A comparison between maternal serum free beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A levels in first-trimester twin and singleton pregnancies

OBJECTIVES: To determine the levels of first-trimester free beta-human chorionic gonadotrophin (free betahCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT) in twin pregnancies. METHODS: The study included 93 patients with twin pregnancy and 4,977 with singletons who underwent first-trimester testing using free betahCG, PAPP-A and NT at 10-13 weeks of gestational age. RESULTS: In twin pregnancies, the maternal serum free betahCG level was 2.18 higher and the PAPP-A level was 2.38 higher than in singleton pregnancies. These marker levels were significantly higher than the expected 2.0 multiples of the median (MoM). In contrast, NT values did not differ between twins and singletons. CONCLUSION: These data may be used to establish first-trimester combined screening for twin pregnancies.     

First and second-trimester biochemical markers of chromosomal anomalies and their relationship to maternal haemoglobin levels

OBJECTIVE: To evaluate a previous hypothesis that maternal serum biochemical markers used in the assessment of Down syndrome risk are related to maternal haemoglobin concentrations. METHODS: A series of 1306 second-trimester prenatal screening records were retrieved including information on marker levels (AFP and fbetahCG MoMs), Down's risk, a priori age risk, maternal weight and maternal height. Each individual record was merged with data from haematological investigations on samples collected on the same day. A similar series of 1688 first-trimester screening records were also retrieved including the maker levels for PAPP-A, and fbetahCG MoMs were merged with data from haematological investigations carried out on the same day. The two groups were categorised according to their haemoglobin levels; anaemic (less than 11.0 g/dL in first trimester and 10.5 g/dL in the second trimester), high haemoglobin (greater than 14.0 g/dL and 13.2 g/dL) or normal (between these ranges). An analysis was made of marker levels in the various groups before and after correction for ethnicity and of the screen-positive rate in the various groups. Using a formula based on maternal height and weight, variation of marker levels with plasma volume was assessed. RESULTS: In the first trimester, 12.6% of the pregnant population was anaemic and 1.6% had elevated haemoglobin levels. In the second trimester this was 12.7 and 3.9%. These figures varied considerably with ethnic origin, with Asian and Afro-Caribbean women being more anaemic than Caucasian women. Haemoglobin levels declined by 7% between the 11- and 21-week period. Maternal plasma volume (as calculated by a widely used maternal height and weight relationship) was not correlated with weight-corrected biochemical marker MoMs in either trimester. A weak but significant correlation of maternal plasma volume and haemoglobin concentration was observed. There was no significant correlation between biochemical marker MoMs and haemoglobin concentration. Although the proportion of pregnancies designated screen positive decreased as haemoglobin levels increased, this was paralleled by a decrease in the maternal age a priori risk. CONCLUSIONS: There is no relationship between maternal haemoglobin levels and the levels of Down syndrome markers in either the first or second trimester. Biochemical marker levels do not need to be corrected for haemoglobin concentrations when used in screening for Down syndrome.     

Gender impact on first trimester markers in Down syndrome screening

The influence of fetal gender on the level in the first trimester of the serological markers alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (betahCG) and on nuchal translucency is described for 2637 singleton pregnancies with normal outcome. Mean log MoM values for pregnancies with female and male fetuses were calculated using regression of log marker values on gestational age expressed as crown rump length and on maternal weight. A pronounced gender impact was found for free betahCG, being 16% higher for female than for male fetuses.     

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

BACKGROUND: ADAM 12 is a placenta-derived glycoprotein that is involved in growth and differentiation. The maternal serum concentration of ADAM 12 is a potential first-trimester maternal serum marker of Down syndrome (DS). Here we examine the potential of ADAM 12 as a second-trimester maternal serum marker of DS. MATERIALS AND METHODS: The concentration of ADAM 12 was determined in gestational week 14-19 in 88 DS pregnancies and 341 matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and the distribution of log(10) MoM ADAM 12 values in DS pregnancies and controls determined. Correlations with alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (free beta-hCG) were established and used to model the performance of maternal serum screening with ADAM 12 in combination with other second-trimester serum markers. RESULTS: The ADAM 12 maternal serum concentration was significantly increased with a median MoM of 1.85 and a mean log(10) MoM (SD) of 0.268 (0.2678) compared to a mean log(10) MoM (SD) of 0.013 (0.4318) in controls. ADAM 12 correlated with maternal weight and ethnicity (with the serum concentration increased in Afro-Caribbeans), but neither with maternal age nor gestational age, and only marginally with AFP (r(DS) = 0.078, r(controls) = 0.093) and free beta-hCG (r(DS) = 0.073, r(controls) = 0.144. The increase in detection rate-for a false positive rate of 5%--by adding ADAM 12 to the double test (AFP + free beta-hCG) was 4%, similar to that of adding uE3 to the double test. CONCLUSION: ADAM 12 is an efficient second-trimester marker for DS. Further studies should be conducted to determine whether it may be a useful additional or alternative marker to those currently used in the second-trimester.     

