Low Pregnancy-associated Plasma protein-A Levels Research Articles

First-Trimester Biochemical Markers of Aneuploidy and the Prediction of Small-for-Gestational Age Fetuses

Measurement in the first trimester of blood levels of the placentally derived biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG), together with ultrasound measurement of nuchal translucency thickness, are increasingly being used as part of screening programs for trisomy 21 and other aneuploidies. Preliminary studies have suggested that reduced levels of PAPP-A and free β-hCG could be useful for identifying pregnancies that result in small-for-gestational age (SGA) infants and other adverse outcomes. This study evaluated the ability of measurement of free β-hCG and PAPP-A levels to predict SGA in a cohort of 49,801 British women prospectively screened in the first trimester. Between 1998 and 2003, singleton pregnant women presenting for maternity care at United Kingdom hospitals were screened for trisomy 21 by combined measurement of maternal serum free β-hCG and PAPP-A and nuchal translucency thickness scans at 11 + 0 to 13 + 6 weeks of gestation. All study participants had complete outcome data and normal fetal karyotypes. The free β-hCG and PAPP-A measurements were expressed as multiples of the expected normal median (MOM) for a pregnancy of the same gestational age. The control group consisted of 46,262 pregnancies resulting in live births at full term; the study group included 3539 pregnancies resulting in live births of SGA infants, divided into 3 subgroups based on birth weight below the 10th, fifth, and third centiles for gestational age. The association between these 2 biochemical markers and the frequency of SGA were investigated by comparing the relative incidence of each marker at a number of MoM cutoffs and various birth weight centile cutoffs. The median PAPP-A level was significantly lower in the SGA group than in the normal group for all 3 categories of SGA (P < 0.001). When the PAPP-A level was 0.415 MoM, which corresponded to the fifth percentile in the normal group, the odds ratios for SGA below the 10th, fifth, and third percentiles were 2.70, 3.21, and 3.66, respectively, and the respective detection rates for SGA were 12.0%, 14.0%, and 16.0%. Significant differences in free β-hCG MoM between the SGA group and the normal group were not found (P = ns). The investigators believe that these findings together with earlier studies provide sufficient evidence to use low levels of maternal serum PAPP-A to help in identifying the pregnancies at increased risk for delivery of an SGA infant.

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.

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.

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.

Embryonic delay in growth and development related to confined placental trisomy 16 mosaicism, diagnosed by I-Space Virtual Reality

To demonstrate the use of a novel three-dimensional (3D) virtual reality (VR) system in the visualization of first trimester growth and development in a case of confined placental trisomy 16 mosaicism (CPM+16). Case report. Prospective study on first trimester growth using a 3D VR system. A 34-year-old gravida 1, para 0 was seen weekly in the first trimester for 3D ultrasound examinations. Chorionic villus sampling was performed because of an enlarged nuchal translucency (NT) measurement and low pregnancy-associated plasma protein-A levels, followed by amniocentesis. Amniocentesis revealed a CPM+16. On two-dimensional (2D) and 3D ultrasound no structural anomalies were found with normal fetal Dopplers. Growth remained below the 2.3 percentile. At 37 weeks, a female child of 2010 g (<2.5 percentile) was born. After birth, growth climbed to the 50th percentile in the first 2 months. The I-Space VR system provided information about phenotypes not obtainable by standard 2D ultrasound. In this case, the delay in growth and development could be observed very early in pregnancy. Since first trimester screening programs are still improving and becoming even more important, systems such as the I-Space open a new era for in vivo studies on the physiologic and pathologic processes involved in embryogenesis.

First-Trimester Markers of Aneuploidy and the Prediction of Small-for-Gestational Age Fetuses

