Low Pregnancy-associated Plasma Protein Research Articles

Adverse pregnancy outcome in low PAPP-A levels: First trimester screening hospital based study

To assess the adverse pregnancy outcome in Low Pregnancy Associated Plasma Protein -A (PAPP-A) levels in serum.This is a prospective cohort study, which included 2150 pregnant women who attended the antenatal clinic of Obstetrics and Gynecology in the Lok Nayak Hospital, New Delhi, India. Blood samples were collected by the venipuncture method for First trimester screening to assess free β-hCG and PAPP-A concentrations were measured by Auto DELFIA (Perkin Elmer, Turku, Finland).In this study a total of 210 women who have the low PAPP-A value less than 0.4 MoM were under the closer surveillance for serious pregnancy outcome. 33(15.6%) women had pre-eclempsia, 27 (12.9%) cases showed intra-utrine growth retardation (IUGR), 6 (3.0%) cases have intra-utrine death. 48 (22.8%) women have pregnancy induced hypertension, and 96(45.6%) cases have other pregnancy related complication. Low PAPP-A levels gives an indication of adverse pregnancy outcome in the early gestation age during the first trimester.

"Low Pregnancy Associated Plasma Protein A as a Predictive Tool for Pregnancy Outcome"

"Low Pregnancy Associated Plasma Protein A as a Predictive Tool for Pregnancy Outcome"

Prenatal Diagnosis of Congenital Heart Diseases and Associations with Serum Biomarkers of Aneuploidy: A Multicenter Prospective Cohort Study.

PurposeWe assessed prenatal detection rates of congenital heart disease (CHD) and associations between maternal serum biomarkers and non-chromosomal CHD in singleton pregnancies.Materials and MethodsThis study was conducted as a secondary analysis of data obtained during a multicenter prospective cohort study that investigated the cost-effectiveness of prenatal testing for fetal aneuploidy. We analyzed the prenatal detection rate and accuracy for CHD screening via ultrasound during the second trimester, as well as associations between serum biomarkers and CHDs, in singleton newborns without chromosomal abnormalities.ResultsAmong 6715 women, 142 (2.1%) newborns were born with CHDs, of which 67 (1.0%) newborns had major CHDs. The prenatal detection rate for all CHDs and major CHDs were 34.5% and 58.2%, respectively. After excluding isolated ventricular septal defects, the detection rate for critical CHDs was 85.9%. Women with low pregnancy-associated plasma protein A (PAPP-A) (<0.4 multiples of the median, MOM) face increased risks of non-chromosomal CHDs [adjusted odds ratio (aOR) 2.76; 95% confidence interval (CI) 1.36–5.13] and major CHDs (aOR 7.30; 95% CI 3.18–15.59), compared to those without CHDs. A higher inhibin A level (≥2.5 MOM; aOR 4.84; 95% CI 1.42–12.46) was associated with non-chromosomal major CHDs.ConclusionUltrasonography performed during the second trimester by obstetricians detected over 85% of critical CHDs. Low maternal serum PAPP-A or high inhibin-A was associated with non-chromosomal CHDs. These results may contribute to an improvement in prenatal diagnosis of CHDs.

Prenatal sonographic features can accurately determine parental origin in triploid pregnancies.