First trimester screening for Down's syndrome after assisted reproductive technology: non-male factor infertility is associated with elevated free beta-human chorionic gonadotropin levels at 10-14 weeks of gestation

We retrospectively compared the first trimester Down's syndrome serum screening markers free beta-hCG (fbetahCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks of gestation in 4,088 women with naturally conceived pregnancies and in women pregnant after ICSI (n = 163), IVF (n = 59) and frozen-thawed embryo transfer (n = 31), and we searched for a potential relationship between infertility cause and marker levels. We found lower serum PAPP-A levels in pregnancies after IVF and ICSI compared with spontaneously conceived pregnancies and non-male factor infertility was associated with elevated serum fbetahCG levels at 11-14 weeks of gestation.     

Human placental lactogen is a first-trimester maternal serum marker of Down syndrome

BACKGROUND: Human placental lactogen (hPL) is synthesised by the placenta and found in maternal serum. We analysed the potential of hPL as a first-trimester maternal serum-screening marker for fetal Down syndrome (DS). MATERIALS AND METHODS: hPL was quantified by ELISA in 47 DS pregnancies and 136 controls in gestational weeks 8-13. Distributions of log multiples of the median (MoMs) were established. The quantity of hPL in DS screening was estimated using Monte Carlo simulation methods. RESULTS: The mean log10 MoM hPL was - 0.1995 (SD: 0.1993) in affected and 0.0026 (SD: 0.2129) in control pregnancies. This corresponds to a MoM of 0.63 in DS pregnancies. hPL correlated significantly with log10 MoM values of hCGbeta (r = 0.320) and PAPP-A (r = 0.590) in controls, but not with hCGbeta (r = 0.228) or PAPP-A (r = 0.090) in DS pregnancies. The inclusion of hPL in the double test (PAPP-A + hCGbeta) increased the detection rate from 67 to 75% for a false-positive rate of 5%. CONCLUSION: hPL is a DS screening marker that is applicable at weeks 9-13 and could be included in multiple marker first-trimester screening for DS.     

2nd-trimester maternal serum human chorionic gonadotropin and alpha-fetoprotein levels in male and female fetuses with Down syndrome

BACKGROUND/OBJECTIVE: Several studies have shown that the 2nd-trimester maternal serum alpha-fetoprotein (AFP) level is significantly lower and that the maternal serum human chorionic gonadotropin (hCG) level is significantly higher in the presence of a female fetus. This may potentially affect Down syndrome (DS) screening such that a higher false-positive rate may occur in women carrying a female fetus, whereas a lower detection rate may result in those carrying males. The purpose of this study was to evaluate the gender impact on marker levels in DS pregnancies and its effect on DS screening. METHODS: The study included 62 DS pregnancies with a single fetus of known gender (31 male and 31 female). Only pregnancies with chromosomal analysis showing trisomy 21 were included. The maternal serum levels of hCG, AFP, and unconjugated estriol were measured at 16-20 weeks of pregnancy. These levels were expressed as gestational-age-corrected multiples of the median. RESULTS: No statistically significant differences were noted in maternal serum levels of hCG or AFP in DS pregnancies between women carrying a female and those carrying a male DS fetus. No statistically significant differences in 'screen-negative' rates were noted among male and female fetuses. CONCLUSIONS: In normal pregnancies, the maternal serum hCG level is higher, and the AFP level is lower in the presence of a female fetus. However, this gender-related difference is not apparent in DS pregnancies. Therefore, the gender-related differences in serum marker levels would not result in a lower detection rate of DS in male fetuses.     

