Sensitivity and specificity of screening for Down syndrome with alpha-fetoprotein, hCG, unconjugated estriol, and maternal age.

The sensitivity and specificity of maternal serum screening for Down syndrome with different biochemical markers were evaluated. Detection rates with different combinations of maternal serum alpha-fetoprotein (MSAFP), hCG, and unconjugated estriol (uE3) were established by retrieving and analyzing 54 serum specimens from women with confirmed Down syndrome pregnancies, compared with 657 specimens from women with normal outcomes. With a risk cutoff of 1:270 at the second trimester, the detection rate with MSAFP, hCG, and uE3 was two to three times higher than with MSAFP alone. With all three markers, the detection rate for Down syndrome increased from 50 to 77% as maternal age increased, and was 60% in a representative screened population. If uE3 was omitted, the detection rate decreased from 60 to 48%. One thousand women were screened prospectively, either with MSAFP or with all three markers prospectively, either with MSAFP or with all three markers and 4.1% with MSAFP. With the three markers, the positive predictive value for Down syndrome was 2.2% overall and as high as 5.9% in older women. Therefore, the addition of hCG and uE3 to the maternal serum screen increases the positive predictive value by 50-300%, depending on maternal age. These results confirm the efficacy of screening for Down syndrome using maternal age and three serum markers.     

Extreme second-trimester serum analyte values in Down syndrome pregnancies with hydrops fetalis

Objective: To compare second-trimester maternal serum analyte values in Down syndrome pregnancies with, and without, hydrops fetalis. Methods: Seven hydropic and 85 non-hydropic Down syndrome pregnancies were identified among women with positive second-trimester maternal serum screening results. Values for maternal serum α-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), unconjugated estriol and inhibin-A, and risks for Down syndrome were compared using the non-parametric Mann-Whitney statistical test. Results: Hydropic Down syndrome pregnancies had significantly lower MSAFP and estriol concentrations, while hCG levels were higher. For subgroups of five hydropic and 42 non-hydropic cases, no statistically significant difference in the inhibin-A levels could be demonstrated. Conclusion: Second-trimester Down syndrome screening risks are significantly higher in affected pregnancies that are complicated by fetal hydrops.     

Down syndrome screening in women under 35 with maternal serum hCG.

Human chorionic gonadotropin and maternal serum alpha-fetoprotein (MSAFP) concentrations were measured in frozen maternal serum samples from 16 pregnancies with Down syndrome and from 614 unaffected pregnancies in women younger than 35. By using only maternal age and MSAFP level to determine Down syndrome risk, four of 16 (25%) Down syndrome pregnancies were identified, using risk estimates as a screening variable. This detection rate required performing amniocentesis on 4.8% of pregnancies with a normal outcome. By adding hCG level as a third risk parameter, ten of 16 (62.5%) Down syndrome pregnancies were detected. To achieve this detection rate, 4.7% of women under 35 would be recommended for amniocentesis. These results indicate that the estimation of risk for Down syndrome based on the addition of maternal hCG level to MSAFP level and maternal age will substantially improve the detection rate for Down syndrome, with no change in the amniocentesis rate. These findings are in agreement with other studies that suggest that hCG is a valuable addition to screening programs for Down syndrome.     

Unexplained elevated midtrimester maternal serum levels of alpha fetoprotein, human chorionic gonadotropin, or low unconjugated estriol: recurrence risk and association with adverse perinatal outcome

