Analysis of Predictive Information From Biomarkers Added to Clinical Models of Preeclampsia: Consideration of PAPP-A2, Activin A, and sFlt-1:PlGF Ratio.

BACKGROUND: Preeclampsia remains a major cause of maternal and fetal adverse outcomes in pregnancy; however, accurate and universally acceptable predictive tools remain elusive. We investigated whether a panel of biomarkers could improve risk prediction for preeclampsia when measured at various pregnancy time points. METHODS: In this prospective cohort study, 192 women with first-trimester high-risk singleton pregnancies were consecutively recruited from tertiary obstetrics clinics in Montréal, Canada. Clinical information (height, pre-pregnancy weight, personal and family medical history, medication use) was collected at baseline. Blood pressure was measured and blood samples collected at each trimester to quantify soluble Fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), pregnancy-associated plasma protein A2 (PAPP-A2), PAPP-A, activin A, inhibin A, follistatin, and glycosylated fibronectin. A random-effects hierarchic logistic regression model was used to relate change in biomarker levels to incidence of preeclampsia. RESULTS: When added to a clinical model composed of maternal age, pre-pregnancy body mass index, race, and mean arterial pressure, a positive third-trimester result for both PAPP-A2 and activin A had a better positive predictive value than the sFlt-1:PlGF ratio added to the clinical model (91.67% [95% confidence interval (CI) 78.57%-100%] vs 66.67% [57.14%-100%]), while maintaining a comparable high negative predictive value (97.69% [95% CI 95.34%-100%] vs 96.00% [92.19%-99.21%]). CONCLUSIONS: Whereas the third-trimester sFlt-1:PlGF ratio can predict short-term absence of preeclampsia, PAPP-A2 and activin A had both high positive and negative predictive values and therefore could serve as biomarkers to predict the occurrence (and absence) of preeclampsia; these findings will be validated in future studies.

Biomarkers for Early Prediction and Management of Preeclampsia: A Comprehensive Review.

Preeclampsia is a common complication of pregnancy. It is a multi-organ disorder that remains one of the main causes of maternal morbidity and mortality. Additionally, preeclampsia leads to many complications that can occur in the fetus or newborn. Preeclampsia occurs in about 1 in 20 pregnant women. This review focuses on the prediction of preeclampsia in women, using various biomarkers, in particular, a factor combining the use of soluble FMS-like tyrosinokinase-1 (sFlt-1) and placental growth factor (PlGF). A low value of the sFlt-1/PlGF ratio rules out the occurrence of preeclampsia within 4 weeks of the test result, and its high value predicts the occurrence of preeclampsia within even 1 week. The review also highlights other factors, such as pregnancy-associated plasma protein A, placental protein 13, disintegrin and metalloprotease 12, ß-human chorionic gonadotropin, inhibin-A, soluble endoglin, nitric oxide, and growth differentiation factor 15. Biomarker testing offers reliable and cost-effective screening methods for early detection, prognosis, and monitoring of preeclampsia. Early diagnosis in groups of women at high risk for preeclampsia allows for quick intervention, preventing the undesirable effects of preeclampsia. However, further research is needed to validate and optimize the use of biomarkers for more accurate prediction and diagnosis. This article aims to review the role of biomarkers, including the sFlt1/PlGF ratio, in the prognosis and management of preeclampsia.

The role of second trimester uterine artery Doppler in predicting obstetric and neonatal outcomes in abnormal first trimester maternal serum pregnancy-associated plasma protein-A and free ß-human chorionic gonadotropin values.

AIM: This study aims to determine whether second-trimester uterine artery (UtA) Doppler combined with first-trimester abnormal pregnancy-associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-Hcg) levels predicts adverse obstetric and neonatal outcomes. MATERIALS AND METHODS: This study of 289 pregnant women included 196 with normal PAPP-A and free ß-HCG values (control group) and 93 with abnormal values (study group) in the first-trimester screening test. Second-trimester UtA Doppler sonography was done in these pregnancies. The perinatal prediction and screening potential of UtA Doppler pulsatility index (PI) parameters were examined in the study group. RESULTS: UtA PI >95 percentile increased birth before the 37th week by 4.46 times, birth before the 34th week by 7.44 times, preeclampsia risk by 3.25 times, fetal growth restriction (FGR) risk by 4.89 times, and neonatal intensive care unit (NICU) admission rates by 3.66 times in the study group (p < 0.05 for all). UtA PI >95 percentile had 49.2% sensitivity and 82.1% specificity for birth before 37 weeks. For birth before 34 weeks, sensitivity was 80.0% and specificity 65.0%. FGR has 70.5% sensitivity and 67.1% specificity. Screening for preeclampsia has 66.6% sensitivity and 61.9% specificity. CONCLUSION: Adding UtA Doppler in the second trimester to pregnancies with abnormal PAPP-A and/or free ß-Hcg values in the first trimester may be a useful screening method for adverse outcomes.

