Maternal Serum Levels Of Pregnancy-associated Plasma Protein A Research Articles

P-769 Endometrial thickness is not associated with birthweight as well as serum levels of pregnancy-associated plasma protein-A: a retrospective analysis of 560 newborns following frozen cycles

Abstract Study question Does endometrial thickness (EMT) affect birthweight and maternal serum evels of pregnancy-associated plasma protein-A (PAPP-A) in singleton pregnancies following frozen-thawed blastocyst transfer (FET)? Summary answer EMT does not significantly affect birthweight and maternal serum evels of PAPP-A in singleton pregnancies following FET. What is known already Several studies have shown an association between EMT and low birth weight in pregnancies resulting from fresh embryo transfers. Supraphyiological levels of steroid hormone during ovarian stimulation may be responsible for poor fetal growth. Few studies have investigated the relationship between EMT and fetal growth potential in frozen-thawed embryo transfers. Study design, size, duration This retrospective study included women who underwent first-trimester combined screening for aneuploidy after frozen-thawed blastocyst transfer and subsequently delivered a singleton live birth after 24 weeks of gestations between January 2016 and July 2020 in a private IVF center. Participants/materials, setting, methods A total of 560 women met the inclusion criteria and were stratified into three groups based on the EMT percentiles: <7.7 mm (<10th percentile), 7.7–12 mm (10-90th percentile), and >12 mm (>90th percentile). The primary outcome measures were mean birth weight and mean PAPP-A level. A multivariable linear regression analysis was carried out to identify the association between birth weight and EMT after adjusting for variables found at < 0.1 level in the univariate analysis. Main results and the role of chance The mean birth weight was 3127 ± 783 g in those with EMT <7.7 mm 3225 ± 644 g in those with EMT 7.7-12 mm, and 3256 ± 599 g in those with EMT >12 mm (p = 0.577). The mean PAPP-A levels and PAPP-A<0.5 rates were similar in the groups, as well. In multivariate analysis, the number of previous ART attempts and maternal serum levvels of PAPP-A were found to be significant predictors of birth weight (p = 0.001 and p = 0.013, respectively). EMT was not a predictor of birth weight in both univariate and multivariate analyses. The multivariate logistic regression analysis indicated that the number of previous ART attempts was an independent factor for low birth weight (OR:1.39, 95%CI:1.09-1.76, p = 0.006). Limitations, reasons for caution The study has inheret limitations due to its retrospective nature. Further studies are needed to investigate the relationship between EMT and birth weight along with maternal serum levels of PAPP-A. Wider implications of the findings Our study provided a new angle of view for evaluating the association between EMT and neonatal birth weight by analyzing this association along with maternal serum levels of PAPP-A as a marker for placental function, suggesting that EMT is not an independent factor for neonatal birth weight. Trial registration number NA

First-Trimester Uterine Artery Pulsatility Index and Maternal Serum PAPP-A and PlGF in Prediction of Preeclampsia in Primigravida.

Preeclampsia is a heterogeneous disorder affecting different body systems and frequently associated with morbidity and mortality. Early preeclampsia prediction will reduce this associated morbidity and mortality as it will give the chance for frequent maternal and fetal surveillance and application of prophylactic procedures. The aim of this work is to evaluate the role of mean pulsatility index (PI) of the uterine arteries and maternal serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and placental growth factor (PlGF) in early preeclampsia prediction in primigravida. Three hundred primigravida attending the antenatal care clinic in Zagazig University Hospitals were included in the study. The mean PI of the uterine arteries was calculated. Maternal serum levels of PAPP-A and PIGF were analyzed by specific immunoassay. Three hundred women were included in the final analysis, of them 30 patients (10%) suffered from preeclampsia. There was a significant difference between preeclamptic and normal women as regards the mean PI of the uterine arteries and levels of PAPP-A and PIGF at 11-13weeks. When combining the cutoff levels of the three methods, mean PI of the uterine arteries ≥1.69, PAPP-A assay <0.96 multiple of median (MoM) and PlGF assay <0.91 MoM, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy were 56.7, 99.3, 89.5, 95.4 and 67%, respectively. The combined measurement of maternal serum PAPP-A and PlGF concentrations and mean PI of the uterine arteries at 11-13weeks of pregnancy may help to predict preeclampsia in primigravida when other parameters of preeclampsia prediction are normal. However, we need more studies on larger and variable populations to evaluate the use of those combined methods in preeclampsia prediction.

