Low Pregnancy-associated Plasma protein-A Research Articles

PAPP‐A, free β‐hCG, and early fetal growth identify two pathways leading to preterm delivery

To evaluate early fetal growth and the biomarkers, pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG), in relation to preterm delivery. A cohort study of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007, was conducted. PAPP-A and free β-hCG were measured in the first trimester. Early fetal growth was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects the gestational age in days calculated from the crown-rump length at a 12-week scan, GA(20) reflects the gestational age in days calculated from the biparietal diameter at a 20-week scan, and Days(calendar) is the number of calendar days between the two scans. Low PAPP-A and low free β-hCG were significantly associated with preterm delivery (<37 weeks). The association was even stronger when low PAPP-A and slow early fetal growth were combined, resulting in an adjusted odds ratio of 3.8 (95% CI, 1.6-8.7). Fast early fetal growth, but neither high PAPP-A nor high free β-hCG, was significantly associated with preterm delivery. Two different biological pathways leading to spontaneous preterm delivery are suggested: fast early fetal growth and the combination of low PAPP-A and slow early fetal growth.

The relationship between first trimester fetal growth, pregnancy‐associated plasma protein A levels and birthweight

We sought to define the relationship between first trimester fetal growth, pregnancy-associated plasma protein A (PAPP-A) levels and birthweight. Two-hundred and one women with repeat first trimester crown-rump length (CRL) measurements were included. In 194, the first trimester PAPP-A value was known and in 169 there was complete data including birthweight. Fetal growth curves were derived using functional linear discriminant analysis (FLDA) and growth compared between those with < 10th percentile, 10th to 90th and > 90th percentile PAPP-A multiple of median (MoM) levels and birthweight percentiles. Median maternal age was 35 years, gestation at PAPP-A sampling and of first scan was 11 weeks. Median delivery gestation was 40 weeks and birthweight 3425 g. There was no association between first trimester fetal CRL growth and either PAPP-A MoM percentile or birthweight percentile. There was a significant positive correlation between PAPP-A MoM and birthweight percentile (p = 0.0004). First trimester fetal growth rate is not related to birthweight percentile or first trimester PAPP-A levels. Irrespective of gestation, a low PAPP-A is associated with delivery of a smaller baby, and a high PAPP-A with a larger baby.

Low PAPP‐A in the first trimester is associated with reduced fetal growth rate prior to gestational week 20

To evaluate the association between maternal pregnancy-associated plasma protein-A (PAPP-A) and fetal growth from the first to the second trimester. A prospective cohort study including 8347 pregnant women attending prenatal care at Aarhus University Hospital were conducted. PAPP-A was measured during 8 to 14 gestational weeks. Fetal growth between the two scans in the first and second trimesters was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects gestational age in days calculated from crown-rump length at a 12-week scan, GA(20) reflects gestational age in days calculated from biparietal diameter at a 20-week scan, and Days(calendar) reflects the number of calendar days between the two scans. Fetal growth rate from the first to the second trimester was correlated with PAPP-A, with a regression coefficient of 0.009 (95% CI, 0.007-0.012, P < 0.001). PAPP-A below 0.30 MoM was associated with a fetal growth rate below the tenth centile, with an adjusted OR of 2.05 (95% CI, 1.24-3.38). Low levels of PAPP-A are associated not only with low birth weight at term but also with slower fetal growth prior to 20 weeks of gestation.