OBJECTIVE: To determine if women experiencing an unexplained elevated maternal serum alpha fetoprotein (MSAFP; > or =2.0 MoM) or human chorionic gonadotropin (hCG; > or =2.0 MoM), or low unconjugated estriol (E3; < or =0.5 MoM) in one pregnancy are at increased risk for similar results in a subsequent pregnancy, and to determine if recurrence of these analyte extremes is associated with adverse perinatal outcome. METHODS: We identified all women delivering two consecutive singleton pregnancies at one hospital between 1992-1997 for whom second trimester trisomy 21 serum screen was performed in each pregnancy. All screens were performed in a single laboratory. Each pregnancy delivered after 20 weeks and had gestational age confirmed by ultrasound prior to 24 weeks. Subjects were excluded if a fetal anomaly or aneuploidy was present. Adverse outcomes included abruption, oligohydramnios, preeclampsia, preterm membrane rupture, preterm delivery, stillbirth, birthweight <10th centile, and admission to neonatal intensive care unit (NICU). RESULTS: A total of 538 women had 1,076 pregnancies meeting inclusion criteria; 12/515 (2.3%) of women with a normal MSAFP, 28/470 (6.0%) with a normal hCG, and 11/504 (2.2%) with a normal E3 in the first pregnancy had an anomalous result for the respective analyte in the second pregnancy. In contrast, only 4/23 (17.4%) patients with an elevated MSAFP (P = 0.003), 14/44 (31.8%) with an elevated hCG (P < 0.001), and 2/10 (20.0%) with a low E3 (P < 0.025) in the first pregnancy had the same analyte anomaly recur in the second pregnancy. The odds ratios for recurrent elevated MSAFP, hCG, and low E3 were 7.5, 5.3, and 9.2, respectively. Adverse perinatal outcomes occurred with similar frequency, regardless of MSAFP, hCG, or E3 results in consecutive pregnancies, using women with normal MSAFP, hCG, and E3 results in one or both pregnancies as controls. CONCLUSIONS: Women experiencing an anomalous serum analyte in one pregnancy are at significant risk to experience the same analyte result in a subsequent pregnancy.     

Second-trimester maternal serum screening for Down syndrome in in vitro fertilization pregnancies

OBJECTIVES: To examine whether second-trimester maternal serum triple marker screening results differ between in vitro fertilization (IVF) pregnancies and naturally conceived pregnancies. METHODS: Second-trimester maternal serum triple marker screening results from 88 IVF pregnancies were compared with 596 naturally conceived pregnancies (controls). Controls were matched to each IVF pregnancy by maternal age, gestational age and date of blood collection. All pregnancies in the study were known to have normal outcome. Multiple of the median (MoM) levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and alpha-fetoprotein (AFP), and the false-positive rate for Down syndrome were compared between the two groups. RESULTS: No statistically significant differences in analyte levels or in Down syndrome false-positive rate were observed between the IVF and naturally conceived pregnancies. CONCLUSION: IVF patients can be counselled about maternal serum triple marker screening in the same manner as patients with naturally conceived pregnancies. There is no evidence to support the general use of analyte correction factors in the interpretation of second-trimester maternal serum screen results in IVF pregnancies.     

Comparison of triple-risk assessment of fetal trisomy 21 including total human choriogonadotropin (hCG) or its free beta-subunit (free beta hCG)

OBJECTIVE: Second trimester total hCG and free betahCG levels in maternal serum samples of 33 pregnancies affected by fetal trisomy 21 and of 188 matched controls were compared in a retrospective study. To find out differences of discriminating efficacy by using one of these markers a multivariate discriminant analysis was performed. METHOD: Statistical evaluation was performed for hCG/free betahCG frequency distributions. Discriminant analysis was carried out using the status 'affected' or 'unaffected' as the group variable and the serum markers unconjugated estriol (uE3), alpha-fetoprotein (AFP), and alternatively, hCG or free betahCG, as discriminant variables. RESULTS: The median of free betahCG MoM values in affected pregnancies was slightly higher (1.90 MoM) than the median of total hCG MoM values (1.72 MoM) but a lower standard deviation was stated for the logarithmic hCG MoM values (SD = 0.49) compared with free betahCG MoM values (SD = 0.51). A two-tailed Student's t test revealed no significant differences of hCG and free betahCG MoM values in both the affected and unaffected pregnancies. By inclusion of free betahCG the discriminant analysis classified 26 out of 33 affected cases correctly and 45 out of 188 unaffected cases incorrectly. For the inclusion of hCG these ratios were 25/33 and 41/188, respectively. Taking in account the individual maternal age risks at a defined false-positive rate of 5% including free betahCG yielded a higher detection rate than including hCG. However, using 1:380 (age-related at-term risk of a 35-year-old woman) as a cut-off risk including hCG yielded a higher detection rate than including free betahCG. CONCLUSION: For the observed cases none of the markers, hCG or free betahCG, was superior in Down syndrome screening.     

