Primary alcohols and phosphatidylcholine metabolism in rat brain synaptosomal membranes via phospholipase D

The prognostic value of maternal serum triple analyte screening with AFP, hCG and uE3 (unconjugated estriol) was studied early in the second trimester of pregnancy. In this case-control study of 38 women and 76 matched controls derived from a consecutive screened population of 28,897, case selection was based upon elevated MSAFP and MShCG (> or = 2 MOM) and low MSuE3 (< or = 0.6 MOM). Adverse pregnancy outcome was found in 65.8% of cases and 2.6% of controls (RR 25, 95% CI 6.3-100.0). When increased odds (> or = 1 in 270) for Down's syndrome were considered with the abnormal analyte screen, fetal/congenital defects, fetal neonatal loss or low birth weight were noted in 17/26 cases (65.4%). Elevated MSAFP and MShCG with low values for estriol, with or without increased odds for Down's syndrome, imply an unfavorable prognosis for both the fetus and the child.     

Endocrine analytes in multiple-marker screening

Prenatal serum screening is based on the observation that secretory products of the placenta and fetus are altered in maternal serum of pregnancies affected with certain birth defects. Most of these products are hormones that have been previously characterized, although the pathophysiologic basis of the altered maternal serum levels of these products that occurs in association with fetal chromosome for the most part is unknown. Prenatal serum screening is in a period of transition, with the relatively recent advance of second trimester triple-marker screening (AFP, uE3, hCG) and now the improved performance of the four-marker test that adds inhibin. A. Proposed first trimester screening and other new second trimester serum markers may dramatically change prenatal screening practices as we enter the next century.     

Quantitative study on the effect of osthole on proximal tibiae in ovariectomized (OVX) rats

OBJECTIVE: To determine if a correlation exists between the level of maternal serum alpha-fetoprotein (MSAFP) elevation and the rate of adverse pregnancy outcome, to examine the timing of pregnancies ending in fetal or neonatal death, and to develop a protocol for antepartum surveillance in an effort to prevent these adverse outcomes. STUDY DESIGN: Singleton pregnancies with a single second-trimester elevated MSAFP > or = 2.0 multiples of the median (MoM) were eligible if a targeted ultrasound evaluation (< 24 weeks) was in agreement with the dates and no fetoplacental anomaly was detected. Three groups were established based on the second-trimester MSAFP elevation: 2.0-2.49, 2.5-2.99 and > or = 3.0 MoM. RESULTS: Among the 383 patients enrolled, delivery data were available on 333 infants. Stratified by MSAFP elevations of 2.0-2.49, 2.5-2.99 and > or = 3.0 MoM, the rates of adverse pregnancy outcome were: (1) preterm birth: 14.3%, 15.6%, 20.3%; (2) small for gestational age at birth: 7.4%, 11.1%, 22.2%; and (3) perinatal deaths (neonatal and fetal): 2.6%, 3.3%, 5.6%. Seven pregnancy losses (three neonatal and four fetal deaths) occurred prior to 28 weeks. Of these seven, six fetuses exhibited intrauterine growth retardation by 23-26 weeks' gestation, and five of six were associated with MSAFP levels > or = 2.5 MoM. Four losses (two neonatal and two fetal deaths) occurred after 28 weeks. Of these, three involved structurally normal infants with normal growth who died after 34 weeks. All three of these pregnancies exhibited MSAFP elevations < 2.5 MoM. CONCLUSION: In pregnancies with an unexplained elevated second-trimester MSAFP, the rate of adverse pregnancy outcomes is increased with higher elevations. Any proposed program to improve pregnancy outcome in patients with unexplained MSAFP elevations must include efforts aimed at preventing preterm delivery, repeat ultrasound at 24-26 weeks to rule out early-onset intrauterine growth retardation in pregnancies with elevations > or = 2.5 MoM and fetal biophysical monitoring, even in normally grown fetuses, instituted at 32 weeks to detect fetuses at risk for intrauterine death.     