Histomorphometric characteristics of first trimester chorionic villi in pregnancies with low serum pregnancy-associated plasma protein-A levels: relationship with placental three-dimensional power doppler ultrasonographic vascularization

Objective. To evaluate histomorphometric vascular characteristics from samples obtained by chorionic villus sampling (CVS) in pregnancies with low serum pregnancy-associated plasma protein-A (PAPP-A) levels and to relate these findings to three-dimensional (3D) placental volume and power Doppler vascularization.Methods. Immediately before CVS, placental 3D-power Doppler ultrasonography was performed at 11 + 0 to 13 + 6 weeks in 12 pregnancies with PAPP-A concentrations <0.3 multiples of median (MoM) as well as in 11 control women. Using a standardized setting placental volume, vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were measured. Histomorphometric parameters of villi were blindly evaluated with a video-computerized-image-analysis system.Results. Pregnancies with low PAPP-A showed a significantly reduced number of capillary vessels per villus cross-section (p = 0.005) and a smaller capillary diameter (p = 0.041). Placental vascular indices were significantly related to the number of fetal capillary vessels per villus (VI: r = 0.51, p = 0.03; FI: r = 0.48, p = 0.04; VFI: r = 0.56, p = 0.01).Conclusions. Differences in placental vascularization are present in first trimester in pregnancies with low PAPP-A and they are associated to altered 3D placental Doppler indices.

Correlation between First-Trimester Maternal Serum Markers, Second-Trimester Uterine Artery Doppler Indices and Pregnancy Outcome

Aims: The aim of this study was to assess the correlation between first trimester maternal serum free beta-human chorionic gonadotropin (fBHCG), pregnancy-associated plasma protein A (PAPPA), second-trimester uterine artery (UA) Doppler measurements and adverse pregnancy outcomes. Methods: Serum levels of PAPPA and fBHCG were determined at the first trimester, and patients underwent bilateral UA Doppler assessments at 20–25 weeks of gestation. A serum PAPPA level <0.4 MoM was termed as low and the abnormal Doppler findings were the presence of bilateral notches and RI >0.52 (mean) or unilateral notch and RI >0.66 (90th percentile). Results: Mean PAPPA level was significantly lower in cases with unilateral or bilateral notches (1.09; 0.79 and 0.80 MoM for 0, 1 and 2 notches, p < 0.001). Fifty-two cases (12.8%) had a low PAPPA level; in this group the incidence of abnormal Doppler was significantly higher (34.6 vs. 18.4%, p = 0.011). In the presence of abnormal Doppler in a case with a low serum PAPPA the risk of pregnancy-induced hypertension (OR = 4.56, p = 0.0067), low birth weight (OR = 6.8, p = 0.0002) and the risk of at least one complication (OR = 7.6, p = 0.00001) were significantly high. Conclusion: Combination of first- and second-trimester findings might improve the efficiency of screening for pregnancy complications.

Association offirst‐trimester low PAPP‐A levels with preterm birth

To determine the association of, and predictive ability of, pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotrophin (beta-hCG), and nuchal translucency (NT) with preterm birth (PTB). A 5-year retrospective cohort study of women who underwent first-trimester combined screening was performed. Maternal medical, antepartum, and pregnancy outcome data were obtained. PAPP-A and beta-hCG were converted to multiples of the median (MoM), and primary exposure was defined as < or =10th percentile MoM for PAPP-A. Secondary exposures were defined as > or = 90th percentile MoM for beta-hCG and NT values of > or = 20 and 25 mm. The primary outcome was PTB before 35 weeks and the secondary outcome was PTB before 32 weeks. Univariate, bivariate, multivariate, and receiver-operator analyses were used. Of the 2231 patients meeting inclusion criteria with complete outcome data available, 222 had a PAPP-A level < or =10th percentile MoM. Abnormally low PAPP-A was associated with an increased risk for PTB < 35 weeks [adjusted odds ratio (aOR) 2.0, 1.0-3.8] and < 32 weeks (aOR 2.7, 1.1-6.4), even after adjusting for prior PTB, tobacco exposure, chronic hypertension, and body mass index. PAPP-A < or =10th percentile was not sufficiently predictive of PTB < 35 weeks (area under curve = 0.63, 95% CI 0.53-0.72). Neither abnormally high beta-hCG nor increased NT was associated with an increased risk for PTB. PAPP-A < or =10th percentile is associated with an increased risk for PTB, but is not sufficiently predictive to be used clinically.