Detection of maternal serum hCG glycoform variants in the second trimester of pregnancies affected by Down syndrome using a lectin immunoassay

AIM: To assess whether glycoform variants of human chorionic gonadotrophin (hCG) are present in altered concentrations in the maternal serum in pregnancies affected by Down syndrome. METHODS: In a series of 50 cases of pregnancies complicated by Down syndrome and 278 unaffected pregnancies, we have examined maternal serum levels of hCG glycoforms (GlyhCG) in samples collected in the second trimester (14 to 21 weeks) using a sialic acid binding lectin immunoassay. We have compared these levels with those of other second trimester serum markers (Free beta-hCG, alpha fetaprotein (AFP) and Total hCG) and modelled detection rates and false positive rates of various biochemical markers in conjunction with maternal age using a maternal age standardized population. RESULTS: Maternal serum GlyhCG in cases of Down syndrome was significantly elevated (Median MoM 1.81) with 15 of 50 (30%) cases above the 95th centile for unaffected pregnancies. Free beta-hCG was also elevated (Median MoM 2.16) with 18 of 50 (36%) cases above the 95th centile. AFP levels were reduced (Median MoM 0.75) with 9 of 50 (18%) cases below the 5th centile. Total hCG levels whilst elevated (Median MoM 1.88) had only 15 of 50 (30%) cases above the 95th centile. Maternal serum GlyhCG levels showed significant correlation with total hCG and free beta-hCG (r = 0.6880 and 0.6922) in the Down group but not with AFP (r = 0.1237). When GlyhCG was combined together with AFP and maternal age, at a 5% false positive rate, the modelled detection rate was 53%, some 13% lower than when free beta-hCG was used and some 7% lower than when total hCG was used. CONCLUSION: Maternal serum GlyhCG, as measured by the sialic acid-binding lectin immunoassay is unlikely to be of additional value when screening for Down syndrome in the second trimester.     

The level of ADAM12-S in maternal serum is an early first-trimester marker of fetal trisomy 18

BACKGROUND: ADAM12-S is a pregnancy-associated insulin-like growth factor binding protein-3 (IGFBP-3) and IGFBP-5 protease present in human gestational serum. Recently, maternal serum levels of ADAM12-S were found to be markedly reduced during the first trimester of pregnancies with a Down syndrome (DS) fetus. On the basis of this finding, it was suggested that ADAM12-S might be a useful maternal serum marker of fetal chromosomal disease. OBJECTIVE: Retrospective examination of the use of ADAM12-S as a marker for fetal trisomy 18. METHOD: Serum samples were obtained from ten women during the first semester of their pregnancies with fetuses that had trisomy 18. An ELISA was used to determine the levels of ADAM12 in maternal serum. Results were compared to ADAM12-S levels, previously measured in the serum of 170 women carrying normal pregnancies during the first trimester. RESULTS: In all cases, the ADAM12-S concentration in maternal serum samples was lower in trisomy 18 pregnancies than in normal pregnancies, with a median multiple of the median (MoM) of 0.28 (p < 0.001) CONCLUSION: A reduced concentration of ADAM12-S in maternal serum is a promising marker for foetal trisomy 18, as well as for DS.     

First trimester biochemical screening for Down syndrome: free beta hCG versus intact hCG

To compare free beta hCG versus intact hCG in first trimester Down syndrome screening we analysed 63 cases of Down syndrome and 400 unaffected control pregnancies between 10 and 13 weeks' gestation. The Down syndrome median multiple of the median (MoM) was significantly higher (p=0.001) for free beta hCG (1.89 MoM) than for intact hCG (1.37 MoM). Although distributions for free beta hCG (unaffected, 0.2157; DS, 0.2322) are wider than for intact hCG (unaffected, 0.1697; DS, 0.2158), overall 27% of Down syndrome cases were above the 95th percentile for free beta hCG compared to 19% for intact hCG. Combined with maternal age, free beta hCG detected 45% of Down syndrome pregnancies at a 5% false positive rate. Intact hCG combined with maternal age demonstrated a detection efficiency comparable to maternal age alone (35% versus 32%). In contrast, a recent study (Haddow et al., 1998-NEJM 338: 955-961) indicated that intact hCG yielded a higher first trimester Down syndrome detection efficiency than free beta hCG (29% versus 25% respectively). Re-analysis of distribution parameters in the Haddow et al. study, however, show that free beta hCG was actually the better marker (23% detection for intact hCG versus 29% for free beta hCG).     