First-Trimester Inflammatory Markers for Risk Evaluation of Pregnancy Hypertension.

Hypertension in pregnancy is one of the potential causes of maternal and fetal morbidity and mortality. It complicates 7-10% of pregnancies. As of today, prediction of pregnancy hypertension is not possible. Evaluation of pregnancy associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin, tumor necrosis factor-α (TNF-α) and interferon gamma (INF-γ) in establishing a biomarker or combination of biomarkers for the early identification of pregnancy hypertension. This prospective study was carried out in two phases. Phase I was a cohort study in which 2000 pregnant women were enrolled in their first trimester (11+0 to 13+6 weeks of gestation) and followed till delivery. Women who developed hypertension were compared with normotensive cohort (women who remained normotensive till term). Phase II was a case-control study. The women who were diagnosed with hypertension in phase I were cases and their controls were matched for gestational age and sample storage time from normotensive cohort population. Two additional proinflammatory markers TNF-α and INF-γ were evaluated in this case-control population. Out of 2000 women, 199 women developed hypertension and 1454 women remained normotensive throughout their pregnancy. Among 199 hypertensive women, 151 (9.13%) cases had gestational hypertension, 45 (2.72%) had preeclampsia (PE) and 3 (0.18%) had eclampsia(E).First trimester mean arterial pressure(MAP) (p<0.001) andbody mass index (BMI) (p<0.001) were found significantly higher in hypertensive women when compared with normotensive women. Maternal serum levels of PAPP-A (p<0.001) were significantly low in hypertensive women as compared to normotensive women, while free β-hCG (p=0.59) was high, but the difference was not statistically significant. TNF-α (p<0.001) and INF-γ (p=0.014) both were high in hypertensive women. When all biomarkers were combined we found the positive predictive value(PPV) of 51.6% an negative predictive value (NPV) of 71.4%. Increased levels of proinflammatory cytokines suggest the role of underlying inflammation in pathogenesis of pregnancy hypertension, and low PAPP-A may be attributed to impaired implantation. Combining biomarkers may improve the prediction of pregnancy hypertension in the early stages of gestation. NPVof 71.4% depicts that if woman has all biomarkers in normal ranges during first trimester, she will have 71.4% chances of remaining normotensive during pregnancy.

Combination of PAPPA, fhCGβ, AFP, PlGF, sTNFR1, and Maternal Characteristics in Prediction of Early-onset Preeclampsia.

OBJECTIVETo evaluate the efficacy of first-trimester markers—pregnancy-associated plasma protein A (PAPPA), free human chorionic gonadotropin β (fhCGβ), alpha-fetoprotein (AFP), placental growth factor (PlGF), and soluble tumor necrosis factor receptor-1 (sTNFR1) together with maternal characteristics (MC) for prediction of early-onset preeclampsia (EOPE).METHODSDuring 2005–2010, the abovementioned biomarkers were analyzed with logistic regression analysis in 64 EOPE and 752 control subjects to determine whether these biomarkers separately and in combination with MC would predict development of EOPE.RESULTSPAPPA, fhCGβ, and PlGF levels were lower, whereas AFP and sTNFR1 levels were higher in mothers with EOPE compared to controls. The combination of all markers with MC (age, weight, and smoking status) detected 48% of the mothers with EOPE, with a 10% false-positive rate (FPR).CONCLUSIONSFirst-trimester maternal serum levels of PAPPA, fhCGβ, AFP, PlGF, and sTNFR1, together with MC, are predictive of development of subsequent EOPE. These markers, along with MC, form a suitable panel for predicting EOPE.

Early fetal growth, PAPP‐A and free β‐hCG in relation to risk of delivering a small‐for‐gestational age infant

To examine early fetal growth, pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) in relation to the risk of delivering a small-for-gestational age (SGA) infant. Included in the study were 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital, Denmark, between January 2005 and December 2007. Maternal serum levels of PAPP-A and free β-hCG were measured between gestational weeks 8 and 13. Two ultrasound examinations were performed, the first at 11-13 weeks and the second at 18-22 weeks, from which gestational age was estimated based on crown-rump length and biparietal diameter, respectively. Early fetal growth was expressed as an index: the ratio between the estimated number of days from the first to the second scan and the actual calendar time elapsed in days. SGA was defined as birth weight < 5(th) centile for gestational age, and the risk of SGA was evaluated according to different cut-offs of the early fetal growth index and the serum markers. PAPP-A < 0.4 MoM combined with an early fetal growth index < 10(th) centile resulted in an increased risk of SGA (odds ratio (OR), 5.8; 95% CI, 2.7-12.7). Low PAPP-A, low free β-hCG and slow early fetal growth were statistically, independently associated with SGA, and the association between free β-hCG < 0.3 MoM and SGA was as strong as that between PAPP-A < 0.3 MoM and SGA (OR, 3.1 and 3.0, respectively). The combination of slow early fetal growth and low PAPP-A resulted in a nearly six-fold increased risk of delivery of an SGA infant. These findings might improve our chances of early identification of fetuses at increased risk of growth restriction.

