Compromise ultrasound dating policy in maternal serum screening for Down syndrome.

Routine ultrasound biometry is the method of choice for gestational dating when screening for Down syndrome. However, it is costly and an alternative policy is to restrict ultrasound to women most likely to have menstrual dating errors. This was evaluated by statistical modelling with parameters from 14,274 women screened between January 1997 and July 2001 using free beta-human chorionic gonadotrophin (free beta-hCG), alpha-fetoprotein (AFP) and unconjugated estriol (uE(3)). A total of 12,711 (89%) women had both ultrasound and menstrual gestations, but in 4101 (29%) women either the last menstrual period (LMP) was uncertain or a pill-withdrawal period, or there were irregular or abnormal length cycles. The LMP was not entered in the test request form for a further 1404 (9.8%) women. Routine ultrasound dating yielded a predicted detection rate higher than for menstrual dating by 3.9-7.1%, depending on the marker combination and cut-off. The false-positive rate was reduced by 0.2-1.1%. Selectively scanning the 39% with unreliable dates increased detection by 2.6-4.6%, and reduced the false-positive rate by 0.04-0.6%. Some centres only use the ultrasound estimate of gestation when it differs from the menstrual estimate by more than 7 days. Such a rule reduces the gain in detection rate to 2.5-4.6% for routine ultrasound and 1.7-3.1% with the compromise policy; the false-positive rate reductions are 0.06-0.6% and 0.0-0.3%, respectively. We conclude that if routine ultrasound is not financially and practically feasible, the compromise policy yields a clinically important improvement in screening performance compared to menstrual dating.

Maternal serum human chorionic gonadotrophin levels in systemic lupus erythematosus and antiphospholipid syndrome.

Maternal serum human chorionic gonadotrophin (hCG) levels were measured during the second and the third trimesters of pregnancy in patients with either systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). All results were expressed in multiples of the gestation-specific normal medians (MoM). The median MoM level in 17 samples from SLE patients was 1.48 compared with 0.79 MoM in 99 controls of similar gestation (p < 0.002, Wilcoxon Rank sum test). In contrast the median MoM level in 19 samples from primary APS patients was only 1.14. These preliminary findings should be further studied to evaluate the implications for Down syndrome screening, detection of SLE cases during pregnancy and the prediction of adverse outcome in SLE gestations.

Current awareness in prenatal diagnosis.

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of prenatal diagnosis. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General Interest; 3 Normal Fetal Development; 4 Gametogenesis and Pre-implantation Diagnosis; 5 First Trimester Diagnosis; 6 Second Trimester Diagnosis; 7 Fetal Diagnosis by Ultrasound and Other Imaging; 8 Maternal Screening; 9 Screening for Carriers of Genetic Abnormality; 10 Technological Developments; 11 Confined Placental Mosaicism and Uniparental Disomy; 12 Molecular Cytogenetics; 13 Fetal Cells in Maternal Circulation; 14 Fetal Therapy; 15 Psychosocial Aspects; 16 Epidemiology and Environmental Factors; 17 Developmental Pathology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

Serum inhibin A levels in pregnant women with systemic lupus erythematosus or antiphospholipid syndrome.

Maternal serum inhibin A levels are increased on average in pregnancies affected by Down syndrome (DS). However, some reports have found increased serum levels in women with pre-eclamptic toxaemia as well. In the current study, maternal serum inhibin A was retrospectively measured in a series of 32 serum samples from pregnant women previously diagnosed as having either systemic lupus erythematosus (SLE) or primary antiphospholipid syndrome (APS). For comparison, normal medians were calculated from 57 unaffected control pregnancies together with a total of 854 samples tested at 13-19 weeks of gestation as part of the routine antenatal DS screening. All results were expressed in multiples of the gestation specific normal medians (MoM). A cubic regression formula was fitted, weighting for the number of women tested at each gestation. The median MoM value in the 16 cases of SLE and the 16 cases of primary APS is 0.60 (95% confidence interval 0.40-0.91) and 0.88 (95% confidence interval 0.66-1.17), respectively. For primary APS this was not statistically significant, whereas the SLE patients had a highly statistically significant reduction of serum inhibin A (p<0.002, Wilcoxon Rank sum Test, 2 tailed). Six pregnancies in the SLE group had a complicated obstetric outcome, i.e. missed abortion, placental abruption, exacerbation of the underlying disease which necessitated delivery, and severe postpartum haemorrhage. In 85% of this subgroup, serum inhibin A levels were below the normal 10th centile. The current data suggest that serum inhibin A is decreased on average in SLE patients. Those preliminary results might have various obstetric implications such as antenatal DS screening of SLE patients, identification of pregnant women at risk of developing SLE, who have presented for routine DS screening and for monitoring SLE patients throughout their pregnancy.