ObjectiveTo describe the prenatal sonographic features and maternal biochemical markers in triploid pregnancies and to assess whether prenatal phenotype can determine genetic origin.MethodsWe performed a retrospective multicenter cohort study that included all triploid pregnancies diagnosed between 2000 and 2018 in two Fetal Medicine Units in Amsterdam. Fetal growth, presence of structural anomalies, extra‐fetal anomalies, and maternal biochemical markers were retrieved. Asymmetrical intrauterine growth restriction was diagnosed when the head‐to‐abdominal circumference (HC/AC) ratio was >95th centile. Parental origin was analyzed via molecular genotyping in 46 cases (38.3%).ResultsOne hundred and twenty triploid pregnancies were identified, of which 86 cases (71.6%) were detected before 18 weeks of gestation. Triploidy of maternal origin was found in 32 cases (69.6%) and was associated with asymmetrical growth restriction, a thin placenta, and low pregnancy‐associated plasma protein A and free beta‐human chorionic gonadotrophin (β‐hCG) levels. Triploidy of paternal origin was found in 14 cases (30.4%) and was associated with an increased nuchal translucency, placental molar changes, and a high free β‐hCG. Prospective prediction of the parental origin of the triploidy was made in 30 of the 46 cases based on phenotypical ultrasound presentation, and it was correct in all cases.ConclusionAsymmetrical growth restriction with severe HC/AC discrepancy is pathognomonic of maternal triploidy. Placental molar changes indicate a paternal triploidy. Moreover, triploidy can present with an abnormal first trimester combined test, with serum levels on the extreme end. When available results of maternal serum markers can support the diagnosis of parental origin of the triploidy, an accurate assessment of the parental origin based on prenatal sonographic features is possible, making DNA analysis redundant.

Prenatal Biochemical Screening and a Woman’s Long-Term Risk of Cancer: A Population-Based Cohort Study

BackgroundSome hormones measured in pregnancy are linked to certain hormone-sensitive cancers. We investigated whether routine serum screening in pregnancy is associated with a woman’s subsequent risk of hormone-sensitive cancer.MethodsThis population-based cohort study included women aged 12–55 years who underwent prenatal screening between 11 weeks + 0 days of gestation to 20 weeks + 6 days of gestation in Ontario, Canada, 1993–2011, where universal health care is available. The hazard ratio of newly diagnosed breast, ovarian, endometrial, and thyroid cancer—arising at 21 weeks + 0 days of gestation or thereafter—was estimated in association with an abnormally low (≤5th) or high (>95th) percentile multiple of the median (MoM) for alpha-fetoprotein (AFP), total human chorionic gonadotropin (hCG), unconjugated estriol, pregnancy-associated plasma protein A, and dimeric inhibin A.ResultsAmong 677 247 pregnant women followed for a median of 11.0 years (interquartile range = 7.5–16.1), 7231 (1.07%) developed breast cancer, 515 (0.08%) ovarian cancer, 508 (0.08%) endometrial cancer, and 4105 (0.61%) thyroid cancer. In multivariable adjusted models, abnormally high hCG greater than the 95th percentile MoM was associated with a doubling in the risk of endometrial cancer (adjusted hazard ratio [aHR] = 1.98, 95% confidence interval [CI] = 1.33 to 2.95), and abnormally low AFP at the fifth percentile or less MoM conferred a moderately greater risk of thyroid cancer (aHR = 1.21, 95% CI = 1.07 to 1.38). Abnormally low pregnancy-associated plasma protein A at the fifth percentile or less MoM was not statistically significantly associated with breast cancer after multivariable adjustment (aHR = 1.19, 95% CI = 0.98 to 1.36).ConclusionsWomen with abnormally high levels of serum hCG or low AFP in early pregnancy may be at a greater future risk of certain types of hormone-sensitive cancers.

Association of Low Maternal Pregnancy-associated Plasma Protein A with Adverse Perinatal Outcome.

The aim is to provide an overall view of the association of low pregnancy-associated plasma protein A (PAPP-A) levels with adverse perinatal outcomes. The available literature in PubMed/Medline regarding PAPP-A and adverse pregnancy outcomes was searched for related articles, including terms such as “PAPP-A,” “intrauterine growth restriction (IUGR),” “small for gestational age (SGA),” “stillbirth,” “adverse outcome,” and others. The fifth percentile is supported by many recent studies to be PAPP-A’s cutoff for adverse outcome detection and the increased risk seems to be extremely high below 0.2 PAPP-A MoM (multiple of the median). Apart from chromosomal abnormalities, preeclampsia, intrauterine fetal demise, and pregnancy loss have been associated with maternal serum PAPP-A. For results below the first centile, PAPP-A has a strong positive predictive value for SGA and IUGR. Except for its vital role on the cleavage of insulin-like growth factor binding proteins (IGFBP), PAPP-A has proven to be a reliable marker for prenatal screening. Even though PAPP-A as a single predictor proved to be valuable for the prediction of some adverse perinatal outcomes, in some cases, a combination of PAPP-A to other maternal serum markers led to an increase in detection rates. PAPP-A is a promising maternal serum marker for pregnancy outcome prediction with more studies needed in order for its potentials to be fully understood and exploited.

