Dose dependency between cigarette consumption and reduced maternal serum PAPP-A levels at 11-13+6 weeks of gestation

OBJECTIVE: To examine whether in smokers there is a significant dose dependency between the number of cigarettes per day and levels of free ss-hCG and pregnancy-associated plasma protein A (PAPP-A) at 11-13(+6) weeks of gestation. METHODS: This was a retrospective analysis of the maternal serum free ss-hCG and PAPP-A levels in relation to the maternal smoking status in 109 263 chromosomally normal singleton pregnancies that had undergone first-trimester screening for Down syndrome by a combination of fetal nuchal translucency thickness and maternal serum biochemistry. RESULTS: There were 95 287 nonsmokers and 13 976 cigarette smokers. The overall median PAPP-A MoM among cigarette smokers was 0.827, which was 19.6% lower than the value of 1.029 in nonsmokers (p < 0.0001 for log(10) MoM). The respective values for beta-hCG MoM were 1.003 for smokers and 1.035 for nonsmokers (p < 0.0001 for log(10) MoM) which corresponds to a reduction of 3.1%. There was a significant inverse relationship between the number of cigarettes per day and the level of PAPP-A MoM (r = 0.989, p < 0.0001) but not the level of free beta-hCG MoM (r = 0.733; p = 0.098). Using a statistical modeling approach we found that the screen-positive rate when correcting the PAPP-A MoM by an all or nil smoking factor was reduced by only 0.1% (3.75 vs 3.85%) when compared to correcting with a factor related to the smoking dose per day. CONCLUSION: In first-trimester screening for Down syndrome by maternal serum PAPP-A and free beta-hCG the impact of correcting for the dose dependant rather than the all or nil effect of smoking is marginal. However, a dose dependent correction improves the accuracy of the individual patient-specific risk.     

Influence of maternal systemic lupus erythematosus on first-trimester combined screening for chromosomal abnormalities

OBJECTIVE: To explore the effect of maternal systemic lupus erythematosus (SLE) on first-trimester screening markers for Down syndrome. METHODS: A retrospective study was conducted on 1150 normal singleton fetuses that underwent first-trimester combined screening for Down syndrome. Fetal delta nuchal translucency (NT), maternal serum PAPP-A and free beta-hCG were compared between pregnancies with SLE (n = 10) and without preexisting maternal disease (n = 1140). RESULTS: The medians +/- SD for delta NT, log(10) MoM of PAPP-A and free beta-hCG +/- SD in pregnancies with SLE and without maternal disease were - 0.18 +/- 0.29 versus - 0.18 +/- 0.33, 0.005 +/- 0.32 versus 0.02 +/- 0.26, and 0.22 +/- 0.19 versus - 0.014 +/- 0.28, with a p value of 0.7, 0.98 and 0.03, respectively. CONCLUSIONS: Patients with preexisting SLE have increased maternal serum-free beta-hCG levels in the first-trimester. But, because of the multimodal procedure of risk calculation there is no significant difference in the screen-positive rate after the combined first-trimester screening for trisomy 21.     

Does vaginal bleeding influence first-trimester markers for Down syndrome?

OBJECTIVES: To examine the effect of early vaginal bleeding on first-trimester screening markers for Down syndrome. METHODS: A retrospective study was conducted on 1755 normal singleton fetuses that underwent first-trimester combined screening for Down syndrome on the basis of ultrasound and maternal serum markers. Fetal delta-nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG were compared between pregnancies with (n = 252) and without (n = 1503) an episode of vaginal bleeding. Subgroup analysis for the intensity of bleeding (spotting n = 191; light n = 32; heavy n = 29) was performed. RESULTS: The median +/- SD (log(10)) for delta-NT, multiple of medians (MoM) PAPP-A and MoM free beta-hCG (corrected for maternal weight, smoking and ethnicity) was - 0.17 +/- 0.62, 1.10 +/- 0.28, 1.1 +/- 0.28 and - 0.15 +/- 0.51, 0.98 +/- 0.26, 0.94 +/- 0.3 in pregnancies with and without a history of early vaginal bleeding, which were not significantly different. Exclusion of patients with spotting from the vaginal bleeding group revealed significantly higher maternal serum free beta-hCG MoM values (median +/- SD (log(10))) compared to patients without bleeding, 1.29 +/- 0.27 vs 0.96 +/- 0.3(p = 0.011). Screen-positive (cut off of 1:350) rate after combined first-trimester screening was 28.1% in patients with light vaginal bleeding and 8.4% in patients without bleeding (p = 0.001). CONCLUSIONS: Light vaginal bleeding before first-trimester combined screening for Down syndrome leads to a higher screen-positive rate after combined first trimester screening, without a significant difference in serum levels of the screening markers.     