96: Low pregnancy-associated plasma protein-A (PAPP-A) and elevated alpha-fetoprotein (AFP) – a bad combination?

To evaluate the clinical significance of elevated AFP during the second trimester in those pregnancies with low first trimester PAPP-A. Retrospective cohort study of singleton gestations at a single tertiary care institution that underwent both a first trimester serum PAPP-A screen and a second trimester AFP screen between 2006 and 2008. Patients with fetal karyotype, neural tube or abdominal wall abnormalities and those that did not deliver at our institution were excluded. Two groups were identified: the study group which consisted of patients with both low PAPP-A (below the 10%ile for gestational age) and elevated maternal serum AFP (greater than 2.0 multiples of the median for gestational age) and the control group which included patients with low PAPP-A in combination with a normal AFP. Pregnancy outcomes were compared between the groups. Fisher′s exact test and Mann-Whitney U were used for comparison. 410 patients were identified. Mean maternal age was 33.3 years. 17 (4.1%) patients were found to have an elevated AFP. There were no differences between the groups with regards to maternal age, parity and use of assisted reproduction techniques. Compared to the control group, the combination of low PAPP-A and elevated AFP was associated with higher rates of small for gestational age neonates at birth (52.9% vs. 6.5%, p < 0.0001, RR 8.0) and an earlier median gestational age at delivery (34.6 weeks vs. 38.2 weeks, p= 0.04). When comparing the preterm births in each group, the study group had a higher rate of iatrogenic preterm delivery due to suspected fetal growth restriction (7/8 deliveries (87.5%) vs. 6/31 deliveries (19.3%), p = 0.0003) and fetal heart rate abnormalities (50% vs. 10.8%, p = 0.024). The combination of elevated AFP in women with low PAPP-A is associated with poor outcomes, particularly small for gestational age neonates and iatrogenic preterm birth. This combination of serum markers should prompt concern and be included in the counseling of patients with regards to the possibilities of clinical outcomes.

97: Low pregnancy associated plasma protein-A (PAPP-A) in combination with elevated alpha feto-protein (AFP): relationship to the placenta

97: Low pregnancy associated plasma protein-A (PAPP-A) in combination with elevated alpha feto-protein (AFP): relationship to the placenta

First-Trimester Uterine Artery Doppler and Serum Pregnancy-Associated Plasma Protein-A in Preeclampsia and Chromosomal Defects

Objective: We examined the potential value of the uterine artery pulsatility index (PI) in pregnancies with fetal aneuploidies and in those that developed preeclampsia (PE) with the aim of distinguishing between these complications in pregnancies with low pregnancy-associated plasma protein-A (PAPP-A). Methods: Uterine artery PI and serum PAPP-A at 11–13 weeks were measured in 165 cases of PE, including 33 that required delivery before 34 weeks (early PE) and 132 with late PE, and in 301 cases with aneuploidies, including 200 with trisomy 21. Each case of aneuploidy and PE was matched with 4 unaffected controls. Results: Serum PAPP-A was lower in early PE (0.58 multiples of the normal median, MoM) and in trisomy 21 (0.54 MoM), trisomy 18 (0.22 MoM) and Turner syndrome (0.51 MoM) – but not in late PE (0.90 MoM) – than in controls (1.01 MoM). Uterine artery PI was higher in early PE (1.52 MoM), late PE (1.20 MoM), trisomy 18 (1.20 MoM) and Turner syndrome (1.29 MoM) – but not in trisomy 21 (1.02 MoM) – than in controls (1.0 MoM). Conclusion: The uterine artery PI at 11–13 weeks may be useful in distinguishing between low PAPP-A due to trisomy 21 and early PE.

Is placental size a good predictor of obstetric complications?

Is placental size a good predictor of obstetric complications?