Whole-exome sequencing for diagnosis of Peters-plus syndrome after prenatal diagnosis of recurrent low PAPP-A and multiple fetal anomalies in two consecutive pregnancies.

We report a case of two consecutive pregnancies in the same couple presenting with very low pregnancy-associated plasma protein A (PAPP-A), with both pregnancies affected by multiple anomalies of a similar phenotype identified during mid-trimester ultrasound, and eventual diagnosis of Peters-plus syndrome. This case is important in expanding the differential for very low PAPP-A. It also demonstrates the diagnostic value of whole-exome sequencing (WES) after prenatal diagnosis of recurrent fetal ultrasonographic findings. The importance and complexity of providing patient education to enable informed consent for next generation sequencing technologies is discussed.

Are Women with a History of Low PAPP-A at Risk for Adverse Perinatal Outcomes in a Subsequent Pregnancy?

To determine if patients with a history of low pregnancy-associated plasma protein A (PAPP-A) in an initial pregnancy are at higher risk for adverse obstetric outcomes in a subsequent pregnancy. This was a retrospective cohort study in patients who underwent first trimester screening for PAPP-A in two consecutive pregnancies. Two groups were examined: patients who had low PAPP-A in the first pregnancy followed by normal PAPP-A in the second pregnancy and patients who had recurrent low PAPP-A. Maternal and neonatal outcomes were compared between the groups, with the primary outcome being intrauterine growth restriction (IUGR) or preeclampsia. A total of 124 patients were included, representing 248 pregnancies. Ninety-two (74.2%) patients had normal PAPP-A in the second pregnancy, and 32 (12.9%) patients had recurrent low PAPP-A. Patients with recurrent low PAPP-A had a higher rate of IUGR or preeclampsia compared with patients with normal PAPP-A in the second pregnancy but this was not significantly different (12.5 vs. 10.9%, p = 0.51). There were no significant differences for all other outcomes. Among patients with a history of low PAPP-A, patients with normal PAPP-A in the subsequent pregnancy have a similar risk of adverse neonatal outcomes compared with patients with recurrent low PAPP-A.

First-Trimester Biochemical Screening For Low Birth Weight: Clinical Effectiveness of Low Pregnancy-Associated Plasma Protein-A and High Thyroid-Stimulating Hormone.

Low birth weight (LBW) can be an important adverse neonatal outcome in terms of morbidity and mortality. The aim of this study is to investigate the screening effectiveness of first-trimester low pregnancy-associated plasma protein A (PAPP-A) and high serum thyroid-stimulating hormone (TSH) and the combination of both markers for predicting LBW. We performed a retrospective cohort study of women undergoing first-trimester assessment in our center. We considered low PAPP-A as < 5th percentile for gestational age. High serum TSH was defined as > 2.5 mU/L, according to the American Thyroid Association (ATA) recommendation. Receiver-operating characteristic (ROC) curves were plotted to evaluate screening performance. Multivariate logistic regression was accomplished to calculate adjusted risks to identify the association between both parameters with LBW. Overall, 4,396 women met the inclusion criteria. Of these, 277 (6.3%) delivered a LBW baby. The use of either low PAPP-A or high TSH yielded the highest sensitivity (21.1%) with a specificity of 85.7%. Combining both markers showed an increased association (adjusted OR 9.07 [95% CI 3.34 - 24.6]) at the expense of a significant reduction in sensitivity (7.8%). First-trimester low PAPP-A is associated with LBW at delivery. Neither of these biomarkers or their combination are acceptable predictors to be clinically useful tools for LBW.

Is there any relationship between low PAPP-A levels and measures of umbilical vein and placental thickness during first trimester of pregnancy?

