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.     

The first trimester 'combined test' for the detection of Down syndrome pregnancies in 4939 unselected pregnancies

The high detection rate (DR) for Down syndrome (DS) pregnancies which can be achieved by measuring fetal nuchal translucency (NT) early in pregnancy can be improved by combining it with placental hormones [pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotrophin (fbeta-hCG)] and maternal age ('combined test'). In this study we wanted to assess the DR using the 'combined test' in an unselected population of self-referred pregnant women at a false-positive rate (FPR) of about 5%. NT, PAPP-A, fbeta-hCG and maternal age were measured in all women with singleton pregnancies who booked for delivery in our hospital from 1 December 1997 to 31 April 2000 and who were between 10 and 13 completed weeks of gestation [crown-rump length (CRL) 35-70 mm]. The specific DS risk was calculated using the computer program Alpha Version 5aa (Logical Medical Systems, London, UK). A total of 4939 women were tested. Out of 14 DS pregnancies that occurred during this period of time, 12 were detected with the test. A total of 246 women had a false-positive test result in a non-DS pregnancy (FPR 5.0%). This makes the 'combined test' by far the best test for the detection of DS pregnancies in a low-risk population. The constant increase in maternal age at the time of delivery can also lead to an improved DR if a simple age-dependant protocol for DS detection is used, but only at the price of a much higher number of amniocenteses and subsequent abortions. The DR for DS can be increased much more markedly using the 'combined test' with a FPR that still remains at the level as it was in the early 1970s.     

First-trimester biochemical markers for Down syndrome

The value of maternal serum pregnancy-associated protein A (PAPP-A), free and total beta human chorionic gonadotrophin (fbetahCG, betahCG) and alpha-fetoprotein (AFP) in screening for Down syndrome (DS) in early pregnancy has been assessed. To evaluate the different biochemical markers, 32 DS pregnancies and 267 controls were used for AFP, betahCG and PAPP-A. A subgroup of those (17 DS and 136 controls) were used to evaluate fbetahCG. All analytes were determined in fresh serum samples. Our results give support to the feasibility of maternal serum levels of PAPP-A as the best biochemical marker for DS in the first trimester, and either betahCG or fbetahCG as the second marker. No differences were found between betahCG and fbetahCG distribution levels as expressed as MoMs in normal and DS pregnancies in this study.     

Pregnancy-associated plasma protein A in the prediction of early pregnancy failure

Maternal circulating pregnancy-associated plasma protein A (PAPP-A) was measured in 51 patients with vaginal bleeding in the first half of pregnancy. Concentrations of PAPP-A were consistently lower in pregnancies which failed. In the prediction of early pregnancy failure, the predictive value of depressed maternal PAPP-A levels was 58%, the sensitivity was 91.9%, and specificity was 95.1%. These results compared favorably with other biochemical tests of placental function. However, if fetal life was demonstrated ultrasonically, depressed levels of PAPP-A substantially differentiated between those pregnancies which continued normally and those which did not, suggesting that PAPP-A estimations would be of clinical value in cases previously beyond the reach of any diagnostic measure.     

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

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

产前行妊娠相关血浆蛋白A筛查联合FISH诊断Down综合征

目的 :应用单项妊娠相关血浆蛋白A(PAPP A)筛查与羊水间期荧光原位杂交 (FISH)产前诊断相结合预防妊娠Down综合征胎儿。方法 :采用酶联免疫方法 (ELISA)对孕周分别为 6～ 2 7周的 1839例孕妇进行母血PAPP A单项筛查 ,以低于同一孕周的中位数时视为可能妊娠Down综合征胎儿的高风险孕妇。取高风险孕妇羊水细胞直接进行间期FISH产前诊断并同时用部分羊水细胞遗传学检查作对照。结果 :检出 1例孕 7周孕妇其PAPP A值为 0 0 5 1U/L ,低于同一孕周中位数 2 0多倍。羊水细胞间期FISH结果显示 ,含 5个杂交信号的核占所有杂交核的 38 5 % ,与细胞遗传学分析的 2 1三体核型完全一致。结论 :单项PAPP A筛查与羊水间期细胞FISH相结合是早期防治妊娠Down综合征有效可行的方法。     

Amniotic fluid and plasma concentrations of pregnancy-associated plasma protein-A (PAPP-A) throughout pregnancy: comparison with other fetoplacental products

The development of a sensitive radioimmunoassay has enabled measurements of pregnancy-associated plasma protein-A (PAPP-A) to be performed from early pregnancy. The present paper compares the plasma concentrations of PAPP-A with the levels of two trophoblastic proteins, human placental lactogen (hPL) and the beta-subunit of human chorionic gonadotrophin (beta-hCG), with a steroid of fetoplacental origin, total oestriol (total E3), and with a fetal protein, alpha-fetoprotein (AFP). PAPP-A was also measured in amniotic fluid and in maternal urine. In contrast with the secretion of the other substances studied, which either reach a plateau or even decrease during the last 4 weeks of pregnancy, PAPP-A steadily increased in the maternal circulation from 7 to 40 weeks gestation. It is proposed that PAPP-A production is either not related to placental mass or that PAPP-A is not of trophoblastic origin. The increase of PAPP-A in amniotic fluids parallels the increase in maternal blood; virtually no PAPP-A is excreted in urine.     

