Trimester Pregnancy-associated Plasma protein-A Research Articles

First trimester maternal serum PAPP-A and free β-hCG levels and risk of SGA or LGA in women with and without GDM

BackgroundMaternal gestational diabetes (GDM), small (SGA) and large (LGA) for gestational age neonates are associated with increased morbidity in both mother and child. We studied how different levels of first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotropin (fβ-hCG) were associated with SGA and LGA in GDM pregnancies and controls.MethodsAltogether 23 482 women with singleton pregnancies participated in first trimester combined screening and delivered between 2014 and 2018 in Northern Finland and were included in this retrospective case-control study. Women with GDM (n = 4697) and controls without GDM (n = 18 492) were divided into groups below 5th and 10th or above 90th and 95th percentile (pc) PAPP-A and fβ-hCG MoM levels. SGA was defined as a birthweight more than two standard deviations (SD) below and LGA more than two SDs above the sex-specific and gestational age-specific reference mean. Odds ratios were adjusted (aOR) for maternal age, BMI, ethnicity, IVF/ICSI, parity and smoking.ResultsIn pregnancies with GDM the proportion of SGA was 2.6% and LGA 4.5%, compared to 3.3% (p = 0.011) and 1.8% (p < 0.001) in the control group, respectively. In ≤ 5th and ≤ 10th pc PAPP-A groups, aORs for SGA were 2.7 (95% CI 1.5–4.7) and 2.2 (95% CI 1.4–3.5) in the GDM group and 3.8 (95% CI 3.0–4.9) and 2.8 (95% CI 2.3–3.5) in the reference group, respectively. When considering LGA, there was no difference in aORs in any high PAPP-A groups. In the low ≤ 5 percentile fβ-hCG MoM group, aORs for SGA was 2.3 (95% CI 1.8–3.1) in the control group. In fβ-hCG groups with GDM there was no association with SGA and the only significant difference was ≥ 90 percentile group, aOR 1.6 (95% CI 1.1–2.5) for LGA.ConclusionAssociation with low PAPP-A and SGA seems to be present despite GDM status. High PAPP-A levels are not associated with increased LGA risk in women with or without GDM. Low fβ-hCG levels are associated with SGA only in non-GDM pregnancies.

Abstract P357: Health Behaviors in Early Pregnancy Are Associated With Mid-Pregnancy Biomarkers of Placental Health and Function

Introduction: Placental blood biomarkers are dysregulated in adverse pregnancy outcomes (APO). While health behaviors are associated with APO risk, it is not well-characterized whether health behaviors impact placental blood biomarkers. Thus, we examined the associations between health behaviors and placental biomarkers of angiogenesis in mid-pregnancy. Hypothesis: Pregnant people engaging in healthier behaviors in the 1 st trimester would demonstrate more favorable 2 nd trimester concentrations of placental biomarkers. Methods: Data from 2,078 participants with available analytes from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be were included, representing an enriched sample of APO (preterm birth, preeclampsia/eclampsia, small-for-gestational age, or stillbirth; n=1,284) and 12% of those without these diagnoses (n=794). Health behaviors of physical activity, sleep, smoking, and diet assessed in the 1 st trimester were scored from 0-100 according to the Life’s Essential 8 algorithm; a higher score is more favorable. Biomarkers assayed included total endoglin, pregnancy-associated plasma protein A (PAPP-A), vascular endothelial growth factor, placental growth factor, and soluble FMS-like tyrosine 1. The association between health behaviors and each biomarker was examined using linear (continuous) or logistic (odds of concentration below multiple of the median [MoM] cut point) regression adjusted for demographics, BMI, resilience (Connor-Davidson Scale), and perceived discrimination (Krieger Racism Scale) using a backwards stepwise approach; analyses were repeated stratified by APO status. Bonferroni-corrected significance was p&lt;0.001. Results: The overall APO rate in this enriched sample was 62%; this was significantly lower in those with ≥150 min/week compared with no physical activity (58% vs 66%, p=0.04). Lower (worse) smoking score was associated with lower (adverse) PAPP-A concentration in those who developed APO (p&lt;0.001). Higher physical activity score (healthier) was associated with lower PAPP-A concentration (adverse) regardless of APO occurrence; for every 10-point higher physical activity score, odds of PAPP-A &lt; 0.3 MoM increased 10% (OR 1.10; 95% CI 1.05, 1.16). No associations were observed between the other health behaviors and biomarkers. Conclusions: Higher levels of physical activity were associated with lower APO occurrence. In contrast, PAPP-A concentrations were lower in those with higher physical activity regardless of pregnancy outcome. Lower 2 nd trimester PAPP-A was observed in those with higher smoking exposure who developed APO. Our findings support prior work demonstrating lower risk of APO with more physical activity in pregnancy, but also indicate that PAPP-A concentrations may be sensitive to physical activity and smoking. Further work to elucidate the mechanisms of these associations is warranted.

