Serum total oestrone, 17 beta-oestradiol and oestriol concentrations and FSH, LH and prolactin values were measured radioimmunologically in post-menopausal women before and after intra-vaginal application of 0.5 mg oestriol. While oestrone and oestradiol were not altered, there was a 3100% increase in the mean oestriol values within 1 or 2 h; pre-treatment levels were again reached 8 h later. Both gonadotropins were moderately decreased, the serum prolactin values appeared to be slightly elevated. Repeated intra-vaginal application of oestriol resulted in a significant rise of the mean serum oestriol levels while the other oestrogens remained unchanged. The same was true for FSH and LH, a considerable negative feedback was therefore excluded. Again there seemed to be a slight rise of the prolactin secretion. It was concluded that intra-vaginal administration of oestriol is a most suitable local and systemic oestrogen replacement therapy, which is more effective than the oral regimen.

Between September 1st 1990 and Juli 31st 1993, 5071 pregnant women were screened prospectively by the "triple-test", including maternal serum alpha-fetoprotein, human chorionic gonadotropin and unconjugated oestriol in order to detect chromosomal anomalies and open neural tube defects. The serum samples were collected in collaboration with the obstetricians of the region of West-Mecklenburg and North-West-Brandenburg. Laboratory testing using radioimmunoassays was performed between weeks 15 and 20 of gestation, all serum specimens being investigated in only one institution. The original alpha-software from Wald et al. was the basis for calculating the statistical risk for Down's syndrome. Pregnant women with a high risk for Down's syndrome (cutoff>> or = 1:250) were taken care of in a special outpatient clinic including procedures like amniocentesis and fetal blood sampling. Amongst 5071 pregnant women, 21 fetal anomalies were seen. Five cases of Down's syndrome, three of trisomy 18, one trisomy 13, two cases of triploidy and four cases of open neural tube defects, one 46 xy/45 x mosaic karyotype and one case of gastroschisis could be diagnosed correctly. One case of trisomy 21, one case of trisomy 18 and two open neural tube defects showed false negative results. Using the cutoff of 1:250 for prenatal detection of Down's syndrome and performing ultrasound routinely to determine gestational age, the sensitivity of the "triple-test" was 83.33% having a specificity of 92.68%. The predictive value of a positive test for prenatal diagnosis of Down's syndrome was 1.33%.(ABSTRACT TRUNCATED AT 250 WORDS)

Problems can arise in prenatal screening for Down syndrome when tests are performed in the first and second trimester and some women who have a negative first trimester test have a second trimester serum test. The second test result does not usually take account of the previous one being negative. Even if it does, it is often inaccurate. Using published data the extent of the error was examined. The age-specific risk of an affected pregnancy in such women will be lower than if no first trimester test had been performed. The distributions of the screening markers in affected and unaffected pregnancies will be different from those in unscreened women. If the appropriate age-specific risk and marker distributions are not used, error will arise. For example, a 35-year-old woman with nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (hCG) levels at the normal median would have a risk of 1 in 6500. If she then had the Triple Test with alpha-fetoprotein (AFP), unconjugated oestriol, and hCG levels of 0.7, 0.7 and 1.5 multiples of the median (MoM), respectively, her risk, ignoring the previous result, would be overestimated (1 in 95 compared with the correct estimate of 1 in 705). If the previous result was included, but the age-specific risk and second trimester marker distributions were not revised, her risk would be underestimated (1 in 820). If the correct age-specific risk and screening marker distributions were used, risk estimates would be accurate, but two tests would be less efficient than integrating all the screening information into a single test. The practice of offering second trimester serum screening to women who have already been screened is best avoided.

BACKGROUND

The incidence of Down syndrome (DS) in Egypt varies between 1:555 and 1:770 and its screening by triple test is becoming increasingly popular nowadays. Results, however, seem inaccurate due to the lack of Egyptian-specific information needed for risk calculation and a clear policy for programme implementation. Our study aimed at calculation and validation of the triple marker medians used in screening Egyptian females as well as to recommend programme conventions to unify screening in this country.