Early vaginal bleeding and first-trimester markers for Down syndrome

OBJECTIVES: To assess the effect of early vaginal bleeding on first-trimester markers for Down syndrome. METHODS: A retrospective study was conducted on 2330 normal singleton fetuses who underwent first-trimester combined screening for Down syndrome based on ultrasound and maternal serum markers. Fetal nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-hCG and the false-positive rate of the test were compared between pregnancies with (n = 253) and without (n = 2077) a history of early vaginal bleeding. RESULTS: The mean +/- SD log(10) MoM for NT, PAPP-A and free beta-hCG was -0.024 +/- 0.101, 0.007 +/- 0.244, 0.047 +/- 0.273 and -0.011 +/- 0.108, -0.006 +/- 0.223, 0.008 +/- 0.264 in pregnancies with and without a history of early vaginal bleeding, with a p value of 0.07, 0.40 and 0.03 respectively. The false-positive rate was 2.4% and 3.6% (p = 0.33). CONCLUSIONS: An earlier episode of vaginal bleeding is associated with an increase in maternal serum free beta-hCG levels at first-trimester combined screening for Down syndrome. However, this phenomenon is unlikely to significantly affect the false-positive rate of the test.     

The influence of maternal insulin-dependent diabetes on fetal nuchal translucency thickness and first-trimester maternal serum biochemical markers of aneuploidy

OBJECTIVE: To evaluate the influence of maternal insulin dependent diabetes mellitus (IDDM) on maternal serum free beta-hCG, PAPP-A and fetal nuchal translucency (NT), thickness at 11 to 13(+6) weeks of gestation in a large cohort of women screened prospectively for chromosomal anomalies. METHODS: Information on maternal IDDM status, maternal serum biochemical marker levels and fetal NT were collected from the prenatal screening computer records in two first-trimester screening centres. In total the control group included 33 301 pregnancies of which 16 366 had NT and maternal serum biochemistry results and 16 305 with NT only. The IDDM group included 195 pregnancies of which 79 had NT and maternal serum biochemistry results and 127 with NT only. The median maternal weight corrected free beta-hCG and PAPP-A, expressed as multiple of the median (MoM), and fetal NT, expressed as delta values, in the IDDM and non-IDDM groups were compared. RESULTS: There were no significant differences between the IDDM and non-IDDM groups in median maternal weight corrected free beta-hCG (IDDM 0.87 MoM, 95% Confidence Interval 0.75 to 1.16 MoM, non-IDDM 1.00 MoM), median maternal weight corrected PAPP-A (IDDM 1.02 MoM, 95% Confidence Interval 0.83 to 1.05 MoM, non-IDDM 1.01 MoM), or mean delta NT (IDDM 0.0358 mm, non-IDDM 0.0002 mm). CONCLUSIONS: In pregnancies with maternal IDDM, first-trimester screening for chromosomal defects does not require adjustments for the measured fetal NT. However, more data are required before the possible reduction in maternal serum free beta-hCG and the reduction of PAPP-A suggested by the published world series can be considered sufficiently important to take into account in the calculation of risks for chromosomal defects.     

