Early amniocentesis and fetal nuchal translucency in women requesting karyotyping for advanced maternal age

Fetal nuchal translucency was measured at 11–14 weeks' gestation in 97 pregnancies referred for early amniocentesis for advanced maternal age. The nuchal translucency was abnormal in 11 fetuses and the fetal karyotype was abnormal in five of these 11 cases. The karyotype was normal in 86 cases with normal nuchal translucency. The culture failure and miscarriage rates associated with early amniocentesis were 3·3 per cent and 2·2 per cent respectively. Amniotic fluid leakage occurred in 6 per cent of cases. In women requesting fetal karyotyping for advanced maternal age without additional biochemical screening, fetal nuchal translucency should be measured at 11–14 weeks. If the nuchal thickness is ≥ 3 mm, a first-trimester diagnostic procedure is indicated; however, if it is <3 mm, amniocentesis should be delayed until 16 weeks' gestation.     

Examination of fetuses after induced abortion for fetal abnormality—a follow-up study

In the North-Western Region we offer a service to examine fetuses aborted after the diagnosis of fetal abnormalities. Many obstetricians use this service. We examined 343 mid-trimester fetuses over the last 5 years: 215 following an abnormal scan and 128 abnormal amniotic fluid or villus findings. When necessary, investigations were performed. A post-mortem examination was always required. As a result of fetal investigation, the scan diagnosis was modified or refined in 91 cases (42·3 per cent). In three of these cases, no fetal abnormality was found. For the fetuses diagnosed as abnormal by amniocentesis or chorionic villus biopsy, in one (0·8 per cent) the pre-termination diagnosis was not confirmed. The results were similar to those of our previous 5-year study except (a) diagnosis of neural tube defects was rarely based on amniocentesis in the present study (2/62, 3·2 per cent) compared with the previous one (32/103, 31 per cent), and (b) renal abnormalities were more often diagnosed in the pre-termination scan in the present study. We conclude that the examination of aborted mid-trimester fetuses by dysmorphologists continues to improve diagnosis, allowing more accurate genetic counselling for the families.     

Fetal choroid plexus cysts and trisomy 18: Assessment of risk based on ultrasound findings and maternal age

This paper examines the association between fetal choroid plexus cysts (CPCs) and trisomy 18 and proposes a method by which risks can be derived taking into account both sonographic findings and maternal age. Data from our centre on the sonographic findings of 58 fetuses with trisomy 18 and 387 fetuses with CPCs as well as data from published series were used. It was calculated that the prevalence of CPCs in the general population is approximately 1 per cent and at mid-gestation the incidence of CPCs in fetuses with trisomy 18 is approximately 50 per cent. In the 387 fetuses with CPCs, the incidence of trisomy 18 increased with maternal age and the likelihood ratio for trisomy 18 increased with the number of additional abnormalities, from 0·03 for those with isolated CPCs to 0·4 if there was one additional abnormality and 20·5 if there were two or more additional abnormalities. It was concluded that if the cysts are apparently isolated, the risk for trisomy 18 is only marginally increased and maternal age should be the main factor in deciding whether or not to offer fetal karyotyping. If one additional abnormality is found, the maternal age-related risk is increased, so that even for a 20-year-old the risk for trisomy 18 is at least as high as the risk for trisomy 21 in a 35-year-old. In this respect, it may be considered desirable to offer such patients the option of karyotyping.     

Isolated choroid plexus cysts—the need for routine offer of karyotyping

The management of isolated fetal choroid plexus cysts remains controversial. We have prospectively studied 15 565 pregnancies at two large obstetric units for the presence of choroid plexus cysts. In all cases where cysts were present at 19 weeks' gestation or greater, and were multiple, bilateral or solitary and greater than 5 mm maximum diameter, women were offered amniocentesis or placental biopsy, irrespective of the presence or absence of other abnormalities. Choroid plexus cysts were present in 152 (0·98 per cent) of cases. Four cases (2·6 per cent) of autosomal trisomy (three of trisomy 18, one of trisomy 21) were detected on prenatal karyotyping. In all cases, choroid plexus cysts were the only detectable prenatal anomaly. This study and a review of other large studies do not support the view that isolated choroid plexus cysts are a benign variant, the risk of trisomy being 1 in 82. Until further evidence is available, we recommend that cases of isolated fetal choroid plexus cysts at 19 weeks' gestation or greater should be offered prenatal karyotyping.     

