another pregnancy.     

Use of the chemical cleavage of mismatch method for prenatal deficiency diagnosis of alpha-1-antitrypsin

The most common mutation in alpha-1-antitrypsin deficiency, conversion of a G to an A at base 9989 (PI-Z), was detected with the chemical cleavage of mismatch method, demonstrating the power of the method for prenatal diagnosis. Exon V of the gene was amplified using the polymerase chain reaction and heteroduplexes were formed to test for the presence of the mutation. The predicted C mismatch was readily detectable with hydroxylamine, and by making the probe from the chorionic villus sample it was possible to determine that the fetus was heterozygous, not homozygous, for the mutation.     

Microvillar enzyme analysis in amniotic fluid and the prenatal diagnosis of cystic fibrosis

The activities of two microvillar enzymes, gamma-glutamyltranspeptidase (GGTP) and alkaline phosphatase (ALP) have been determined in amniotic fluid (AF) samples from 39 pregnancies with a 1-in-4 risk of cystic fibrosis. Seventeen of these were investigated prospectively. A reduced proportion of the fetal specific intestinal ALP isoenzyme was found in 7 of a total of 13 pregnancies with cystic fibrosis and in one pregnancy of confirmed normal outcome. Eight of the affected pregnancies were tested for AF GGTP activity and depressed levels were found in 15. None of the 3 liveborn cystic fibrosis cases in the prospective series was identified by the ALP assay although 2 had significantly reduced GGTP activity. There were several amniotic fluid samples from cases of cystic fibrosis, trisomy 18 and normal outcome which had discordant GGTP and ALP results. Four of the 6 cases of cystic fibrosis misclassified by the ALP assay had amniocentesis at 15 or 16 weeks gestation. Evidence is presented which confirms a previous suggestion that amniocentesis after 17 weeks gestation improves the predictability of the ALP isoenzyme assay for the prenatal diagnosis of cystic fibrosis.     

Alphafetoprotein,cholinesterases and rapidly adhering cells in the prenatal diagnosis of neural tube defects

Amniotic fluid cholinesterases tested on polyacrylamide gel and rapidly adhering cell analysis were compared in their efficiency at diagnosing fetal neural tube defects in three cases where the alphafetoprotein results were equivocal. While rapidly adhering cells were also equivocal, the cholinesterases consistently gave a clear indication of fetal abnormality.     

Neonatal form of the hyperornithinaemia,hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis

We describe here the first case of neonatal death due to the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and the first prenatal diagnosis of this disorder in a subsequent pregnancy in this family.     

DNA polymorphism and globin chain analysis in the prenatal diagnosis of β-thalassaemia major in Taiwan

Thirty-six pregnancies in 25 families at risk of β-thalassaemia major received prenatal diagnosis. Chorionic villus sampling or amniocentesis was done in 35 pregnancies to obtain fetal cells for DNA linkage study, for which Southern blotting and DNA hybridization were used to detect seven restriction fragment length polymorphisms (RFLPs) within the β-globin gene cluster: ϵ-HincII, ^Gγ-HindIII, ^Aγ-HindIII, Φβ-HincII, 3′Φβ-HincII, β-AvaII, and 3′β BarnHI. β-Thalassaemia major was diagnosed in seven and excluded in 22 pregnancies. In the remaining six cases, β-thalassaemia major could not be excluded. In these six pregnancies and another one with late booking, ultrasound-guided cordocentesis was performed at the 22nd to 27th week of gestation. Globin chain composition was determined with urea-acetic acid-Triton X-100-12 per cent polyacrylamide gel electrophoresis. β-Thalassaemia major was diagnosed in two fetuses and excluded in the other five. Eleven fetuses (in which β-thalassaemia major was excluded) have been delivered and are healthy at more than 5 months old DNA linkage analysis coupled with globin chain electrophoresis provides an effective way for prenatal diagnosis of β-thalassaemia major, although these methods are being replaced by more direct detection techniques using oligonucleotide probes.     

Ultrasonographic scanning of placental thickness and the prenatal diagnosis of homozygous alpha-thalassaemia 1 in the second trimester

In order to evaluate the association between placental thickness (PT) and fetal homozygous alpha-thalassaemia 1 before the appearance of classic ultrasound findings of haemoglobin (Hb) Bart's hydrops fetalis, a total of 473 pregnancies were collected. The control group included 422 normal pregnancies with a gestational age from 14 to 23 weeks and the study group included 51 affected fetuses in the same gestational period. Fetal biparietal diameter (BPD) and PT were measured by high-resolution ultrasound. PT was evaluated against BPD. In the control group, the PT generally increased in parallel with the advancement of gestational age. All PT measurements in the study group were above the mean PT of their respective gestational week in the control group. Forty-six (90 per cent) of the pregnancies in the study group had PT larger than the mean plus two standard deviations of the control group. This study suggests that ultrasound measurement of PT may be a useful aid in the prenatal diagnosis of Hb Bart's hydrops fetalis before its classic findings become apparent in the late second trimester or third trimester.