METHODS

The study was conducted on 668 Egyptian women, in weeks 15-20 of pregnancy as proven by sonar. Chorionic gonadotropin (CG), α-fetoprotein (AFP) and unconjugated oestriol (uE3) were measured on Siemens Immulite analyzer. Medians of the three parameters were calculated, regressed against gestational age (GA) and weighted by the number of participants/week. Equations were derived to adjust each parameter to the maternal weight and were centered on the median Egyptian weight. Prisca software was fed with the above data, multiples-of-median (MoM) and DS risks were calculated and the screening performance was evaluated at a mid-trimester risk cutoff of 1:270.

RESULTS

Log-linear [AFP/uE3 = 10(A+B*GA)] and exponential equations [CG = A*e (B*GA)] were derived and the regressed medians were found to follow similar patterns to other Asian and Western medians. Oestriol was always lowest (even halved) while CG and AFP were intermediate. A linear reciprocal model best fitted weight distribution among Egyptians and successfully adjusted each parameter to a weight of 78.2 kg. Epidemiological monitoring of these recommendations revealed satisfactory performance in terms of 6.7% initial positive rate and 1.00 grand MoM.

CONCLUSIONS

Adoption of the above recommendations is hoped to pave the way to a successful DS screening programme tailored to Egyptian peculiarities.

This study was designed to examine whether fetuses with Down syndrome (DS) identified through serum screening are different from those whose mothers have normal serum screening results. It was a retrospective follow-up study of pregnancies where maternal serum alpha-fetoprotein (MSAFP) concentrations were measured to identify women at increased risk of having a baby with a neural tube defect (NTD). An enhanced risk for NTD was the only reason for intervention in the screened population. Clinical features of fetuses or children with DS were related to the screening results. A retrospectively calculated term risk of 1/250 classified a pregnancy as having been at an elevated risk of DS. The outcome measures were fetal or neonatal death and severe somatic disease. Human chorionic gonadotrophin (hCG) and unconjugated oestriol (uE3) were measured retrospectively in frozen samples of the DS pregnancies and the same cut-off level was used for classification (so-called 'triple test'). Ten thousand women were included in the study. Pregnancy outcome was known in 93.5 per cent of the cases. Children with and without anatomic defects were found in all subgroups of test results combinations. All mothers of children with a congenital heart defect (CHD) had a DS risk of>> or = 1/250 according to the triple test.

Both a cross-sectional and a longitudinal study were performed to investigate whether or not the collection time should be taken into consideration when generating a patient's risk for fetal Down syndrome with multiple marker screening. Diurnal variations of third-trimester alpha-fetoprotein (AFP) levels and first-trimester human chorionic gonadotropin (hCG) levels have been previously reported. In addition, large episodic fluctuations of conjugated and unconjugated oestriol (uE3) as well as a diurnal variation have also been reported in the third trimester. If the levels of these analytes routinely fluctuate during the day, they could affect a patient's risk calculation for fetal Down syndrome. The longitudinal study evaluated ten non-diabetic women who underwent sequential sampling for AFP, hCG, and uE3. The cross-sectional study evaluated 1953 patients for these three markers whose time of sampling was recorded between 8.00 a.m. and 5.59 p.m. Using either study design, no significant effect was seen in the median MOM levels of the screening analytes as a function of the time of day.

Published studies have reached varying conclusions as to the benefit of replacing human chorionic gonadotropin (hCG) measurements with the free beta-subunit of hCG (the free beta-subunit) for Down syndrome screening. One study reports 14 per cent higher detection for the free beta-subunit, while another finds an actual loss in detection. To explore this issue further, we directly compared the screening performance of hCG and the free beta-subunit, alone and in combination with other serum markers, using banked sera obtained prior to amniocentesis and karyotyping. Altogether, 52 Down syndrome and 5065 unaffected pregnancies were studied. Sera were thawed and assayed for hCG and the free beta-subunit over 1 year. At a 5 per cent false-positive rate, the detection rate for hCG in combination with maternal age and alpha-fetoprotein was higher than when the free beta-subunit was substituted (62 versus 57 per cent). Ultrasound dating and adding unconjugated oestriol both increased detection. The present findings, along with those from six case control studies (our re-analysis), indicate that the screening performances of hCG and the free beta-subunit are similar (median change in detection 0, range -8 to +3 per cent). Under optimal sample collection and transportation conditions, laboratories can expect to achieve similar screening performance using either hCG or the free beta-subunit measurements.