Predicting complications of pregnancy with first-trimester maternal serum free-betahCG, PAPP-A and inhibin-A

OBJECTIVE: To find whether fbetahCG, PAPP-A and inhibin-A levels in maternal serum or fetal nuchal translucency (NT) thickness at the first-trimester screening for trisomy 21 (T21) might detect women at high risk for adverse pregnancy outcomes. METHODS: A retrospective analysis of 1136 women with singleton pregnancy between 10 and 14 weeks. Women with pregnancy complications were allotted to five subgroups: small for gestational age (SGA), large for gestational age (LGA), gestational diabetes (GDM), hypertensive disorders, preterm delivery; women with normal pregnancy represented the control group. NT, maternal serum fbetahCG, PAPP-A and inhibin-A were measured. Mann-Whitney test was used for the comparison of fbetahCG, PAPP-A, inhibin-A and NT between a subgroup of a certain pregnancy complication and the control group. Multivariate logistic regression models were built to explore the relationship among different variables and the occurrence of pregnancy complications. RESULTS: PAPP-A values were significantly lower in women who delivered SGA babies (n=51, 0.76 MoM; p=0.002) and significantly higher in women who delivered LGA babies (n=120, 1.12 MoM; p=0.036). In women with GDM (n=27), fbetahCG, PAPP-A and inhibin-A were insignificantly lower than in controls, whereas in women with hypertensive disorders (n=56) no significant differences between the groups were found. In women with a preterm delivery (<34 weeks) (n=17), inhibin-A levels were significantly higher (1.25 MoM; p=0.015). CONCLUSION: Low PAPP-A level is associated with the delivery of an SGA baby and high PAPP-A with the delivery of an LGA baby. High inhibin-A is associated with preterm delivery before 34 weeks. Feto-placental products in the first trimester do not prove to be useful as a screening tool for predicting pregnancy complications.     

Screening for Down's syndrome: changes in marker levels and detection rates between first and second trimesters

Objective To monitor changes with gestation in levels of alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (FβhCG) and pregnancy associated plasma protein-A (PAPP-A) in Down's syndrome pregnancies and to compare risks estimated in the first trimester with those obtained by routine screening in the second trimester for the same pregnancies.
Design In each of 47 Down's syndrome pregnancies two maternal serum samples were obtained, one in the first trimester and one in the second trimester. Comparison of marker levels with 10,600 first trimester controls and a smaller sample of second trimester controls allowed case identification criteria based on optimum marker combinations to be developed and compared directly between trimesters.
Setting Biochemical genetics laboratory.
Results FβhCG was an effective marker of Down's syndrome in both the first and second trimesters. PAPP-A levels were significantly reduced in trisomy 21 pregnancies in the first trimester only. Using a population model, these two markers in combination with maternal age gave an overall detection rate of 55% for a 5% false positive rate in the first trimester. For the paired first and second trimester samples, three of six cases classified as low risk by routine second trimester screening were classified as high risk by the first trimester screening protocol of FβhCG/PAPP-A/matemal age. However, fifteen cases identified as high risk by routine second trimester screening were classified as low risk in the first trimester, a net loss in detection of 12 cases by first trimester screening.
Conclusion The data suggest that first trimester detection rates for Down's syndrome using a combination of FβhCG and PAPP-A may vary with gestation and will be lower than those currently obtained by routine second trimester screening with AFP/hCG.     

The best marker combination using the integrated screening test approach for detecting various chromosomal aneuploidies

AIMS: To evaluate the cross-trimester multiple marker correlation and the minimum marker combination needed for detecting various chromosomal aneuploidies. MATERIALS AND METHODS: Parturient women with singleton pregnancies who underwent non-interventional sequential screening test and followed prospectively were recruited. They all underwent first trimester combined nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A), and free beta-human chorionic gonadotrophin (f-betahCG), followed by second trimester measurement of unconjugated estriol (uE3), human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP). Pearson correlation was applied to compute any cross-trimester marker correlation and logistic regression analysis was used to determine the minimum marker combination for detecting various categories of chromosomal aneuploidies. RESULTS: The current study included 552 normal and 43 chromosomal-affected pregnancies (24 Down's syndrome [DS], 7 Turner's syndrome, 8 Edward's syndrome, 4 Klinefelter syndrome and 5 triploidy) for which the results of both the screening tests and the pregnancy outcome were available. In the normal cases, a significant correlation was found between f-betahCG and hCG (r=0.52), as well as between PAPP-A and uE3 (r=0.174). In DS pregnancies, the NT correlated with both hCG (r=0.45) and uE3 (r=-0.39). In Turner's syndrome, uE3 correlated both with PAPP-A (r=0.97) and f-betahCG (r=0.97). No other significant correlations were found. Furthermore, with the exception of f-betahCG and hCG in the unaffected cases, all other markers correlation appeared very weak. For detecting all the above categories of aneuploidies, the combination of NT, PAPP-A and uE3 and the maternal age background risk were found adequate, with a 74% detection rate (DR) for a 5% false positive rate (FPR). For DS only, the combination of maternal age-related background risk and the combination of NT, PAPP-A, hCG and AFP yielded a 79% DR for a 5% FPR. CONCLUSIONS: The current study agrees with a previous report that, overall, there is no strong correlation between first and second trimester markers. The extension of the integrated test for detecting various categories of common chromosomal aneuploidies using NT, PAPP-A and uE3 deserves further evaluation.     