Triploidy identified through second-trimester serum screening

OBJECTIVES: To describe the maternal serum marker patterns of triploid pregnancies and estimate the second-trimester prevalence of triploidy. METHODS: Forty-two cases of triploidy were identified in six serum screening programmes, five in the United Kingdom, one in Canada. This study describes the serum marker patterns, serum screening results for Down syndrome, trisomy 18 and open neural tube defects, and maternal age of these triploidy cases. The risk cut-off levels were > or = 1 in 250 for Down syndrome, > or =2.5 MoMs alpha-fetoprotein for open neural tube defects and > or =1:100 for trisomy 18 screening. The estimated second-trimester prevalence of triploidy was based on 22 triploidy cases ascertained in 599 934 pregnancies from three routine screening programmes, which attempted complete ascertainment of aneuploidy cases. RESULTS: The observed second-trimester rate of triploidy was 0.37 per 10 000 fetuses. Two different serum marker patterns were seen in triploid pregnancies, distinguished from each other by typically very high or very low levels of total hCG or free beta-hCG. The median maternal ages were respectively 33 years for triploidy with human chorionic gonadotrophin levels < 1.0 MoM, and 26 years for those with hCG levels > or =1.0 MoM. Fifty-seven percent of the pregnancies with a triploid fetus had a risk estimate > or =1:100 for trisomy 18 alone, 10% had an alpha-fetoprotein > or =2.5 MoM, 5% were screen positive for Down syndrome alone, and 19% had an increased risk or positive results for more than one anomaly. CONCLUSION: The simultaneous use of maternal serum tests designed to screen prenatally for Down syndrome, neural tube defects, and an increased risk of trisomy 18 resulted in a screen-positive result for 90% of pregnancies with triploidy.     

Second-trimester double or triple screening for Down syndrome: a comparison of Chinese and Caucasian populations.

OBJECTIVES: To compare the performance of double screening (measuring maternal serum levels of alpha-fetoprotein [AFP] and total beta-human chorionic gonadotrophin [hCG] as markers for Down syndrome) with that of triple screening (also measuring levels of unconjugated estriol [uE3]) in the second trimester of pregnancy, and to compare ethnic variance between Chinese and Caucasian populations. METHODS: The study investigated 15096 normal singleton pregnancies and 24 pregnancies affected with Down syndrome. Frequency distributions of AFP, hCG, and uE3 levels were analyzed. Likelihood ratios (LRs) were calculated using the multiple of median value (MoM) of AFP, hCG, and uE3 as variables. After multiplying maternal age risk by the LR values for the markers used in double and triple screening, the specific risks obtained with double and triple screening were estimated. The detection rate (DR) and false-positive rate (FPR) were calculated at different cut-off points. The serum markers' levels were also compared with those of Caucasian women. RESULTS: The median MoM value of hCG was higher in women with affected pregnancies (1.40) than those with unaffected pregnancies (1.00). However, the median MoMs of AFP and uE3 (0.79 and 0.68) were lower in affected than in unaffected pregnancies. At a FPR of 5%, the detection rates reached with double and triple screening were 50% and 66.7%, respectively. Ratios of the 3 serum markers' medians to those in a study with Caucasian women were 1.06 (range=1.04-1.09) for AFP, 1.14 (range=1.10-1.17) for hCG, and 1.28 (range=1.23-1.41) for uE3 for the relevant gestational weeks. CONCLUSION: Triple screening performed better than double screening in the second trimester. Ethnic variance should be taken into account in Down syndrome screening.     