Maternal urine hyperglycosylated hCG in pregnancies with Down syndrome.

Stored maternal urine samples were used to determine the distribution of hyperglycosylated human chorionic gonadotrophin (H-hCG) levels in pregnancies with Down syndrome. A total of 349 samples from singleton pregnancies, including 45 with Down syndrome, were tested at 10-19 weeks' gestation. Urinary concentration was allowed for by expressing H-hCG in ng per mmol creatinine. The median level in Down syndrome was 3.63 multiples of the gestation-specific median in unaffected pregnancies (p<0.0001, Wilcoxon rank-sum test, two-tail). However, creatinine levels were relatively low in cases and creatinine did not fully correct for concentration. When this bias was allowed for, the median level was 3.34 multiples of the normal median (MoM). The H-hCG elevation in affected pregnancies was more marked at 14 weeks' gestation or later: a median of 4.64 MoM and allowing for creatinine bias 4.46 MoM.

The effect of smoking in pregnancy on maternal serum inhibin A levels.

To assess the effect of smoking on maternal serum, second-trimester inhibin A levels, we studied a database of 1277 women undergoing antenatal serum screening. There were 75 smokers, 1008 non-smokers and 194 women in whom smoking status was undetermined. All groups were matched for age, gestation and parity. The median level of inhibin A in smokers was 1.47 multiples of the normal gestation-specific median (MOM) as compared with 1.01 MOM in non-smokers and 0.95 MOM in the undetermined group. The increase was highly statistically significant (p<0.0001, Wilcoxon rank sum test, two-tail). On the basis of these results we conclude that if inhibin A is used as a marker, adjustment for maternal smoking status may be necessary.

Measures of urine concentration in maternal urine screening for Down syndrome.

A study was carried out to assess eight methods of normalizing the level of urinary beta-core human chorionic gonadotropin (hCG) for variable urine concentration. We compared the standard approach--creatinine determination by the Jaffe method--with high performance liquid chromatography (HPLC) measurement of creatinine, osmolarity and optical density at five wavelengths. Urine samples were included from a total of 472 women with unaffected singleton pregnancies at 15 weeks' gestation. The median beta-core hCG value was determined for each decile group when the results were ranked in turn according to the different measures of urine concentration. Creatinine using the Jaffe method had a much stronger relationship with median beta-core hCG than the other measures. Linear regression across the decile groups gave an R2 value for Jaffe of 0.85 compared with HPLC of 0.53, osmolarity of 0.52, optical density at 405 nm of 0.72, at 450 nm of 0.57, at 490 nm of 0.33, at 570 nm of 0.34 and at 630 nm of 0.33. We conclude that when screening with urinary beta-core hCG measuring creatinine appears to be an adequate method of allowing for variable urine concentration.

Nomograms to help inform women considering Down's syndrome screening.

OBJECTIVE: To derive graphical information for use in counselling women considering whether or not to have maternal serum screening for Down's syndrome. DESIGN: Statistical modelling of the frequency distribution of estimated Down's syndrome risk for four marker combinations. RESULTS: Nomograms are provided showing for each maternal age: (a) the detection and false-positive rates, and (b) the proportion of pregnancies with different estimated risks. CONCLUSION: When screening is offered, clinicians need to have information readily available on test accuracy and the likely result, which is specific to the individual.

Urinary multiple marker screening for Down's syndrome.

We have examined the possibility of using multiple markers in maternal urine rather than serum in order to screen for Down's syndrome. Urine samples were available from 36 cases (24 Down's syndrome, five Edwards' syndrome, three Turner's syndrome, one Klinefelter's syndrome, one triploidy, one triple-X, one twin discordant for Down's syndrome) and 294 controls, including three twins. Three markers were tested: the beta-core fragment of human chorionic gonadotrophin (hCG), total oestrogen (tE) and the free alpha subunit of hCG. Levels were corrected for creatinine excretion and expressed as multiples of the gestation-specific median (MOM) level from the singleton controls. The median value for the singleton Down's syndrome cases was 6.02, 0.74, and 1.08 MOM for beta-core-hCG, tE, and alpha-hCG, respectively. The increases in beta-core-hCG and the reduction in tE levels were highly significant (P < 0.0001 and 0.005, respectively; Wilcoxon rank sum test) but the increase in free alpha-hCG was not (P = 0.40). On the basis of a mathematical model, the expected detection rate for a 5 per cent false-positive rate was 79.6 per cent for beta-core-hCG alone, which increased to 82.3 per cent when combined with tE. Aneuploidies other than Down's syndrome were characterized by low levels of tE and either low or high beta-core-hCG.