First-trimester Down syndrome screening: component analytes and timing for optimal performance

The most effective first-trimester Down syndrome screening protocol in current use employs three independent markers: maternal serum levels of PAPP-A and free beta hCG, and measurement of fetal nuchal translucency (NT). Eleven weeks appears to be the optimum gestational age for performing first trimester DS risk assessment. Although the discrimination of free beta hCG improves with increasing gestational age and is greatest at 13 weeks, PAPP-A and NT perform optimally at 10 and 11 weeks, respectively. In addition to accurate pregnancy dating, first trimester screening performance is improved by using a consistent NT measurement technique, NT cut-offs adjusted for gestational age or crown-rump length, and possibly center- or operator-specific NT medians. Whether or not absence or presence of the nasal bone adds to screening accuracy is a matter of some debate. Finally, because enlarged NT has been associated with cardiac defects and other structural anomalies, even in euploid fetuses, its presence should prompt a targeted second trimester ultrasound examination.     

Amniotic fluid and plasma concentrations of pregnancy-associated plasma protein-A (PAPP-A) throughout pregnancy: comparison with other fetoplacental products

Summary. The development of a sensitive radioimmunoassay has enabled measurements of pregnancy-associated plasma protein-A (PAPP-A) to be performed from early pregnancy. The present paper compares the plasma concentrations of PAPP-A with the levels of two trophoblastic proteins, human placental lactogen (hPL) and the β-subunit of human chorionic gonadotrophin (β-hCG), with a steroid of fetoplacental origin, total oestriol (total E₃), and with a fetal protein, α-fetoprotein (AFP). PAPP-A was also measured in amniotic fluid and in maternal urine. In contrast with the secretion of the other substances studied, which either reach a plateau or even decrease during the last 4 weeks of pregnancy, PAPP-A steadily increased in the maternal circulation from 7 to 40 weeks gestation. It is proposed that PAPP-A production is either not related to placental mass or that PAPP-A is not of trophoblastic origin. The increase of PAPP-A in amniotic fluids parallels the increase in maternal blood; virtually no PAPP-A is excreted in urine.     

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

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

First trimester maternal serum free beta human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications

Objective To examine the value of first trimester maternal serum free β human chorionic gonadotrophin (β hCG) and pregnancy associated plasma protein A (PAPP-A) as predictors of pregnancy complications.
Design Screening study.
Setting Antenatal clinics.
Population Singleton pregnancies at 10–14 weeks of gestation.
Methods Maternal serum free β hCG and PAPP-A were measured at 10–14 weeks of gestation in 5584 singleton pregnancies. In the 5297 (94.9%) pregnancies with complete follow up free β hCG and PAPP-A were compared between those with normal outcome and those resulting in miscarriage, spontaneous preterm delivery, pregnancy induced hypertension or fetal growth restriction and in those with pre-existing or gestational diabetes.
Results Maternal serum PAPP-A increased and β hCG decreased with gestation. The multiple of median maternal serum PAPP-A was significantly lower in those pregnancies resulting in miscarriage, pregnancy induced hypertension, growth restriction and in those with pre-existing or gestational diabetes mellitus, but not in those complicated by spontaneous preterm delivery. The level was < 10th centile of the reference range in about 20% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 27% of those that developed gestational diabetes. Maternal serum free β hCG was < 10th centile of the reference range in about 15% of the pregnancies that subsequently resulted in miscarriage or developed pregnancy induced hypertension or growth restriction, and in 20% of those that developed gestational diabetes.
Conclusion Low maternal serum PAPP-A or β hCG at 10–14 weeks of gestation are associated with subsequent development of pregnancy complications.     