A statistical investigation of parameters associated with low cell-free fetal DNA fraction in maternal plasma for noninvasive prenatal testing

Background Noninvasive prenatal testing (NIPT) is the most common method for prenatal aneuploidy screening. Low fetal fraction (LFF) is the primary reason for NIPT failure. Consequently, factors associated with LFF should be elucidated for optimal clinical implementation of NIPT. Methods In this study, NIPT data from January 2019 to December 2022 from the laboratory records and obstetrical and neonatal data from the electronic medical records were collected and analyzed. Subjects with FF >3.50% were assigned to the control group, subjects with FF <3.50% once were assigned to the LFF group, and subjects with FF <3.50% twice were assigned to the repetitive low fetal fraction (RLFF) group. Factors, including body mass index (BMI), gestational age, maternal age, twin pregnancy, and in vitro fertilization (IVF) known to be associated with LFF were assessed by Kruskal–Wallis H test and logistic regression. Clinical data on first trimester pregnancy-associated plasma protein-A (PAPP-A), beta-human chorionic gonadotropin (β-hCG), gestational age at delivery, birth weight at delivery, and maternal diseases were obtained from the hospital’s prenatal and neonatal screening systems (twin pregnancy was not included in the data on gestational age at delivery and the control group did not include data on maternal diseases.), and were analyzed using Kruskal–Wallis H test and Chi-square test. Results Among the total of 63,883 subjects, 63,605 subjects were assigned to the control group, 197 subjects were assigned to the LFF group, and 81 subjects were assigned to the RLFF group. The median of BMI in the three groups was 22.43 kg/m2 (control), 25.71 kg/m2 (LFF), and 24.54 kg/m2 (RLFF). The median gestational age in the three groups was 130 days (control), 126 days (LFF), and 122/133 days (RLFF). The median maternal age in the three groups was 29 (control), 29 (LFF), and 33-years-old (RLFF). The proportion of twin pregnancies in the three groups was 3.3% (control), 10.7% (LFF), and 11.7% (RLFF). The proportion of IVF in the three groups was 4.7% (control), 11.7% (LFF), and 21.3% (RLFF). The factors significantly associated with LFF included BMI [2.18, (1.94, 2.45), p < 0.0001], gestational age [0.76, (0.67, 0.87), p < 0.0001], twin pregnancy [1.62, (1.02, 2.52), p = 0.0353], and IVF [2.68, (1.82, 3.86), p < 0.0001]. The factors associated with RLFF included maternal age [1.54, (1.17, 2.05), p = 0.0023] and IVF [2.55, (1.19, 5.54), p = 0.016]. Multiples of the median (MOM) value of β-hCG and pregnant persons’ gestational age at delivery were significantly decreased in the LFF and RLFF groups compared to the control group. Conclusion According to our findings based on the OR value, factors associated strongly with LFF include a high BMI and the use of IVF. Factors associated less strongly with LFF include early gestational age and twin pregnancy, while advanced maternal age and IVF were independent risk factors for a second LFF result.

First trimester low maternal serum pregnancy associated plasma protein-A (PAPP-A) as a screening method for adverse pregnancy outcomes.

To evaluate different cut-off values of first trimester pregnancy associated plasma protein-A (PAPP-A) in screening for adverse pregnancy outcomes in a retrospective cohort study. During the study period of 1.1.2014-31.12.2018, total of 23,482 women with singleton pregnancies participated in first trimester combined screening for chromosomal abnormalities. Maternal serum PAPP-A multiple of medians (MoM) levels were measured, and study population was divided into three study groups of PAPP-A≤0.40 (n=1,030),≤0.35 (n=630) and≤0.30 (n=363) MoM. Small for gestational age (SGA), preterm birth (PTB) and composite outcome (SGA, hypertensive disorder of pregnancy (HDP) and/or PTB) were more frequent in all three PAPP-A MoM study groups and pre-eclampsia in≤0.40 and≤0.35 study groups than in their control groups (p<0.05). The odds ratio (OR) for SGA varied from 3.7 to 5.4 and sensitivity and specificity from 6.9 to 13.8% and from 95.9 to 98.6%, between study groups. Using PAPP-A≤0.30 MoM as a screening cut-off instead of PAPP-A≤0.40 MoM, resulted in approximately 50% reduction in screening detection of SGA and PTB. PAPP-A≤0.40 MoM should be considered asa primary screening cut-off for adverse pregnancy outcomes as approximately 23% will develop either SGA, HDP or PTB. It seems to be the best cut-off to screen for SGA.

