解整合素-金属蛋白酶12作为子(癇)前期筛查标志物的初步研究

目的 初步评价孕中期血清解整合素-金属蛋白酶12(a disintegrin and metalloprotease 12,ADAM 12)可否作为子癇前期筛查的一种标志物. 方法 通过病例-对照研究,采用初步建立的间接竞争法ELISA检测100例子癇前期患者与200例正常妊娠妇女孕14～18周血清标本中的ADAM 12水平,将其转换成MoM值后比较其有无明显差异. 结果 正常孕妇孕14～18周血清ADAM 12中位数分别为680/μg/L、738 μg/L、801 μg/L、849μg/L和900/μg/L,子癇前期患者孕14～18周血清ADAM 12中位数分别为598μg/L、664 μg/L、729/μg/L、791 μg/L和839μg/L.子癇前期组患者血清ADAM 12 LogMoM平均值-0.05242,明显低于正常孕妇组血清ADAM 12 LogMoM平均值-0.003 68(P＜0.01). 结论 子癇前期组患者孕14～18周血清ADAM 12水平明显低于正常孕妇,孕中期血清ADAM 12可能作为子癇前期筛查的一种标志物.     

ADAM12s in maternal serum as a potential marker of pre-eclampsia

OBJECTIVE: To examine whether maternal serum ADAM12s, a potential first- and second-trimester marker of fetal aneuploidy and fetal growth, had altered concentrations in the first or second trimester of pregnancies subsequently developing pre-eclampsia. METHODS: ADAM12s was measured by a time-resolved fluoroimmunoassay developed by PerkinElmer Life Science. Maternal serum samples from women taking part in early first-trimester aneuploidy screening in whom the pregnancy resulted in pre-eclampsia (64) were identified from a cohort of 4,390 singleton pregnancies in which uterine artery Doppler mean Pulsatility Index (PI) had been measured at 22-24 weeks. From amongst those cases delivering a normal term infant with birth weight greater than the 10th centile for gestational age 240 cases were selected as gestational age-matched controls. A second study group consisting of maternal serum taken at 22-24 weeks at the time of uterine artery Doppler in a group of 12 women developing pre-eclampsia were compared with 86 matched controls from a previously studied cohort of 24 cases and 144 controls. Serum ADAM12s concentrations were converted to multiple of the median (MoM) to take account of gestational age variation. RESULTS: First-trimester maternal serum ADAM12s levels in women who developed pre-eclampsia were reduced with a median MoM of 0.71 which was further reduced in those delivering prior to 35 weeks (0.50). At the 5th centile of normal (0.48 MoM) ADAM12s identified 27% of cases with pre-eclampsia and 47% of those with early pre-eclampsia. Combining ADAM12s with PAPP-A from a previous study only resulted in a further 1% increase in detection of all women developing pre-eclampsia. However combining ADAM12s with mean PI increased the detection rate to 66%. In the second trimester at 22-24 weeks the maternal serum ADAM12s levels were increased in those women developing pre-eclampsia compared to controls (709 vs 486 ug/L, p = 0.045). CONCLUSION: ADAM12s in addition to being a potential marker of aneuploidy may also be a marker of pre-eclampsia. Further studies are required to see if this can improve on the clinical discrimination already provided by PAPP-A in the early first trimester.     

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.     

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.     

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.     

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 ADAM12 in Chinese women undergoing screening for aneuploidy in the first trimester

Objective.?To evaluate the potential of maternal serum using a disintegrin and metalloprotease 12 (ADAM12) as a marker for Trisomy 21 in Chinese pregnant women.

Methods.?Serum samples were collected and stored from women having a viable singleton pregnancy undergoing first trimester screening for Trisomy 21 between 2006 and 2007. Serum concentration of ADAM12 was measured using an automated time-solved immuno-fluorometric assay from 608 stored serum samples (601 Euploidy and 7 Trisomy 21). Regression analysis was used to determine the expected median in Euploidy pregnancies after adjusting for pregnancy characteristics. The level of ADAM12 MoM was compared between Trisomy 21 and Euploidy pregnancies. Expected median levels in Chinese were compared to that published for Caucasians and Afro-Caribbeans.