Maternal serum free-beta-chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency thickness at 10-13(+6) weeks in relation to co-variables in pregnant Saudi women

OBJECTIVE: To establish normative values and distribution parameters of first-trimester screening markers, namely, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A), at 10 to 13(+6) weeks of gestation in Saudi women and to evaluate the effect of co-variables including maternal body weight, gravidity, parity, fetal gender, twin pregnancy, smoking and ethnicity on these markers. METHODS: A cohort of Saudi women (first cohort n = 1616) with singleton pregnancies prospectively participated in the present study, and fetal NT together with maternal serum free beta-hCG and PAPP-A were determined at 10 to 13(+6) weeks of gestation. The distribution of gestational age-independent multiples of the median (MoM) of the parameters was defined and normative values were established, and correction for maternal body weight was made accordingly. The influence of various co-variables was examined using the data collected from the first and the second (n = 1849) cohorts of women and 62 twin pregnancies, and compared with other studies. RESULTS: All markers exhibited log-normally distributed MoMs. Gestational age-independent normative values were established. Maternal body weight was corrected, particularly for maternal free beta-hCG and PAPP-A using standard methods. Fetal NT showed a negative relationship with increasing gravidity (r = -0.296) or parity (r = -0.311), whereas both free beta-hCG and PAPP-A exhibited a significant positive relationship. There was a significant increase in the MoM of free beta-hCG in female fetuses. Smoking decreased MoM values of free beta-hCG (by 14.6%; P < 0.01) and PAPP-A (by 18.8%; P < 0.001). Twin pregnancy showed significant increases in MoM values of free beta-hCG (by 1.87-fold) and PAPP-A (by 2.24-fold), with no significant changes in fetal NT MoM values. Fetal NT MoM values were lower in Africans and Asians but higher in Orientals, as compared to Saudi women (P < 0.05; in each case). MoM values (body weight-corrected) of free beta-hCG were 25.2% higher in Africans and 19.4% higher in Orientals but 6.8% lower in other Arabian and Asian (by 5.8%) women as compared to Saudi women (P < 0.05; in each case). CONCLUSIONS: The normative values and distribution parameters for fetal NT, maternal serum free beta-hCG and PAPP-A were established in Saudi singleton pregnancies, the maternal body weight together with smoking, twin pregnancy and ethnicity being important first-trimester screening co-variables. Gravidity, parity and fetal gender are also considered to influence one or more of the first-trimester markers examined.     

Between pregnancy biological variability of first trimester markers of Down syndrome and the implications for screening in subsequent pregnancies: an issue revisited

OBJECTIVES: To assess the level of correlation of first trimester biochemical and biophysical markers of Down syndrome between different pregnancies in the same individual. To assess the impact that between pregnancy biological variability has on the likelihood that women who are at increased risk in a first pregnancy being also at increased risk in a subsequent pregnancy. METHODS: During a three period women attending the OSCAR clinic at Harold Wood Hospital have had the opportunity to have first trimester screening for Down syndrome and other aneuploidies using the maternal serum biochemical markers free beta-human chorionic gonadotrophin (hCG) and pregnancy associated plasma protein-A (PAPP-A) in conjunction with fetal nuchal translucency (NT) thickness and maternal age. Of the 111,105 women undergoing such screening, the computer records were examined for women who had more than one pregnancy. The results from 1002 women with two normal singleton pregnancies were available for analysis. Marker correlations (as MoM) were established between the pregnancies and the proportion of women likely to be at increased risk in each pregnancy estimated, as was the likelihood of women being at increased risk in both pregnancies. RESULTS: For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r = 0.0959, p > 0.10). For maternal serum free beta-hCG MoM a significant correlation was found (r = 0.3976, p < 0.001), as was also found for PAPP-A MoM (r = 0.4371, p < 0.001). CONCLUSION: The implication for such between pregnancy marker association is that women who have an increased risk of Down syndrome in one pregnancy are two or three times more likely to repeat this event in their next pregnancy. This information may be useful in counselling women when undergoing first trimester screening in a subsequent pregnancy.     

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.     

Maternal serum screening for down syndrome in pregnancies conceived by intra-uterine insemination

The purpose of our study was to assess the influence of intra-uterine insemination (IUI) on the results of maternal serum Down syndrome screening. 43 women with IUI pregnancies and 4507 healthy women who conceived were studied. Ovulation in IUI pregnancies was induced by clomiphene and/or human menopausal gonadotrophin (hMG). Maternal serum levels of free beta-human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) were measured for Down syndrome screening. It was considered screen-positive when the risk of Down syndrome was 1 in 270 or greater in the second trimester. The value of maternal serum AFP was significantly lower in the IUI group (median=0.760 MoM) than in the control group (median=1.050 MoM). However, the value of free beta-hCG was not significantly different between the two groups. The positive rate of maternal serum Down syndrome in IUI pregnancies was similar to that of the control group. Our results indicate that IUI pregnancy may be associated with a lower level of AFP, although the mechanism for this difference remains unknown.     