Placental size and the prediction of severe early‐onset intrauterine growth restriction in women with low pregnancy‐associated plasma protein‐A

Screening studies for trisomy 21 demonstrate that low maternal serum pregnancy-associated plasma protein-A (PAPP-A) at 11-13 weeks' gestation is associated with stillbirth, intrauterine growth restriction (IUGR) and pre-eclampsia in chromosomally normal fetuses. However, the strength of these associations is too weak to justify screening for these placental insufficiency syndromes. Our objective was to evaluate placental size and uterine artery (UtA) Doppler imaging as second-stage screening tests for women with low PAPP-A. We prospectively studied 90 normal singleton pregnancies with first-trimester PAPP-A </= 0.30 multiples of the median. Maternal serum alpha-fetoprotein (AFP) at 15-18 weeks' gestation, and second-trimester placental size and UtA Doppler indices were assessed as predictors of pregnancy outcome. The risks of IUGR, preterm delivery before 32 weeks' gestation and stillbirth were significantly associated with small placental size (relative risk (RR), 3.96; 95% CI, 2.21-5.98; RR, 3.96; 95% CI, 2.21-5.98; and RR, 6.44, 95% CI, 2.74-14.54, respectively) and elevated AFP (RR, 3.67; 95% CI, 1.78-7.71; RR, 2.48; 95% CI, 1.23-4.94; and RR, 5.14; 95% CI, 1.66-16.85, respectively), but not with abnormal UtA Doppler indices. The combination of elevated AFP and small placental size further increased the risk of IUGR (RR, 4.88; 95% CI, 2.88-5.31), delivery before 32 weeks' gestation (RR, 4.25; 95% CI, 2.38-4.98) and stillbirth (RR, 7.44; 95% CI, 3.04-3.75). Small placental size and elevated AFP, but not UtA Doppler indices, identify women with low PAPP-A at high risk of IUGR, extreme preterm delivery and stillbirth. These additional screening tests may directly improve perinatal outcomes in women with low PAPP-A.

First-trimester maternal serum screening and the risk for fetal distress during labor

The purpose of this study was to assess whether low pregnancy-associated plasma protein-A (PAPP-A) levels in the first trimester are related to the risk of emergency cesarean section delivery (CS) for fetal distress during labor and fetal intrapartum acidemia. We prospectively studied patients who requested first-trimester biochemical screening for Down syndrome. Among the 1037 women who were enrolled, 152 women (14.7%) had a low first-trimester PAPP-A value, and 855 women (85.3%) had a normal first-trimester PAPP-A value. Excluding elective CS, 19 of 117 women (16.2%) with low PAPP-A values vs 59 of 749 women (7.9%) with normal PAPP-A values underwent CS for concerning fetal status during labor (P = .003; odds ratio, 2.27; 95% confidence interval, 1.30-3.97). This difference remained significant after correction for possible confounders (hypertension, preterm delivery, small for gestational age, labor induction). Among these 78 women, umbilical artery pH was significantly lower in fetuses from mothers with low vs normal PAPP-A values (pH = 7.19 [range, 6.95-7.39] vs pH = 7.26 [range, 7.02-7.39]; P = .022). Low PAPP-A levels at first-trimester screening are associated independently with higher rates of emergency CS for nonreassuring fetal status during labor and lower pH.

Role of uterine artery Doppler in interpreting low PAPP‐A values in first‐trimester screening for Down syndrome in pregnancies at high risk of impaired placentation