OBJECTIVE:Low pregnancy-associated plasma protein A (PAPP-A) level is associated with adverse perinatal outcomes. The purpose of this study was to evaluate relationship between umbilical cord diameter (UCD), umbilical vein and artery diameters (UVD, UAD), placental thickness, and PAPP-A level at gestational age of between 11 and 14 weeks.METHODS:UCD, UVD, UAD, and placental thickness of 246 women were assessed during ultrasound examination at between 11 and 14 weeks of gestation, as well as measurement of nuchal translucency (NT) and crown-rump length (CRL). Patients were divided into 2 groups according to PAPP-A percentile. Group 1 comprised 23 patients who had low PAPP-A (<0.44 multiple of medians [MoM], <10th percentile) and Group 2 was made up of 223 patients with PAPP-A of >0.44 MoM, >10th percentile. Calipers used for measurement were placed inner edge to inner edge of echogenic boundaries of the vessel. Largest sections of all vessels (UV and both arteries) were evaluated. Thickest part of the placenta was used for placental thickness measurement.RESULTS:Narrow UCD (<4.5±0.6 mm) was associated with low PAPP-A level (p=0.02). There was no significant difference in UVD, UAD, or placental thickness between groups. There was no significant difference in gestational age, CRL, or NT between groups. Fetal birth weight was significantly lower in Group 1 (p=0.03).CONCLUSION:Closer attention to women with low-risk, healthy pregnancies and low PAPP-A level in first trimester screening results is recommended. They should be routinely screened for background medical risk factors and umbilical cord morphology in first trimester scan.

Analysis of first-trimester combined test results in preparation for a cell-free fetal DNA era

ObjectiveTo survey experience with the first-trimester combined test (FCT) for trisomy 21 (T21) in different risk score groups to determine the most useful clinical application of cell-free fetal DNA (cffDNA) screening. MethodsIn a retrospective study, the records of FCT results obtained at a center in Turkey between January 2009 and January 2014 were reviewed. The FCT results and rates of uptake of invasive diagnostic testing were compared among different risk score groups. ResultsFCT results were available for 4804 pregnancies; 276 (5.7%) had IDT results. Ten (72.7%) of 11 cases of T21 had a risk score of 1:300 or more. The IDT uptake rates were 54.5%, 51.9%, and 47.4% at risk scores of 1:100 or more, 1:200 or more, and 1:300 or more, respectively. In the group at intermediate risk (1:1001–1:3000), no pregnancy had an FCT result of both low pregnancy-associated plasma protein A and high free β-human chorionic gonadotropin, but 30 (3.9%) of 766 pregnancies had both advanced maternal age and high β-human chorionic gonadotropin. ConclusioncffDNA screening should be used to optimize IDT uptake in pregnancies with a risk score of 1:101–1:1000. The selective power of the FCT diminishes beyond the 1:1001 score and cffDNA screening cannot yet be recommended routinely.

Early Prognostic Factors for the Progress of Preeclampsia - Our Experience in the Period 2010-2011.

AIM:To determine the prognostic value of the low Pregnancy-associated plasma protein A (PAPP-A) levels in the early stages of pregnancy (11–13 weeks GA) independently and in combination with a Doppler test of the uterine arteries during the second half of pregnancy (22–23 weeks GA).MATERIAL AND METHODS:The study covered the period 2010–2011 and included 106 pregnant women, aged 35–40, with a single child pregnancy. The research excluded pregnant women with anomalies of the fetus, smokers and women taking prophylactically low doses of aspirin.RESULTS:Thirty-six pregnant women had PAPP-A level below 0.4 MoM, whereas 20 of them developed preeclampsia and 7 – early preeclampsia. The combination of the low PAPP-A values and the abnormal Doppler test of the uterine arteries is with a considerably better prognostic value in regards to the risk of developing preeclampsia.CONCLUSION:The Doppler test is a non-invasive, quick and easy method for assessment of the uterine-placental blood flow.

Abnormal Biochemical Analytes Used for Aneuploidy Screening and Adverse Pregnancy Outcomes in Twin Gestations.