The impact of correcting for smoking status when screening for chromosomal anomalies using maternal serum biochemistry and fetal nuchal translucency thickness in the first trimester of pregnancy

OBJECTIVES: To evaluate the influence of cigarette smoking status on maternal serum free beta-hCG, PAPP-A and fetal nuchal translucency (NT) thickness at 11 to 14 weeks of gestation in a large cohort of women screened prospectively for chromosomal anomalies. METHODS: Information on maternal cigarette smoking status, maternal age, maternal serum biochemical marker levels and fetal NT were collected from the prenatal screening computer records in two OSCAR screening centres. Data was available from 32,730 unaffected pregnancies and from 124 with Down syndrome. Statistical analysis of the marker levels in the smoking and non-smoking group were carried out. The impact on false-positive rate of correcting for smoking status was assessed from a modelling exercise. RESULTS: Prevalence of smoking was significantly affected by maternal age with an overall incidence of 11.5%, which varied from 35% in women under 20 to 7% in women over 35. In the unaffected population, the median free beta-hCG MoM was significantly lower in the smoking group (0.97 vs 1.00) as was that for PAPP-A (0.84 vs 1.02). The standard deviation of the log(10) MoM free beta-hCG was lower in the smoking group and that for PAPP-A was higher in the smoking group. The difference in median marker levels did not seem to be related to the number of cigarettes smoked per day. In the group with Down syndrome, the median MoM free beta-hCG was not significantly different in the smokers (1.69 vs 1.86) as was that for PAPP-A (0.53 vs 0.57). Fetal delta NT was not significantly different in the unaffected smokers (0.11 vs 0.0 mm) or in those with Down syndrome (1.96 vs 2.25 mm). In the smoking group, when screening using maternal serum biochemistry and age alone, the false-positive rate was 6.17%, compared to 4.67% in an age-matched group of non-smokers. Correcting for smoking status by dividing the measured MoM by the median found in the smoking group resulted in the false-positive rate falling to 4.40%. When screening using NT, maternal serum biochemistry and age, the false-positive rate in smokers was 4.48%, which reduced to 3.46% after correction-in line with the 3.76% in the non-smoking group. The impact on detection rate was too small to be accurately measured. CONCLUSIONS: The impact of smoking on first-trimester biochemical marker levels does not seem to be dose related. Whilst correcting first-trimester biochemical markers for maternal smoking status has little impact at the population level for detection rates, a considerable reduction in false-positive rate can be achieved, reducing the level to that seen in non-smokers. However, the effect on the individual patient-specific risk can be substantial and could certainly make a difference to the patient's decision on whether to have an invasive test.     

Maternal serum pregnancy-associated plasma protein-A and free beta-human chorionic gonadotrophin in pregnancies conceived with fresh and frozen-thawed embryos from in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVE: Maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) are useful markers in the screening of Down syndrome in the first trimester. We investigated the effect of intracytoplasmic sperm injection (ICSI), freezing and thawing of embryos on the levels of these two analytes in assisted reproduction pregnancies. METHODS: We recruited 149 women who conceived after assisted reproduction with fresh embryos (92 from conventional IVF and 57 from ICSI), 85 women who conceived with frozen-thawed embryos (54 from conventional IVF and 31 from ICSI) and 401 women with spontaneous conceptions as controls. The concentrations of PAPP-A and free beta-hCG were measured between 10 and 14 weeks and were converted to multiples of medians (MoM) for comparisons. RESULTS: Median PAPP-A MoMs were significantly reduced in ICSI pregnancies in the fresh and frozen-thawed embryo subgroups (0.70 and 0.66 MoM respectively) and in the IVF fresh embryo subgroups (0.83 MoM), as compared to controls (1.00 MoM). Free beta-hCG MoM was significantly reduced in the IVF fresh embryos subgroup (0.87 MoM), but not in the other three subgroups. CONCLUSION: Further studies for exploring the underlying pathophysiology and adjustment in the marker levels for screening of Down syndrome are warranted in pregnancies conceived after assisted reproduction.     