Results.?In Euploidy pregnancies, the concentration of ADAM12 increased with CRL and decreased with maternal weight. The expected median level of ADAM12 in Chinese was significantly lower than Caucasian and Afro-Caribbeans (F?=?14.2, p?<?0.0001). There was a significant correlation between log₁₀ADAM12 MoM both log₁₀ pregnancy-associated plasma protein A MoMs (r?=?0.46; p?<?0.001) and log₁₀free βhCG MoMs (r?=?0.08; p?=?0.048). The median ADAM12 MoM in Trisomy 21 pregnancies was not significantly different from that in Euploidy pregnancies (z?=?0.18; p?=?0.88).

Conclusion.?ADAM12 concentrations in Chinese are lower than those of Caucasians and Afro-Carribeans; that ADAM12 MoM levels in Euploidy and Trisomy 21 pregnancies were not statistically different.     

First trimester sex hormone-binding globulin and subsequent development of preeclampsia or other adverse pregnancy outcomes.

OBJECTIVE: To investigate whether first trimester maternal serum sex hormone-binding globulin (SHBG) concentrations are altered in women who subsequently develop preeclampsia or other pregnancy complications. POPULATION: Women undergoing first trimester combined ultrasound and biochemical screening for chromosomal anomalies. We searched the database and identified 32 pregnancies resulting in miscarriage, 64 pregnancies with preexisting or gestational diabetes mellitus, 107 with fetal growth restriction, 103 with preeclampsia, 64 with pregnancy-induced hypertension, and 26 with spontaneous preterm delivery. We also selected 400 controls from among the population of pregnancies that had a delivery of a normal baby with no pregnancy complications. METHODS: Maternal serum SHBG concentrations were measured retrospectively using a competitive chemiluminescent immunoassay. The levels between those with normal outcome and those resulting in adverse outcome were compared. RESULTS: The median maternal serum SHBG concentration was not significantly different from controls, in those that subsequently developed preeclampsia (median MoM 1.05), non-proteinuric hypertension (median MoM 0.94) or preterm delivery (median MoM 1.15). The levels were significantly lower in those with diabetes (median MoM, 0.81 p=0.0005) and those pregnancies resulting in miscarriage (median MoM 0.80, p=0.008). CONCLUSION: First trimester maternal serum SHBG concentrations are no different from controls in women who subsequently develop preeclampsia, pregnancy-induced hypertension, fetal growth restriction, or preterm delivery. Levels are reduced in those who subsequently miscarry or in those presenting with diabetes.     

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.     

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.     

Role of second trimester maternal serum markers as predictor of preeclampsia

Objectives

To evaluate the variations and potential clinical use of second trimester serum markers as predictor of preeclampsia.

Methods

In a prospective study β HCG, α feto protein and inhibin A levels were estimated in 50 antenatal women in the second trimester (12–24 weeks) by ELISA technique. Results were noted in terms of development of preeclampsia, mean serum levels of all three markers, mode of delivery and fetal outcome.

Resuflts

Out of 50 women, 10 developed preeclampsia (20%). A significant rise of mean serum β HCG level (16130.2 MIU/ml, >2.5 MoM,p <0.001), mean serum AFP level (161.7 ng/ml, >2.5 MoM, P<0.001) and mean inhibin-A level (1248.49 pg/ml, >2.0 MoM, P<0.001) was present in those who developed preeclampsia. Out of 10 preeclamptic women one had IUD, four fetuses were growth retarded, two babies were born before term and six were low birth weight babies, whereas out of 40 normotensive women only five had IUGR, three preterm delivery and 32 delivered at term without and complication.

Conclusions

A significant positive correlation between second trimester serum markers and development of preeclampsia was observed (p<0.001). Thus with the second trimester serum marker study, prediction of preeclampsia is possible at incipient stage and its adverse pregnancy outcome can be minimized.     