Maternal smoking: age distribution, levels of alpha-fetoprotein and human chorionic gonadotrophin, and effect on detection of Down syndrome pregnancies in second-trimester screening

OBJECTIVES: To study the levels of maternal serum alpha-fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the second trimester in smokers and non-smokers with unaffected and Down syndrome pregnancies; to examine the rate of smoking in different maternal age groups in a population having routine prenatal screening; and to assess the effect of smoking on the detection rates for Down syndrome and corresponding false-positive rates, both overall and in different maternal age groups. METHODS: Information on maternal smoking status, maternal age and serum marker levels was collected from case note searches and the screening programme database on 2272 unaffected singleton pregnancies, 36 unaffected twin pregnancies and 103 singleton Down syndrome pregnancies. RESULTS: In unaffected pregnancies the smokers had a median age 3.3 years less than the non-smokers, while in the Down syndrome cases the corresponding age difference was 2.0 years. Median analyte levels in multiples of the median (MoM) in the unaffected singleton pregnancies were, for non-smokers: AFP=0.97, hCG=1.04; and for smokers, AFP=1.04, hCG=0.80. In the Down syndrome pregnancies the medians were, for non-smokers: AFP=0.69, hCG=2.49; and for smokers, AFP=0.70, hCG=1.53. Correction for smoking status gave median MoMs of 1.0 for both AFP and hCG in the unaffected pregnancies in both smokers and non-smokers. In the Down syndrome cases the corrected medians were, for non-smokers: AFP=0.67, hCG=2.29; and for smokers, AFP=0.73, hCG=1.99. Before correction for maternal smoking the overall detection rate for Down syndrome was 66.7% with a false-positive rate of 6.2%. After correction the detection rate was 67.7% with a false-positive rate of 4.9%. Between the smoking and non-smoking groups there was a significant difference in the detection rate (37.5% versus 76.0%) and the false-positive rate (1.8% versus 8.1%), which disappeared after correction for smoking status (detection rate 62.5% versus 69.3%, false-positive rate 3.9% versus 5.4%). No evidence of a lower incidence of Down syndrome in smokers was found. CONCLUSIONS: While correcting AFP and hCG results for maternal smoking status will have little impact on the overall detection rate for Down syndrome, it may reduce the false-positive rate and will improve the accuracy of the risks given to individual women.     

Maternal serum hyperglycosylated human chorionic gonadotrophin (HhCG) in the first trimester of pregnancies affected by Down syndrome,using a sialic acid-specific lectin immunoassay

In a series of 54 cases of pregnancies complicated by Down syndrome and 224 unaffected pregnancies we examined maternal serum levels of hyperglycosylated human chorionic gonadotrophin (HhCG) in samples collected in the first trimester (11-13 weeks) using a sialic acid-specific lectin immunoassay. We compared these levels with those of other potential first trimester serum markers [free beta-hCG, pregnancy-associated plasma protein A (PAPP-A) and total hCG (ThCG)] and modeled detection rates and false-positive rates of various biochemical markers in conjunction with fetal nuchal translucency (NT) and maternal age using an maternal age standardized population. Maternal serum HhCG in cases of Down syndrome were significantly elevated (median MoM 1.97) with 24/54 (44%) of cases above the 95th centile for unaffected pregnancies. Free beta-hCG was also elevated (median MoM 2.09) with 33% of cases above the 95th centile. PAPP-A levels were reduced (median MoM 0.47) with 38% below the 5th centile. ThCG levels, whilst elevated (median MoM 1.34), had only 20% of cases above the 95th centile. Maternal serum HhCG levels were not correlated with fetal NT but showed significant correlation with ThCG and free beta-hCG and with PAPP-A in the Down syndrome group (r=0.536). Maternal serum HhCG levels in cases with Down syndrome had a significant correlation with gestational age, increasing as the gestation increased. When HhCG was combined together with fetal NT, PAPP-A and maternal age, at a 5% false-positive rate the modeled detection rate was 83%, some 6% lower than when free beta-hCG was used and some 4% better than when ThCG was used. Maternal serum HhCG is unlikely to be of additional value when screening for Down syndrome in the first trimester.     

Raised maternal serum placenta growth factor concentration during the second trimester is associated with Down syndrome.