Diagnosis of fetal acrania during the first trimester nuchal translucency screening for Down syndrome.

OBJECTIVES: Prenatal screening during the first-trimester using fetal nuchal translucency (NT) measurement and maternal serum levels of free beta-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) has become an established method for the detection of fetal Down syndrome. Increasing evidence has shown that some of the fetal structural abnormalities could be identified during NT scanning. Second trimester maternal serum alpha-fetoprotein (MSAFP) measurements and ultrasound scans have been widely used in clinical practice to identify fetal neural tube defects (NTDs). In this study, we evaluated the effectiveness of early diagnosis of fetal acrania during NT scanning. METHODS: We reviewed the medical records of 5890 pregnancies that were delivered in our hospital between January 1, 1999 and January 31, 2001. Among them, 3600 pregnant women received NT-based Down syndrome screening at 10-13 weeks' gestation. Pregnancies with fetal NTDs were evaluated and their maternal serum levels of free beta-hCG and PAPP-A were compared with those of the normal control pregnancies. RESULTS: Seven of the 3600 pregnancies were identified with fetal acrania and all of them were detected during first-trimester NT scanning. Among the seven cases, five had measurements of maternal serum concentration free beta-hCG and PAPP-A concentration, yet there were not significant difference between the pregnancies with fetal acrania and those of the control pregnancies (PAPP-A, 1.13 vs. 0.96; free beta-hCG, 1.10 vs. 1.06; P>0.05). Two of the seven affected patients did not have maternal serum biochemical measurements due to the immediate termination of pregnancies. CONCLUSIONS: We demonstrated that pregnancies with fetal acrania could be easily identified at the time of NT scanning. Careful ultrasound inspection of fetal structure during NT measurements at 10-13 weeks of gestation provides an encouraging advantage for early diagnosis of fetal acrania.     

Co-variables in first trimester maternal serum screening

The objective of this study was to determined the influence of maternal weight, maternal smoking habits, gravidity, parity and fetal gender on the level of maternal serum marker used in first trimester screening for Down syndrome. A total of 2449 singleton unaffected pregnancies from two centres were studied. Maternal serum free beta-human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) concentrations had been measured in all pregnancies, and pregnancy associated plasma protein (PAPP)-A levels had been measured in 924. All results were expressed as multiples of the gestation specific median (MoM) values after regression, using each centre's own medians. Information on maternal weight was available in 2259 pregnancies, on self-reported current cigarette smoking in 1364 (of whom 117 (8.6%) were smokers), on gravidity in 1371, parity in 1303 and fetal gender in 253. All three markers showed a statistically significant negative association with maternal weight (p<0.0005) and in the subsequent analyses MoM values were weight adjusted using standard methods. The median PAPP-A level in smokers was 0.81 MoM, a significant reduction (p<0.005); free beta-hCG was also reduced (median 0.89 MoM) but not significantly (p=0.17), and AFP was unaltered. The median AFP level in primagravidas was highly significantly greater than that in gravid women (p<0.0005). In PAPP-A the reverse effect was seen but it did not reach statistical significance (p=0.15) and there was no effect for free beta-hCG. Results of a similar magnitude and direction were found for parity. The median level of free beta-hCG was higher (p=0.0005), and the median AFP lower in female pregnancies. Maternal weight and, for PAPP-A, maternal smoking are important first trimester screening co-variables. Gravidity, parity and fetal gender also seem to influence one or more first trimester markers.     

Between pregnancy biological variability of first trimester markers of Down syndrome: implications for screening in subsequent pregnancies.

In a group of 149 women who had undergone routine first trimester screening using fetal nuchal translucency thickness (NT) and maternal serum free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) in two consecutive pregnancies the within person between pregnancy biological variability of these markers has been assessed. For fetal NT there was no correlation between NT MoM in the first and second pregnancy (r=0.0800). For maternal serum free beta-hCG MoM a significant correlation was observed (r=0.4174) as was also found for PAPP-A MoM (r=0.3270). The implications for such between pregnancy marker association is that women who have an increased risk of Down syndrome in their first pregnancy are 1.5-2 times more likely to repeat this event in their next pregnancy. This observation may be useful in counselling women in the first trimester screening of a subsequent pregnancy.     