The predictive value of maternal serum AFP to PAPP-A or b-hCG ratios in spontaneous preterm birth

The use of the second trimester alpha-fetoprotein (AFP) along with the first trimester pregnancy-associated plasma protein-A (PAPP-A) has been found to be useful in the estimation of unfavourable pregnancy outcome. Our aim in this study was to determine the relationship between maternal PAPP-A and b-hCG and AFP concentrations in spontaneous preterm birth (sPTB). This prospective cohort study included 372 singleton pregnancies with PAPP-A, b-hCG and AFP levels in the first trimester, which were converted to multiples of the median (MoM). The predictive ability of AFP-to-PAPP-A and AFP-to-b-hCG ratios for sPTB was evaluated. The risk for sPTB ≤34 weeks increased in women with AFP-to-PAPP-A ratio >7 (OR 2.9, 95% CI 1.2–6.4). Women with AFP-to-b-hCG ratio >0.6 had a 3.5-fold higher risk for sPTB ≤32 weeks. Increased maternal AFP-to-PAPP-A or AFP-to-b-hCG ratios in the first trimester may help to predict pregnant women at high risk for sPTB, and this may be beneficial in developing management plans. Impact Statement What is already known on this subject? There is a synergistic association between the combination of low pregnancy-associated plasma protein-A (PAPP-A) in the first trimester with alpha-fetoprotein (AFP) in the second trimester with subsequent development of PTB. Maternal serum biochemical markers measured as a part of aneuploidy screening are reflective of pregnancy adverse outcomes related with placental insufficiency. PAPP-A and AFP have a low predictive ability to determine women at high risk for preterm birth. What do the results of this study add? Elevated AFP:PAPP-A or AFP:B-HCG ratio in the first trimester is associated with increased risk for sPTB. The ratios of these biochemical markers in the first trimester may be beneficial to identify women at high risk for sPTB. What are the implications of these findings for clinical practice and/or further research? The ratios may predict pregnant women at high risk for sPTB, and such risk may be helpful in the development of a management plan. Incorporation of AFP:PAPP-A or AFP:B-HCG ratios in the first trimester may help to improve the screening efficacies, and provide a simple alternative tool.

Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia

BackgroundAbnormal levels of maternal biochemical markers used in multiple marker aneuploidy screening have been associated with adverse pregnancy outcomes. This study aims to assess if a combination of maternal characteristics and biochemical markers in the first and second trimesters can be used to screen for preeclampsia (PE). The secondary aim was to assess this combination in identifying pregnancies at risk for gestational hypertension and preterm birth.MethodsThis case-control study used information on maternal characteristics and residual blood samples from pregnant women who have undergone multiple marker aneuploidy screening. The median multiple of the median (MoM) of first and second trimester biochemical markers in cases (women with PE, gestational hypertension and preterm birth) and controls were compared. Biochemical markers included pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), human chorionic gonadotropin (hCG), alpha feto-protein (AFP), unconjugated estriol (uE3) and Inhibin A. Logistic regression analysis was used to estimate screening performance using different marker combinations. Screening performance was defined as detection rate (DR) and false positive rate (FPR). Preterm and early-onset preeclampsia PE were defined as women with PE who delivered at < 37 and < 34 weeks of gestation, respectively.ResultsThere were 147 pregnancies with PE (81 term, 49 preterm and 17 early-onset), 295 with gestational hypertension, and 166 preterm birth. Compared to controls, PE cases had significantly lower median MoM of PAPP-A (0.77 vs 1.10, p < 0.0001), PlGF (0.76 vs 1.01, p < 0.0001) and free-β hCG (0.81 vs. 0.98, p < 0.001) in the first trimester along with PAPP-A (0.82 vs 0.99, p < 0.01) and PlGF (0.75 vs 1.02, p < 0.0001) in the second trimester. The lowest first trimester PAPP-A, PlGF and free β-hCG were seen in those with preterm and early-onset PE. At a 20% FPR, 67% of preterm and 76% of early-onset PE cases can be predicted using a combination of maternal characteristics with PAPP-A and PlGF in the first trimester. The corresponding DR was 58% for gestational hypertension and 36% for preterm birth cases.ConclusionsMaternal characteristics with first trimester PAPP-A and PlGF measured for aneuploidy screening provided reasonable accuracy in identifying women at risk of developing early onset PE, allowing triage of high-risk women for further investigation and risk-reducing therapy. This combination was less accurate in predicting women who have gestational hypertension or preterm birth.

Low first trimester maternal serum PAPP-A concentrations in women with non-cavity-distorting intramural uterine fibroids.