Antenatal screening for Down's syndrome

BACKGROUND: In 1968 the first antenatal diagnosis of Down's syndrome was made and screening on the basis of selecting women of advanced maternal age for amniocentesis was gradually introduced into medical practice. In 1983 it was shown that low maternal serum alpha fetoprotein (AFP) was associated with Down's syndrome. Later, raised maternal serum human chorionic gonadotrophin (hCG), and low unconjugated oestriol (uE3) were found to be markers of Down's syndrome. In 1988 the three biochemical markers were used together with maternal age as a method of screening, and this has been widely adopted. PRINCIPLES OF ANTENATAL SCREENING FOR DOWN'S SYNDROME: Methods of screening need to be fully evaluated before being introduced into routine clinical practice. This included choosing markers for which there is sufficient scientific evidence of efficacy, quantifying performance in terms of detection and false positive rates, and establishing methods of monitoring performance. Screening needs to be provided as an integrated service, coordinating and managing the separate aspects of the screening process. SERUM MARKERS AT 15-22 WEEKS OF PREGNANCY: A large number of serum markers have been found to be associated with Down's syndrome between 15 and 22 weeks of pregnancy. The principal markers are AFP, hCG or its individual subunits (free alpha- and free beta-hCG), uE3, and inhibin A. Screening performance varies according to the choice of markers used and whether ultrasound is used to estimate gestational age (table 1). When an ultrasound scan is used to estimate gestational age the detection rate for a 5% false positive rate is estimated to be 59% using the double test (AFP and hCG), 69% using the triple test (AFP, hCG, uE3), and 76% using the quadruple test (AFP, hCG, uE3, inhibin A), all in combination with maternal age. Other factors that can usefully be taken into account in screening are maternal weight, the presence of insulin dependent diabetes mellitus, multiple pregnancy, ethnic origin, previous Down's syndrome pregnancy, and whether the test is the first one in a pregnancy or a repeat. Factors such as parity and smoking are associated with one or more of the serum markers, but the effect is too small to justify adjusting for these factors in interpreting a screening test. URINARY MARKERS AND FETAL CELLS IN MATERNAL BLOOD: Urinary beta-core hCG has been investigated in a number of studies and shown to be raised in pregnancies with Down's syndrome. This area is currently the subject of active research and the use of urine in future screening programmes may be a practical possibility. Other urinary markers, such as total oestriol and free beta-hCG may also be of value. Fetal cells can be identified in the maternal circulation and techniques such as fluorescent in situ hybridisation can be used to identify aneuploidies, including Down's syndrome and trisomy 18. This approach may, in the future, be of value in screening or diagnosis. Currently, the techniques available do not have the performance, simplicity, or economy needed to replace existing methods. DEMONSTRATION PROJECTS: Demonstration projects are valuable in determining the feasibility of screening and in refining the practical application of screening. They are of less value in determining the performance of different screening methods. Several demonstration projects have been conducted using the triple and double tests. In general, the uptake of screening was about 80%. The screen positive rates were about 5-6%. About 80% of women with positive screening results had an invasive diagnostic test, and of those found to have a pregnancy with Down's syndrome, about 90% chose to have a termination of pregnancy. ULTRASOUND MARKERS AT 15-22 WEEKS OF PREGNANCY: There are a number of ultrasound markers of Down's syndrome at 15-22 weeks, including nuchal fold thickness, cardiac abnormalities, duodenal atresia, femur length, humerus length, pyelectasis, and hyperechogenic bowel. (ABSTRA     

Biochemical markers of trisomy 21 and the pathophysiology of Down's syndrome pregnancies

Using biochemical and immunocytochemical methods, we have investigated endogenous levels of various markers in tissues obtained from 67 Down's syndrome pregnancies after therapeutic abortion in the second trimester and in corresponding tissues from unaffected abortuses. Alpha-fetoprotein (AFP), intact and free beta human chorionic gonadotrophin (hCG), pregnancy-specific beta-1 glycoprotein (SP-1), placental alkaline phosphatase (PALP), pregnancy-associated plasma protein A (PAPP-A), and gamma glutamyl transferase (GGT) were investigated in placental tissue; AFP and GGT in fetal liver; and GGT in fetal intestine. The results indicate that maternal serum levels of placental products reflect those found in the placenta: intact hCG, free beta hCG, and SP-1 levels were elevated in Down's syndrome pregnancies, while PAPP-A and PALP levels were little changed. This suggests that membrane passage of these markers is not affected but there is altered synthesis of hCG and SP-1. AFP levels were strikingly elevated in placental homogenates and unchanged in liver homogenates from Down's syndrome pregnancies, while the levels in maternal serum were reduced, pointing to a possible transport defect specific to AFP. GGT levels were high in placenta and liver from Down's syndrome pregnancies but low in fetal intestine.     

Serum screening of pregnant women reveals Down syndrome. Analysis of biochemical markers for earlier detection

Second trimester maternal serum screening for fetal Down's syndrome (DS), using the AFP (alpha-fetoprotein), hCG (human chorionic gonadotrophin) and uE3 (unconjugated oestriol) triple test, is as well documented procedure associated with a DS-detection rate of about 70 per cent, for an amniocentesis rate of about 7 per cent. The triple test is relatively little used in the Nordic countries, though its wider use would result in more efficient diagnosis of DS and various fetal malformtions. The maternal age indication currently used leaves gravidae under 35 years of age without prenatal diagnostics, although it is in just this age group that the majority (70 per cent) of cases of fetal DS occur. In Denmark, where 12 per cent of gravidae undergo invasive diagnostic procedures, the proportion of induced abortions due to the procedures is far too high, in relation to the DS detection rates obtained. Maternal serum screening yields a much better ratio between the risk of abortion after amniocentesis and the likelihood of DS detection than does maternal age alone. Maternal serum screening at 7-14 weeks of gestation, using pregnancy-associated plasma protein A and free hCG beta subunit concentrations, will become available within the next few years, thus reducing the incidence of some of the psychological and technical problems associated with second trimester screening, especially that of third trimester abortion. Irrespective of whether it is performed in the first or the second trimester, maternal serum screening will be the cornerstone of prenatal DS diagnosis in the future.     

Contents of alpha-fetoprotein in the blood of pregnant women as a criterion of the presence of congenital heart defects in the fetus

alpha-Fetoprotein (AFP) was measured in the blood of 16 women pregnant with twins at various terms of gestation and 24 pregnant women whose fetuses were found to have anencephaly, patent spina bifida, gastroschisis, renal polycystosis, or Down's disease. In Down's disease AFP level was 7 ng/ml (0.17 multiple of medians, MoM) at 17 weeks gestation and 6 ng/ml (0.12 MoM) at 19 weeks. In the fetal abnormalities studied AFP level was 372 ng/ml on average (6.8 MoM) at 16 to 18 weeks gestation, this being about 10 times higher than the normal level. AFP level in twin pregnancy at the same period was 2.3 MoM. AFP measurements are important for the prenatal diagnosis of fetal status in order to plan follow-up of pregnancy and labor management.     

Amniotic fluid alpha-fetoprotein levels during midtrimester of trisomy pregnancies

To investigate the association between low amniotic fluid alpha-fetoprotein (AFP) and trisomy pregnancies, we retrospectively reviewed 26 trisomy pregnancies including 18 fetuses with Down's syndrome and eight with trisomy 18. The amniotic fluid AFP median values of Down's syndrome, trisomy 18, and the study groups were 0.73 MoM, 1.15 MoM, and 0.85 MoM, respectively. There was a significant difference between the mean values of the Down's syndrome-affected fetuses (0.78 +/- 0.29 MoM) and that of the control group (p < 0.001), whereas no such difference was found for that of trisomy 18-affected fetuses (1.16 +/- 0.38 MoM). Only three patients in the study group (3/26, 11.5%) had an amniotic fluid AFP value below 0.5 MoM, including the two cases of Down's syndrome (2/18, 11.1%) and one case of trisomy 18 (1/8, 12.5%). Most of the values for the trisomy pregnancies were within the normal range, thereby precluding the possibility of using this measurement as an alternative to fetal karyotyping as a screening test for Down's syndrome or other trisomy pregnancies.     