ADAM 12 as a first-trimester maternal serum marker in screening for Down syndrome

BACKGROUND: A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples. MATERIALS AND METHODS: The concentration of ADAM 12 was determined in 10-14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free beta-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored. RESULTS: The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log(10) MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10-11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free beta-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00).Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8-9 weeks and combined with NT and free beta-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8-9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free beta-hCG at 11-12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free beta-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy. CONCLUSION: ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models.     

Combined measurement of fetal nuchal translucency, maternal serum free beta-hCG, and pregnancy-associated plasma protein A for first-trimester Down's syndrome screening.

PURPOSE: It has been proposed that first-trimester Down's syndrome screening has a higher detection rate compared to second-trimester biochemical screening. This study investigated the accuracy of Down's syndrome screening during gestational weeks 10 to 13 using the combination of fetal nuchal translucency (NT) measurement with maternal serum concentrations of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). METHODS: A total of 1,514 women with singleton pregnancies were enrolled in this study. Fetal NT was measured using the criteria published by the Fetal Medicine Foundation. Maternal serum concentrations of free beta-hCG and PAPP-A were determined by microtiter-plate ELISA. Down's syndrome risk was calculated using multivariate Gaussian distribution and Alpha software. RESULTS: Seventeen (1.12%) of the 1514 screened pregnancies had a fetal NT of at least 3 mm, and 41.2% of these had a poor pregnancy outcome, including four fetal aneuploidies. The odds of a fetal aneuploidy when the NT was greater than 2.0 multiples of median (MoM) was 90, when serum PAPP-A concentration was less than 0.45 MoM, it was 8.6, and when serum free beta-hCG concentration was greater than 2.2 MoM, it was 4.7. Using a risk cut-off level of 1 in 400, nine of 10 fetal aneuploidies were identified with a 4.7% false-positive rate, including two with trisomy 21, one with trisomy 18, and three with Turner's syndrome. CONCLUSIONS: This study demonstrated that Down's syndrome screening using the combined test in the first trimester had a higher detection rate than that of serum screening in the second trimester. Implementation of NT measurement in the first trimester provides substantial advantages for Down's syndrome detection and early diagnosis of fetal structural abnormalities.     

First trimester maternal serum placenta growth factor (PIGF)concentrations in pregnancies with fetal trisomy 21 or trisomy 18

Placenta growth factor (PIGF), an angiogenic factor belonging to the vascular endothelial growth factor family, pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotrophin (beta-hCG) were measured in maternal serum from 45 pregnancies with trisomy 21, 45 with trisomy 18 and 493 normal controls at 10-13 completed weeks of gestation. In the normal pregnancies maternal serum PIGF levels increased exponentially with gestation. The median multiple of the median (MoM) PIGF concentration in the trisomy 21 group (1.26 MoM) was significantly higher (p<0.0001) than in the control group (1.00 MoM). In the trisomy 18 group the median PIGF was lower (0.889 MoM) but this did not quite reach significance (p=0.064). The corresponding median MoM values for PAPP-A were 1.00 MoM for the controls, 0.49 MoM for trisomy 21 and 0.16 MoM for trisomy 18. The median MoM values for free beta-hCG were 1.00 MoM for the controls, 2.05 MoM for trisomy 21 and 0.38 MoM for trisomy 18. In the control group there was a small but significant correlation of PIGF with free beta-hCG (r=+0.1024) and PAPP-A (r=+0.2288). In the trisomy 18 group there was a significant association between PIGF and free beta-hCG (r=+0.2629) but not with PAPP-A (r=+0.0038). In the trisomy 21 group there was a small but significant association with PAPP-A (r=+0.1028) but not with free beta-hCG (r=+0.0339). The separation of affected and unaffected pregnancies in maternal serum PIGF is small, and therefore it is unlikely that measurement of PIGF would improve screening for these abnormalities provided by the combination of fetal nuchal translucency and maternal serum PAPP-A and free beta-hCG.     