Reliable aneuploidy risk estimation in first trimester is prominently interconnected with accurate assessment of maternal serum biomarkers. Some maternal factors like insulin-dependent diabetes, weight, and rhesus status are known to alter levels of these biomarkers. Adjustment of biomarker values for specific factor is crucial to avoid excessive invasive procedures or missed diagnoses. We aimed to investigate the effects of noncavity distorting intramural uterine fibroids on first trimester aneuploidy screening test maternal serum biomarkers. Pregnant women who underwent first trimester aneuploidy screening test in a single tertiary center between 2011 and 2020 were retrospectively assessed. One hundred ninety-eight women were found to have at least one noncavity distorting intramural uterine leiomyoma (Figo type 3-6) of at least 2cm diameter and remaining women were assigned as controls. First trimester aneuploidy screening test parameters were compared. Pregnancy associated plasma protein-A (PAPP-A) MoMs were found significantly lower in leiomyoma group in comparison to control group (1.19 ± 0.60 MoM vs. 1.40 ± 0.73 MoM, p=0.002). PAPP-A MoMs in women with leiomyomas larger than 5.5cm were significantly lower in comparison to both control group and women with ≤5.5cm leiomyomas (0.82 ± 0.376 vs. 1.40 ± 0.73, p < 0.001; 0.82 ± 0.376 vs. 1.33 ± 0.61 p < 0.001, respectively). PAPP-A MoM and size of leiomyoma were found inversely correlated when fibroid size exceeds 5.5cm (r=-0.467, p < 0.001). Noncavity distorting intramural uterine leiomyomas >5.5cm are associated with low first trimester PAPP-A MoMs (<0.5). PAPP-A concentrations are inversely correlated with fibroid size in women with >5.5cm intramural uterine leiomyomas. Fibroids ≤5.5cm are not associated with alterations in first trimester aneuploidy screening test parameters.

Prediction of Preeclampsia Using First-Trimester Uterine Artery Doppler and Pregnancy-Associated Plasma Protein-A (PAPP-A): A Prospective Study in Chhattisgarh, India

IntroductionPreeclampsia is a major contributor of maternal and perinatal morbidity and mortality. Uterine artery waveform and biomarkers like pregnancy-associated plasma protein-A (PAPP-A) may reflect the pathophysiology of preeclampsia. Thus, we aim to find out whether abnormal uterine artery pulsatility index (PI) and low serum PAPP-A in the first trimester can predict preeclampsia.MethodologyAntenatal women at 11-13+6 weeks of gestation visiting All India Institute Of Medical Science (AIIMS) in Raipur were enrolled after informed consent. Uterine artery Doppler was done with the early anomaly scan at 11-13+6 weeks. Serum levels of PAPP-A were analyzed. The women were followed up at intervals up to delivery. Incidence of preeclampsia and gestational hypertension was noted.ResultsThe incidence of preeclampsia was 12.7%, and that of gestational hypertension was 4.9%. The mean uterine artery PI among those who developed hypertension in pregnancy was 2.007, which was significantly higher than the unaffected group (p=0.01). The first-trimester uterine artery PI as a screening tool showed a sensitivity of 68%, specificity of 52.99%, and detection rate (DR) of 55.63%.The mean PAPP-A MoM of the affected group was 0.67 which was significantly higher than the unaffected group (p<0.001). The first trimester PAPP-A as a screening tool showed a sensitivity of 28%, specificity of 90.6%, and DR of 79.58%.ConclusionBoth the tests were concluded to be good predictors of hypertension in pregnancy. Identification of high-risk factors, screening, and surveillance are of utmost importance in order to predict preeclampsia and initiation of preventive therapy.

The relationship between first and second trimester biochemical parameters used to screen down syndrome and intrahepatic cholestasis of pregnancy

Objective: To assess the role of first and second-trimester screening biomarkers pregnancy-associated plasma protein-A(PAPP-A), free beta-human chorionic gonadotropin(free ß-hCG), estriol, alpha-fetoprotein and total β-hCG in the early diagnosis of intrahepatic cholestasis of pregnancy (ICP). Materials and Methods: Patients with ICP admitted to Mersin University Hospital for delivery between 2015 and 2019 and had first and second-trimester aneuploidy screening tests performed in the same facility were retrospectively assessed. Randomly 60 pregnant women without comorbid conditions during the same period were included as controls. Data regarding demographic characteristics, laboratory values including free ß-hCG and PAPP-A in first-trimester screening and total ß-hCG, estriol and alpha- fetoprotein in second-trimester screening were compared. Results: There were 46 eligible patients with ICP. In first trimester screening, it was found that PAPP-A MoM was significantly lower (0.89±0.55 vs. 1.94±0.73; p=0.035) while free ß-hCG MoM was significantly higher in ICP group when compared to controls (1.84±0.59 vs. 0.99±0.47; p=0.018). In second trimester screening, no significant difference was detected in aneuploidy markers between groups. For prediction of ICP development, first trimester free β-hCG &gt;1.44 MoM was found to have a sensitivity of 50%, a specificity of 80% and positive and negative predictive values of 33% and 88.9% respectively. Similarly first trimester PAPP-A values &lt;1.075 MoM was found to have 80% and 75% sensitivity and specificity with positive and negative predictive values of 75% and 44% respectively. Conclusion: Low PAPP-A MoM value and elevated free ß-hCG in first trimester seem to be associated with ICP development.