First trimester aneuploidy screening combining biochemical and ultrasound markers

The different strategies applied for Down syndrome (DS) screening in a single center are presented and the results are analyzed taking into account the number of invasive procedures needed for the diagnosis of one affected pregnancy. The use of advanced maternal age as a single criterion, from 1980 to 1992 proved to be poorly effective since 102 amniocentesis are needed to diagnose one DS affected pregnancy (1:102) or 52 to diagnose any aneuploidy (1:52) With the use of second trimester screening with serum markers (AFP and hCG) at 14-18 weeks in 8711 women less than 38 years, from 1993 to 1999 the ratios were improved to 1:82 and 1:47 respectively. With the introduction of the combined test in 1999 using free hCG, PAPP-A (sampling at 9-10 weeks) and NT (measured at 12 weeks) in 3644 women under 38 years, and gestational weeks adjusted by US in 3644 singleton pregnancies with complete follow-up, the ratios were substantially improved to 1:16 procedures for DS or 1:8 for any aneuploidy. The detection rate achieved was 90% for a false positive rate of 3.4%. Comparing the different strategies applied in our Unit it is clear that the combined test applied in the first trimester provides a substantial improvement in detection rates and reduction of unnecessary invasive testing.     

Placental protein measurements in complicated pregnancies. I. Intrauterine growth retardation

Summary. Maternal serum levels of human placental lactogen (hPL), schwangerschaftsprotein l (SP1) and pregnancy-associated plasma protein A (PAPP-A) were measured serially throughout pregnancy in 753 women who had a normal pregnancy when recruited during the second trimester. Thirty-three women were delivered of an infant with low birth-weight and with phenotypic features of intrauterine growth retardation (IUGR). The predictive value of an abnormal (< 10th centile) hPL result (PVpos) in the identification of IUGR was between 28 and 32%, the sensitivity (36–54%) being greatest at 35 weeks gestation. The predictive value of a normal result (PVneg) was 87–96% at various stages of pregnancy, also greatest at 35 weeks gestation. For SP1, the sensitivity and predictive values were also greatest at 35 weeks gestation (PVpos, 20%; sensitivity, 32%; PVneg, 95%), but for PAPP-A these values were considerably less at all gestations. The trends in levels of hPL, SP1 and PAPP-A observed in individual patients with IUGR were not apparently related to any clinically recognizable feature of the pregnancy or the degree of fetal compromise, irrespective of whether the levels were within or outside the 80% confidence limits of the normal range or whether the levels fell from within the normal range. These data suggest that maternal hPL measurements are superior in the identification of IUGR in samples obtained at 30–35 weeks gestation.     

Studies on pregnancy-associated plasma protein A in the third trimester of pregnancy.

The plasma concentration of pregnancy-associated plasma protein A (PAPP-A) was measured in 34 women during the last 10 weeks of pregnancy. From 30 to 36 weeks the concentration of this protein increased steadily. Thereafter the concentration of PAPP-A rose more steeply, the highest amounts being found in early labour. The concentration of PAPP-A in peripheral venous blood and in the uterine vein was much the same. It was less in the retroplacental blood and a great deal less in the peritoneal fluid. The day-to-day variation was small; the coefficient of variation at 38 weeks was only 7.3 per cent. After delivery, the concentration of PAPP-A fell more slowly than other placental proteins and steroids, the average half-life being 51 hours. Although there is no doubt that PAPP-A is a product of the syncytiotrophoblast, our findings suggest that it is not simply secreted by the chorionic villi directly into the intervillous space but makes its way into the maternal circulation by a more circuitous route.     

Placental protein measurements in complicated pregnancies. I. Intrauterine growth retardation

Maternal serum levels of human placental lactogen (hPL), schwangerschaftsprotein 1 (SP1) and pregnancy-associated plasma protein A (PAPP-A) were measured serially throughout pregnancy in 753 women who had a normal pregnancy when recruited during the second trimester. Thirty-three women were delivered of an infant with low birth-weight and with phenotypic features of intrauterine growth retardation (IUGR). The predictive value of an abnormal (less than 10th centile) hPL result (PVpos) in the identification of IUGR was between 28 and 32%, the sensitivity (36-54%) being greatest at 35 weeks gestation. The predictive value of a normal result (PVneg) was 87-96% at various stages of pregnancy, also greatest at 35 weeks gestation. For SP1, the sensitivity and predictive values were also greatest at 35 weeks gestation (PVpos, 20%; sensitivity, 32%; PVneg, 95%), but for PAPP-A these values were considerably less at all gestations. The trends in levels of hPL, SP1 and PAPP-A observed in individual patients with IUGR were not apparently related to any clinically recognizable feature of the pregnancy or the degree of fetal compromise, irrespective of whether the levels were within or outside the 80% confidence limits of the normal range or whether the levels fell from within the normal range. These data suggest that maternal hPL measurements are superior in the identification of IUGR in samples obtained at 30-35 weeks gestation.     

Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss

OBJECTIVE: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. METHODS: Study subjects were recruited for a National Institute of Child Health and Human Development-sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free beta-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free beta-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). RESULTS: The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free beta-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free beta-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. CONCLUSION: Normal values of PAPP-A, free beta-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks.     