Investigation of cardiovascular risk parameters in adolescents with metabolic syndrome.

BACKGROUND: Metabolic syndrome leading to type 2 diabetes mellitus and cardiovascular diseases is a chronic multifactorial syndrome, associated with low-grade inflammation status. In our study, we aimed at assessing the serum levels of follistatin (FST), pregnancy-associated plasma protein-A (PAPP-A), and platelet/endothelial cell adhesion molecule-1 (PECAM-1) in adolescent patients with metabolic syndrome. METHODS: This study was performed in 43 (19 males, 24 females) metabolic syndrome adolescents and 37 lean controls matched for age and sex. The serum levels of FST, PECAM-1, and PAPP-A were measured by using ELISA method. RESULTS: Serum FST and PAPP-A levels in metabolic syndrome were significantly higher than those of controls (p < 0.005 and p < 0.05). However, there was no difference in serum PECAM-1 levels between metabolic syndrome and control groups (p = 0.927). There was a significant positive correlation between serum FST and triglyceride (r = 0.252; p < 0.05), and PAPP-A and weight, (r = 0.252; p < 0.05) in metabolic syndrome groups. Follistatin was determined statistically significant in both univariate (p = 0,008) and multivariate (p = 0,011) logistic regression analysis. CONCLUSIONS: Our findings indicated a significant relationship between FST and PAPP-A levels and metabolic syndrome. These findings offer the possibility of using these markers in diagnosis of metabolic syndrome in adolescents as the prevention of the future complications.

Value Analysis of Four-Dimensional Color Ultrasound Combined with Maternal Serological Index in Prenatal Screening for Fetal Anomalies.

Objective: This study aimed to assess the efficacy of combining four-dimensional (4D) color ultrasound with maternal serological index testing in prenatal screening for fetal anomalies. Methods: A retrospective analysis was conducted on data from 864 pregnant women who underwent prenatal checkups at the hospital between January 2020 and January 2021. During the mid-pregnancy period, serological tests were performed to determine levels of alpha-fetoprotein (AFP), free ß-subunit of human chorionic gonadotropin (Free-HCG ß), pregnancy-associated plasma protein A (PAPP-A), and vitamin B12 (VitB12). Additionally, 4D color ultrasound examinations were conducted. The gold standard for evaluation was the results of delivery or labor induction. AFP, Free-HCG ß, PAPP-A, and VitB12 levels were compared between the anomaly group and the normal group. The diagnostic efficacy of single and combined detection of serological indexes and 4D color ultrasound was analyzed, with the calculation of the areas under the curve (AUC) for different detection methods. Results: Among the 864 pregnant women, 44 cases (5.09%) exhibited fetal anomalies, while 820 cases (94.91%) did not. The anomaly group showed significantly higher multiples of the median (MOM) values for AFP and Free-HCG ß (P < .001) and significantly lower PAPP-A MOM and VitB12 levels (P < .001) compared to the normal group. The sensitivity of single detections for AFP MOM, Free-HCG ß MOM, PAPP-A MOM, VitB12, 4D color ultrasound, and combined detection were 63.64%, 68.18%, 65.91%, 54.55%, 77.27%, and 97.93%, respectively. The corresponding AUC values were 0.805, 0.829, 0.818, 0.761, 0.885, and 0.974. Conclusions: The combination of 4D color ultrasound with maternal serological index testing demonstrated high sensitivity in prenatal screening for fetal anomalies.

Clinical Application of a Graphene Oxide-Based Surface Plasmon Resonance Biosensor to Measure First-Trimester Serum Pregnancy-Associated Plasma Protein-A/A2 Ratio to Predict Preeclampsia.