Simultaneous placentacentesis and amniocentesis for prenatal karyotyping: Report on 250 cases

The efficacy and risks of simultaneous transabdominal chorionic villus biopsy (placentacentesis) and amniocentesis in the second and third trimesters were evaluated in 250 singleton pregnancies. The major indications were advanced maternal age (36·0 per cent), abnormal ultrasound findings (23·2 per cent), and low maternal AFP value (17·6 per cent). Nine abnormal karyotypes were found in placental tissue (3·6 per cent). The karyotypes of placental and amniotic cells were different in three cases, including two cases of false-positive mosaicism (08 per cent) and one case of a false-negative result (0·4 per cent) obtained by placental karyotyping. The problem of discrepant karyotypes in embryonic and extra-embryonic tissue does not seem to be restricted to the first trimester. The post-procedure fetal loss rate was estimated as approximately 1·8 per cent. We conclude that the procedure presented here combines the advantages of rapid karyotyping (placentacentesis) and high diagnostic reliability (amniocentesis). It does not seem to be necessary to restrict its use to late presentations and suspicious ultrasound findings.     

Risk assessment of amniocentesis between 11 and 15 weeks: Comparison to later amniocentesis controls

We studied 693 consecutive early amniocenteses (prior to 15 weeks) and found a spontaneous abortion rate to 28 weeks' gestation of 1·5 per cent. A control group of women having standard amniocentesis (15–20 weeks) experienced a 0·6 per cent fetal loss in the same period. There were no other apparent differences between the two groups. Early amniocentesis results are generally available 4–6 weeks before standard amniocentesis and 1–3 weeks after chorionic villus sampling (CVS). Alpha-fetoprotein (AFP) can be accurately assayed in 11- to 15-week amniotic fluid samples but additional studies are necessary to determine the accuracy of neural tube defect (NTD) detection. Including the present study, over 5800 early amniocenteses have been reported and the results suggest that this is a relatively safe prenatal diagnostic test and an alternative to CVS and later amniocentesis.     

An infant with trisomy 9 mosaicism presenting as a complete trisomy 9 by amniocentesis

We present a case in which amniocentesis performed at 33 weeks' gestation because of symmetrical intrauterine growth retardation and decreased amniotic fluid volume led to the prenatal diagnosis of a fetus with a karyotype of 47,XX,+9, t(1;20)(q42;p11.2) pat, i.e., with an extra chromosome 9 and a balanced translocation between chromosomes 1 and 20. At delivery, the baby showed clinical features of trisomy 9, yet chromosome analysis of the cord blood revealed no trisomy 9 cells, a finding confirmed by neonatal blood karyotyping. The balanced translocation was present in all cells. A skin biopsy confirmed trisomy 9 mosaicism with 10 per cent trisomy 9 cells. The baby died at 6 weeks and an autopsy was obtained. Chromosome analysis of different organs demonstrated different frequencies of the mosaicism of trisomy 9. The possible underlying mechanism for the discrepancy between the karyotype results by amniocentesis and those of other tissues is discussed.     