Evaluation of pregnancy-associated plasma protein A (PAPP-A) and free beta subunit of human chorionic gonadotropin (beta hCG) levels and sonographic assesement of fetal nuchal translucency (NT) in singleton pregnancies between 11 and 14 weeks of gestation--Polish multi-centre research

Evaluation of pregnancy-associated plasma protein A (PAPP-A) and free beta subunit of human chorionic gonadotropin (beta hCG) levels and sonographic assessment of fetal nuchal translucency (NT) in singleton pregnancies between 11 and 14 weeks of gestation--Poland's multi-centers research. OBJECTIVES: Pregnancy-associated plasma protein A has been reported to be low in Down syndrome affected pregnancies during the first trimester of pregnancy. Enlarged nuchal translucency (NT) is observed in about 80% of fetuses affected with chromosomal abnormalities and congenital heart defects (CHD). MATERIAL AND METHODS: The aim of this study were to determine value and the medians of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) and nuchal translucency thickness in the first trimester in a prospective study of a non-selected Polish population. RESULTS: All examinations have been performed according to the Fetal Medicine Foundation (FMF) rules. We have included 800 women between 11 weeks 0 days and 13 weeks 6 days gestation into a biochemical examination. Women booked into the clinic were offered screening, using a combination of maternal serum free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A) and fetal nuchal translucency thickness. The maternal serum were measured using the Kryptor analyzer (Brahms Diagnostica). All pregnant women have been divided into 2 groups younger than (first group) and older than (second group) 35 years of age. CONCLUSIONS: Nomogrames for free beta-hCG and PAPP-A levels in physiological pregnancy between 11(+0) and 13(6) weeks were determined in the examined population. A positive correlation between PAPP-A and CRL levels, as well as a weak negative correlation between free beta-hCG and CRL, were demonstrated.     

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

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

Low levels of maternal serum PAPP-A in early pregnancy and the risk of adverse outcomes

OBJECTIVES: To determine if low maternal serum level of pregnancy associated plasma protein A (PAPP-A) measured in early pregnancy can predict adverse pregnancy outcomes and to examine the gestational age (GA) sampling interval for these outcomes. METHODS: This was a nested case-control study from a prospective cohort of women recruited at <20 weeks of gestation in Halifax, NS. Cases (n=248) were defined as women who had a fetal loss or developed preeclampsia, severe pregnancy-induced hypertension (PIH), or small for gestational age infant (SGA). Controls (n=244) were frequency matched to cases by GA at the time of serum sampling (6 to <20 weeks GA). Participant information was obtained from questionnaires and medical chart reviews. RESULTS: Women with a low PAPP-A measure [0.4 MoM). However, performance as a screening test was poor [sensitivity=38.7%; specificity=81.6%; positive likelihood ratio (LR)=2.1; negative LR=0.75]. In the adjusted model, the 10- to 14-week GA period was the only time period where low PAPP-A was significantly associated with adverse outcomes. CONCLUSIONS: Women with a low PAPP-A early in their pregnancy have twice the risk of an adverse outcome, though PAPP-A as a one-time single marker test has limited value.     

Role of maternal factors,PAPP-A,and Doppler in screening for early- and late-onset pregnancy hypertension in Asian population

Objective: To determine the predictive value of biochemical markers, uterine artery Doppler, and maternal factors in predicting early-onset (EO) and late-onset (LO) pregnancy hypertension. Methodology: All singleton pregnancies between 11 and 13 weeks and 6 days gestation underwent estimation of body mass index (BMI), mean arterial pressure (MAP), uterine artery Doppler pulsatality index (PI, and resistance index), biomarker PAPP-A, and free β-hCG. Women who developed hypertension were treated as cases and normotensives were taken as controls. The cases were further divided into EO and LO hypertension. The comparison was undertaken by appropriate statistical analysis. Results: Pregnancy hypertension was seen in 399 (13.2%) women. EO hypertension was seen in 153 (38.3%), whereas LO was observed in 246 (61.7%). The significant markers for predicting hypertension in pregnancy were maternal age, BMI, MAP, uterine artery Doppler PI, and PAPP-A. A combination of MAP and BMI was a better predictor (sensitivity and specificity 80% and 52%, respectively) than PAPP-A and Doppler combined (sensitivity and specificity 62% and 52%, respectively). When all the above markers were combined, the sensitivity and specificity of the test was 73% and 70%, respectively. EO hypertension was better predicted compared with LO. The negative predictive value (NPV) of the test was above 90%, suggesting that if a woman had the marker below the cutoff, there was more than 90% chance that she would not develop hypertension later in pregnancy. Conclusion: A combination of variables increased the sensitivity and specificity of the test for hypertension in pregnancy. The markers examined were a predictor of EO hypertension, with a high NPV, making it a good screening test.