OBJECTIVE

To check whether serum screening for Down syndrome and open neural tube defects satisfies the criteria set by the 'Committee Genetic screening' of the Dutch Health Council.

METHODS

Theoretical evaluation.

METHODS

Serum screening (the combined serum assessment of alpha-fetoprotein, human chorionic gonadotrophin and unconjugated oestriol, taking into consideration maternal age) was assessed against the Dutch Health Council criteria. The absolute criteria could be subdivided into a group of general conditions not related to a particular screening programme, and a group of programme-specific conditions.

RESULTS

Population serum screening satisfied some of the absolute criteria, while the programme-specific conditions should be realised in an actual screening programme. Psychological and community consequences of such a screening have not yet been investigated in the Dutch population.

OBJECTIVE

The object of this study is to examine the influence of maternal opiate use on the levels of second trimester biochemical markers for Down syndrome. Maternal opiate use is known to be associated with problems of placental origin and it is possible that the secretion of alpha-feto protein (AFP), free-beta human chorionic gonadotrophin (HCG) and unconjugated oestriol (UE) differs from that of a normal population.

METHODS

Seventy nine women who used opiates in pregnancy were compared to a control group of seventy nine women who did not use opiates and their adjusted marker levels analysed.

RESULTS

The adjusted median MoM in the opiate and control groups respectively were: AFP (1.00 vs 0.94), HCG (0.95 vs 1.04) and UE (0.96 vs 1.02), with no significant difference between these groups.

CONCLUSIONS

This study suggests that the current practice of calculating the risk of Down syndrome from second trimester biochemistry in women using opiate can be performed using data derived from a normal population.

Retarded BPD growth (less than 5th centile) is associated with low birth weight, preterm delivery, and increased perinatal mortality. However, 50% of the fetuses with deviating BPD growth in the 32nd week have normal weight at birth. In this study other biochemical and physical tests were applied to a group of fetuses with deviating BPD growth in order to improve the discriminatory rate between infants subsequently born AGA or SGA. Measurements of the ratio abdomen to head diameter were above the 50th centile in 72% of the infants born AGA and below the 50th centile in 75% of those born SGA. Circumference measurements were less useful in our hands. Urinary oestriol levels were not directly proportional to the intrauterine growth retardation. Recording of fetal breathing movements and nonstressed monitoring of fetal heart rate FHR) had little or no predictive value in the individual case although the incidence of fetal breathing movements was significantly lower in the group with retarded BPD growth.

Four serum biochemical fetoplacental function tests (HPL, unconjugated and total oestriol and AFP) were used to screen for intrauterine growth retardation in 793 patients attending an antenatal clinic. The birthweight corrected for sex, birth ranking and maternal size was used as an index of growth. The sensitivity and specificity of each test was calculated at varying cut-off points and plotted as 'Receiver Operator Curves'. HPL is clearly better than the oestriols or AFP with 80% sensitivity in detecting birth weights of less than the 5th centile when the 25th HPL centile is used as the cut-off point. However, the sensitivity of HPL is sufficiently low to make the value of screening questionable, particularly since 40% of all growth retarded infants were in mothers who did not attend antenatal clinic for screening and 25% of all growth retarded infants were detected by clinical examination.

Over a 15-month period, maternal serum screening (alpha fetoprotein, oestriol, chorionic gonadotrophin) and ultrasound were evaluated in the detection of all chromosomal abnormalities. Of the 981 screened, there were 8 chromosomally abnormal pregnancies. Six of these were considered to be at increased risk on serum screening, all of which were detected. Of the remaining 2, one was detected by ultrasound and the other resulted in a liveborn baby with trisomy 21. The positive and negative predictive values for serum screening for all chromosomal abnormalities was 7.8% and 99.9% respectively. The sensitivity and specificity was 87.5% and 91.5% respectively. Serum screening is useful in the detection of many chromosomal abnormalities, not just Down syndrome. The combination of maternal serum screening and ultrasound has a high negative predictive value and is valuable in providing reassurance of no underlying chromosomal abnormality. With a positive predictive value of 7.8% a chromosomal abnormality will be found once in every 13 amniocenteses performed.