PAPP‐A and free β‐hCG measured prior to 10 weeks is associated with preterm delivery and small‐for‐gestational‐age infants

To evaluate whether measuring pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG) before 10 weeks of gestation affect the association between these biomarkers and adverse pregnancy outcomes. Singleton pregnant women (9450) who attended the prenatal screening program, Aarhus University Hospital, Denmark, were included. Maternal serum levels of PAPP-A and free β-hCG were measured between week 8 and 13 weeks and 6 days. The risk of preterm delivery (<37 weeks) and small for gestational age (SGA) (<the fifth centile) was evaluated in relation to PAPP-A and free β-hCG < 0.4 multiples of the median, stratified according to early (<10 weeks) or late (≥ 10 weeks) biochemical testing. A stronger association between low PAPP-A and SGA was found with early serum sampling compared to late, but the difference was not statistically significant [odds ratio (OR) 3.2 vs 1.8; P value = 0.11]. This difference did not apply to PAPP-A and preterm delivery. For free β-hCG, a stronger association with preterm delivery was found with early testing (OR 1.9 vs 1.1; P value = 0.31), whereas this difference was not found regarding SGA. Biochemical testing before 10 weeks does not affect the association between low PAPP-A and free β-hCG and adverse pregnancy outcomes. Whether the association is actually stronger with early testing, requires further study.

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.

Association between birth weight and first-trimester free β–human chorionic gonadotropin and pregnancy-associated plasma protein A

To assess the relationship between first-trimester maternal serum PAPP-A and free beta-hCG and birth weight. Observational study. Teaching hospital. Singleton pregnancies (n = 1,630) at 10-14 weeks of gestation. Fluorimetric immunoassays for maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG. Customized birth weight percentiles, calculated taking into account maternal height, weight, ethnic origin, parity, smoking status, and fetal gender. There was a significant positive correlation between birth weight and PAPP-A, but not free beta-hCG levels. Maternal serum levels of PAPP-A were significantly lower in small-for-gestation (SGA) newborns than in control subjects and were significantly higher in large-for-gestation (LGA) newborns than in control subjects. Maternal serum free beta-hCG levels were lower in pregnancies complicated by pre-eclampsia than in normotensive ones. Multivariable analysis found PAPP-A to be an independent predictor of absolute birth weight, SGA, and LGA. Free beta-hCG was found to be an independent predictor of gestational hypertension and pre-eclampsia. Neither of the two markers was associated with preterm delivery. Maternal serum PAPP-A levels in the late first trimester of pregnancy are associated with subsequent fetal growth (including both physiologic variation and abnormal growth), and decreased free beta-hCG is more predictive of hypertensive disorders of pregnancy.

Correlation between first trimester fetal bone length and maternal serum pregnancy-associated plasma protein-A (PAPP-A)

Pregnancy-associated plasma protein-A (PAPP-A) is produced by the embryo and placenta during pregnancy, and its maternal serum concentrations are related to subsequent fetal growth. Evidence from animal models and in vitro experiments suggests that PAPP-A is particularly involved in the regulation of bone development. The aim of this study was to assess the correlation between late first trimester fetal bone length and maternal serum levels of PAPP-A. In a cross-sectional observational study, ultrasound measurements of fetal long bones and fluorimetric immunoassays for maternal serum PAPP-A were performed in 514 singleton pregnancies at 10-14 weeks of gestation. There were 501 uncomplicated pregnancies. There were significant correlations between PAPP-A values and length of humerus, femur and tibia [r values 0.12 (P = 0.01), 0.11 (P = 0.01) and 0.10 (P = 0.03), respectively]. The association with the length of ulna and foot did not reach statistical significance (r values 0.08 and -0.03, respectively). Maternal serum PAPP-A levels at 10-14 weeks of gestation are significantly associated with the length of fetal long bones such as humerus, femur and tibia. This provides further evidence that PAPP-A may be involved in the regulation of bone development.