OBJECTIVES: To compare early second-trimester maternal serum placenta growth factor concentrations in Down syndrome pregnancies and those in normal pregnancies. METHODS: A case-control study was performed to evaluate the maternal serum placenta growth factor concentrations in 36 Down syndrome and 320 normal pregnancies with matched gestational age during the second trimester. For the detection of serum concentrations of placenta growth factor, a quantitative sandwich enzyme immunoassay technique (R & D Systems Inc., Minneapolis, Minnesota, USA) was performed. RESULTS: Using a multiple linear regression model, maternal serum placenta growth factor level was associated with gestational age (p<0.001) and the existence of Down syndrome pregnancy (p<0.001). After converting maternal serum placenta growth factor concentrations of each analyte to multiples of the appropriate gestational median (MoM), placenta growth factor MoM (p<0.001) was revealed to be an independent variable for Down syndrome pregnancies after adjusting for the effects of maternal age (p<0.001), free beta-hCG (p<0.001) and AFP (p=0.014) by multivariate logistic regression analysis. CONCLUSIONS: Maternal serum placenta growth factor concentration was elevated in Down syndrome pregnancies during the early second trimester. Placenta growth factor might be a novel marker for maternal serum Down syndrome screening.     

The relationship between maternal serum alpha-fetoprotein and maternal haemoglobin

OBJECTIVES: To test the hypothesis that both second-trimester maternal serum alpha-fetoprotein (MSAFP) levels and Down syndrome-screening test are related to maternal haemoglobin concentration. METHODS: Three hundred and seventeen women in three groups according to their haemoglobin levels: normal haemoglobin concentration (between 10.5 and 13.2 g/dL) (n = 262; 82.6%), anaemia (less than 10.5 g/dL) (n = 11; 3.5%), or high haemoglobin levels (greater than 13.2 g/dL) (n = 44; 13.9%) were studied. MSAFP and Down syndrome risk (on the bases of maternal age, MSAFP and maternal serum beta-hCG concentrations) were recorded. RESULTS: MSAFP (MoM) was lower in women with high haemoglobin levels (0.79 MoM (0.66-1.14)) (p = 0.001) than in women with normal haemoglobin concentrations (1.00 MoM (0.81-1.26)). It was also decreased in women with anaemia (0.90 MoM (0.65-0.94)), even though the difference with women with normal haemoglobin levels was of borderline statistical significance (p = 0.06). The Down syndrome risk was higher in both anaemic women (1:850 (1:380-1:1400)) (p = 0.009) and women with high haemoglobin levels (1:1425 (1:460-1:3100)) (p = 0.036) than in women with normal haemoglobin concentration (1:1950 (1:800-1:5000)). A quadratic model was the best predictive model for both MSAFP (p = 0.02) and Down syndrome risk (p = 0.001) when considering maternal haemoglobin as the independent variable. CONCLUSIONS: MSAFP is decreased and Down syndrome risk is increased in both anaemic and pregnant women with high haemoglobin concentration. Further studies are needed to establish whether adjustments for maternal haemoglobin are needed when giving Down syndrome risks based on biochemical markers. Copyright 2004 John Wiley & Sons, Ltd.     

ADAM12: a novel first-trimester maternal serum marker for Down syndrome

OBJECTIVES: The concentration of bioavailable insulin-like growth factor (IGF) I and II is important to foetal growth. It is regulated by insulin-like growth factor binding proteins (IGFBP) 1 through 6. Proteolytic cleavage of IGFBP-3 takes place in human pregnancy serum; accordingly, IGFBP-3 serum levels decrease markedly during pregnancy. ADAM12 (A disintegrin and metalloprotease) is an IGFBP-3 and IGFBP-5 protease and is present in human pregnancy serum. The goal of this study was to determine whether ADAM12 concentration in maternal serum is a useful indicator of foetal health. METHODS: We developed an enzyme-linked immunosorbent assay (ELISA) for the quantification of ADAM12 in serum. The assay range was 42 to 667 micro g/L. Recombinant ADAM12 was used as the standard for calibration. RESULTS: We found that ADAM12 was highly stable in serum. Serum concentration increased from 180 micro g/L at week 8 of pregnancy to 670 micro g/L at 16 weeks, and reached 12 000 micro g/L at term. In 18 first-trimester Down syndrome pregnancies, the concentration of ADAM12 was decreased, thus the median multiple of mean (MoM) value was 0.14 (0.01-0.76). A detection rate for foetal Down syndrome of 82% for a screen-positive rate of 3.2% and a 1:400 risk cut-off was found by Monte Carlo estimation using ADAM12 and maternal age as screening markers. CONCLUSION: ADAM12 is a promising marker for Down syndrome.     