Bioactivity of serum hCG in preeclampsia

OBJECTIVE: To compare hCG levels, obtained by biologic and immunologic means, in women with normal pregnancies and women with preeclampsia. METHODS: Peripheral blood samples from women in the third trimester with preeclampsia (n = 30) or normal pregnancies (n = 30) were assayed for immunoactive and bioactive hCG (mouse Leydig cell testosterone production assay). RESULTS: Serum bioactive hCG levels tended to be lower than normal, and immunoactive hCG levels tended to be higher in women with preeclampsia, but the differences were not statistically significant. However, the ratio of bioactive to immunoactive hCG was significantly lower than normal for preeclamptic women (0.70 +/- 0.28 vs. 1.15 +/- 0.35 for normotensive pregnant women [mean +/- standard deviation], P <.001). CONCLUSION: The ratio of bioactive to immunoreactive serum hCG is lower among preeclamptic than among normotensive pregnant women.     

妊娠中、晚期血清瘦素、β-hCG及ADAM12水平的变化及其与子痫前期发生的关系

目的：探讨妊娠中、晚期妇女血清瘦素、人绒毛膜促性腺激素β亚单位（β-hCG）及解整合素-金属蛋白酶12（ADAM12）的水平变化及这些指标对子痫前期（PE）发生的预测价值.方法：选择2007年6月-2008年5月在福建省妇幼保健院定期产检和住院分娩的189例妊娠妇女,分别测定妊娠中期（20～24周）和妊娠晚期（30～34周）血清瘦素、β-hCG、ADAM12的浓度,其中25例发展为PE者为病例组,164例正常妊娠者为正常组.根据受试者工作特征（ROC）曲线确定预测界限值.结果：①妊娠中期病例组血清β-hCG、ADAM12浓度显著高于正常组（P＜0.001）.②妊娠晚期病例组血清瘦素、β-hCG、ADAM12浓度明显高于正常组（P＜0.001）.③病例组妊娠晚期血清瘦素、β-hCG及ADAM12水平均较妊娠中期升高（P＜0.05）,正常组妊娠晚期血清瘦素水平较妊娠中期升高（P＜0.001）,而血清β-hCG与ADAM12水平2组间差异无统计学意义（P＞0.05）.④妊娠中期以血清β-hCG≥32 μg/L、血清ADAM12≥818 μg/L为预测界值,两者联合阳性预测值为82.61%,高于单项阳性预测值（P＜0.05）.两者联合ROC曲线下面积与单项ROC曲线下面积比较差异无统计学意义（P＞0.05）.⑤妊娠晚期以血清瘦素≥23 μg/L、血清β-hCG≥37 μg/L及血清ADAM12≥900 μg/L为预测界值,三者联合阳性预测值达92.31%,高于单项阳性预测值（P＜0.05）.三者联合ROC曲线下面积大于单项β-hCG及瘦素ROC曲线下面积（P＜0.05）,但与单项ADAM12曲线下面积差异无统计学意义（P＜0.05）.⑥联合妊娠中、晚期血清β-hCG预测PE发生的阳性率为81.25%;联合妊娠中、晚期血清ADAM12预测PE发生的阳性率为90.48%,均比单一指标的阳性预测值高.结论：检测妊娠中、晚期妇女血清β-hCG及ADAM12水平可作为PE发生的有效预测指标;联合多项指标并动态监测可进一步提高对PE发生的阳性预测值及准确率.     

Preeclampsia is associated with reduced serum levels of placenta growth factor

Objectives: Adequate vascular development of the placental bed is essential for normal pregnancy. We assessed serum levels of placenta growth factor, an angiogenic factor, throughout normal pregnancy and determined its association with preeclampsia. Study Design: Serum samples were collected from (1) 308 healthy pregnant women throughout normal gestation, (2) at delivery from 30 each gestational age–matched patients with normal pregnancy and preeclampsia, and (3) maternal and cord blood samples from normal deliveries with and without labor (n = 37 each). Placenta growth factor levels were determined with an antigen-capture enzyme-linked immunosorbent assay. Results: Maternal placenta growth factor levels during normal pregnancy increased from the first trimester to the late second trimester; they subsequently declined from 30 weeks’ gestation to delivery. Significantly less maternal placenta growth factor (P < .0001) was found in pregnancies complicated by preeclampsia, and labor significantly lowered placenta growth factor levels in both maternal (P = .0189) and cord serum samples (P < .0001). Conclusion: Decreased levels of placenta growth factor during preeclampsia could influence endothelial cell and trophoblast function, thereby contributing to the pathogenesis of the disease. (Am J Obstet Gynecol 1998;179:1539-44.)     

