Down syndrome and cell-free fetal DNA in archived maternal serum

OBJECTIVE: Increased levels of cell-free fetal DNA (f-DNA) in the maternal circulation are a potential noninvasive marker for fetal Down syndrome. Our objectives were to (1) determine whether f-DNA could be quantified by using archived serum and amniotic fluid, (2) examine whether serum f-DNA levels are elevated in Down syndrome pregnancies in a case-control series matched for gestational age and duration of sample storage, and (3) determine whether f-DNA levels are elevated in the amniotic fluid of Down syndrome fetuses. STUDY DESIGN: Eleven serum and six amniotic fluid samples previously collected and stored at -20 degrees C from gravid women carrying a 47,XY,+21 fetus were each paired with five matched control samples of identical specimen type from gravid women carrying a presumed euploid male fetus. f-DNA concentration was quantified blindly by real-time polymerase chain reaction amplification for a Y-chromosome sequence. Matched rank-sum analysis and analysis of variance were used for analysis. RESULTS: The mean observed rank of 5.0 in the Down syndrome group was significantly higher than expected (P 相似文献   

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.     

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.     

Unexplained elevated serum hCG is associated with raised amniotic fluid erythropoietin levels in second-trimester pregnancies.

OBJECTIVE: This study was designed to investigate the association between the concentrations of maternal serum hCG and amniotic fluid erythropoietin during the second trimester of pregnancy. METHODS: In a prospective case-control study, 42 consecutive singleton pregnancies showing unexplained elevated serum hCG concentrations (>2.0 multiples of the median, MoM) in Down's syndrome screening and 27 control pregnant women undergoing midtrimester amniocentesis because of a previous cytogenetic abnormality were studied. RESULTS: The mean amniotic fluid erythropoietin concentration in the study group was 1.8 (range 0.61-8.7) MoM, whereas it was 1.1 (range 0.71-3. 96) MoM in the controls (p = 0.035). A significantly increasing relationship (p < 0.05) was found between the concentrations of maternal serum hCG and amniotic fluid erythropoietin. CONCLUSIONS: The results of the current study revealed in vivo the association between elevated hCG and amniotic fluid erythropoietin levels which, in turn, supports the concept of early placental damage. The underlying pathology seems to be sufficient to cause an erythroblastic response.     

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.     

Placenta growth factor levels in second-trimester maternal serum in Down syndrome pregnancy and in the prediction of preeclampsia

OBJECTIVES: To determine the levels of placenta growth factor (PlGF) in second-trimester maternal serum samples from pregnancies affected with fetal Down syndrome and from those that developed preeclampsia and to assess the utility of PlGF as a screening tool for these conditions. METHODS: Residual second-trimester maternal serum samples were retrieved from freezer storage for 39 cases of Down syndrome and 44 pregnancies that later developed preeclampsia. Each case was matched to 5 control samples for gestational age at collection and duration of freezer storage. PlGF levels were measured in each sample by enzyme-linked immunosorbent assay (ELISA). RESULTS: PlGF levels increased with gestational age between 15 and 20 gestational weeks. After adjusting for gestational-age effects, the median level of PlGF was 1.01 MoM in Down syndrome pregnancy and 0.74 MoM in pregnancies that developed preeclampsia, which were not significantly different from matched controls. The duration between sampling and onset of preeclampsia did not have an effect on the PlGF level. CONCLUSION: PlGF levels are not significantly altered in second-trimester maternal serum samples from cases of Down syndrome or in pregnancies that develop preeclampsia.     

Collaborative study of maternal urine beta -core human chorionic gonadotrophin screening for Down syndrome.

Several studies have shown that second-trimester maternal urine beta-core human chorionic gonadotrophin (hCG) levels are raised on average in Down syndrome pregnancies. However, in all but one, testing was retrospective after extended sample storage and so we carried out a large international multicentre prospective study. 16 centres provided 6730 samples from 14-19 week pregnancies: 39 with Down syndrome, 12 with Edwards' syndrome, 42 with other aneuploidies, 52 unaffected twins and 6585 singleton unaffected pregnancies. Samples were from those having routine maternal serum screening in 6 centres and invasive prenatal diagnosis for reasons unrelated to maternal serum screening in 10 centres. Normalized levels of beta-core hCG (nmom/mmol creatinine) were expressed as multiples of the gestation-specific normal median (MoMs). The median beta-core hCG level in Down syndrome was 1.70 MoM (95 per cent confidence interval, 1.26-2.30); 14 (36 per cent) exceeded the normal 90th centile and 9 (23 per cent) the 95th centile. The median level in Edwards' syndrome was 0.23 MoM. On the basis of our results alone it is unlikely that urinary beta-core hCG will be a useful marker in Down syndrome screening practice. But the considerable variability in results between studies means that further research is needed before a reliable conclusion can be drawn.     