Low maternal serum levels of pregnancy-associated plasma protein-A (PAPP-A) are associated with both increased risk of aneuploidies and impaired trophoblastic invasion, while high uterine artery (UtA) resistance is associated with impaired trophoblastic invasion but not with an increased risk of aneuploidies. The aim of this study was to determine whether high UtA resistance plays a role in explaining low PAPP-A levels in the absence of aneuploidies. This was a prospective study of 116 singleton pregnancies at high risk for impaired placentation (having at least one major risk factor: prior history of pre-eclampsia, pregestational diabetes mellitus, chronic hypertension, chronic kidney disease, body mass index >30, autoimmune disorder, thrombophilia or recurrent pregnancy loss), booked for routine assessment of risk for aneuploidies by means of the first-trimester combined screening test (nuchal translucency thickness (NT) + PAPP-A + beta-human chorionic gonadotropin (beta-hCG)). Measurement of NT and the mean UtA pulsatility index (PI) were carried out at the 11 to 13 + 6-week scan. All values were calculated in multiples of the median (MoM) adjusted for gestational age. A cut-off risk of 1/270 at time of sampling was adopted to differentiate high- from low-risk groups for trisomy 21. There were 108 patients deemed to be at low risk for trisomy 21 and eight at high risk. None had chromosomal defects, giving a false-positive rate for trisomy 21 of 6.9%. The greatest differences between patients at low risk and those at high risk for trisomy 21 were found in their PAPP-A (0.98 vs. 0.38 MoM, P < 0.01) and beta-hCG (1.09 vs. 1.77 MoM, P = 0.04) values. Greater NT thickness (1.02 vs. 0.90 MoM) and higher mean UtA-PI (1.05 vs. 0.96 MoM) were recorded in the high-risk group, although the differences did not reach statistical significance (P = 0.19 and 0.40, respectively). After log-transformation there were no significant correlations between mean UtA-PI and NT and between mean UtA-PI and beta-hCG. There was a significant negative linear correlation between mean UtA-PI and PAPP-A (r = -0.331; P < 0.01). After adjusting the PAPP-A values by UtA-PI, the false-positive rate for trisomy 21 decreased to 2.6%. Mean UtA-PI at the 11 to 13 + 6-week scan may be an effect-modifier variable for PAPP-A that should be taken into account in the first-trimester combined screening for aneuploidies, at least in pregnancies at high risk for impaired placentation.

Decreased First-trimester Maternal Serum Free-β Subunit Human Chorionic Gonadotropin and Preterm Birth in Twin Gestations

We investigated whether abnormal concentrations of first-trimester free-beta subunit human chorionic gonadotropin (fsshCG) and pregnancy-associated plasma protein A (PAPP-A) are associated with preterm delivery in twin gestations. This was a hospital-based, retrospective study of 70 twin gestations between 11 (1)/ (7) and 13 (6)/ (7) weeks' gestation undergoing first-trimester screening. Free betahCG and PAPP-A multiples of the median were determined by our laboratory standards. Odds ratios (ORs) were estimated that compared the prevalence of very preterm (< 32 weeks), preterm (> or = 32 and < 37 weeks), and term birth (> or = 37 weeks) between the lower and higher percentile groups for each analyte. FsshCG levels < or = 25th percentile were associated with very preterm birth < 32 weeks' gestation (OR 5.10; 95% confidence interval [CI]: 1.19 to 21.95), but not with preterm birth > or = 32 and < 37 weeks' gestation (OR 0.50; 95% CI: 0.16 to 1.61). PAPP-A was not associated with very preterm (OR 2.95; 95% CI: 0.69 to 12.60) or preterm birth (OR 0.71; 95% CI: 0.23 to 2.21). Low first-trimester fsshCG was a strong predictor for very preterm birth in twin gestations. Low first-trimester PAPP-A was associated with a trend in increased risk of very preterm birth.