Can first trimester pregnancy-associated plasma protein-A predict the surfactant needs of preterm neonates?

Low values of pregnancy associated plasma protein A (PAPP-A), have been shown to be associated with some poor gestational outcomes, especially those related to placental deficiency such as pre-eclampsia and fetal growth restriction as well as preterm labor. The aim of this study was to compare first trimester PAPP-A MoM values with the surfactant needs of newborns of pregnant women who had a preterm delivery. This study included 216 pregnant women who had a preterm delivery, who were found to be in the low-risk group based on their aneuploidy screening. The women were separated into two groups based on the surfactant receipts of their newborns. A record was made of the obstetric history, birth characteristics of the preterm infants, and whether or not there was a need for surfactant. A comparison of the PAPP-A values of the two groups revealed that the group that received surfactant had statistically significantly lower PAPP-A values (t(-3.97) = 0.203, p < 0.001). When the cut-off value of PAPP-A was taken as 1 MoM and the gestational age was analyzed together with the birth weight, PAPP-A alone was found to be a significant independent variable for the prediction of respiratory distress syndrome (RDS) (p = 0.031; OR:8.2 (1.2-55.6)). The result of this study demonstrated that PAPP-A MoM values may be significant in predicting the need for surfactant in RDS, which is a frequently seen condition in the neonatal period.

Low First Trimester Pregnancy-Associated Plasma Protein-A Levels Are Not Associated with an Increased Risk of Intrapartum Fetal Compromise or Adverse Neonatal Outcomes: A Retrospective Cohort Study.

The aim of this study was to assess if women with a low first trimester maternal pregnancy-associated plasma protein-A (PAPP-A) level are at increased risk of emergency cesarean (EmCS) for intrapartum fetal compromise (IFC) and/or adverse neonatal outcomes. This was a retrospective cohort study performed at Mater Mother’s Hospital, Brisbane, Australia, between 2016 and 2018. All women with a singleton, euploid, non-anomalous fetus with a documented PAPP-A level measured between 10 +0 and 13 +6 weeks gestation during the study period were included. Data were extracted from the institution’s perinatal database and dichotomized according to PAPP-A level (≤0.4 Multiples of Medium (MoM) vs. >0.4 MoM). The primary outcomes were EmCS-IFC and a composite of severe adverse neonatal outcomes (SCNO). Nine thousand sixty-one pregnancies were included, 3.3% with a PAPP-A ≤ 0.4 MoM. Low maternal PAPP-A was not associated with an increased risk of EmCS-IFC (adjusted odds ratio (aOR) 0.77, 95% confidence interval (CI) 0.24–2.46, p = 0.66) or SCNO (aOR 0.65, 95% CI 0.39–1.07, p = 0.09). Low PAPP-A was associated with increased odds of pre-eclampsia, preterm birth and birthweight < 10th centile. In conclusion, low maternal PAPP-A level is not associated with an increased risk of EmCS IFC or adverse neonatal outcomes despite greater odds of low-birthweight infants and preterm birth.

First trimester PAPP-A serum levels and long-term metabolic outcome of mothers and their offspring

Low maternal serum levels of pregnancy associated plasma protein A (PAPP-A) are known to be associated with the development of pregnancy-related complications like small for gestational age infants, intrauterine fetal demise, gestational diabetes and preeclampsia. The study aims to find possible long-term correlations with the development of metabolic and cardiovascular complications in the mothers and their progeny in later life. This is a retrospective cohort study conducted on consecutive unselected women screened for chromosomal anomalies in the first trimester of pregnancy between 2004 and 2010. PAPP-A values as well as clinical data collected at childbirth were considered. A maternal and neonatal follow-up was performed through a telephone interview with the mother during 2015. The body-mass-index and the presence of cardiovascular diseases, dyslipidaemia and diabetes mellitus were evaluated. The analysis included 988 patients. The median time of follow-up was 7 years (IQR 6–9). Lower first trimester maternal blood PAPP-A quartiles were associated with small stature of the offspring (z-score 1st-2nd quartile 0.37 IQR −0.42 and 1.17 vs 3rd-4th quartile 0.67 IQR −0.17 and 1.36, p < 0.05). Furthermore, low first trimester PAPP-A in pregnancy without other gestations following the index one, in Kaplan-Meier analysis was associated to a significant increase of hypoglycemic agents use at 7 and 10 years (respectively 1.12% CI.95 0–2.38% and 5.45% CI.95 0–10.82%) compared to the control group of high first trimester PAPP-A values (0% CI.95 0–0%) (p < 0.05). Low PAPP-A serum levels in the first trimester of pregnancy are associated with short stature in offspring and de-novo development of maternal diabetes mellitus in later life.

The utility of pregnancy associated plasma protein-A MoM values in prediction of term respiratory distress syndrome

This study aimed to investigate if the pregnancy associated plasma Protein-A (PAPP-A) multiples of median (MoM) levels could be used as a marker for the early prediction of RDS. The present study was designed with data gathered from 1773 patients who were referred to our institution for first trimester fetal chromosomal anomaly screening. First trimester PAPP-A MoM values and postnatal RDS occurrences in these pregnancies were retrospectively analysed. Of the 1773 neonates that were included in the study, 28 were delivered at or beyond 37 weeks, and 42 were delivered less than 37 weeks of gestation. In the group of neonates at or beyond 37 weeks, the cut-off value for RDS prediction was determined as 1.02. For this cut-off value, sensitivity was 72.41% and specificity was 91.84%. The area under curve (AUC) was determined to be statistically significant (p < .01). In conclusion, it was determined that in neonates that were delivered at or beyond 37 weeks of gestation, RDS occurrence could be predicted at a significant rate by utilising PAPP-A MoM values.IMPACT STATEMENTWhat is already known on this subject? Respiratory distress syndrome (RDS) is one of the major global healthcare problems, and continues to effect newborns despite the improvements in diagnosis and treatments of the disease. Studies have shown that pregnancy associated plasma protein-A (PAPP-A) has a critical role in cellular proliferation and differentiation, and it is closely associated with many physiological and pathological processes via regulation of local insulin like growth factor (IGF) concentrations. In majority of the past studies in the literature regarding PAPP-A values in pregnancies, the association between low values of PAPP-A MoM and maternal-fetal complications were investigated.What do the results of this study add? This study retrospectively examines the PAPP-A MoM levels and the occurence of RDS. In neonates that were delivered at or beyond 37 weeks of gestation, RDS occurrence could be predicted at a significant rate by utilising PAPP-A MoM values which was measured at the first trimester fetal anomaly screening test.What are the implications of these findings for clinical practice and/or further research? In the light of these findings, in order to reduce RDS related neonatal morbidity and mortality, pregnancies with PAPP-A MoM values greater than 1.02 at the first trimester fetal anomaly screening should be more closely followed up and a higher rate of suspicion should be kept for RDS occurrence.

First trimester prenatal screening biomarkers and gestational diabetes mellitus: A systematic review and meta-analysis.

Biomarkers commonly assessed in prenatal screening have been associated with a number of adverse perinatal and birth outcomes. However, it is not clear whether first trimester measurements of prenatal screening biomarkers are associated with subsequent risk of gestational diabetes mellitus (GDM). We aimed to systematically review and statistically summarize studies assessing the relationship between first trimester prenatal screening biomarker levels and GDM development. We comprehensively searched PubMed/MEDLINE, EMBASE, CINAHL, and Scopus (from inception through January 2018) and manually searched the reference lists of all relevant articles. We included original, published, observational studies examining the association of first trimester pregnancy associated plasma protein-A (PAPP-A) and/or free β-human chorionic gonadotropin (free β-hCG) levels with GDM diagnosis. Mean differences were calculated comparing PAPP-A and free β-hCG multiples of median (MoM) levels between women who developed GDM and those who did not and were subsequently pooled using two-sided random-effects models. Our meta-analysis of 13 studies on PAPP-A and nine studies on free β-hCG indicated that first trimester MoM levels for both biomarkers were lower in women who later developed GDM compared to women who remained normoglycemic throughout pregnancy (MD -0.17; 95% CI -0.24, -0.10; MD -0.04; 95% CI -0.07–0.01). There was no evidence for between-study heterogeneity among studies on free β-hCG (I2 = 0%). A high level of between-study heterogeneity was detected among the studies reporting on PAPP-A (I2 = 90%), but was reduced after stratifying by geographic location, biomarker assay method, and timing of GDM diagnosis. Our meta-analysis indicates that women who are diagnosed with GDM have lower first trimester levels of both PAPP-A and free β-hCG than women who remain normoglycemic throughout pregnancy. Further assessment of the predictive capacity of these biomarkers within large, diverse populations is needed.

Is pregnancy associated plasma protein-A (PAPP-A) a marker for adverse perinatal outcomes in preterm isolated oligohydramnios cases?

ObjectiveIsolated oligohydramnios is defined as an amniotic fluid index below five centimeter with no other coexisting condition. There are still controversies about the management and pregnancy outcomes. A marker predicting these is crucial. Low pregnancy associated plasma protein-A levels were reported to be related with adverse pregnancy outcomes. We aimed to determine the role of first trimester pregnancy associated plasma protein-A for poor outcomes in preterm isolated oligohydramnios cases. Material and MethodsFifty-one patients with singleton pregnancies diagnosed as isolated oligohydramnios at 28/0–36/6 weeks of gestation and 110 gestational age matched healthy controls between January and December 2015 were included. Maternal age, gestational age at delivery, mode of delivery, indication for cesarean section, Apgar scores at first and fifth minutes, birth weight, neonatal intensive care unit admission and mortality were recorded. Pregnancy associated plasma protein-A levels were compared between groups and its role in adverse perinatal outcomes was evaluated. ResultsPregnancy associated plasma protein-A levels and pregnancy outcomes were similar in two groups (p > 0.050) except birth weight, gestational age at delivery and presence of fetal distress. Pregnancy associated plasma protein-A levels did not differ in terms of delivery mode, presence of fetal distress, first and fifth minutes Apgar scores and neonatal intensive care unit admission (p = 0.323,0.650,0.990,0.112,0.853). Also, it was not determined as a risk factor for cesarean section, presence of fetal distress, low Apgar scores and neonatal intensive care unit admission. ConclusionPregnancy associated plasma protein-A, a well-known prognostic factor for some of high risk pregnancy conditions, may not be used as a marker in preterm isolated oligohydramnios cases.

Does Low PAPP-A Predict Adverse Placenta-Mediated Outcomes in a Low-Risk Nulliparous Population? the Great Obstetrical Syndromes (GOS) Study.

First-trimester low concentration of pregnancy-associated plasma protein A (PAPP-A) has been associated with adverse perinatal outcomes in high-risk populations. This study aimed to estimate the ability of PAPP-A to identify adverse outcomes in a low-risk population. The study investigators recruited nulliparous women with singleton pregnancy at their 11-13-week ultrasound scan. Serum samples were collected, and maternal PAPP-A concentration was measured using the B⋅R⋅A⋅H⋅M⋅S PAPP-A KRYPTOR (ThermoFisher Scientific, Hennigsdorf, Germany) automated assay. PAPP-A was reported in multiple of median (MoM) adjusted for GA. Participants were followed until delivery for pregnancy outcomes including preeclampsia (PE), SGA <3rd percentile, and fetal death. Receiver operating characteristic curves with the area under the curve (AUC) were used to evaluate the predictive value of PAPP-A. The investigators calculated the detection rates (DRs) and positive predictive values (PPVs) of a PAPP-A < 0.4 MoM. The study investigators recruited 4739 eligible participants at a mean GA of 13 ± 6 weeks. The investigators observed 232 (4.9%) cases of PE, 84 (1.8%) cases of SGA, and 14 (0.3%) fetal deaths. PAPP-A was moderately associated with PE (AUC 0.57; 95% CI 0.53-0.61) and SGA (AUC 0.62; 95% CI 0.56-0.69), but not with fetal death (AUC 0.43; 95% CI 0.23-0.63). PAPP-A < 0.4 MoM was observed in 364 (7.7%) participants and had poor predictive values for PE (DR 9.8%; PPV 6.3%), SGA (DR 18.1%; PPV 4.4%), and fetal death (DR 21.4%; PPV 0.9%). Isolated first trimester PAPP-A has a limited predictive value for adverse pregnancy outcomes (other than trisomies). Low PAPP-A (<0.4 MoM) should be used in combination with other markers for the prediction of PE, SGA, or fetal death, and it does not constitute an indication for low-dose aspirin.

Performance of first trimester biochemical markers and mean arterial pressure in prediction of early-onset pre-eclampsia

ObjectiveTo develop a predictive risk model for early-onset pre-eclampsia (EO-PE) using maternal characteristics, combined screening markers, previously reported biomarkers for PE and mean arterial pressure (MAP). MethodsThis retrospective study was conducted at Oulu University hospital between 2006 and 2010. Maternal serum from first trimester combined screening was further analyzed for alpha fetoprotein (AFP), placental growth factor (PlGF), soluble tumor necrosis factor receptor-1 (sTNFR1), retinol binding protein-4 (RBP4), a disintegrin and metalloprotease-12 (ADAM12), soluble P-selectin (sP-selectin), follistatin like-3 (FSTL3), adiponectin, angiopoietin-2 (Ang-2) and sex hormone binding globulin (SHBG). First, the training sample set with 29 cases of EO-PE and 652 controls was developed to study whether these biomarkers separately or in combination with prior risk (maternal characteristics, first trimester pregnancy associated plasma protein-A (PAPP-A) and free beta human chorionic gonadotrophin (fβ-hCG)) could be used to predict the development of EO-PE. Second, the developed risk models were validated with a test sample set of 42 EO-PE and 141 control subjects. For the test set MAP data was also available. ResultsSingle marker statistically significant (ANOVA p<0.05) changes between control and EO-PE pregnancies were observed with AFP, RBP4 and sTNFR1 with both training and test sample sets. Based on the test sample set performances, the best detection rate, 47% for a 10% false positive rate, was achieved with PlGF and sTNFR1 added with prior risk and MAP. ConclusionBased on our results, the best first trimester biomarkers to predict the subsequent EO-PE were AFP, PlGF, RBP4 and sTNFR1. The risk models that performed best for the prediction of EO-PE included prior risk, MAP, sTNFR1 and AFP or PlGF or RBP4.