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.     

Prenatal screening for Down syndrome: the problem of recurrent false-positives

OBJECTIVES: It has been reported that, in prenatal screening programmes for Down syndrome, women who have false-positive results in one pregnancy have an increased risk of a false-positive result in a subsequent pregnancy. We examined the effect of this in the screening programme conducted from the Wolfson Institute of Preventive Medicine with a view to determining the magnitude of the effect, and to describe a method of avoiding the problem. METHODS: Six thousand four hundred and forty-eight women were identified who had had two singleton pregnancies without Down syndrome in the screening programme based at the Wolfson Institute of Preventive Medicine, in which both pregnancies were screened using a Quadruple test (maternal age with alphafetoprotein (AFP), unconjugated oestriol (uE(3)), total or free beta-human chorionic gonadotrophin (hCG) and either free alpha-hCG or inhibin-A as the fourth serum marker). RESULTS: Among women who had a false-positive result in their initial pregnancy, the false-positive rate in the subsequent pregnancy was high: 20% (46/229), about three times higher than both the overall observed false-positive rate (6.6%), and the expected false-positive rate, in subsequent pregnancies that were false-positive in their initial pregnancy (7.5%) (p < 0.001). This arises because serum marker levels in one pregnancy are associated with the levels in a subsequent pregnancy. Using the slope (the regression coefficient b) of each marker level in a subsequent pregnancy regressed on the value in the first pregnancy, it is possible to adjust all marker values in a subsequent pregnancy to allow for the higher-than-expected false-positive rate. This can be done by dividing the observed MoM value for each marker by the 'expected' MoM, which is the MoM value in a previous pregnancy raised to the power b. CONCLUSIONS: If a woman has had a false-positive result in one pregnancy, she is much more likely to have a false-positive screening result in a subsequent pregnancy than women in general. The problem can be avoided by adjusting the serum markers in all women who have been screened in a previous pregnancy and who have not had a previous pregnancy with Down syndrome.     

Second trimester levels of maternal serum inhibin A in pregnancies affected by fetal neural tube defects

Inhibin A is effective as a second trimester maternal serum marker for Down syndrome screening. In the present study, inhibin A levels were measured in second trimester maternal serum samples from 28 pregnancies affected with open neural tube defects; 12 associated with open spina bifida and 16 associated with anencephaly. Each measurement was expressed as a multiple of the median (MoM) for control singleton pregnancies (n=1464) of the same completed week of gestation. Inhibin A levels were not significantly altered in cases of open neural tube defects; the median value was 0.96 MoM in cases of open spina bifida and 1.19 MoM in cases of anencephaly. Therefore, second trimester maternal serum inhibin A levels will not have an impact on prenatal detection of open neural tube defects.     

First-trimester maternal serum progesterone in aneuploid pregnancies

BACKGROUND: First-trimester maternal serum screening for Down syndrome (DS) can be improved by the use of additional serum markers. We examined whether progesterone (P), synthesized by placenta, might be a first-trimester maternal serum marker for fetal DS. MATERIALS AND METHODS: P was quantified in first-trimester maternal serum from 42 DS, six trisomy 18 and two trisomy 13 pregnancies and 115 controls. Log-regression of P versus gestational age in days was used to convert P concentrations into multiples of the median (MoM). RESULTS: The P concentrations in controls increased with gestational age (p = 9.5 x 10(-7)). The log10MoM P distribution in DS pregnancies was not significantly different from that in controls. However, from day 58-67, the log10MoM P was elevated in DS pregnancies (n = 10) with a mean (SD) of 0.1040 (0.0956), compared to a mean (SD) of - 0.0109 (0.1661) in controls (n = 24) (p = 0.05). Five out of six trisomy 18 and both trisomy 13 pregnancies had a P MoM < 1. CONCLUSION: P is not a useful marker for DS in first trimester, except perhaps in a narrow gestational age window from day 58 to 67. P is a trisomy 18/13 marker.     

