Decreased maternal serum placenta growth factor in early second trimester and preeclampsia

OBJECTIVE: To compare early second-trimester maternal serum placenta growth factor concentrations in patients with subsequent development of preeclampsia and those with normal pregnancies. METHODS: We conducted a case-control analysis of stored maternal serum of 27 women who subsequently developed preeclampsia and 227 randomly selected normal controls during the gestational period of 14-19 weeks. Using such a sample size, there was a greater than 95% power to test a difference in the primary study interest. A quantitative sandwich enzyme immunoassay was used to measure the maternal serum placenta growth factor concentration. For statistical analysis, Mann-Whitney U tests, multiple linear regression analysis, multivariable logistic regression model, and receiver-operating characteristic (ROC) curve were used. P <.05 was considered statistically significant. RESULTS: Maternal serum placenta growth factor concentration was associated with the occurrence of subsequent preeclampsia (P <.001) and gestational age (P <.001). The median (interquartile range) of multiples (MoM) of the gestational age stratified median for placenta growth factor in preeclampsia was 0.55 (0.33, 0.85). The ROC curve revealed that the specificity was 70% when the diagnostic sensitivity was 70%, and the optimal cutoff value of placenta growth factor MoM was 0.76. The risk of developing preeclampsia subsequently was increased 2.5-fold for maternal serum placenta growth factor concentration decrements of 0.1 MoM. CONCLUSION: A decreased maternal serum placenta growth factor concentration in the early second trimester is highly associated with the subsequent development of preeclampsia, but a large prospective study is needed to explore its use as an early predictor for the condition.     

Maternal serum second trimester AFP and hCG in pregnancies with placenta previa

This study was undertaken to investigate the association between placenta previa and Down syndrome screening analytes-alpha-fetoprotein (AFP) and hCG-during the second trimester. Measurements of maternal serum AFP and hCG concentrations were retrospectively analysed in relation to placenta previa in a cohort of 46 consecutive singleton pregnancies affected by placenta previa from January 1993 through December 1997 at the University Hospital of Kuopio, Finland, and then compared with those in healthy singleton control pregnancies (N=9560) from the same clinic over the same period of time. Geometric means of maternal serum AFP and hCG concentrations in pregnancies with placenta previa were 1.13 and 0. 85 multiples of the median (MoM), respectively. The mean maternal age was higher in the subjects than in the controls (30.9 years compared with 28.8 years) (p<0.01). In relation to Down syndrome risk assessment, the pattern of the two markers together with maternal age indicated high risk as often in the study subjects as in the controls. Even though the maternal serum AFP and hCG differences were not statistically significant, they may be of some clinical importance, and further studies are needed to evaluate whether placental site should be taken into account in maternal serum screening.     

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.     

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.     

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.     

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.     

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

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

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.     

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.     

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 and amniotic fluid levels of macrophage inhibitory cytokine 1 in Down syndrome and chromosomally normal pregnancies

OBJECTIVES: To measure maternal serum and amniotic fluid levels of macrophage inhibitory cytokine-1 (MIC-1) in Down syndrome and normal pregnancies, assessing the utility of MIC-1 as a prenatal marker of Down syndrome. METHODS: Stored serum from 64 Down syndrome and 399 control pregnancies, collected at 8 to 17 weeks of pregnancy, and stored amniotic fluid from 17 Down syndrome and 53 controls, collected at 15 to 19 weeks of pregnancy, were retrieved for analysis. MIC-1 was measured using an established in-house ELISA, blinded to sample type. RESULTS: In maternal serum, MIC-1 levels are not altered in Down syndrome in either the first or second trimester. Levels, expressed as median (95% CI) multiples of the median (MoM), in the Down syndrome cases and controls were 1.07 (0.9-1.1) MoM and 1.0 (0.95-1.03) MoM respectively. In amniotic fluid, MIC-1 levels were significantly decreased compared to controls, 0.52 (0.44-0.64) MoM versus 1.0 (0.85-1.08) MoM (p < 0.0001). CONCLUSION: MIC-1 is decreased in amniotic fluid but not in maternal serum in Down syndrome pregnancies. MIC-1 will not be useful as a prenatal marker of Down syndrome.     

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

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

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.     

Maternal serum leptin concentration during the second trimester of pregnancy: association with fetal chromosomal abnormalities

Recent studies suggest that leptin, the product of the obese gene, is produced by the placenta during pregnancy. The present study addressed the question whether second trimester maternal serum leptin could be altered by fetal Down syndrome or Edwards syndrome. Maternal serum leptin concentrations were measured in 18 pregnancies complicated with Down syndrome, six pregnancies complicated with Edwards syndrome and 183 uncomplicated pregnancies during the second trimester of pregnancy. The present results demonstrate that leptin concentrations in uncomplicated pregnancies slightly decrease from the 16th week of pregnancy, reaching a minimum of 18.8 ng/ml around the 20th week, and then rapidly increase to 28.2 ng/ml by the 24th week. Leptin correlation with maternal body weight decreases from r=0.695 at 16-17 week of gestation to r=0.544 at >22 weeks of gestation. There was no significant difference between the mean MoMs of Down syndrome- (0.926) or Edwards syndrome- (0.960) affected pregnancies and normal pregnancies (1.002). A weak correlation (r=0.18, p<0.02) was observed between corrected leptin MoMs and human chorionic gonadotrophin (hCG) MoMs in normal pregnancies. It is assumed that around the 20th week of pregnancy placental leptin production is activated or at least is accelerated and it is added to the amount of leptin produced by maternal adipose tissue. Fetal Down syndrome or Edwards syndrome does not seem to alter maternal leptin concentration and therefore leptin cannot be used as a marker for these chromosomal abnormalities in the early second trimester of pregnancy.     