妊娠中、晚期血清瘦素、β-hCG及ADAM12水平的变化及其与子痫前期发生的关系

目的：探讨妊娠中、晚期妇女血清瘦素、人绒毛膜促性腺激素β亚单位（β-hCG）及解整合素-金属蛋白酶12（ADAM12）的水平变化及这些指标对子痫前期（PE）发生的预测价值。方法：选择2007年6月—2008年5月在福建省妇幼保健院定期产检和住院分娩的189例妊娠妇女,分别测定妊娠中期（20～24周）和妊娠晚期（30～34周）血清瘦素、β-hCG、ADAM12的浓度,其中25例发展为PE者为病例组,164例正常妊娠者为正常组。根据受试者工作特征（ROC）曲线确定预测界限值。结果：①妊娠中期病例组血清β-hCG、ADAM12浓度显著高于正常组（P＜0.001）。②妊娠晚期病例组血清瘦素、β-hCG、ADAM12浓度明显高于正常组（P＜0.001）。③病例组妊娠晚期血清瘦素、β-hCG及ADAM12水平均较妊娠中期升高（P＜0.05）,正常组妊娠晚期血清瘦素水平较妊娠中期升高（P＜0.001）, 而血清β-hCG与ADAM12水平2组间差异无统计学意义（P＞0.05）。④妊娠中期以血清β-hCG≥32 μg/L、血清ADAM12≥818 μg/L为预测界值,两者联合阳性预测值为82.61%,高于单项阳性预测值（P＜0.05）。两者联合ROC曲线下面积与单项ROC曲线下面积比较差异无统计学意义（P＞0.05）。⑤妊娠晚期以血清瘦素≥23 μg/L、血清β-hCG≥37 μg/L及血清ADAM12≥900 μg/L为预测界值,三者联合阳性预测值达92.31%,高于单项阳性预测值（P＜0.05）。三者联合ROC曲线下面积大于单项β-hCG及瘦素ROC曲线下面积（P＜0.05）,但与单项ADAM12曲线下面积差异无统计学意义（P＜0.05）。⑥联合妊娠中、晚期血清β-hCG预测PE发生的阳性率为81.25%;联合妊娠中、晚期血清ADAM12预测PE发生的阳性率为90.48%,均比单一指标的阳性预测值高。结论：检测妊娠中、晚期妇女血清β-hCG及ADAM12水平可作为PE发生的有效预测指标;联合多项指标并动态监测可进一步提高对PE发生的阳性预测值及准确率。     

Metalloprotease (ADAM12-S) as a Predictor of Preeclampsia: Correlation with Severity,Maternal Complications,Fetal Outcome,and Doppler Parameters