The objective of this study was to determine if first- and second-trimester biochemical markers for aneuploidy have an association with adverse pregnancy outcomes in twin gestations. A retrospective cohort study of patients who presented with dichorionic diamniotic twin gestations was performed. Patients with first-trimester low pregnancy-associated plasma protein A (PAPP-A) or low free β human chorionic gonadotropin (β-hCG), or second-trimester elevated α-fetoprotein (AFP), elevated inhibin A, elevated hCG, or low unconjugated estradiol were identified. The rates of adverse pregnancy outcomes were compared between patients with or without abnormal analytes with p < 0.05 used as significance. In this study, 340 pregnancies were included. Patients with a low PAPP-A had an increased risk for delivery < 37 weeks. Patients with an elevated second-trimester hCG had an increased risk for spontaneous delivery < 28 weeks and neonatal intensive care unit (NICU) admission. Patients with an elevated inhibin A had an increased risk of spontaneous delivery at < 37 and NICU admission. Patients with an elevated AFP had an increased risk of a NICU admission. Certain abnormal aneuploidy markers are associated with an increased risk of adverse pregnancy outcomes in twin gestations.

Efficiency of first‐trimester growth restriction and low pregnancy‐associated plasma protein‐A in predicting small for gestational age at delivery

To evaluate the efficiency of first-trimester fetal growth restriction (FGR), low pregnancy-associated plasma protein A (PAPP-A), and their combination for predicting small for gestational age (SGA) at delivery. Retrospective cohort study of women undergoing first-trimester aneuploidy screening. Fetal crown-rump lengths (CRLs) were at 10 to 14 weeks' gestation and converted to gestational age adjusted Z-scores. Low PAPP-A was defined as levels<5th percentile for GA. Receiver-operating characteristic curves were used to assess screening efficiencies. Among 3269 pregnancies meeting the inclusion criteria 185 (5.7%) infants were SGA. CRL Z-score< -1.0 standard deviation was identified as the optimal definition of early FGR. Using either CRL Z-score< -1.0 standard deviation or PAPP-A<5th percentile had the highest sensitivity (33%) with a specificity of 82.1% when screening for SGA. Using a combination resulted in an increased association (adjusted odds ratio 4.23[confidence interval 1.37-13.03]) at the expense of significantly reduced sensitivity (3.13%). First-trimester FGR and PAPP-A<5th percentile are associated with delivery of an SGA infant. Neither of these parameters or the combination of the two are sufficient powerful predictors of SGA to be clinically useful screening tools.

347: Are first trimester growth restriction (FGR) and low pregnancy-associated plasma protein A (PAPP-A) efficient for predicting small for gestational (SGA) at delivery?

Recent studies suggest that early FGR and low PAPP-A is associated with growth abnormalities in late pregnancy. Our objective is to evaluate the efficiency of first-trimester FGR, low PAPP-A, and their combination for predicting SGA at delivery.

The efficiency of first-trimester serum analytes and maternal characteristics in predicting fetal growth disorders

To evaluate the association between first-trimester serum analytes, pregnancy-associated plasma protein A and free beta-human chorionic gonadotropin, and fetal growth disorders, and to determine whether a prediction model for these growth disorders can be developed. Retrospective cohort study of patients seen for first-trimester aneuploidy screening. Pregnancy-associated plasma protein A and free beta-human chorionic gonadotropin multiples of the median were evaluated for association with small- and large-for-gestational-age infants in combination with maternal characteristics. Univariate and backward stepwise logistic regression analyses were performed and the area under the receiver-operator curves used to determine the best prediction models. Neither pregnancy-associated plasma protein A nor free beta-human chorionic gonadotropin levels were associated with an increased risk of large-for-gestational-age infants. For small-for-gestational-age infants, the final model included black race, free beta-human chorionic gonadotropin multiples of the median >90th percentile, and pregnancy-associated plasma protein A multiples of the median <5th percentile as significant predictors (area under the curve = 0.58). Low pregnancy-associated plasma protein A and high free beta-human chorionic gonadotropin levels are associated with a small-for-gestational-age growth pattern; however, additional factors to improve the prediction model are needed.