The proform of eosinophil major basic protein: a new maternal serum marker for Down syndrome.

The proform of eosinophil major basic protein (proMBP), the most abundant protein in the eosinophil specific granule, is synthesized by the placenta and secreted into the maternal circulation, where it is found complex-bound to pregnancy-associated plasma protein-A (PAPP-A) and other proteins. We examined the potential of proMBP as a maternal serum marker for fetal Down syndrome (DS) by determining its maternal serum concentration (MSpMBP) in 25 Down syndrome (DS) pregnancies and 152 control pregnancies in the first trimester, and in 105 DS pregnancies and 156 control pregnancies in the second trimester. The median (95 per cent confidence interval) MSpMBP MoM in DS pregnancies (n=15) was 0.66 (0.49-0.79) in gestational weeks 5-9; 1.06 (0.71-1.97) in weeks 10-12 (n=10) and 1.62 (1.18-1.98) in weeks 14-20 (n=105). Using parameterized receiver operator characteristics analysis for proMBP as a single marker for DS, detection rates (DRs) of 22 per cent and 38 per cent, for false-positive rates (FPRs) of 5 per cent, were found in weeks 5-9 (using MSpMBP/=cut-off), respectively. When age and MSpMBP were used as markers in combination, a DR of 36.8 per cent for an FPR of 5.5 per cent was obtained in weeks 5-9 using a risk cut-off of 1:250. In weeks 14-20 the DR was 48.4 per cent for an FPR of 5.3 per cent using the same risk cut-off. This makes proMBP a marker comparable in diagnostic efficiency to human chorionic gonadotrophin (hCG), and exceeding that of alpha-fetoprotein (AFP) and unconjugated oestriol (uE3), in the second trimester.     

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.     

Pregnancy associated plasma protein-A2: A novel biomarker for down syndrome

IntroductionIn an effort to improve prenatal screening for Trisomy 21, we evaluated pregnancy associated plasma protein-A2 (PAPP-A2) as a potential novel second trimester biomarker for Trisomy 21.MethodsTrisomy 21 and normal control mid-trimester placental samples were subjected to quantitative rt PCR analysis of seven genes we had previously found to be differentially expressed in Trisomy 21 placentae. The localization and differential expression of PAPP-A2 in second trimester placentae from normal and Trisomy 21 pregnancies was determined by immunohistochemistry. PAPP-A2 maternal serum protein levels in ten Trisomy 21 and ten diploid pregnancies were compared by Western blotting. Maternal serum PAPP-A2 levels were measured in 30 Down syndrome cases and 142 normal controls, using ELISA. Regression analysis was used to determine the correlation of PAPP-A2 with other existing markers of Trisomy 21.ResultsPAPP-A2 (aka PLAC 3) mRNA and protein expression were both increased in Down syndrome placentae as compared to diploid placentae. PAPP-A2 was also increased in maternal serum from Down syndrome pregnancies as compared to diploid pregnancies. PAPP-A2 expression correlated weakly with established markers.DiscussionThis work takes advantage of our previously performed systematic approach to the discovery of novel maternal serum biomarkers for Trisomy 21, using cDNA microarray analysis. Beginning with the validation of the microarray results, we have tracked PAPP-A2 overexpression in Down syndrome from placental mRNA to maternal serum protein.ConclusionPAPP-A2 could serve as an additional maternal serum marker in prenatal screening for Trisomy 21.     

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.     

