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).     

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996–1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into ‘isolated’ when only a cardiac malformation was present and ‘associated’ when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20–24 weeks for the majority of associated cardiac defects. Copyright © 2001 John Wiley & Sons, Ltd.     

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.     

The value of sonographic diagnosis of fetal malformations: Different results between indication-based and screening-based investigations

The advantages of a routine screening or indication-based ultrasound investigation during pregnancy are still under debate. This is the first study where both methods are compared in two different time periods. More malformations were diagnosed before the 24th week of gestation by means of screening-based than indication-based investigation (18 per cent vs. 5 per cent, P<0·005), and before 28 weeks in 26 per cent compared with 15 per cent respectively (P<0·01). Twenty-six per cent of all malformations were detected by means of screening-based investigations as opposed to 15 per cent by means of indication-based scans. Primary fetal malformations were also diagnosed much earlier (25 weeks vs. 30 weeks). Except for the fetal head, the detection rate of malformations was higher in nearly all other body regions of the fetus in the screening-based investigation. The most important advantage of a screening-based ultrasound investigation during pregnancy is to detect the malformations early enough in pregnancy for possible intrauterine treatment or to offer safe termination of pregnancy for the woman, at least for those anomalies that are lethal or significantly handicapping.     

A comparison of amniotic fluid alpha-fetoprotein and acetylcholinesterase in the prenatal diagnosis of open neural tube defects and anterior abdominal wall defects

Amniotic fluid samples received for routine prenatal diagnosis of open neural tube defects were used for a study to compare amniotic fluid acetylcholinesterase (AChE) determination using a monoclonal antibody (4F19) enzyme antigen immunoassay and amniotic fluid alpha-fetoprotein (AFP) measurement as diagnostic tests for open neural tube defects. The study was based on 9964 women with singleton pregnancies and known outcome (including 6 with anencephaly and 18 with open spina bifida) having an amniocentesis at 14–23 weeks of gestation. The AChE immunoassay yielded detection rates for anencephaly of 100 per cent (95 per cent confidence interval (CI) 54·07–100 per cent), for open spina bifida of 100 per cent (95 per cent CI 81·47–100 per cent), for anterior abdominal wall defects of 20 per cent (95 per cent CI 0-51-71-64 per cent), and a false-positive rate of 0·22 percent (95 per cent CI 0·14–0·34 per cent) excluding anencephaly, open spina bifida, and anterior abdominal wall defects. For similar detection rates the false-positive rate of the AFP test was significantly higher, 0·74 per cent (95 per cent CI 0·58–0·94 per cent). On the basis of these findings, it is recommended that the technically simple AChE immunoassay should be used on all samples; the AFP test should only be used on the 0·5 per cent of the samples with concentrations of AChE activity ⩾ 8·5 nkat/1 for clear samples and blood-stained samples becoming clear after centrifugation, and ⩾ 25·0 nkat/1 for blood-stained samples that are discoloured after centrifugation; an AFP cut-off level of 2·0 MOM is recommended for this policy. Thereby, the detection rates for anencephaly, open spina bifida, and anterior abdominal wall defects would be 100, 100, and 20 per cent, respectively (95 per cent CIs 54·07–100, 81·47–100, and 0·51–71·64 per cent, respectively), and the false-positive rate would be 0·08 per cent (95 per cent CI 0·03–0·16 per cent) (excluding anencephaly, open spina bifida, and anterior abdominal wall defects).     

Chromosomal prenatal diagnosis: Study of 936 cases of intrauterine abnormalities after ultrasound assessment

Nine hundred and thirty-six prenatal chromosomal analyses were performed by four cytogenetic centres after ultrasound diagnosis of fetal abnormalities, amniotic fluid disorders, fetal growth retardation, and fetal or placental abnormalities. During the same period, 6515 fetal karyotypes were analysed because of maternal age. Frequencies of chromosomal aberrations in each case were respectively 4·4, 6·7 and 15·8 per cent, compared with 3·18 per cent when the fetal karyotype was performed because of maternal age. High rates of chromosomal aberrations are observed in cases of cervical hygroma, limb abnormalities, omphaloceles, duodenal stenosis, hydrocephalus, and facial abnormalities. In the case of polymalformations, this rate was 29·2 per cent. When malformations were seen together with an amniotic fluid disorder or growth retardation, 21·5 per cent chromosomal aberrations were observed. This frequency was 10·4 per cent when growth retardation was associated with an amniotic fluid disorder. Trisomy 13, 18, 21 and monosomy X accounted for 4/5 of all abnormalities in which we observed a high rate of triploidies (4·9 per cent) and balanced (3·3 per cent) or unbalanced (9·8 per cent) non-Robertsonian structural abnormalities. Sonographic ascertainment of these aberrations and prenatal characteristics of major anomalies are discussed.     