Is there an association between maternal ABO and rhesus blood groups and the first-trimester serum markers free beta-hCG and PAPP-A used for the detection of fetal aneuploidy?

OBJECTIVES: To evaluate whether first-trimester levels of PAPP-A and serum free-beta-human chorionic gonadotrophin (free beta-hCG) vary with maternal blood group and rhesus status and to assess whether this has implications for first-trimester screening for chromosomal anomalies. METHODS: Blood group and rhesus status information was extracted from birth records for women undergoing first-trimester screening. The birth records were combined with prenatal screening records by an in-house developed record linkage software. In 2252 singleton pregnancies of normal obstetric outcome, the median weight-corrected, ethnicity-corrected and smoking-corrected MoM were compared in the various blood groups, using t-tests after log10 transformation of the marker MoM against the whole study group. RESULTS: Only those women with a B rhesus positive blood group had statistically significant higher MoM levels of PAPP-A (0.995 v 0.937). CONCLUSIONS: A larger study is required to establish the validity of this increase in PAPP-A in the B rhesus positive group. If this can be substantiated, the elevation in PAPP-A in this group may require correction when screening for chromosomal anomalies.     

Urine free beta-hCG and total estriol for Down syndrome screening during the second trimester in an Asian population.

OBJECTIVE: To evaluate second-trimester free beta-hCG and total estriol (E3) in the maternal urine as markers for Down syndrome screening in an Asian population. METHODS: Free beta-hCG and total E3 were measured in the urine samples of 28 Taiwanese Down syndrome pregnancies and 268 unaffected singleton pregnancies at 14-25 weeks. Results were normalized to urine creatinine concentrations and converted to multiples of the median (MoM) levels. Gestational ages were estimated by ultrasound measurements. RESULTS: Median values of free beta-hCG, total E3, free beta-hCG to total E3 ratio, and the free beta-hCG to total E3 MoM ratio in Down syndrome pregnancies were 4.75 MoM, 0.66 MoM, 8.99 MoM, and 9.51, respectively. At a 5% false-positive rate, the observed detection rates were 36% (ten of 28) with total E3, 71% (20 of 28) with free beta-hCG, 68% (19 of 28) with free beta-hCG/total E3, and 71% (20 of 28) with free beta-hCG/total E3 MoM. When combined with maternal age, the expected detection rates were 65% with total E3, 71% with free beta-hCG, 76% with free beta-hCG/total E3, 80% with free beta-hCG/total E3 MoM, and 89% when combining free beta-hCG, total E3, and maternal age. CONCLUSION: Urine free beta-hCG and total E3 are useful markers for Down syndrome screening during the second trimester in Taiwanese women.     

Practical strategies in contingent sequential screening for Down syndrome

OBJECTIVE: To design and assess the performance of protocols for contingent sequential Down syndrome screening that can be implemented in practice. METHODS: Protocols were designed in which all women received first-trimester measurement of nuchal translucency (NT) together with maternal serum pregnancy-associated plasma protein-A (PAPP-A) and either free beta- or total human chorionic gonadotrophin (hCG). Those women with borderline Down syndrome risks received follow-up second-trimester maternal serum involving double, triple, or quadruple serum screening markers: alpha-fetoprotein, free beta-hCG or total hCG, unconjugated estriol and inhibin-A. Specific ranges of risks were used to define the borderline group. Separate protocols were developed for the United Kingdom and the United States to reflect differences in commonly used tests, cut-offs, and the gestational age at testing. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling with Monte Carlo simulation. RESULTS: Proposed protocols based on first-trimester NT, PAPP-A and free beta-hCG or total hCG, followed by selective use of second-trimester quadruple markers can result in a 91% detection rate and 2.1% false-positive rate for the United Kingdom and a detection rate of 89% and false-positive rate of 3.1% for the United States. For both countries, over 60% of affected pregnancies would be detected in the first trimester and less than 20% of women would require a second-trimester Down syndrome risk assessment. Use of alternative cut-offs to define those with borderline risks or different combinations of second-trimester markers also yielded high detection rates and low false-positive rates. CONCLUSION: With appropriate patient counselling, it should be possible to provide highly effective Down syndrome screening using contingent sequential protocols.