Prediction and Prevention of Recurrent Stillbirth

Stillbirth is one of the most common adverse pregnancy outcomes in the United States, occurring in one out of every 200 pregnancies. There is a paucity of information on the outcome of pregnancies after stillbirth. Prior stillbirth is associated with a twofold to 10-fold increased risk of stillbirth in the future pregnancy. The risk depends on the etiology of the prior stillbirth, presence of fetal growth restriction, gestational age of the prior stillbirth, and race. Categorization of the cause of the initial stillbirth will allow better estimates of individual recurrence risk and guide management. A history of stillbirth also increases the risk of other adverse pregnancy outcomes in the subsequent pregnancy such as placental abruption, cesarean delivery, preterm delivery, and low birth weight infants. Prospective studies have revealed an increased risk of stillbirth with low pregnancy-associated plasma protein A, elevated maternal serum alpha fetoprotein, abnormal uterine artery Doppler studies, and antiphospholipid antibodies. However, the positive predictive value of these factors individually is poor. Because fetal growth restriction is associated with almost half of all stillbirths, the correct diagnosis of fetal growth restriction is essential. The use of individualized or customized growth standards will improve prediction of adverse pregnancy outcome by distinguishing growth-restricted fetuses from constitutionally small, healthy fetuses. Antepartum fetal surveillance and fetal movement counting are also mainstays of poststillbirth pregnancy management.

Prediction and Prevention of Recurrent Stillbirth

Stillbirth is one of the most common adverse pregnancy outcomes in the United States, occurring in one out of every 200 pregnancies. There is a paucity of information on the outcome of pregnancies after stillbirth. Prior stillbirth is associated with a twofold to 10-fold increased risk of stillbirth in the future pregnancy. The risk depends on the etiology of the prior stillbirth, presence of fetal growth restriction, gestational age of the prior stillbirth, and race. Categorization of the cause of the initial stillbirth will allow better estimates of individual recurrence risk and guide management. A history of stillbirth also increases the risk of other adverse pregnancy outcomes in the subsequent pregnancy such as placental abruption, cesarean delivery, preterm delivery, and low birth weight infants. Prospective studies have revealed an increased risk of stillbirth with low pregnancy-associated plasma protein A, elevated maternal serum alpha fetoprotein, abnormal uterine artery Doppler studies, and antiphospholipid antibodies. However, the positive predictive value of these factors individually is poor. Because fetal growth restriction is associated with almost half of all stillbirths, the correct diagnosis of fetal growth restriction is essential. The use of individualized or customized growth standards will improve prediction of adverse pregnancy outcome by distinguishing growth-restricted fetuses from constitutionally small, healthy fetuses. Antepartum fetal surveillance and fetal movement counting are also mainstays of poststillbirth pregnancy management.

First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: A population-based screening study (The FASTER Trial)

The purpose of this study was to determine whether maternal serum levels of pregnancy-associated plasma protein A, free-beta subunit human chorionic gonadotropin, or nuchal translucency size are associated with obstetric complications. Data were obtained from the First and Second Trimester Evaluation of Risk trial. Pregnancy-associated plasma protein A and free-beta subunit human chorionic gonadotropin levels were analyzed, and nuchal translucency was measured between 10 weeks 3 days and 13 weeks 6 days of gestation in 34,271 pregnancies. Women with pregnancy-associated plasma protein A of < or =5th percentile were significantly more likely to experience spontaneous fetal loss at < or =24 weeks of gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth ( P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption ( P < .02). Nuchal translucency at > or =99th percentile and free-beta subunit human chorionic gonadotropin at < or =1st percentile were associated with an increased risk of spontaneous loss at < or =24 weeks of gestation (adjusted odds ratios, 3.90, 3.62, respectively; P < .001). Low pregnancy-associated plasma protein A levels in the first trimester were associated strongly with a number of adverse pregnancy outcomes. Low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss.