Second-trimester unconjugated oestriol levels in maternal serum from chromosomally abnormal pregnancies using an optimized assay

Second-trimester unconjugated oestriol (UE3) levels were measured retrospectively in maternal serum from 78 chromosomally abnormal pregnancies and 390 matched controls using a radioimmunoassay kit (Amersham AMERLEX-M) optimized for use in the second trimester. Reduced levels of UE3 were found in a group of 49 Down's syndrome pregnancies with a median UE3 level of 0·79 multiples of the median (MOM) of the controls. Four trisomy 18 pregnancies had UE3 levels less than 0·7 MOM. There was a highly significant level of correlation between alpha-fetoprotein (AFP) and UE3 levels in the controls (r = 0·25, P <0·01), the Down's syndrome pregnancies (r = 0·44, p 0·01), and the other chromosome abnormalities (r = 0·61, p0·01). When used as an additional marker to AFP and human chorionic gonadotrophin in screening for Down's syndrome, UE3 does not appear to add to the sensitivity of such screening.     

Urinary β-core human chorionic gonadotrophin: A new approach to Down's syndrome screening

Human chorionic gonadotrophin (hCG) is the most discriminatory maternal serum marker of Down's syndrome. We have carried out a study to establish whether urinary β-core-hCG, a major metabolic product of hCG, might be an even better marker. Urine samples were available from seven singleton pregnancies with Down's syndrome, and one each of Edwards' syndrome, triploidy, and twins discordant for Down's syndrome. β-Core-hCG levels were corrected for creatinine and expressed as multiples of the normal gestation-specific median (MOM) level derived from 67 singleton controls. There was a highly statistically significant elevation in level among the singleton Down's syndrome cases (P<0·0005; Wilcoxon rank sum test). All had levels exceeding 2 MOM with a median of 6·11 MOM (95 per cent confidence interval 3·7–10·0). The levels were extremely low in Edwards' syndrome (0·08 MOM) and triploidy (0·02 MOM), but the twin pregnancy discordant for Down's syndrome did not have a raised β-core-hCG level (0·64 MOM). The findings are sufficiently encouraging to investigate the possibility of urinalysis as a routine modality in the prenatal screening for Down's syndrome and other common serious aneuploidies.     

Prenatal detection of limb defects after chorionic villus sampling

Prenatal sonographic diagnoses of two cases of severe limb defects after first-trimester chorionic villus sampling (CVS) are presented. Pathological examination after elective termination correlated well with the prenatal sonographic findings. Although the relationship between CVS and limb defects remains controversial, careful ultrasound examination for possible limb defects in cases receiving CVS is recommended.     

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.     

Prospective intervention trial of a screening protocol to identify fetal trisomy 18 using maternal serum alpha-fetoprotein,unconjugated oestriol,and human chorionic gonadotropin

Two prenatal centres in New England, routinely using a screening protocol for fetal Down syndrome that included maternal serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), and human chorionic gonadotropin (hCG) measurements in combination with maternal age, adopted a separate screening protocol for trisomy 18. That protocol identified a pregnancy as being at high risk when AFP, uE3, and hCG measurements all fell at or below specified cut-offs (0.75, 0.60, and 0.55 multiples of the median, respectively), regardless of maternal age. Among the first 19 491 women screened, 98 (0.5 per cent) were found to have values which placed them in the high-risk category. Four of these women were subsequently found not to be pregnant. In two others, samples from non-pregnant individuals were found to have been incorrectly submitted for analysis in place of the samples from the pregnant women. All of the remaining 92 women were counselled and offered amniocentesis and fetal karyotyping. Eighty-eight (96 per cent) accepted. Karyotypes or birth outcomes were available on all 92 pregnancies. Six cases of trisomy 18 and one case of Turner syndrome were identified by karyotype. One case of trisomy 18 was identified for every 14 unaffected pregnancies offered amniocentesis. In the present prospective study, an estimated 85 per cent of the cases of trisomy 18 were identified. However, given the small number ofcases (six), the 95 per cent confidence interval for the detection rate is broad (40–95 per cent).     

A misdiagnosis of X-linked adrenoleucodystrophy in cultured chorionic villus cells by the measurement of very long chain fatty acids

A case is reported of a male fetus at risk of X-linked adrenoleucodystrophy who showed a normal cultured chorionic villus cell very long chain fatty acid (VLCFA) profile but at birth exhibited grossly abnormal plasma and cultured fibroblast VLCFAs. Maternal contamination or a sample mix-up was excluded by chromosome analysis and analysis of polymorphic markers. This is the second report of a fetus affected with this disorder who showed normal cultured chorionic villus cell VLCFAs. It highlights the importance of a proper audit of all prenatal diagnoses to evaluate method reliability.     

Prenatal diagnosis of glutaryl-CoA dehydrogenase deficiency: Experience using first-trimester chorionic villus sampling

We have performed prenatal diagnosis for glutaryl-CoA dehydrogenase (GDH) deficiency in 16 pregnancies at risk by measuring the enzyme activity in chorionic villus samples. In most cases, GDH activity was measured both in uncultured chorionic villus samples and in cultured chorionic cells. In 4 of the 16 cases, an affected fetus was predicted, while the remaining cases were found to be normal. In three of the four affected cases, GDH activity was measured in both uncultured and cultured chorionic cells and the correct diagnosis established by both measurements. In the fourth case, only cultured cells were investigated because the chorionic villus sample was too small for the direct assay. All four pregnancies predicted to be affected were interrupted and the diagnoses confirmed on the aborted material in three of the cases. In the fourth case, no material was available for investigation. Of the 12 pregnancies predicted to be unaffected, ten cases resulted in the birth of healthy unaffected babies while two pregnancies are still in progress.     

CA-125 as a maternal serum marker for Down's syndrome in the first and second trimesters

CA-125, alpha-fetoprotein (AFP), and human chorionic gonadotropin (HCG) were determined in maternal serum in the first trimester from 14 women with a Down's syndrome fetus and 61 women with a healthy fetus. In the second trimester, 15 and 60 serum samples were determined from women with a Down's syndrome and a healthy fetus respectively. In both trimesters, maternal serum CA-125 was found to be elevated in Down's syndrome pregnancies compared with controls. Using discrimination functions, our preliminary results indicate that CA-125 is a better marker than AFP and HCG respectively for a Down's syndrome fetus in the first trimester and improves the detection rate in the second trimester.     

Second-trimester levels of maternal urinary gonadotropin peptide in down syndrome pregnancy

Urinary gonadotropin peptide (UGP; β-core fragment), a major metabolite of human chorionic gonadotropin (hCG), was shown recently to be markedly elevated in Down syndrome pregnancy between 19 and 22 weeks of gestation. To confirm and extend this finding, we obtained maternal urine and matching maternal serum samples from 14 cases of Down syndrome and six other aneuploidies between 17 and 21 weeks of gestation. UGP was measured in all these samples and in 91 singleton control urines. Results were corrected for urinary creatinine level and expressed as multiples of the control median (MOM). hCG levels were assayed in all serum samples from the cases and compared with previously established reference values. The median UGP level in Down syndrome cases was 5.34 MOM (range 2.71–12.57); 88 per cent of the values were above the 95th centile of control levels after modelling. The median maternal serum hCG level for the same cases was 2.20 MOM (range 0.84–3.40); 36 per cent of the values were above the 95th centile. The level of UGP in every case including all other aneuploidies was higher than the comparable maternal serum hCG level. Elevated UGP measurements are strongly associated with fetal Down syndrome during the second trimester and could contribute to improved Down syndrome screening protocols that are more accessible and less expensive than are currently available.