Prediction of pre‐eclampsia by uterine artery Doppler ultrasonography and maternal serum pregnancy‐associated plasma protein‐A, free β‐human chorionic gonadotropin, activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation

To investigate the potential value of combining uterine artery Doppler ultrasonography with the measurement of maternal serum pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG), activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation, in the prediction of pregnancies that subsequently develop pre-eclampsia. The maternal serum PAPP-A, free beta-hCG, activin A and inhibin A concentrations at 22 + 0 to 24 + 6 weeks' gestation were measured in samples obtained from women with singleton pregnancies who participated in a screening study for pre-eclampsia by transvaginal color flow Doppler measurement of the uterine artery pulsatility index (PI). A search was made of the database to identify those who subsequently developed pre-eclampsia (n = 24) and a group of controls with normal outcome (n = 144). Regression analysis was performed to establish any relationship between the biochemical markers themselves and between the biochemical markers and uterine artery mean PI. A multivariate Gaussian model combining various biochemical markers with uterine artery mean PI was developed using standard statistical modeling techniques and the performance of such models in discriminating cases with pre-eclampsia was evaluated by receiver-operating characteristics curve (ROC) analysis. In the pre-eclampsia group, compared to the controls, the uterine artery mean PI and the maternal serum levels of PAPP-A, free beta-hCG, activin A and inhibin A were significantly increased. The predicted detection rates of pre-eclampsia, for a false positive rate of 5%, was 50% by uterine artery mean PI, 5% by PAPP-A, 10% by free beta-hCG, 35% by inhibin A and 44% by activin A. Screening by a combination of uterine artery mean PI and maternal serum activin A and inhibin A could detect 75% and 92% of patients who subsequently developed pre-eclampsia, for false positive rates of 5% and 10%, respectively. Screening for pre-eclampsia by uterine artery PI at 22 + 0 to 24 + 6 weeks' gestation can be improved by measurement of activin A and inhibin A levels.

Pregnancy-Associated Plasma Protein A and Alpha-fetoprotein and Prediction of Adverse Perinatal Outcome

To describe the association between pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP) and adverse perinatal outcome. We conducted a multicenter prospective cohort study of 8,483 women attending for prenatal care in southern Scotland between 1998 and 2000. The risk of delivering a small for gestational age infant, delivering preterm, and stillbirth were related to maternal serum levels of PAPP-A and AFP. Women with a low PAPP-A were not more likely to have elevated levels of AFP. Compared with women with a normal PAPP-A and a normal AFP, the odds ratio for delivering a small for gestational age infant for women with a high AFP was 0.9 (95% confidence interval [CI] 0.5-1.6), for women with a low PAPP-A was 2.8 (95% CI 2.0-4.0), and for women with both a high AFP and a low PAPP-A was 8.5 (95% CI 3.6-20.0). The odds ratio for delivering preterm for women with a high AFP was 1.8 (95% CI 1.3-2.7), for women with a low PAPP-A was 1.9 (95% CI 1.3-2.7), and for women with both a low PAPP-A and a high AFP was 9.9 (95% CI 4.4-22.0). These interactions were statistically significant for both outcomes (P = .03 and .04, respectively). There was a nonsignificant trend toward a similar interaction in relation to stillbirth risk. Of the women with the combination of a low PAPP-A and high AFP, 32.1% (95% CI 15.9-52.4) delivered a low birth weight infant. Low maternal serum levels of PAPP-A between 10 and 14 weeks and high levels of AFP between 15 and 21 weeks gestation are synergistically associated with adverse perinatal outcome. II-2.

Second- and third-trimester serum levels of placental proteins in preeclampsia and small-for-gestational age pregnancies