Chorionic villus sampling utilization following reports of a possible association with fetal limb defects

Prenatal diagnosis choices were reviewed in 473 women who presented for genetic counselling prior to 11 weeks' gestation for the indication of advanced maternal age. Group A consisted of 336 patients who were unaware of a possible association between chorionic villus sampling (CVS) and limb defects. Group B consisted of 137 patients who were provided this information. Fifty-one per cent of patients in group A and 45 per cent of patients in group B chose CVS. This difference was not significant by χ² analysis (P = 0·7). Patterns of prenatal diagnosis procedure utilization from 1987 to 1992 revealed a significant reduction in CVS utilization accompanied by a corresponding increase in amniocentesis after the association between CVS and limb defects was publicized. Referrals for CVS counselling also significantly declined. However, acceptance rates did not change for those patients who received genetic counselling. First-trimester genetic counselling, including a discussion regarding a possible association between CVS and limb defects, helps patients make informed decisions concerning prenatal diagnosis options, and, in our population, resulted in no change in CVS acceptance rates.     

Transabdominal chorionic villus sampling and amniocentesis for prenatal diagnosis: 5 years' experience at a University Centre

The fetal loss rates and fetal congenital birth defects in 821 transabdominal (TA) chorionic villus sampling (CVS) and 771 amniocentesis (AC) cases were evaluated from a 5-year period (1987–1991) at the University Central Hospital of Turku. The parents were given the option of choosing between the two sampling procedures. CVS was performed, in most cases, at 11 weeks of gestation; and AC, at 15 weeks. The rate of total post-procedure loss was 6·7 per cent in the CVS group and 4·4 per cent in the AC group (p=0·08). The rate of spontaneous abortions was 1·9 per cent in the CVS group and 1·0 per cent in the AC group (p=0·10). The number of birth defects was low in both study groups. No limb reduction cases were observed. Mosaicism was noted in 14 CVS cases and in five AC cases. We conclude that TA-CVS is a safe and practical alternative to AC in prenatal fetal karyotyping.     

Determinants of parental decisions to abort for chromosome abnormalities

Parental decisions concerning the continuation of pregnancy following prenatal detection of abnormal chromosomes were evaluated for 80 patients whose diagnosis and prenatal counselling were performed in our centre. Twenty-two anomalies were diagnosed by chorionic villus sampling (CVS) and 58 by amniocentesis. The severity of the chromosome anomaly and associated ultrasound findings in the first vs. second trimester were correlated with patients' decisions. No difference was found in the likelihood of parental decisions to interrupt or continue a pregnancy between CVS and amniocentesis for either the‘severe’ or the‘questionable’ group of chromosome anomalies. Ninety-three per cent of patients with severe prognosis and 27 per cent with questionable prognosis opted for pregnancy termination (p <0·0001). The association of ultrasound anomalies and termination was highly significant (p< 0·001). The severity of the chromosome anomaly, and, to a lesser extent, the visualization of anomalies on ultrasound were the major determinants of parental decisions to terminate the pregnancy. The diagnosis of an anomaly in the first trimester was no more likely ito lead to a termination of pregnancy than in the second trimester.     

Four years' experience of maternal alpha-fetoprotein screening and its effect on the pattern of antenatal care

Estimation of alpha-fetoprotein (A.F.P.) in maternal serum was used as a screening method for the detection of fetal neural tube defect (N.T.D.) in 7315 women over a four year period. Of these, 5668 pregnancies were tested between 15 and 21 weeks. Action was advised in 129 patients (2·3 per cent). In 74 patients, the only action required was reviewing the notes, including the report of any ultrasound examination, and repeating the blood A.F.P. Detailed ultrasound including scanning the fetal spine was requested in 47 patients and amniocentesis was advised in 19 of these (0·33 per cent). In practice the incidence of amniocentesis was 0·28 per cent as three patients declined our advice. The programme gave detection rates between 15 and 21 weeks of 100 per cent and 75 per cent respectively for anencephaly and open spina bifida. A high fetal mortality was associated with persistently elevated blood A.F.P. levels whether amniocentesis was performed or not.     

Pure fetal blood samples obtained by cordocentesis: Technical aspects of 322 cases

Three hundred and twenty-two percutaneous umbilical blood samplings were performed over 4 years in our prenatal diagnostic centre. A 3·5 MHz sector ultrasound transducer was used to guide a 22·5-gauge needle under local anaesthesia. Sampling was performed fcir rapid fetal karyotyping (within 72 h) in 120 cases, for diagnosis of fetal toxoplasmosis in 133 cases, for determination of the severity of Rh immunization in 15 cases, and for diagnosis of congenital rubella in 4 cases. Pure fetal blood was obtained in 98·7 per cent of the cases after two attempts. The approach to the cord was either transamniotic or trans-piacental. Puncturing was preferentially done at the placental insertion of the cord (72·2 per cent of the cases) and the mean blood sample volume was 3·5 ml. The rate of fetal death in utero was 1 9 per cent, including two cases of amnionitis, one trisomy 18, and one severe bradycardia. The failures were due to sampling at an early stage of pregnancy (before gestation week 18), to maternal obesity, oligohydramnios, and the inexperience of the operator.     

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.     

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.     

Transabdominal villus sampling in early second trimester: A safe sampling method for women of advanced age

Transabdominal chorionic villus sampling (TA-CVS) was performed in 707 viable singleton pregnancies to exclude chromosomal abnormalities. Maternal age ranged between 36 and 49 years (mean 37·9 years); gestational age varied between 10·2 and 18·3 weeks (mean 13·3 weeks). In 639 women (90·4 per cent), a sufficient amount of chorionic tissue (⩾ 10 mg) was obtained after one needle insertion; in 66 women (9·3 per cent) two insertions were needed. An abnormal chromosome pattern was established in 19 cases (2·9 per cent). Vaginal bleeding or spotting within 28 days after TA-CVS occurred in 11 cases (1·5 per cent). The completed follow-up of 678 chromosomally normal pregnancies showed an overall fetal loss rate of 2·6 per cent before 28 weeks. The overall perinatal mortality was 0·9 per cent. When relating fetal loss to gestational age at TA-CVS, this was 6·6 per cent in women sampled before 12 weeks against only 1·8 per cent after 12 weeks. At the same time, the percentage of fetal loss occurring within 2 weeks following the procedure was 75 and 30 per cent, respectively. It is suggested that these data reflect the decline in spontaneous abortion rate during this particular period of pregnancy. It is concluded that TA-CVS is an effective procedure which, when performed after the natural decrease of fetal loss, appears to be a safe option for women of advanced maternal age.     

Prenatal detection of chromosomal mosaicism

A significant problem associated with cytogenetic prenatal diagnosis is distinguishing between true and pseudomosaicism. This becomes a diagnostic dilemma when fetal mosaicism corresponds with a known clinical entity. True mosaicism reportedly occurs with a frequency of 0·2 per cent and pseudomosaicism in 0·7 per cent to 2·7 per cent of cases. In the past 12 months, our laboratory has completed 522 fetal karyotypes. Nine cases were found to demonstrate mosaicism, 4 true mosaics (0·8 per cent) and 6 pseudomosaics (1·1 per cent). One case demonstrated both true and pseudomosaicism. In all cases of true mosaicism, the pregnancy was continued and karyotypes completed at birth. Our results demonstrate a danger of rigid adherence to the criteria for true and pseudomosaicism in the examination of amniotic fluids. It is suggested that the criteria established for true and pseudomosaicism may not be valid when an aberrant cell line is found in a single flask and when that aberrant cell line is compatible with a known clinical entity due to a chromosome anomaly.     

Prenatal diagnosis in advanced maternal age. Amniocentesis or CVS,a patient's choice or lack of information?

Ninety-six women of advanced maternal age were interviewed about the way they obtained information on prenatal diagnosis and about how the decision was made as to what procedure was to be performed (transabdominal chorionic villus sampling (TA-CVS) or amnio-centesis). In the CVS group, women visited their physician or midwife earlier in pregnancy (mean 7.1 weeks) than those in the amniocentesis group (mean 10.7 weeks). The availability of prenatal diagnosis was not mentioned during the first antenatal visit in 55 per cent of women from the amniocentesis group as opposed to 25 per cent from the TA-CVS group. Approximately 40 per cent of women eligible for prenatal diagnosis did not receive any information from the referring body prior to counselling at our centre. Only 29 per cent of women who underwent amniocentesis had actually chosen this procedure; 71 per cent were too late to undergo TA-CVS at 12 weeks. It is concluded that information to the patient must be improved in order to ensure early referral for prenatal diagnosis.     

A quantitative estimation of the effect of prenatal diagnosis in dizygotic twin pregnancies in women of advanced maternal age

Genetic counselling in a dizygotic twin pregnancy is complicated by the large number of possible pregnancy outcomes and by the conceivable differences in the parental valuation of these outcomes. We present the probability distributions of the pregnancy outcomes in dizygotic twin pregnancies for women from 35 to 45 years old without prenatal diagnosis and with transabdominal chorionic villus sampling (TA-CVS) or amniocentesis (AC), using data from the literature. TA-CVS always gives a higher probability of a favourable pregnancy outcome (the birth of one or two infants with a normal karyotype) than AC. For a 35-year-old woman, a 0·7 per cent risk of an unfavourable pregnancy outcome without prenatal diagnosis has to be weighed against the 2·1 per cent excess risk of loss of the entire pregnancy after TA-CVS. For a 45-year-old woman, a 10·2 per cent risk of an unfavourable pregnancy outcome without TA-CVS has to be balanced against a 4·4 per cent excess risk of pregnancy loss after TA-CVS. This study provides a quantitative tool for the support of individual parents with respect to the decision to undergo prenatal diagnosis in a dizygotic twin pregnancy.     

Comparison of chorionic villus sampling and amniocentesis: Current status of prenatal diagnosis in Japan

Data were tabulated and compared for cases involving prenatal diagnostic procedures performed in the 8 years between January 1985 and December 1992. Of a total of 2781 pregnancies, 2546 cases (91·5 per cent) were diagnosed by amniocentesis, and 235 (8·5 per cent) by chorionic villus sampling (CVS). These findings reflect the fact that amniocentesis has taken deep root as the prenatal diagnostic procedure widely acknowledged by society, whereas even the existence of CVS has yet to be generally recognized. Analysis of our clinical and laboratory results and complication rates, however, suggests that CVS is a safe and accurate alternative to amniocentesis which should and can be positively presented to all patients who are candidates for prenatal diagnosis.     

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.     

First trimester chorionic villus sampling versus mid-trimester genetic amniocentesis-preliminary results of a controlled prospective trial

This controlled prospective study assesses the relative risks of first trimester chorionic villus sampling (CVS) versus mid-trimester gentic amniocentesis (GA). CVS subjects and amnio-centesis controls were comparable with regard to several confounding variables which might influence the risk of pregnancy loss including maternal age, smoking, alcohol consumption, gestational age at study entry, and history of vaginal bleeding or poor prior reproductive outcome. The most common indication for prenatal diagnosis was advanced maternal age (n = 511). In this subgroup, spontaneous abortion (<24 weeks) occurred in 2·9 per cent of CVS subjects versus 4−3 per cent of amniocentesis controls. The sum of spontaneous and therapeutic abortions (<24 weeks) was identical (5·3 per cent) in both groups. Therefore, intervention in the CVS group (i.e., therapeutic abortion for cytogenetic abnormalities) did not influence the observed risk of pregnancy loss. Overall perinatal mortality rates were also similar in both groups. No significant differences were identified for a number of pregnancy outcome parameters including 5 min Apgar score, birth weight, body length, head circumference, gestational age at delivery, preterm delivery, fetal growth retardation, congenital malformations, and neonatal complications. Preliminary results of this controlled prospective study suggest that chorionic villus sampling carries a low and acceptable risk.