First-trimester estimates of 2 biomarkers of placental origin, pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG), are increasingly used along with ultrasound measurement of nuchal translucency thickness to screen for trisomy 21 and other aneuploidies. There are preliminary indications that reduced levels of these markers—especially PAPP-A—may help to identify at-risk pregnancies including those resulting in delivery of a small-for-gestational age (SGA) infant. The study population included singleton pregnancies with chromosomally normal fetuses that were screened at 11 to 14 weeks’ gestation. Biochemical marker levels were converted to multiples of the expected normal median (MoM) for a pregnancy of the same gestational age. Associations between levels of free β-hCG and PAPP-A and the incidence of SGA were assessed by comparing relative incidence rates at MoM cutoffs and birth weight centile cutoffs. A total of 46,262 pregnancies resulted in live births of infants weighing at or above the 10th centile, whereas 3539 others produced SGA infants weighing less than the 10th centile for gestation. The risk of an SGA infant was significantly and inversely associated with maternal serum PAPP-A MoM, but not with free β-hCG MoM. In pregnancies with PAPP-A levels below the 10th, 5th, and 3rd percentile, the incidence of SGA was 12%, 14%, and 16%, respectively, and the odds ratios for SGA were 2.70, 3.21, and 3.66, respectively. Free β-hCG levels did not predict SGA. The investigators believe that, in the presence of a normal fetal karyotype, low maternal serum levels of PAPP-A are associated with an elevated risk of subsequently delivering a SGA infant. Low levels presumably indicate impaired placentation. Present evidence warrants using low PAPP-A to help identify SGA pregnancies.

First‐trimester ultrasound and biochemical markers of aneuploidy and the prediction of preterm or early preterm delivery

To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict preterm delivery. We examined 54 722 singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the median (MoM) of the expected normal median for a pregnancy of the same gestation and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown-rump length. The association between free beta-hCG, PAPP-A and delta NT and the incidence of preterm delivery before 37 weeks or early preterm delivery before 34 weeks was assessed by comparing the relative incidence at a number of MoM or delta NT cut-offs and at various centile cut-offs. At various marker levels the likelihood ratios (LR) for preterm delivery and early preterm delivery were also calculated after excluding other adverse pregnancy complications. The risk of preterm delivery increased with decreasing maternal serum PAPP-A. In the 3132 cases delivering before 37 weeks the PAPP-A MoM was 0.91 and in the 1060 cases delivering before 34 weeks the PAPP-A MoM was 0.90. At the 5th centile of the normal outcome group for PAPP-A (0.415 MoM) the odds ratios for delivery before 37 weeks and before 34 weeks were 1.92 and 2.35, respectively. The respective values for the 5th centile of free beta-hCG (0.41 MoM) were 1.18 and 1.08 and for the 95th centile of delta NT they were 0.91 and 0.77, respectively. Low levels of maternal serum PAPP-A are associated, in the absence of an abnormal karyotype, with an increased risk of preterm or early preterm delivery. The LR profiles provided at various levels of PAPP-A may be of some help in counseling women with such results and may raise awareness among healthcare professionals for increased surveillance in such cases.

Low levels of maternal serum PAPP‐A in the first trimester and the risk of pre‐eclampsia

Low levels of pregnancy associated plasma protein-A (PAPP-A) have been previously shown to be associated with pregnancies that subsequently develop pre-eclampsia. The objective of this study was to establish the relative risk for pre-eclampsia at various PAPP-A levels as an aid to counselling and follow up of pregnancies. Maternal serum PAPP-A and free ss-human chorionic gonadotropin (ss-hCG) levels at 11 to 13 weeks of gestation from 224 singleton pregnancies that subsequently developed pre-eclampsia were compared to those from 47,770 normal singleton pregnancies resulting in live births after 37 weeks with birth weight greater than or equal to the 10th centile of normal for gestation. In all cases, the measured PAPP-A and free ss-hCG levels were expressed as multiple of the median (MoM). The association between metabolite levels and the incidence of pre-eclampsia was assessed by comparing the relative incidence at a number of MoM cut-offs and at various centiles. At various marker levels, the likelihood ratio for pre-eclampsia was also calculated. In the pre-eclampsia group the median PAPP-A MoM was significantly reduced (0.772 MoM, p < 0.0001) whilst the median free beta-hCG MoM was not different from controls (0.981 MoM, p = 0.26). With decreasing levels of PAPP-A, the likelihood ratio for pre-eclampsia increased. At the 5th centile of normal (PAPP-A MoM 0.415) the odds ratio was increased 4-fold and at this cut-off 15% of cases of pre-eclampsia would be identified. The graphical presentation of a likelihood ratio curve for pre-eclampsia at any PAPP-A MoM level is likely to be useful in counselling women with low levels of PAPP-A and a normal karyotype. Use of low levels of PAPP-A for selecting women for further follow-up with uterine artery Doppler may further improve the clinical discrimination.

First‐trimester biochemical markers of aneuploidy and the prediction of small‐for‐gestational age fetuses

To examine the clinical utility of the first-trimester biochemical markers of aneuploidy in their ability to predict subsequent delivery of a small-for-gestational age (SGA) infant. We examined singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the expected normal median (MoM) for a pregnancy of the same gestation. The association between free beta-hCG and PAPP-A and the incidence of SGA were assessed by comparing the relative incidence at MoM cut-offs and birth-weight centile cut-offs. At various marker levels the likelihood ratios (LR) for SGA were also calculated after excluding other adverse pregnancy complications. There were 46,262 pregnancies resulting in live births with birth weight at or above the 10(th) centile, and 3,539 below the 10(th) centile for gestation (SGA). There was a significant inverse association between the risk for SGA and maternal serum PAPP-A MoM but not free beta-hCG MoM. At the 5(th) centile of the normal outcome group for PAPP-A (0.415 MoM) the odds ratios for SGA below the 10(th), 5(th) and 3(rd) centiles of normal were 2.70, 3.21 and 3.66 and the respective detection rates for SGA were 12.0%, 14.0% and 16.0%. Low levels of maternal serum PAPP-A are associated, in the absence of an abnormal karyotype, with an increased risk for subsequent delivery of an SGA infant.

Low Maternal Serum Levels of Pregnancy-associated Plasma Protein-A During the First Trimester are Associated with Subsequent Preterm Delivery with Preterm Premature Rupture of Membranes

To assess the relationship between the first-trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels and pregnancies complicated by preterm delivery. The correlation between PAPP-A levels and gestational age at delivery was analyzed by linear regression. The probabilities of low PAPP-A multiples of the median (MoM) levels between preterm delivery and control population were analyzed by logit model. A positive correlation was noted between the first-trimester PAPP-A MoM levels and gestational age at delivery between 34-38 weeks (p < 0.001). Lower PAPP-A MoM level had a significantly higher likelihood of preterm delivery (p < 0.05). When preterm premature rupture of membranes (PPROM) and preterm labor (PTL) were analyzed separately, there was an increasing likelihood of PPROM with decreasing PAPP-A MoM levels (p < 0.05), but not for PTL with intact membranes. Low maternal serum PAPP-A levels during the first trimester may reflect a trophoblast invasion defect in the maternal-fetal interface, resulting in subsequent preterm delivery, particularly in those of PPROM.

Screening for pre‐eclampsia and fetal growth restriction by uterine artery Doppler and PAPP‐A at 11–14 weeks' gestation

To assess the role of maternal demographic characteristics, uterine artery Doppler velocimetry, maternal serum pregnancy-associated plasma protein-A (PAPP-A) and their combination in screening for pre-eclampsia and small-for-gestational age (SGA) fetuses at 11-14 weeks. This was a prospective study of 878 consecutive women presenting for a routine prenatal ultrasound examination at 11-14 weeks. Pulsed wave Doppler was then used to obtain uterine artery flow velocity waveforms and the mean pulsatility index (PI) of the uterine arteries was calculated. Maternal serum samples for PAPP-A were assayed. Along with maternal history, these measurements were compared in their ability to predict adverse outcome, defined as pre-eclampsia and/or SGA and/or placental abruption. Mean uterine artery PI > or = 95(th) centile and PAPP-A < or = 10(th) centile each predicted 23% of the women that developed pre-eclampsia and 43% of cases of placental abruption. For SGA < or = 5(th) centile, mean uterine artery PI > or = 95(th) centile predicted 23% of cases and PAPP-A < or = 10(th) centile predicted 34%. Independent predictors for subsequent development of pre-eclampsia were increased mean uterine artery PI > or = 95(th) centile (OR, 2.76; 95% CI, 1.11-6.81) and maternal history of pre-eclampsia/hypertension (OR, 50.54; 95% CI, 10.52-242.73). The predicting factors for SGA < or = 5(th) centile were increased mean uterine artery PI > or = 95(th) centile (OR, 2.0; 95% CI, 1.07-3.74) and low PAPP-A (OR, 0.43; 95% CI, 0.20-0.93). Increased uterine artery PI was the only independent factor in the prediction of placental abruption (OR, 8.49; 95% CI, 2.78-25.94). The combination of uterine artery PI and maternal history of pre-eclampsia/hypertension was better than was using uterine artery Doppler alone in predicting pre-eclampsia. Similarly, for the prediction of SGA < or = 5(th) centile, combining uterine artery Doppler and maternal serum PAPP-A was better than was uterine artery Doppler alone. In both cases, the difference approached statistical significance. The combination of maternal history with abnormal uterine artery Doppler and low PAPP-A level at 11-14 weeks achieves better results than does either test alone in the prediction of pre-eclampsia and SGA.

Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development

The objective of this study was to investigate the association between follicular fluid (FF) levels of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and pregnancy-associated plasma protein-A (PAPP-A), which is a protease for IGFBP-4, and the quality of subsequent embryo development from in vitro fertilized oocytes aspirated from the same follicle. Prospective study. University infertility clinic and academic research laboratory. One hundred sixty-two infertile women undergoing controlled ovarian hyperstimulation for IVF and embryo transfer were recruited in a university hospital. During oocyte retrieval, samples of 225 FFs and matched mature oocytes were collected and studied. Concentrations of FF IGF-I, IGF-II, IGFBP-1, IGFBP-3, IGFBP-4, and PAPP-A were determined using ELISA. Progesterone secretion by cultured granulosa cells (GC) was measured by RIA. Levels of IGF-II, IGFBP-3, and IGFBP-4 in FF on the day of oocyte retrieval were significantly correlated with embryo scores on day 3 (72 hours after oocyte retrieval). Levels of IGF-II, IGFBP-3, and IGFBP-4 in FF from follicles in which oocytes developed into day 2 embryos (48 hours after oocyte retrieval; 20 >or= embryo score >or= 6) after fertilization were significantly higher than those from follicles in which oocytes were unable to be fertilized and were arrested in embryo development on day 2, whereas the levels of PAPP-A were significantly lower in the former than the latter group. Using multiple regression analysis, we found that high levels of IGFBP-3 and IGFBP-4 combined with low levels of PAPP-A in FF were significantly correlated with successful fertilization and early development into day 2 embryos. In contrast, high FF IGFBP-1 and IGFBP-4 in combination with low FF IGF-I were significantly correlated with a later (day 2-day 3) embryo development. A significant stimulation of P secretion in cultured GCs by the combination of recombinant IGF-II, IGFBP-3, and IGFBP-4 further strengthened these proteins' functional roles in promoting late follicular development. High IGF-II, IGFBP-3, IGFBP-4, and low PAPP-A levels in FF at the time of oocyte retrieval suggest better oocyte maturation and early embryo development (within 48 hours after oocyte retrieval), whereas high IGFBP-1, IGFBP-4, and low FF IGF-I levels may favor later embryo development (between 48 and 72 hours after oocyte retrieval).

First‐trimester ultrasound and biochemical markers of aneuploidy and the prediction of impending fetal death

To examine the clinical utility of the first-trimester markers of aneuploidy in their ability to predict future fetal loss. We examined 54,722 singleton pregnancies with no chromosomal abnormality and with complete outcome data that had undergone screening for trisomy 21 by a combination of fetal nuchal translucency (NT) thickness, maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 and 13 + 6 weeks' gestation. The biochemical markers were converted to multiples of the expected normal median for a pregnancy of the same gestation (MoM) and the measurements of fetal NT were expressed as the difference (delta) from the normal median NT for crown-rump length (CRL). The association between free beta-hCG, PAPP-A and delta NT and the incidence of fetal loss prior to 24 weeks, at or after 24 weeks or at any time, was assessed by comparing the relative incidence at a number of MoM or delta NT cut-offs and at various centile cut-offs. At various marker levels the likelihood ratio (LR) for fetal loss was also calculated. The rate of fetal loss increased with decreasing maternal serum free beta-hCG and PAPP-A and increasing delta NT. At the 5th centile of the normal outcome group for free beta-hCG (0.41 MoM) the odds ratio for fetal loss before 24 weeks, at or above 24 weeks and at any gestation was 3.1, 1.8 and 2.6, respectively. The respective values for the 5th centile of PAPP-A (0.415 MoM) were 3.3, 1.9 and 2.8 and for the 95th centile of delta NT they were 2.5, 1.9 and 2.2, respectively. There was almost no correlation between reduced levels (<or=0.50 MoM) of PAPP-A and reduced levels of free beta-hCG in either the normal pregnancy group (r = 0.041) or the group with fetal death (r = 0.072), indicating relatively independent prediction by either biochemical marker. Low levels of maternal serum PAPP-A and free beta-hCG and increased fetal NT are associated, in the absence of an abnormal karyotype, with an increased risk of impending fetal death. The likelihood ratio profiles provided at various levels of PAPP-A or free beta-hCG may be of some help in counseling women with such results and raise awareness among health-care professionals for increased surveillance in such cases.

Can First-Trimester Maternal Serum Level Of Pregnancy-associated Plasma Protein-A Predict Subsequent Fetal Growth Restriction?

Summary Objective To evaluate whether the maternal serum level of pregnancy-associated plasma protein-A (PAPP-A) in the first trimester can predict pregnancy complicated by low birth weight (LBW) and fetal growth restriction (FGR). Materials and Methods This retrospective analysis enrolled 3,089 women with singleton pregnancy who underwent screening for Down syndrome in the first trimester of pregnancy and who delivered at Cathay General Hospital. They were divided into five groups according to the birth weight of their infants: three FGR groups of birth weight less than the 10 th , 5 th , and 3 rd centiles, a LBW group of birth weight less than 2,500 g, and a control group of all other women. Results The mean multiples of median (MoM) values of PAPP-A were significantly lower in the LBW group (0.98) and the three FGR groups ( th centile, 1.03; th centile, 0.96; and rd centile, 0.99) than in the control group (1.15). Women with PAPP-A less than 0.3 MoM, 0.5 MoM or in the 5 th centile (0.32 MoM) also had a significantly higher relative risk of pregnancy complicated by LBW and FGR, but the sensitivity of detection was low. The highest sensitivity using a cut-off at 0.5 MoM was 22.5%. Conclusion Our study demonstrated that a low maternal serum PAPP-A level in the first trimester is associated with pregnancy complicated by LBW and FGR, but the sensitivity was low. As a single marker, PAPP-A is not sufficient to predict LBW and FGR.

First-Trimester Placentation and the Risk of Antepartum Stillbirth

Context: Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. Objective: To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. Design, Setting, and Participants: Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. Main Outcome Measures: Antepartum stillbirths and stillbirths due to specific causes. Results: There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval {CI}, 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P=.75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free p subunit of human chorionic gonadotropin and stillbirth risk. Conclusion: The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

First-Trimester Placentation and the Risk of Antepartum Stillbirth

Preterm birth and low birth weight are determined, at least in part, during the first trimester of pregnancy. However, it is unknown whether the risk of stillbirth is also determined during the first trimester. To determine whether the risk of antepartum stillbirth varies in relation to circulating markers of placental function measured during the first trimester of pregnancy. Multicenter, prospective cohort study (conducted in Scotland from 1998 through 2000) of 7934 women who had singleton births at or after 24 weeks' gestation, who had blood taken during the first 10 weeks after conception, and who were entered into national registries of births and perinatal deaths. Antepartum stillbirths and stillbirths due to specific causes. There were 8 stillbirths among the 400 women with levels of pregnancy-associated plasma protein A (PAPP-A) in the lowest fifth percentile compared with 17 among the remaining 7534 women (incidence rate per 10,000 women per week of gestation: 13.4 vs 1.4, respectively; hazard ratio [HR], 9.2 [95% confidence interval [CI], 4.0-21.4]; P<.001). When analyzed by cause of stillbirth, low level of PAPP-A was strongly associated with stillbirth due to placental dysfunction, defined as abruption or unexplained stillbirth associated with growth restriction (incidence rate: 11.7 vs 0.3, respectively; HR, 46.0 [95% CI, 11.9-178.0]; P<.001), but was not associated with other causes of stillbirth (incidence rate: 1.7 vs 1.1, respectively; HR, 1.4 [95% CI, 0.2-10.6]; P = .75). There was no relationship between having a low level of PAPP-A and maternal age, ethnicity, parity, height, body mass index, race, or marital status. Adjustment for maternal factors did not attenuate the strength of associations observed. There was no association between maternal circulating levels of the free beta subunit of human chorionic gonadotropin and stillbirth risk. The risk of stillbirth in late pregnancy may be determined by placental function in the first 10 weeks after conception.

Association Between First-Trimester Maternal Serum Pregnancy-Associated Plasma Protein-A and Adverse Pregnancy Outcome

Pregnancy-associated plasma protein-A (PAPP-A) is a glycoprotein derived from trophoblasts that cleaves insulin-like growth factor-binding proteins and augments the action of insulin growth factor. Maternal levels of PAPP-A are higher in primigravid and multiple pregnancies, and correlate positively with placental weight. Apart from being a marker of aneuploidy, low PAPP-A levels could be evidence of impaired placental formation and implantation. This retrospective review attempted to determine whether first-trimester PAPP-A levels are associated with intrauterine growth restriction, preterm delivery, or stillbirth. Pregnancy outcomes were sought in a medical records review and by postal questionnaire. All 827 women having serum PAPP-A estimates had a normal karyotype. Along with 2 neonatal deaths and 6 intrauterine deaths, 13 newborn infants had a birth weight below the third percentile and 55 weighed below the 10th percentile. Ninety-six women delivered prematurely. Four of the 6 intrauterine deaths were associated with a low maternal serum PAPP-A level less than 0.5 multiples of the median (MOM). Infant mortality was 3.8% in pregnancies with a PAPP-A level less than 0.5 MOM and 0.27% in those with higher levels for a relative risk of 13.75. Low levels of PAPP-A were associated with birth weight below the 10th percentile, but not with weight below the third percentile. Low maternal PAPP-A levels did not correlate with preterm delivery. This study indicates that low first-trimester levels of PAPP-A in maternal serum are associated with adverse fetal outcomes, including fetal death in utero and intrauterine growth retardation. An estimate of PAPP-A, by itself or combined with antenatal ultrasonography, might help assess the risk of such outcomes in high-risk pregnancies.

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

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. 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). 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. 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.

First-trimester nuchal translucency and maternal serum free beta-hCG and PAPP-A can detect triploidy and determine the parental origin.

To evaluate the levels of first-trimester screening markers in triploid pregnancies and to determine the parental origin of triploidy. During the five-year study period, 12322 patients with singleton pregnancies underwent combined first-trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and pregnancy associated plasma protein-A (PAPP-A) at 10 to 14 weeks' gestation. Maternal serum markers and NT were evaluated in cases of triploidy. Molecular analysis was performed using polymorphic markers to establish the parental source of triploidy. Eight cases of triploidy were detected at a rate of at least 1 in 1540. All cases were electively terminated early in gestation or resulted in spontaneous miscarriage. Two patterns of first-trimester markers emerged: type I, characterized by extremely high levels of free beta-hCG and elevated NT; and type II, characterized by very low levels of PAPP-A and free beta-hCG with normal NT. Molecular analysis demonstrated that type I triploidy is of paternal origin (diandric) and type II is of maternal origin (digynic). On the basis of these results, it may be possible to detect triploid pregnancies in the first trimester and determine their origin using combined first-trimester screening.

Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome.

Low levels of maternal serum pregnancy associated plasma protein-A (PAPP-A) have been linked to chromosome anomalies such as trisomy 21, 13 and 18, triploidy and sex chromosome aneuploidy. Low levels of PAPP-A have also been implicated in spontaneous miscarriage. The purpose of this study was to evaluate whether low levels of first trimester PAPP-A are predictive of other adverse pregnancy outcomes. The study included patients with singleton pregnancies who underwent combined first trimester screening using nuchal translucency (NT) and maternal serum free beta-human chorionic gonadotrophin (free beta-hCG) and PAPP-A at 10-13 weeks' gestation. Patients with chromosome aberrations or fetal anomalies were excluded. Serum marker levels were expressed as gestational age-specific multiples of the median (MoMs). The incidences of various adverse pregnancy outcomes (spontaneous preterm labor, fetal growth restriction (FGR), proteinuric and non-proteinuric pregnancy induced hypertension (PIH), intrauterine fetal demise, oligohydramnios, spontaneous miscarriage and placental abruption) were evaluated, according to maternal PAPP-A MoM levels. Of the 1622 patients in the study, pregnancy complications were observed in 184 (11.3%). Patients with PAPP-A < or =0.25 MoM had significantly higher rates of FGR (RR = 3.12), proteinuric PIH (RR = 6.09), spontaneous miscarriage (RR = 8.76). No statistically significant differences were noted for other adverse outcomes evaluated Women with PAPP-A < or =0.50 MoM also had significantly higher rates of FGR (RR = 3.30) and spontaneous miscarriage (RR = 3.78). We conclude that decreased levels of first trimester maternal serum PAPP-A are predictive not only of chromosome anomalies but also of adverse pregnancy outcome.