Maternal serum ADAM12 levels in Down and Edwards' syndrome pregnancies at 9-12 weeks' gestation

BACKGROUND: Maternal serum ADAM12 is reduced, on average, in early first-trimester Down and Edwards' syndrome pregnancies but the extent of reduction declines with gestation. Here we study levels at 9-12 weeks when the marker might be used concurrently with other established markers. METHODS: Samples from 16 Down and 2 Edwards' syndrome cases were retrieved from storage and tested together with 313 unaffected singleton pregnancies using a semi-automated time-resolved immuno-fluorometric assay. Results were expressed in multiples of the gestation-specific median (MoM) based on regression. RESULTS: The median in Down syndrome was 0.94 MoM with a 10th-90th centile range of 0.22-1.63 MoM compared with 1.00 and 0.33-2.24 MoM in unaffected controls (P = 0.21, one-side Wilcoxon Rank Sum Test). The two Edwards' syndrome cases had values 0.31 and 2.17 MoM. CONCLUSIONS: ADAM12 cannot be used concurrently with other markers in the late first trimester. However, it does have the potential to be used earlier in pregnancy either concurrently with other early markers or in a sequential or contingent protocol. More data will be required to reliably predict the performance of either approach.     

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.     

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.     

Prenatal diagnosis of Smith-Lemli-Opitz syndrome in a pregnancy with low maternal serum oestriol and a sex-reversed fetus

A cytogenetically normal male fetus was subsequently found to have female external genitalia, a cardiac malformation and mid-trimester intra-uterine growth retardation by ultrasound examination. The maternal serum oestriol level was low. The combination of low oestriol and sonographic findings suggested Smith Lemli Opitz syndrome (SLO), which was confirmed by a markedly increased amniotic fluid level of 7-dehydrocholesterol. We review the differential diagnosis of apparent sex reversal in a fetus and low maternal serum oestriol level. To further examine the specificity of low maternal oestriol level as a marker for SLO a follow-up study of 12141 pregnancies screened for Down syndrome using three biochemical markers: alpha-fetoprotein, beta-human chorionic gonadotrophin and oestriol was performed. 26 pregnancies had an oestriol level that was 0.25 MoM or less. SLO was not diagnosed clinically in any of the liveborn children ascertained through a low maternal oestriol level. Nine of the pregnancies ended in spontaneous miscarriage. Although the frequency of SLO in pregnancies with low maternal oestriol levels or sex-reversed fetuses is unknown, the diagnosis of SLO should, nevertheless, be considered in both clinical settings.     

Insulin-like Growth Factor Binding Protein-3 in the Detection of Fetal Down Syndrome Pregnancies

Objective: To study the usefulness of maternal serum insulin-like growth factor binding protein-3, a potential cell growth inhibitor, in second trimester prenatal screening for fetal Down syndrome.Methods: Three hundred and forty-two samples from normal pregnancies and nine fetal Down syndrome pregnancies were analyzed for insulin-like growth factor binding protein-3 levels by radioimmunoassay. Data were converted to multiples of median (MoM) and analyzed statistically to compare the differences between control and Down syndrome pregnancies.Results: The mean insulin-like growth factor binding protein-3 MoM of Down syndrome–affected pregnancies (1.09) was significantly higher than that of the normal pregnancies (1.00) (P < .01). Insulin-like growth factor binding protein-3, in combination with maternal serum alpha-fetoprotein (MSAFP), hCG, and maternal age, detected 89% of Down syndrome pregnancies at a screen positive rate of 2.1%. This compares favorably to the standard combination of MSAFP, hCG, and unconjugated estriol (E3), which had a 66.7% Down syndrome detection rate and a 4.1% screen positive rate in our study samples.Conclusion: This retrospective analysis suggested that the inclusion of insulin-like growth factor binding protein-3 into the triple screen program to replace unconjugated E3 might enhance the detection rate of fetal Down syndrome pregnancies. These data need to be confirmed by a larger prospective study.     

Second-trimester cancer antigen 125 and Down's syndrome.

This study explores if assay of cancer antigen 125 (CA 125) in maternal serum might aid the detection of Down's syndrome in the second trimester of pregnancy. CA 125 levels were determined retrospectively in stored maternal serum samples from ten Down's syndrome pregnancies and 78 controls matched for gestational and maternal age. In addition, second-trimester amniotic fluid samples from nine Down's syndrome and 109 unaffected pregnancies were analysed for CA 125. Maternal serum CA 125 values for Down's syndrome pregnancies were lower, with the median being 0.72 multiples of the unaffected population median. The medians for affected and unaffected pregnancies did not differ significantly and there was a considerable overlap in the range of values of cases and controls. The distribution of amniotic fluid CA 125 levels for Down's syndrome pregnancies resembled that for controls. From our present results, we could not find an association between Down's syndrome and second-trimester maternal serum or amniotic fluid CA 125 levels.     

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 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.     

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.