The effect of fetal gender on second-trimester maternal serum inhibin-A concentration

Second-trimester serum inhibin-A is increasingly used as a fourth marker in addition to the triple test to screen for Down syndrome. We investigated whether fetal gender had an effect on serum inhibin-A concentration. A retrospective analysis was done on 316 normal pregnancies and 48 Down syndrome pregnancies in which maternal serum inhibin-A assays were performed between 15 and 20 weeks of gestation and in which the fetal sex was known. The median inhibin-A MoM (95% CI) for normal pregnancies in the presence of a male fetus was 0.93 (range 0.88-1.03). This was significantly lower than that in the presence of a female fetus (median MoM=1.04). The gender difference was not observed in the Down syndrome pregnancies. The increased inhibin-A concentration would lead to a 2.3-fold higher false-positive rate in the presence of a female fetus (10.6% vs. 4.6%; p<0.05, Chi-square test). Because of the small number of cases studied, the results need to be substantiated by a larger series. If the gender effect is confirmed, adjustment for fetal sex may be necessary when inhibin-A is used as a screening marker.     

Detection of trisomy 18 by double screening in a low-risk pregnant population

OBJECTIVE: A combination of low concentrations of maternal serum alpha fetoprotein (MSAFP) and human chorionic gonadotropin (hCG) was used to screen for trisomy 18 in early 2nd-trimester pregnancies in a low-risk child-bearing population. METHODS: Women less than 37 years of age were offered screening between 15 and 20 weeks of gestation. Those pregnancies showing low concentrations of MSAFP (<0. 75 multiples of the median) and hCG (<0.5 multiples of the mean) were considered positive. If gestational age was confirmed, genetic counselling and invasive prenatal diagnosis were offered. RESULTS: Between January 1995 and December 1996, 19,491 women were screened, of whom 252 were found to be positive (1.25%). 145 invasive procedures were carried out, and 3 cases were detected. The odds of a fetus being affected after a positive screen result were 1 in 36. CONCLUSIONS: Measurement of low concentrations of MSAFP and hCG in pregnant women less than 37 years of age is an effective screening test for Edward's syndrome, but with regard to the natural history of this genetic condition, it can result in overuse of invasive tests which in turn can harm chromosomally normal pregnancies. This stresses the need to evaluate these pregnancies further with detailed ultrasonographic assessment and selective fetal karyotyping only.     

First-trimester maternal serum human thyroid-stimulating hormone in chromosomally normal and Down syndrome pregnancies

Maternal serum human thyroid-stimulating hormone (TSH) levels were investigated in chromosomally normal and Down syndrome pregnancies to determine whether TSH can be used as a marker for Down syndrome in the first trimester. Measurements were conducted on stored serum samples collected from 23 Down syndrome pregnancies and 115 unaffected pregnancies before chorionic villus sampling (CVS), between 9 and 11 completed weeks of pregnancy. The samples were matched for gestational age, maternal age, maternal weight and duration of storage of the serum sample. Maternal TSH concentration was slightly decreased in Down syndrome pregnancies, with a median of 0.84 multiples of the median (MoM). Maternal serum human chorionic gonadotropin (hCG) concentration was slightly elevated in Down syndrome pregnancies, with a median of 1.03 MoM. Both differences were not significant applying matched rank analysis (p=0.50 for TSH and p=0.43 for hCG). The association between TSH and hCG in unaffected pregnancies was also measured. The Spearman correlation coefficient between TSH and hCG was -0.21 which was statistically significant (p=0.02, 95% confidence interval -0.38 to -0.03). However, it was concluded that TSH is not a useful marker for distinguishing Down syndrome-affected pregnancies from normal pregnancies in the first trimester.