The Impact of First-Trimester Serum Free β-Human Chorionic Gonadotropin and Pregnancy-Associated Plasma Protein A on the Diagnosis of Fetal Growth Restriction and Small for Gestational Age Infant

Objective: To evaluate the risk of fetal growth restriction (FGR) associated with first-trimester maternal serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG). Methods: A longitudinal study of 2,178 women who underwent first-trimester evaluation of serum PAPP-A and free β-hCG. FGR was defined as a decrement of the fetal abdominal circumference to below the 10th percentile of our standard growth curve in the presence of Doppler signs of impaired placental perfusion. Logistic regression was used to compute multivariable odds ratios and the estimated prevalences of outcomes associated with first-trimester serum marker concentrations. Results: The prevalences of small for gestational age (SGA, <10th percentile birth-weight) neonates and FGR were significantly higher among women with serum PAPP-A concentrations below the 10th percentile than in controls: 40/206 compared to 183/1,928, for SGA, adjusted odds ratio = 2.1, 95% confidence intervals (CI) 1.4–3.03; 24/75 compared to 182/1,900, for FGR, adjusted odds ratio = 3.9, 95% CI 2.3–6.5. The adjusted prevalences of FGR and SGA among women with simultaneous low first-trimester values of PAPP-A and free β-hCG were 0.21 (95% CI 0.13–0.33) and 0.26 (95% CI 0.17–0.36), respectively. Conclusion: Low first-trimester maternal serum PAPP-A concentrations are significantly associated with reduced fetal size and increased risk of FGR with Doppler signs of impaired placental perfusion.

The predictive value of 18 and 22 week uterine artery Doppler in patients with low first trimester maternal serum PAPP‐A

To determine if the addition of uterine artery (UA) Doppler pulsatility index (PI) at 18 and 22 weeks of gestation improves the predictive accuracy of low first trimester pregnancy associated plasma protein A (PAPP-A) in the detection of adverse obstetrical outcomes. This was a prospective interventional study. All women undergoing first trimester combined screening (FTS) at a single center, with a low maternal serum PAPP-A level (<0.4 MoM), were included. Patients underwent bilateral UA Doppler assessments at 18 and 22 weeks of gestation. A positive test was defined as a mean PI > 1.45. Primary outcomes were obtained from chart review, and logistic regression analysis was used to compare outcomes with positive and negative tests. Positive and negative predictive value, specificity and sensitivity were calculated. Between January and October 2007, 5359 women completed FTS. Among the low PAPP-A group (n = 289), 18 week UA Doppler was a significant predictor of low birth weight (OR = 2.28, p = 0.04) while 22 week UA Doppler significantly predicted preterm birth (OR = 12.6, p = 0.001), small for gestational age (OR = 8.24, p = 0.001) and low birth weight (OR = 2.28, p = 0.04). Test characteristics suggested improved positive and negative predictive value for Doppler at 22 versus 18 weeks for these outcomes. UA Doppler at 22 weeks is a useful adjunct in patients with low PAPP-A. However, a negative Doppler does not rule out all adverse outcomes and clinical judgment is advised in the management of these patients.

Second‐trimester fetal growth as a predictor of poor obstetric and neonatal outcome in patients with low first‐trimester serum pregnancy‐associated plasma protein‐A and a euploid fetus

To examine if fetal growth during the second trimester predicts poor pregnancy and neonatal outcome in patients with low first-trimester serum pregnancy-associated plasma protein-A (PAPP-A) and a euploid fetus. We identified all patients with first-trimester PAPP-A<5th centile who had undergone first- and second-trimester ultrasound examination. We excluded multiple pregnancies and those with aneuploidy or major anomalies identified before or after birth. We compared pregnancies with and without ultrasound markers for fetal growth restriction at 18-24 weeks. We identified 239 patients with low PAPP-A, 25 (10.5%) of whom had evidence of fetal growth restriction at 18-24 weeks. These 25 cases had significantly higher rates of third-trimester small-for-gestational age (SGA) fetus, gestational hypertension, preterm birth, indicated preterm birth, low birth weight and birth weight centiles, 1-min Apgar score<7, neonatal intensive care unit admission and fetal or neonatal death. Among patients with low first-trimester PAPP-A and a euploid fetus, fetal growth in the second trimester can predict poor obstetric and neonatal outcome.