Increased incidence of cytogenetic abnormalities in chorionic villus samples from pregnancies established by in vitro fertilization and embryo transfer (IVF–ET)

We studied 201 pregnancies that were established by in vitro fertilization and embryo transfer (IVF–ET) and compared the frequency of cytogenetic abnormalities with that found in a large control population matched for indication group (advanced maternal age) and time of sampling. A total of 252 IVF–ET fetuses were cytogenetically analysed by either chorionic villus sampling (CVS; n = 80) or amniocentesis (n = 172). Eleven chromosome abnormalities were found in the CVS group (13·8 per cent); among them, a 45, X/46, X, dic(q11)/46, X, del(Y)(q11) mosaic that was found in an IVF pregnancy established by intracytoplasmic sperm injection (ICSI), four cases of trisomy 21, and three cases of trisomy 7 confined to the placenta. The results indicate a statistically significant three-to five-fold increase in both confined placental abnormalities (P<0·008) and true fetal chromosome anomalies (P<0·04). In the amniocentesis group, identical rates (1·7 per cent) of chromosome abnormalities were found in the IVF–ET and control groups. It is concluded that late first trimester, but not early second trimester, IVF–ET pregnancies are characterized by an increased frequency of cytogenetic abnormalities found at prenatal diagnosis.     

Sonographically determined anomalies and outcome in 170 chromosomally abnormal fetuses

Structural pathology and outcome were studied in 170 chromosomally abnormal fetuses. Numerical chromosomal abnormalities were established in 158 (93 per cent) cases, of which 110 (71 per cent) represented trisomies, 30 (18 per cent) Turner syndrome, and 18 (11 per cent) triploidy. Structural chromosomal abnormalities were diagnosed in 12 (7 per cent) cases. Gestational age at referral was significantly shorter for pregnancies with Turner syndrome than for the other chromosomal abnormalities. Referral before 20 weeks of gestation was mainly based on fetal structural pathology alone (92 per cent); after 20 weeks, patients were referred because of structural pathology combined with small for gestational age, oligohydramnios, or polyhydramnios. Referral as a result of suspected multiple organ pathology occurred in 73.5 per cent of pregnancies. An abnormal amniotic fluid volume was present in 59/170 (34.5 per cent) chromosomally affected pregnancies, i.e., oligohydramnios in 31 and polyhydramnios in 28 cases. Birth weight was below the tenth percentile in over half of the chromosomally abnormal fetuses, except for Turnersyndrome. Fetal outcome was poor, with a survival rate at 1 month of 30 per cent for trisomies which was mainly determined by trisomy 21 (14/18=77.5 per cent).     

Rare non-mosaic trisomies in chorionic villus tissue not confirmed at amniocentesis

This paper reports eight cases of non-mosaic, rare, and typically lethal trisomies diagnosed in chorionic villi and not confirmed by amniocentesis. Four cases were 47,XX, + 16; two cases were 47,XX, +2; one was 47,XX, + 12; and one was 47,XY, +7. There have been no known complications in any of these gestations. These eight cases were found in a series of approximately 12 000 samples processed in our laboratory (0.07 per cent). We conclude that (1) rare non-mosaic trisomy not reflecting the fetal condition is an occasional source of diagnostic ambiguity in chorionic villus sampling; and (2) when encountered, a follow-up amniocentesis should be recommended to the patient to confirm or rule out the abnormality. We propose the term ‘confined placental abnormality’ to describe non-mosaic trisomies and other related abnormalities found only in chorionic tissue.     

First-trimester maternal serum schwangerschafts protein 1 (SP1) in pregnancies associated with chromosomal anomalies

The relationship between first-trimester maternal serum Schwangerschafts protein 1 (SP1) and the karyotype of the pregnancy was examined in 692 women who underwent chorionic villus biopsy at 6–12 weeks. There were 30 pregnancies with abnormal karyotypes, consisting of 14 Down's syndrome (DS), eight trisomy 18, and eight other anomalies, two of which were mosaics. The normal ranges and medians for gestation were defined from the 662 cases in which the karyotype was normal. The median SP1 (0·5 MOM) of the abnormal group was significantly lower than that of the normal group (10 MOM). This relationship was maintained for the DS pregnancies (0·4 MOM) and for anomalies other than trisomy 18 (0·43 MOM) but not trisomy 18 (1·1 MOM). It is possible that the use of SP1 as a screening test for chromosome anomalies in the first trimester could have a 43 per cent detection rate for a 5 per cent false-positive rate.     

Transabdominal chorionic villus sampling in the second and third trimesters of pregnancy: Chromosome quality,reporting time,and feto-maternal bleeding

Transabdominal chorionic villus sampling (TA-CVS) was performed in 210 pregnancies from 13 to 38 weeks using a double-needle technique. The sampling success was comparable to first-trimester TA-CVS and the diagnostic success rate was 98.2 per cent for the short-term technique and 99.3 per cent for cultured villi. Two fetuses could not be karyotyped. We found the chromosome quality to be similar to that in the first trimester, comparing the number of G-bands and other chromosome attributes. There were no unintended losses in a group (n = 142) with no sonographic abnormality, except for one death in utero at 38 weeks, 20 weeks after sampling. Chromosomal aberrations were seen in 19 per cent of cases with abnormal sonograms (n = 58). One case of a discordant karyotype was found (false-negative prediction of Down's syndrome by the short-term preparation). There were no cases of fetal demise due to feto-maternal bleeding. It is suggested that double-needle TA-CVS in advanced pregnancies combines the advantages of rapid karyotyping of chromosomes of good quality and low risk for the fetus, and seems to be easier to practise and is probably safer than cordocentesis.     

Maternal urinary β-core fragment of hCG/creatinine ratios and fetal chromosomal abnormalities in the second trimester of pregnancy

Our aim was to evaluate the potential value of the ratio of the maternal urinary beta-core fragment of human chorionic gonadotropin (βC-hCG) to creatinine (Cr) in discriminating between normal pregnancies and pregnancies associated with fetal chromosomal abnormalities. We hypothesized that pregnancies with fetal chromosomal abnormalities had abnormal quantities of βC-hCG in the urine. The aims of the present study were to investigate retrospectively whether maternal urinary ratios of βC-hCG/Cr are abnormal in women carrying fetuses with chromosome aberrations and to determine normative median values and a reference range for βC-hCG/Cr between 14 and 19 weeks' gestation. Maternal urinary βC-hCG and Cr concentrations were measured in 150 healthy women from 14 to 19 weeks and compared with ten cases of fetal chromosomal abnormalities matched for gestational age. The preliminary cut-off points corresponded to 0·29 multiple of the normal median (MOM) and 2·83 MOM, which were equivalent to the tenth and 90th centiles of the normal range. Of ten cases of fetal chromosomal abnormalities, one out of one (100 per cent) case with trisomy 18 and three of four (75 per cent) cases of variant 9 chromosome had low βC-hCG/Cr (≤0·29 MOM). One of five (20 per cent) cases with Down syndrome had elevated βC-hCG/Cr (≤2·83 MOM). Urinary βC-hCG/Cr ratios obtained in the second trimester may be useful for improved detection efficiency of Down syndrome, trisomy 18, and inversion of chromosome 9. Second-trimester maternal urinary βC-hCG/Cr should be investigated further as a potential marker for fetal chromosome anomalies.     

Maternal age-specific risks for trisomies at 9—14 weeks' gestation

This study provides data on the incidence of fetal trisomies 21, 18, and 13 at 9–14 weeks' gestation in women aged 35–45 years and estimates of maternal age-specific risks in women aged 20–45 years. Our data from 5814 singleton pregnancies undergoing first-trimester karyotyping for the sole indication of maternal age ⩾ 35 years were combined with those from two previous reports and the incidence of the trisomies was calculated from a total of 15 793 pregnancies. Comparison of incidences at 9–14 weeks' gestation with published data at 15–20 weeks' gestation and in livebirths demonstrated that at birth the maternal age-specific incidence of trisomy 21 is 33 per cent lower than at 15–20 weeks' gestation and 54 per cent lower than at 9–14 weeks' gestation. Furthermore, the relative frequency of trisomies 18 and 13 decreases from 30 per cent at 9–14 weeks to 22 per cent at 15–20 weeks and 14 per cent at birth.     

Tertiary centre referral of small-for-gestational age pregnancies: A 10-year retrospective analysis

Between 1981 and 1991, 461 pregnant women between 15 and 40 weeks of gestation (mean 30 weeks) with completed follow-up were referred to our centre for prenatal diagnosis because of a small-for-gestational age (SGA) fetus or combined SGA and structural abnormality. The referral diagnosis was based either on biparietal diameter measurements or on measurement of the upper-abdominal circumference. SGA in our centre was defined as a fetal upper-abdominal circumference below the tenth centile. SGA was confirmed by ultrasound in 75 per cent of the fetuses, whilst combined SGA and fetal structural abnormality was substantiated in only 16 per cent of the fetuses. However, in our centre structural abnormality was detected in 34 fetuses who were referred because of SGA alone. Nearly half of the structurally normal SGA fetuses displayed a normal head-to-abdomen (H/A), ratio, whereas an increased H/A ratio was found in 13/15 fetuses with an abnormal karyotype. An abnormal karyotype was present in 20 fetuses, which is 7 per cent of the total SGA population. Nearly 50 per cent represented triploidy associated with oligohydramnios. SGA was confirmed by a birth weight below the tenth centile in 89 per cent, below the fifth centile in 77 per cent, and below the 2·3rd centile in 55 per cent of infants. Structural abnormality was confirmed in 65 per cent of infants, whereas in 19 per cent of infants the abnormality was missed or a misclassification was made. Perinatal mortality was 31 per cent for all SGA fetuses, 27 per cent for SGA fetuses without anomalies, and 64 per cent for SGA fetuses with structural abnormality.     

Prenatal diagnosis by chorionic villus sampling: Lessons of the first 600 cases

Chorionic villus sampling (CVS) has emerged as a first trimester alternative to amniocentesis for the prenatal detection of genetic disorders. We report our experience in 600 consecutive CVS procedures to better delineate the safety, efficacy and reliability of this new method of prenatal diagnosis. Adequate samples were obtained at the initial visit in 97 per cent of the cases, and successful cultures were established in 98.7 per cent of these patients. Chromosome abnormalities were detected in 5.9 per cent of those pregnancies tested because of advanced maternal age (≥ 35 years). A discrepancy between the villus karyotype and that of the fetus was found in 2.0 per cent of cases, and most commonly consisted of mosaicism in the villus sample for a chromosomal abnormality that was not found in fetal samples. The risk of spontaneous abortion following the procedure was 6.3 per cent. We conclude that chorionic villus sampling is an acceptably safe and reliable procedure, but further investigation is needed before it can become an established technique in prenatal diagnosis.     

Evaluation of transcervical chorionic villus sampling with a completed follow-up of 1550 consecutive pregnancies

Data from 1550 consecutive pregnancies after first-trimester prenatal diagnosis by transcervical chorionic villus sampling (TC-CVS) are presented. The sampling efficacy was 97.8 per cent; the mean amount of collected villus tissue was 23 mg (range 5–100 mg). There were 97 affected fetuses, mainly (73.2 per cent) with a chromosomal abnormality or a male karyotype in carriers of X-linked disease. Pregnancy termination in these and four other women for social reasons resulted in 1449 continuing pregnancies. In these pregnancies, the fetal loss rate up to 28 weeks of gestation was 5.1 per cent with the highest loss rate (3.9 per cent) before 16 weeks. When relating this fetal loss rate to maternal age, this was 6.1 per cent in the advanced maternal age group (⩾36 years) against 3.1 per cent in the younger age group. In 1376 pregnancies continuing beyond 28 weeks, the perinatal mortality rate was 1.1 per cent; the percentage of non-genetic congenital anomalies was 0.9 per cent. The reproductive pattern of women at high genetic risk after CVS followed by pregnancy termination was evaluated. Within 12 months after the first CVS followed by pregnancy termination, 70 percent of women again requested CVS in a subsequent pregnancy.     