Maternal serum human chorionic gonadotropin as a marker for the delivery of low-birth-weight infants in women with unexplained elevations in maternal serum alpha-fetoprotein

We wished to ascertain whether the measurement of maternal serum human chorionic gonadotropin (MShCG) in the serum of pregnant women with unexplained elevations of maternal serum alpha-fetoprotein (MSAFP) would more precisely define those women at risk of adverse pregnancy outcomes. MShCG was measured in samples of serum obtained from women in the second trimester of pregnancy who had elevated MSAFP, normal Level II ultrasounds, and normal fetal karyotypes. Based on the characteristics of a receiver-operator curve for MShCG and birth weight, patients were divided into two groups and pregnancy outcomes were compared. Pregnant women with an unexplained elevation in MSAFP, who also had an abnormal MShCG (< or = 0.5 MoM > or = 2.5) were at significantly greater risk of delivering a low-birth-weight infant compared to women with a normal MShCG (43% and 15%, respectively; P = 0.013). They were also more likely to deliver a preterm infant (48% and 11.9%), respectively; P = 0.001). In the prediction of low birth weight, an abnormal MShCG had a sensitivity of 50%, a specificity of 81%, and a positive predictive value of 43%; in the detection of preterm delivery the values were 59%, 88%, and 48%, respectively. These findings suggest that in pregnant women with a second trimester unexplained elevation in MSAFP, abnormal MShCG levels may identify a group of women at high risk of preterm delivery or delivery of a low-birth-weight infant.     

A second unrelated bone marrow transplant with an unrelated donor marrow: treatment of a patient with relapsed leukemia

To investigate whether statistical parameters used in Down syndrome screening between 15 and 22 weeks of pregnancy can be used at 14 weeks, we assayed alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and inhibin-A in 16 pregnancies with Down syndrome in the 14th week of pregnancy and expressed values in multiples of the normal median. The median and standard deviation values for these 16 pregnancies were not materially different from those published for 15-22 weeks. It is reasonable, therefore, to offer Down syndrome screening using these markers starting at 14 completed weeks of pregnancy instead of 15 weeks. It needs to be recognized, however, that serum AFP measurement for neural tube defect screening is less effective at this time than between 16 and 18 weeks of pregnancy.     

Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) in the first trimester in association with abnormal fetal karyotype

OBJECTIVE: To assess the relation between maternal serum pregnancy associated plasma protein A (PAPP-A) in the first trimester and the outcome of pregnancy by karyotype. DESIGN: A retrospective study of PAPP-A levels in blood samples collected prior to chorionic villus sampling. SETTING: Milan, Italy. SUBJECTS: Five hundred twenty-two women aged 20 to 47, at 7 to 11 weeks gestation, prior to undergoing chorionic villus sampling. Four hundred forty-five women had a pregnancy with a normal karyotype; in 30 pregnancies the karyotype was abnormal (including 14 cases of Down's syndrome and 7 of trisomy 18). MAIN OUTCOME MEASURES: Normal or abnormal fetal karyotype. Serum PAPP-A at 6 to 11 weeks gestation measured by radioimmunoassay. RESULTS: The median value of PAPP-A in the abnormal group was 0.27 multiples of the normal median (MoM). This is significantly lower than the median value in the normal group (1.01 MoM) (95% CI for the difference 0.46-0.84 MoM; P < 0.00001 Mann-Whitney test). CONCLUSIONS: There is an association between low levels of PAPP-A in the first trimester with chromosome anomalies. Screening by measurement of PAPP-A might detect 60% of cases of Down's syndrome in the first trimester with a false positive rate of 5%.     

Serum markers for Down's syndrome in relation to number of previous births and maternal age

We conducted a study to investigate the effect of parity on the following six serum markers used in screening for Down's syndrome, after adjusting them for ethnic group and maternal weight: alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha-hCG, free beta-hCG, and dimeric inhibin A. We aimed to estimate the effect of adjusting for any differences found on the screening performance. AFP, uE3, and hCG concentrations were available from 16,666 women with singleton pregnancies without Down's syndrome or neural tube defects and without insulin-dependent diabetes mellitus, who were screened between 15 and 22 weeks' gestational age. Stored serum samples were available on a subset of 1347 women and these were used to measure free alpha-hCG, free beta-hCG, and inhibin A. Serum concentrations were expressed as multiples of the median (MOM) for women of the same gestational age, weight, and ethnic group. Of the six markers, only hCG levels were affected by parity; hCG levels decreased by 3.1 per cent per previous birth (95 per cent confidence interval 2.2-4.0 per cent); there was no significant relationship between the number of previous abortions and hCG level after adjustment for the number of previous births. The effect of previous births on hCG was not due to maternal age. Only AFP was affected by maternal age, but the effect was small; levels increased by 4.4 per cent per 10 years of age (3.2-5.7 per cent). It is not worthwhile adjusting serum markers for parity or for maternal age in prenatal screening for Down's syndrome because their effect on the performance of screening is negligible.     