First‐trimester maternal serum pregnancy‐associated plasma protein‐A and pre‐eclampsia

To examine the relationship between low maternal serum pregnancy-associated plasma protein-A (PAPP-A) and uterine artery pulsatility index (UtA-PI) at 11+0 to 13+6 weeks with subsequent development of pre-eclampsia (PE). UtA-PI and serum PAPP-A were measured in women attending for routine care at 11+0 to 13+6 weeks of gestation. In the population, 156 (1.9%) women developed PE, including 32 (0.4%) in whom delivery was before 34 weeks (early PE) and 124 (1.5%) with delivery at 34 weeks or more (late PE); 7895 (98.1%) women had no PE. Regression analysis was used to examine which of the factors amongst maternal characteristics, log PAPP-A multiples of the median (MoM) and log UtA-PI MoM contributed to the prediction of PE. The median PAPP-A MoM was 1.002 (interquartile range (IQR), 0.685-1.411) in the unaffected group, 0.555 (IQR, 0.463-0.922) in early PE and 0.911 (IQR, 0.580-1.247) in late PE. Serum PAPP-A was below the 5th centile in 21.9% of early PE and 6.5% of late PE cases. The PAPP-A-related patient-specific risk for PE was strongly influenced by maternal characteristics. There was a significant association between log UtA-PI MoM and log PAPP-A MoM (P=0.001), and the detection rate of screening for PE by maternal variables and UtA-PI was not improved by inclusion of PAPP-A. Regression analysis was used to establish tables that allow modification of the maternal history and PAPP-A-related patient-specific risk for PE by the measurement of UtA-PI. Low PAPP-A is a marker for subsequent development of PE. The PAPP-A-related patient-specific risk for PE can be modified by the measurement of UtA-PI.

First trimester predictors of adverse pregnancy outcomes

To identify first trimester indicators of adverse pregnancy outcomes. Data were obtained from the statewide evaluation of first trimester screening for Down syndrome in Western Australia which included 22,695 pregnancies screened between August 2001 and October 2003. Screening data were linked with pregnancy outcome information from the Hospital Morbidity Database and the Birth Defects Registry. The odds ratios (OR) of adverse outcomes were analysed for combined risk incorporating maternal age, nuchal translucency (NT) and biochemical parameters and then separately for each parameter (pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (beta-hCG) and NT). Risk assessments for first trimester combined screening are derived from maternal age, ultrasound measurement of fetal NT, maternal serum free beta-hCG and PAPP-A. Increased combined risk for Down syndrome was significantly (P < 0.01) associated with spontaneous loss at or before 24 weeks gestation (OR 13.51), birth defects (OR 6.58) and preterm birth at or before 32 weeks gestation (OR 3.2). Maternal serum PAPP-A below the 5th centile was associated with Down syndrome (OR 8.43), spontaneous loss before 24 weeks (OR 5.04) and later than 24 weeks (OR 4.50), preterm delivery before 32 weeks (OR 3.11) and before 37 weeks (OR 2.24). NT above the 95th centile was associated with Down syndrome (OR 43.91), birth defects (OR 4.02) and spontaneous loss before 24 weeks (OR 6.24). Low levels of free beta-hCG and increased NT were less consistently associated with adverse outcomes and high levels of free beta-hCG showed limited use as an indicator. The detection rates for all outcomes other than Down syndrome were less than 40%. Biochemical indicators and NT that are measured during first trimester screening for Down syndrome show a number of associations with adverse outcomes, but do not show appropriate performance characteristics for screening tests. These data are consistent with the view that the individual components, specifically low PAPP-A levels alone, do not provide an effective screening tool for adverse pregnancy outcomes.

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

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. 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. Women with a low PAPP-A measure [<or=0.4 multiples of the median (MoM)] had an adjusted odds ratio of 2.1 [95% confidence interval (CI) 1.3-3.6] compared to others (>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. 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.