First trimester maternal serum analytes and second trimester uterine artery Doppler in the prediction of preeclampsia and fetal growth restriction

ObjectiveThis study aimed to determine whether pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG), a disintegrin and metalloprotease 12 (ADAM12), and placenta protein 13 (PP13) in the first trimester, and uterine artery Doppler (UAD) in the second trimester, predict preeclampsia and fetal growth restriction (FGR). Materials and methodsMaternal serum levels of PAPP-A, free β-hCG, ADAM12, and PP13 at 11–13+6 weeks of gestation and bilateral uterine artery pulsatility index (PI) at 22–24 weeks of gestation were measured in a nested case–control study within a prospective cohort. The serum analytes and Doppler measurements were compared for uncomplicated pregnancies and pregnancies complicated by preeclampsia and FGR. The efficacy of biochemical and Doppler measurements for the prediction of preelampsia and FGR was investigated. ResultsCompared with gestational age-matched controls (n = 200), the mean PAPP-A and ADAM12 were lower (P < 0.001, P < 0.05) in pregnancies complicated by preeclampsia (n = 462) and FGR (n = 350). The median uterine artery mean PI was higher (P < 0.001) in preeclampsia and FGR groups. However, the median free β-hCG and PP13 were not significantly different from normal (P > 0.05). In screening for preeclampsia and FGR, assuming a fixed false positive rate (FPR) of 10%, the detection rates were 72% and 68% for a combination of PAPP-A, ADAM12, and UAD, respectively. ConclusionFirst trimester PAPP-A and ADAM12 levels and second trimester uterine artery PI are associated with adverse pregnancy outcomes. The combination of biochemical markers and UAD improves the screening efficiency for the prediction of preeclampsia and FGR.

Association of serum PAPP-A levels in first trimester with small for gestational age and adverse pregnancy outcomes: systematic review and meta-analysis.

To determine association, and predictive ability, of first trimester maternal serum pregnancy associated plasma protein A (PAPP-A) with adverse pregnancy outcomes. Searches of Medline, Embase and CINAHL (inception September 2015) for studies including pregnant women with first trimester PAPP-A and assessment of pregnancy outcomes. Study characteristics, quality and results extracted. Meta-analysis of odds ratios (ORs), and likelihood ratios (LRs) and 95% confidence intervals (CI). Thirty-two studies including 175 240 pregnancies. PAPP-A <5th centile had a moderate association with: birth weight <10th centile OR 2.08 (95% CI 1.89-2.29), <5th centile OR 2.83 (95% CI 2.52-3.18); pre-eclampsia OR 1.94 (95% CI 1.63-2.30), preterm birth <37 weeks OR 2.09 (95% CI 1.87-2.33), and composite adverse outcome OR 3.31 (95% CI 1.80-5.11). The predictive ability was poor: Birth weight <10th centile LR + ve 1.96 (95% CI 1.58-2.43), LR-ve 0.93 (95% CI 0.89-0.98); birth weight <5th centile LR + ve 2.65 (95% CI 2.35-2.99), LR-ve 0.85 (95% CI 0.74-0.98); PTB <37 weeks LR + ve 1.84 (95% CI 1.41-2.39), LR-ve 0.92 (95% CI 0.87-0.98). First trimester low maternal serum PAPP-A is associated with adverse pregnancy outcome, but predictive values are poor. Further work should address PAPP-A as a continuous variable in combination with other prognostic markers as a prediction model. © 2016 John Wiley & Sons, Ltd.

The utility of first trimester uterine artery Doppler, placental volume and PAPP-A levels alone and in combination to predict preeclampsia.

In this study, we aimed to evaluate the detection of pre-eclampsia (PE) by integrating uterine artery Doppler, placental volume, and pregnancy-associated plasma protein A (PAPP-A) levels in the first trimester. We prospectively recruited 602 women that underwent 11-13weeks' aneuploidy screening. The mean pulsatility index (PI) of the uterine arteries and the placental volume were measured by ultrasonography. Measurement of PAPP-A levels has been performed at the same day of ultrasonographic examinations. The 90th percentile of uterine artery PI and the 10th percentile of placental volume and PAPP-A levels were used as cut-offs. Uterine artery PI, placental volume, and PAPP-A levels had similar sensitivities in predicting PE (53.66%, 63.41%, and 70.73%, respectively). Use of the parameters in combination had better sensitivity. If one parameter was positive, the sensitivity was 92.68% with 85.20% specificity. If at least two parameters were positive, the sensitivity was 85.37% with 98.89% specificity. In conclusion, the combination of increased PI of uterine artery with low placental volume and low PAPP-A levels in the first trimester achieved better results than either test alone in the prediction of PE.