Background: Poor placentation may perpetuate preeclampsia, but the presence of a major placental pathology has been questioned in cases of preeclampsia where the newborn has an appropriate birthweight for gestational age. On the other hand, poor placentation is also observed in the absence of preeclampsia, in pregnancies with small-for-gestational-age (SGA) fetuses. In late gestation, maternal serum levels of placental protein hormones are changed in both preeclampsia and SGA, but no longitudinal preonset studies are available for pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific β1-glycoprotein (SP1) or human placental lactogen (HPL). Methods: In a nested case-control study we compared maternal serum levels of PAPP-A, SP1, HPL and placenta growth factor (PLGF) at 17, 25 and 33 weeks in pregnancies developing preeclampsia without fetal growth restriction (n = 28), or characterized by a growth-retarded fetus (n = 25), with gestation-matched controls (n = 65). The proteins were quantified using microplate enzyme immunometric assays and the serum levels at 17, 25 and 33 weeks compared between the three groups by nonparametric statistical tests. Results: In pregnancies with subsequent preeclampsia PAPP-A, SP1, HPL and PLGF were reduced at 17 weeks of gestation whereas at 25 and 33 weeks only PLGF remained below the controls. In growth-restricted pregnancies PAPP-A, SP1 and HPL were reduced at 17 weeks, and only HPL continued to be strongly affected thereafter. Conclusion: The reduced serum levels of the placental proteins PAPP-A, SP1 and HPL in the early second trimester (17 weeks) in pregnancies with subsequent preeclampsia or with fetal growth restriction involve an underlying role for the placenta in either pathology independent from the other.

Second‐ and third‐trimester serum levels of placental proteins in preeclampsia and small‐for‐gestational age pregnancies

Poor placentation may perpetuate preeclampsia, but the presence of a major placental pathology has been questioned in cases of preeclampsia where the newborn has an appropriate birthweight for gestational age. On the other hand, poor placentation is also observed in the absence of preeclampsia, in pregnancies with small-for-gestational-age (SGA) fetuses. In late gestation, maternal serum levels of placental protein hormones are changed in both preeclampsia and SGA, but no longitudinal pre-onset studies are available for pregnancy-associated plasma protein A (PAPP-A), pregnancy-specific beta1-glycoprotein (SP1) or human placental lactogen (HPL). In a nested case-control study we compared maternal serum levels of PAPP-A, SP1, HPL and placenta growth factor (PLGF) at 17, 25 and 33 weeks in pregnancies developing preeclampsia without fetal growth restriction (n = 28), or characterized by a growth-retarded fetus (n = 25), with gestation-matched controls (n = 65). The proteins were quantified using microplate enzyme immunometric assays and the serum levels at 17, 25 and 33 weeks compared between the three groups by nonparametric statistical tests. In pregnancies with subsequent preeclampsia PAPP-A, SP1, HPL and PLGF were reduced at 17 weeks of gestation whereas at 25 and 33 weeks only PLGF remained below the controls. In growth-restricted pregnancies PAPP-A, SP1 and HPL were reduced at 17 weeks, and only HPL continued to be strongly affected thereafter. The reduced serum levels of the placental proteins PAPP-A, SP1 and HPL in the early second trimester (17 weeks) in pregnancies with subsequent preeclampsia or with fetal growth restriction involve an underlying role for the placenta in either pathology independent from the other.

Maternal serum screening for trisomy 18 in the first trimester of pregnancy.

The aim of this study was to evaluate the feasibility of first-trimester biochemical screening for trisomy 18, by using pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (hCG) in combination with maternal age. Maternal serum levels of PAPP-A and free beta-hCG were assayed retrospectively in stored sera from 323 singleton pregnancies at 8-13 weeks' gestation. These samples included 23 trisomy 18 pregnancies and 300 unaffected controls, diagnosed either at chorionic villus sampling or at mid-trimester amniocentesis. The median MOM in affected pregnancies was 0.25 for PAPP-A and 0.34 for free beta-hCG. Statistically significant reductions were found in the mean levels of both PAPP-A (t test: P < 0.000001) and free beta-hCG (p < 0.000001) in trisomy 18 affected pregnancies when compared with the unaffected samples. Screening for trisomy 18 using a combination of maternal age, PAPP-A and free beta-hCG would achieve a detection rate of 76.6 per cent for a false-positive rate of 0.5 per cent. These results suggest that first-trimester biochemical screening for trisomy 18 might be possible. Further investigations in a general population are needed before introducing such screening into clinical practice.

First trimester screening for Down's syndrome using maternal serum PAPP-A and free beta-hCG in combination with fetal nuchal translucency thickness.

The aim of this study was to evaluate the potential effectiveness of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG in combination with nuchal translucency thickness in first trimester screening for Down's syndrome. Maternal serum levels of PAPP-A and free beta-hCG were assayed in stored sera from 32 Down's syndrome and 200 unaffected pregnancies. Fetal nuchal translucency was measured by ultrasound at the time of blood sampling. Screening of Down's syndrome using a combination of maternal age, PAPP-A, free beta-hCG and nuchal translucency would achieve a detection rate of 75.8% for a false positive rate of 5%.