Inclusion of serum marker measurements from a previous pregnancy improves Down syndrome screening performance

A predisposition for high or low levels of serum marker concentrations in second trimester Down syndrome screening reflecting itself in consecutive pregnancies in the same woman has been demonstrated, but hitherto the possible effect of including previous marker results in a current risk evaluation has been considered negligible. Using published data on correlations between the markers AFP, hCG and uE3 in different normal pregnancies in the same women and age-related a priori probabilities we found, that in triple marker screening the inclusion of results from a previous pregnancy in a likelihood ratio based risk calculation could increase the detection rate for women having had an earlier pregnancy from 68.0 per cent to 70.2 per cent at a risk cut-off = 1:250. The screen positive rate for normals for the same population of women, being on average older than the total population, fell from 7.1 per cent to 6.8 per cent. These figures, that are based on an assumption of the same correlations between one normal and one Down syndrome pregnancy as between two normal pregnancies, corresponds to an expected reduction, in the population considered, of the number of children born with Down syndrome of 6.7 per cent and of the number of screen positive normals of 4.7 per cent. Considering that this can be achieved at no extra cost, it is concluded that implementation of a procedure for taking information from previous pregnancies into account in second trimester screening should be considered at centres that can handle the software problems involved in doing so. However, better data on the correlations between a normal and a subsequent Down syndrome pregnancy in the same woman should probably be awaited before this is done.     

Effect of allowing for ethnic group in prenatal screening for Down's syndrome

We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.     

Usefulness of cytopathology and histology in the evaluation of Barrett''s esophagus in a community hospital

BACKGROUND: Beh?et's syndrome is an immune-mediated connective tissue disorder, and its primary manifestations are oral and genital ulcerations. To our knowledge no cases of adverse fetal outcome have been reported in pregnancies complicated by this disease. CASE: A 27-year-old primigravid woman with a diagnosis of Beh?et's disease came to our institution during the first trimester. Her pregnancy was complicated by several exacerbations of her disease including vaginal and oral ulcerations and abdominal pain. She was treated with steroids throughout her pregnancy. She had ruptured membranes and evidence of fetal distress at 361/2 weeks and subsequently delivered a severely growth-restricted fetus (< 3rd percentile). CONCLUSION: Pregnancies complicated by Beh?et's disease should be monitored closely for evidence of intrauterine growth restriction and fetal compromise, as are pregnancies complicated by similar connective tissue disorders.     

Hematological malignancies with a deletion of 11q23: cytogenetic and clinical aspects. European 11q23 Workshop participants

OBJECTIVE: Using receiver-operating characteristic (ROC) curves, we tried to determine the diagnostic threshold of amniotic fluid index (AFI) that will identify abnormal fetal size (birth weights under 2500 g or at least 4000 g) at 37 weeks or beyond. METHODS: We analyzed prospectively over 2 years all parturients with intact membranes and known AFI in early labor. Patients with the following conditions were excluded: pregestational or gestational diabetes, known anomalies, and preterm labor. Two ROC curves were constructed, and the areas (+/- standard error of the mean [SE]) under the curves were calculated. P < .05 was considered significant. RESULTS: Of the 1038 subjects meeting study criteria, 3.6% and 11.5% gave birth to infants who were small for gestational age (SGA) or macrosomic, respectively. Overall, 28.7% had oligohydramnios (AFI at most 5.0 cm) and 3.6% had hydramnios (AFI at least 24.0 cm). Small for gestational age was more common in patients with AFI at most 5.0 cm (6.4%) than in those with adequate fluid (AFI 5.1-23.9; 2.5%), or hydramnios (2.7%; P = .012). Macrosomic newborns were less likely to be born to women with oligohydramnios (7.7%) than to those with adequate amniotic fluid (13.1%) or hydramnios (13.5%). Areas under ROC curves are not significantly different from the area under the nondiagnostic line, indicating that AFI (0-34 cm) cannot differentiate between newborns under 2500 g and at or over 2500 g or under 4000 and at or more 4000 g. CONCLUSION: Intraparterium AFI appears to be a poor screening test to identify risk for delivery of SGA or macrosomic fetus.     