Second-trimester maternal serum free-beta-human chorionic gonadotropin and alpha-fetoprotein levels in normal twin and singleton pregnancies: a report of local Chinese population

OBJECTIVES: The study evaluated the differences between Chinese normal twin and singleton pregnancies in the levels of maternal serum free-beta-human chorionic gonadotropin (free beta-hCG) and alpha-fetoprotein (AFP) used in second-trimester Down syndrome (DS) screening. METHODS: The concentrations of maternal serum markers of 456 twin pregnancies and 12 067 singleton controls in gestational 15 to 20 weeks were measured by time-resolved fluoroimmunoassay, and the levels of markers were compared between the twins and singletons. RESULTS: Significant differences were found between the levels of free beta-hCG in twins and twice of those in singletons in 16, 17 and 19 gestational weeks (p < 0.05 for all); while considering AFP, significant differences were found in 16 and 19 gestational weeks (p < 0.05 for both). No correlations were found in twins between the levels of markers and maternal weights in most gestational weeks (Free beta-hCG: p > 0.05 for 15 to 18 and 20 gestational weeks; AFP: p > 0.05 for 16 to 20 gestational weeks). CONCLUSIONS: The Chinese gestational age-specific levels of maternal serum markers in normal twins are not twice as those in singletons. The current weight-correction model for DS screening may be not feasible for twins.     

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.     

Serum leptin in first-trimester Down syndrome pregnancies

BACKGROUND: Leptin is a key regulator of satiety; and the serum concentration is considered to reflect nutritional status. Expressed predominantly by the adipocytes, leptin is also expressed in placenta, which is a major source of both leptin and the leptin receptor in pregnancy serum. As a placenta protein, leptin serum concentrations may be perturbed in Down syndrome (DS) pregnancies as seen for pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotrophin-beta (hCGbeta). We examined whether leptin is a maternal serum marker for foetal DS in the first trimester. MATERIALS AND METHODS: Serum samples from 44 pregnant women with a DS foetus, and 135 control pregnant women in week 8 to 14 had the leptin concentration determined by immunoassay and the concentrations were converted into multiples of the median (MoM) of controls based on log-regression analysis. The distributions of log10 MoM leptin was compared in DS and control pregnancies. RESULTS: Serum leptin increased significantly with gestational age in controls (p = 0.02). The mean log10 MoM in controls was - 0.0486, with a median empirical MoM of 0.89, and - 0.0618, with a median empirical MoM of 0.80, in DS pregnancies. This difference was not significant. The log10 MoM leptin values in DS pregnancies did not change with gestational age (p = 0.32). CONCLUSION: Leptin is not a first-trimester marker for foetal DS.     

Low PAPP-A levels between 11 and 13(+6) weeks of gestation and the risk of preeclampsia

PAPP-A is one of the 2 biochemical markers of the first trimester Down syndrome serum screening. In Bulgaria this screening was first performed in 2006. The threshold values for evaluation of the risk of development of preeclampsia used by the researchers vary in a wide range. Nevertheless in the last several years the most used value is 0.4 MoM. The aim of represented study is evaluate the low PAPP-A levels as a marker for development of preeclampsia alone, or in combination with some risk factors. The data of 194 singleton pregnancies that underwent a first trimester Down syndrome screening between January 2008 and June 2009 had been analyzed. Twenty three patients (11.6%) developed preeclampsia, of which 8 required delivery before 34th gw. The control group includes 134 women who had term deliveries of healthy babies. Nine out of 23 (39%) patients with preeclampsia, 5 out of 8 (62.5%) patients with early onset preeclampsia and 42 out of 134 (30.4%) controls had PAPP-A levels below 0.4 MoM. These levels are associated with relative risk for development of preeclampsia of 1.5 times. Low PAPP-A levels in the first trimester were associated with a low prognostic value for development of preeclampsia and early preeclampsia before 34th gw. When low PAPP-A levels are added to the maternal age and especially results of Doppler evaluation of the uterine arteries significant prognostic value improvement was observed.     

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.     

Maternal serum screening for Down syndrome in the first trimester: experience from Belarus.

We have carried out a large retrospective study of alpha-fetoprotein (AFP), free-beta human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein (PAPP-A) in the first trimester of pregnancy. Unlike other studies all women had routine ultrasound dating, carried out during a nuchal translucency measurement project. A total of 13,477 serum samples were tested for AFP and 11,659 for free beta-hCG. A subset of 1564 samples from unaffected pregnancies were also tested for PAPP-A on a case-control basis. All three markers were also determined in 31 samples from pregnancies with Down syndrome. Equations were derived to express results in multiples of the median using both gestational age and crown rump length and to adjust for maternal weight. Statistical modelling with Gaussian distribution parameters obtained in the study were used to predict the detection rate for a 5 per cent false-positive rate. The predicted rates were: 73.7 per cent for all three markers; 69.1 per cent for PAPP-A and free beta-hCG; 47.4 per cent for PAPP-A and AFP; 57.6 per cent for free beta-hCG and AFP. As these rates are similar to those in the second trimester, health planners may now want to consider a change in policy from second-trimester to first-trimester screening with biochemical markers.