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.     

Unexplained elevated maternal serum beta-HCG concentration and adverse pregnancy outcome

OBJECTIVE: To investigate the association between unexplained elevated maternal serum beta-Human chorionic gonadotrophin (HCG) in the second trimester of pregnancy and adverse pregnancy outcome. METHODS: In a case-controlled study of 3463 women who opted for second-trimester serum screening for Down syndrome, 142 were found to have a serum beta-HCG of > or =3.5 multiples of the median (MoM), 56 of whom had a serum beta-HCG of > or =5.0 MoM. These women were compared with a control group of women with serum beta-HCG within the 95% confidence interval around the median. RESULTS: In the elevated beta-HCG group (> or =5 MoM) significantly more babies required admission to the special care baby unit (p = 0.02) and were small for gestational age (SGA) (p = 0.03). The mean birth weight was also significantly lower in the group with elevated beta-HCG. Women with a serum beta-HCG of > or =5, > or =6, > or =7 or > or =8 MoM were associated with SGA babies in 40, 44, 64 and 86% respectively. All babies born to the six women with beta-HCG of 8.75-24.1 MoM were SGA. CONCLUSION: Increased surveillance is necessary in pregnancies where the maternal serum beta-HCG in the second trimester is inexplicably elevated to > or =5 MoM.     

ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy

Background. ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16–18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy.

Materials and methods. The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers.

Results. The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log₁₀ MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log₁₀ MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14–18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free β-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free β-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%).

Conclusion. ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks.     

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

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

ADAM12 as a marker of trisomy 18 in the first and second trimester of pregnancy.

BACKGROUND: ADAM12 (a disintegrin and metalloprotease 12) is a placentally derived glycoprotein that appears to be involved in growth and differentiation. The maternal serum concentration of ADAM12 appears to be a very good marker of trisomy 21 in the early first trimester when levels are reduced, and in the second trimester around 16-18 weeks levels are elevated. One small preliminary study of first trimester pregnancies with trisomy 18 found reduced levels in the maternal serum, and we examine herein the potential of ADAM12 as a marker of trisomy 18 in both the first and second trimester of pregnancy. MATERIALS AND METHODS: The concentration of ADAM12 was determined by a time-resolved immunofluorometric assay in 132 first and 12 second trimester cases of trisomy 18, and 389 first and 341 second trimester gestational age-matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and used to determine the population distribution parameters for the trisomy 18 and control groups. Correlation with previously established pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG) multiples of the median (MoMs) and nuchal translucency thickness (NT) MoM were determined and used to model the performance of first trimester screening with ADAM12 in combination with other first trimester markers. RESULTS: The maternal serum concentration of ADAM12 in the first trimester was significantly reduced with a median MoM of 0.829 (p < 0.001) and a mean log10 MoM SD of 0.2663 compared to 0.3353 in the controls. In the second trimester small series ADAM12 was significantly increased with a median MoM of 2.09 (p = 0.001) and a mean log10 MoM SD of 0.2607 compared to 0.4318 in controls. There was a significant correlation of ADAM12 MoM with gestational age (r = 0.510) in trisomy 18 cases, and the median MoM increased from 0.51 at 10 weeks to 1.28 at 13 weeks and 2.09 across the 14-18 week window. ADAM12 was correlated with PAPP-A (r = 0.1918) in the first trimester of cases with trisomy 18 but less so with NT (r = 0.1594) and free beta-hCG (r = 0.0938). Modeled detection rates incorporating ADAM12, free beta-hCG, and NT were 92% at 1% false positive rate (88% at 0.5%) A combination of all four markers had a detection rate of 96.5% at a false positive rate of 1% (95% at 0.5%). CONCLUSION: ADAM12 may be a useful addition to early screening for trisomy 18 alongside other chromosomal anomalies, particularly if biochemical screening can occur before 10 weeks.     

Biochemical screening for Down syndrome in pregnancies following renal transplantation

OBJECTIVE: To assess the performance of the double marker test [free beta-human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein (AFP)] as a screening test for Down syndrome in pregnant patients who had a prior renal transplant. DESIGN: A retrospective study. SETTING: The Fetal Medicine Unit, Royal Free Hospital, London, UK. METHODS: Detailed records of 14 post-renal transplant pregnancies were obtained from the Renal Unit of our hospital where the patients were followed up. The serum concentrations of urea, creatinine, free beta-hCG and AFP at the time of the double marker test were recorded, with a cut-off point of 1:250 for the double marker test. A control group of 14 normal pregnancies matched for age, parity and gestational age was used. The Mann-Whitney U-test and t-tests of unequal variance were applied to compare parameters of the study and the control groups. RESULTS: Two patients in each group were high risk for Down syndrome and amniocentesis revealed normal karyotype. No babies with Down syndrome were delivered in either group. Regression analysis showed significant correlation between free beta-hCG and urea concentrations (p<0.001) and free beta-hCG and creatinine concentrations (p<0.001), but not for AFP. CONCLUSIONS: The present study demonstrates that residual renal function alterations persisting after renal transplantation can affect the levels of free beta-hCG and AFP, thus resulting in false-positive screening for Down syndrome. First trimester nuchal translucency (NT) measurement in combination with second trimester ultrasonographic markers can be used in these patients, or alternatively the free beta-hCG levels should be corrected according to the serum creatinine levels.