Maternal thyroid function in multiple pregnancy: the variable thyrotropic activity of human chorionic gonadotropin

The present study was undertaken to evaluate thyroid function and thyrotropic action of hCG in multiple pregnancy. We examined serum samples from 9 multiple pregnant women (3 triplets and 6 twins) and 27 singleton pregnant women as control subjects. Serum hCG levels in multiple pregnancy were higher than those in singleton pregnancy in the second and third trimesters (P < 0.01). The mean free T3 and T4 concentrations in multiple pregnancy did not differ from those in singleton pregnancy in each trimester. Serum hCG levels showed a statistically significant positive correlation with free T3 and T4 levels in singleton pregnancy (P < 0.001). However, these correlations were not observed in multiple pregnancy. Thyroid stimulation activity (TSA) determined by cAMP accumulation in FRTL-5 cells in multiple pregnancy sera was significantly higher than that in singleton pregnancy in the first trimester (P < 0.05), but did not differ in the second and third trimesters. Moreover, TSA did not show any correlation with serum hCG levels in multiple pregnancy in contrast with the results in normal pregnancy. A bioactivity/immunoreactivity ratio of hCG in multiple pregnancy was lower than in singleton pregnancy in the second and third trimesters. The discrepancy between immunoreactivity and thyrotropic activity of hCG may be caused by the variable thyrotropic potency of heterogeneous hCG molecules in multiple pregnancy.     

Taking account of vaginal bleeding in screening for Down's syndrome

OBJECTIVE: To derive a method for revising the risk of Down's syndrome in maternal serum marker screening when there is vaginal bleeding. The effect on screening performance of routinely allowing for the presence or absence of bleeding in all women is also assessed. DESIGN: Overview of published studies on the rate of reported vaginal bleeding in pregnancies with Down's syndrome, on the rate according to maternal age and on the association of bleeding with alpha-fetoprotein (AFP) level. The publications are supplemented with data on unconjugated oestriol (uE3), human chorionic gonadotrophin (hCG) and AFP levels in a consecutive series of screened women. SETTING: Routine Down's syndrome screening tests carried out on women having antenatal care at the St James's University Hospital, Leeds. SUBJECTS: Eight hundred and nine screened women. RESULTS: In five studies the rate of vaginal bleeding in Down's syndrome pregnancies was 1.7 times that in unaffected pregnancies on average. In three studies, the vaginal bleeding rate increased proportionally by 2.2% on average for each year of maternal age. Three studies and our own data were consistent with a 10% increase in the mean AFP level associated with vaginal bleeding, but it did not appear to materially alter uE3 and hCG levels or the standard deviations and correlation coefficients for any of the three analytes. An individual woman's risk was calculated by multiplying her age-specific odds of Down's syndrome by two likelihood ratios, one relating to the vaginal bleeding itself and one from the marker levels. Routine allowance for the presence or absence of vaginal bleeding was estimated to increase the detection rate by less than 1%. CONCLUSION: Our method is of clinical value in revising the risk when there is concern that vaginal bleeding might be responsible for a negative maternal serum Down's syndrome screening result. A policy of routinely incorporating information on vaginal bleeding in risk estimation for all women would have too small an effect on overall screening performance to recommend it.     

Screening of maternal serum for fetal Down's syndrome in the first trimester

BACKGROUND: Screening of maternal serum to identify fetuses with Down's syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester. METHODS: We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Down's syndrome. RESULTS: A total of 48 pregnancies affected by Down's syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Down's syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations. CONCLUSIONS: Screening for Down's syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.