Objectives. To compare the first trimesteric serum level of ADAM12-S in women who developed mild and severe preeclampsia and in healthy gravidas and to correlate these changes with the severity of the disease, maternal complications, fetal outcome, and Doppler cerebroplacental ratio (CPR). Design. Comparative prospective observational study. Setting: University hospital. Methods: Serum samples were obtained from 414 women in their first trimester, of which 259 women completed their pregnancy without complications and 155 women developed preeclampsia later in their pregnancies. All were subjected to history taking, examination, laboratory investigations, obstetric ultrasound, and Doppler CPR. Results. ADAM12-S was significantly decreased in patients with severe and in mild preeclampsia compared with the controls. Moreover, there was strong negative correlation with disseminated intravascular coagulopathy (DIC) and HELLP syndrome, cesarean delivery, postpartum hemorrhage, and neonatal intensive care unit admission. ADAM12-S had medium negative correlation with systolic blood pressure and diastolic blood pressure, accidental hemorrhage, cesarean hysterectomy, prematurity, and low birth weight. In addition, it had a weak negative correlation with intracranial hemorrhage, residual hypertension, and intrauterine fetal death. ADAM12-S had strong positive correlation with CPR. There were no correlation with eclampsia, intrauterine growth retardation, acute pulmonary edema, and acute renal failure. Conclusion. ADAM12-S is significantly decreased in severe and mild preeclampsia and is correlated with CPR, severity of preeclampsia, maternal complications, and fetal outcome. It is recommended to measure ADAM12-S in the first trimester to predict maternal complications and fetal outcome in pregnancies complicated by preeclampsia.     

Severe preeclampsia is associated with high inhibin A levels and normal leptin levels at 7 to 13 weeks into pregnancy

OBJECTIVE: The purpose of this study was to determine whether maternal serum inhibin A and leptin concentrations changed in the first trimester of pregnancy in patients in whom severe preeclampsia subsequently developed. STUDY DESIGN: Blood samples were collected prospectively from patients during the first trimester of prenatal care. Patients in whom severe preeclampsia with no evidence of glucose intolerance or gestational diabetes mellitus subsequently developed were identified (study group, 30 patients) and matched with control subjects in a 1:2 ratio (control group, 60 patients). Inhibin A and leptin concentrations were determined in these first-trimester serum samples for both the study and control groups. RESULTS: Leptin levels were correlated highly with body mass index in both groups but were not correlated with the subsequent onset of preeclampsia. Serum inhibin A concentrations were significantly higher in women in whom preeclampsia subsequently developed than in women in whom it did not. With a specific cutoff value, the estimated odds for severe preeclampsia were almost five times higher in women with high inhibin A concentrations than in women with normal levels (odds ratio, 4.93; 95% CI, 1.83, 13.28). CONCLUSION: High serum inhibin A levels in the first trimester of pregnancy could be used as an early risk marker for preeclampsia.     

Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler

BACKGROUND: Previous studies have shown an association between low first trimester maternal serum free beta-hCG and PAPP-A and subsequent development of pregnancy complications. Similarly, uterine artery Doppler in the late second trimester has shown that high impedance to flow is associated with increased risk for preeclampsia and fetal growth restriction. The objective of this study is to determine whether there is an association between the maternal serum concentration of PAPP-A and free beta-hCG at 11-13(+6) weeks with the uterine artery pulsatility index (PI) at 22-24 weeks, and secondly, to compare the screening characteristics of the two methods in the prediction of adverse pregnancy outcome. METHODS: Maternal serum PAPP-A and free beta-hCG at 11-13(+6) weeks and uterine artery PI at 22-24 weeks were measured in 4390 women with singleton pregnancies. Pregnancies with chromosomal defects or fetal anomalies were excluded. The biochemical and Doppler measurements were compared between those with normal outcome and those resulting in spontaneous preterm delivery, pre-eclampsia and fetal growth restriction (FGR). Detection rates using a combination of the biochemical and Doppler measurements were investigated. RESULTS: In the pregnancies resulting in pre-eclampsia (n = 64) and FGR (n = 172), the median PAPP-A was lower (0.844 and 0.813 MoM), the median uterine artery mean PI was higher (1.56 and 1.18) but the median free betahCG was not significantly different (0.923 and 0.933 MoM) than in the normal outcome group. In the preterm delivery group (n = 159), the median free beta-hCG (0.944 MoM) and uterine artery mean PI (1.06) were not significantly different from normal but the median PAPP-A (0.928 MoM) was significantly lower than normal. In screening for pre-eclampsia, the detection rate, for a 5% false-positive rate, was 14.1% for PAPP-A, 54.7% for uterine artery mean PI and 62.1% for a combination of PAPP-A and uterine artery mean PI. CONCLUSION: Maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes. The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia.     

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

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

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.