Amniotic fluid levels of human chorionic gonadotropin and its alpha and beta subunits in second-trimester chromosomally abnormal pregnancies

Amniotic fluid from 135 pregnancies was assayed for human chorionic gonadotropin (hCG) and its free alpha (ahCG) and free beta (bhCG) subunits. Forty-six chromosomally abnormal pregnancies between 14 and 20 weeks' gestation were matched with 89 chromosomally normal samples. Compared with controls, trisomy 21 pregnancies exhibited significantly elevated levels of all three peptides, whereas trisomy 18 gestations gave rise only to significant elevation of ahCG. Female fetuses in both the trisomy 21 and trisomy 18 pregnancies provided significantly elevated levels of hCG and bhCG compared to their male counterparts. On converting the values to multiples of the median, it was determined that 6 of 7 trisomy 18 samples had abnormally elevated alpha/beta ratios, as did 6 of 21 Down's syndrome pregnancies. Further, 11 of 21 trisomy 21 gestations had abnormal amniotic fluid hCG levels. Using only ahCG, bhCG and their ratio, a 61 per cent sensitivity was found for these trisomies, with a 96 per cent specificity.     

Comparison of first-trimester transvaginal amniocentesis with chorionic villus sampling and mid-trimester amniocentesis

Between August 1989 and December 1991, 356 patients underwent first-trimester transvaginal amniocentesis (10–12 weeks). The same number of patients referred in the same period for mid-trimester amniocentesis (14–21 weeks) was matched also for maternal age and indication. A third group consisted of the first 356 cases in which chorionic villus sampling (CVS) was attempted. The overall success rate was 99·7 and 100 per cent for early and mid-trimester amniocentesis, respectively, and 97·2 per cent for CVS. The mean harvesting time was 12·8, 11, and 7·9 days, respectively. The percentage of patients rescheduled was 3·4 per cent in first-trimester amniocentesis, 1·7 per cent in mid-trimester amniocentesis, and 6·2 per cent in the CVS group. The early (less than 2 weeks) pregnancy loss was 1·7 and 0·6 per cent in early and mid-trimester amniocentesis, respectively, and 1·7 per cent in CVS. The total pregnancy loss was 3·2, 0·9, and 2·9 per cent, respectively. The rate of preterm birth was 6·0, 5·2 and 6·9 per cent, respectively. The results indicate that CVS has the shortest procedure-result interval, but the highest rescheduling rate. First-trimester amniocentesis has a higher procedure and laboratory success rate but, until otherwise proved, mid-trimester amniocentesis is the most efficient and safest procedure.     

Discrepant karyotypes after second- and third-trimester combined placentacentesis/amniocentesis

Cytogenetic data are presented from a total of 1306 consecutive pregnancies with successful diagnosis obtained from both chorionic villi after short-time culture (CVS-SC) and amniotic fluid cell cultures (AC); samples had been taken simultaneously at combined placentacentesis (placental biopsy) and amniocentesis during the second (92·8 per cent) and third (7·2 per cent) trimesters. Concordant results were obtained in 1218 pregnancies with a normal karyotype and in 62 pregnancies with an aberrant fetal karyotype. Discrepant, i. e. false-positive and false-negative, results were found in 26 cases (2 per cent). From these data the accuracy of CVS-SC, defined as the proportion of all correct diagnoses, is calculated to be 98 per cent. Three non-mosaic and 14 mosaic false-positive results obtained after CVS-SC could not be confirmed by AC. Related to 1235 true normal fetal karyotypes, the specificity of CVS-SC, i.e. the proportion of normal karyotypes correctly diagnosed, amounts to 98·6 per cent. In nine pregnancies, an aberrant fetal karyotype detected after AC was missed by CVS-SC. The sensitivity of CVS-SC, i.e. the proportion of abnormal fetuses correctly diagnosed (62 out of 71), amounts to 87·3 per cent in our study group.