Background: Preeclampsia, a major cause of adverse pregnancy outcomes, involves metalloproteinases pregnancy-associated plasma protein (PAPP)-A and PAPP-A2 from placental trophoblasts. The graphene oxide (GO)-based surface plasmon resonance (SPR) biosensor has higher sensitivity, affinity, and selective ability than the traditional SPR biosensor. The aim of this study was to explore the feasibility of measuring first-trimester serum PAPP-A/PAPP-A2 ratio as a novel predictor of preeclampsia using the GO-SPR biosensor. Methods: This prospective case-control study of pregnant women was conducted at MacKay Memorial Hospital, Taipei, Taiwan between January 2018 and June 2020. The SPR angle shifts of first-trimester serum PAPP-A, PAPP-A2, and PAPP-A/PAPP-A2 ratio measured using the GO-SPR biosensor were compared between preeclampsia and control groups. Results: Serum samples from 185 pregnant women were collected, of whom 30 had preeclampsia (5 early-onset; 25 late-onset). The response time between the antibody-antigen association and dissociation only took about 200 seconds. The SPR angle shift of PAPP-A in the preeclampsia group was significantly smaller than that in the control group (median (interquartile range): 5.33 (4.55) versus 6.89 (4.10) millidegrees (mDeg), P = 0.008). Conversely, the SPR angle shift of PAPP-A2 in the preeclampsia group was significantly larger than that in the control group (5.70 (3.81) versus 3.63 (2.38) mDeg, P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict all preeclampsia of ≤ 0.76, with an area under the ROC curve (AUC) of 0.79 (95% CI 0.73-0.85, P < 0.001). Sub-group analysis revealed a cut-off PAPP-A/PAPP-A2 ratio to predict early-onset preeclampsia of ≤ 0.53 (AUC 0.99, 95% CI 0.96-1.00, P < 0.001), and ≤ 0.73 to predict late-onset preeclampsia (AUC 0.75, 95% CI 0.68-0.81, P < 0.001). Conclusion: Measuring first-trimester serum PAPP-A/PAPP-A2 ratio using the GO-SPR biosensor could be a valuable method for early prediction of preeclampsia.

Correlation between PAPP-A serum levels in the first trimester of pregnancy with the occurrence of gestational diabetes, a multicenter cohort study.

OBJECTIVE: This study aimed to investigate the association between first-trimester Pregnancy-associated plasma protein A (PAPP-A) levels and subsequent gestational diabetes mellitus (GDM) development. METHOD: The study was conducted on 5854 pregnant women who attended routine prenatal care. Maternal biomarkers, including PAPP-A and free beta hCG, were measured for all women in a referral laboratory and converted to MoM values. Pregnant women were divided into two groups, based on the serum concentration of PAPP-A, (PAPP-A > 0.4 (normal) and PAPP-A < 0.4 (low)). Data on the screening test for GDM and pregnancy outcomes were collected and analyzed with appropriate tests. RESULT: Of the 5854 pregnant women, 889 (15.19%) developed GDM. The maternal PAPP-A MoM concentrations were significantly lower in GDM cases compared to controls. Indeed, gestational age at delivery and birth weight were significantly lower (p < 0.001) in PAPP-A MoM < 0.4, and the rate of intrauterine growth restriction (IUGR) was significantly higher (p < 0.001). ROC analysis revealed that the sensitivity and specificity of MoM concentration for predicting GDM were 53.3% and 51.9%, respectively. CONCLUSION: Lower maternal PAPP-A in early pregnancy can lead to glucose intolerance and increase the risk of subsequent GDM development. In addition, decreased serum concentration of PAPP-A is significantly correlated to lower birth weight and IUGR.

A new contingent screening strategy increased detection rate of trisomy 21 in the first trimester.

BACKGROUND: Although the traditional contingent screening strategy is effective, there are still undetected low-risk trisomy 21. This study aims to define appropriate cut-off values of serum biochemical markers at low-risk and develop a strategy for sequential prenatal testing associated with first-trimester screening to increase the detection rate of trisomy 21. METHODS: This was a 9-year retrospective analysis of singleton pregnant women who underwent serum biochemical screening or combined first-trimester screening (CFTS) in the first trimester. For the low-risk group, the cut-off values of the serum biochemical markers were adjusted to determine the appropriate detection efficiency. Gravidas with abnormal serum biochemical markers at low-risk were advised to undergo further non-invasive prenatal screening (NIPS), whereas others continued with routine prenatal care. RESULTS: When cut-off values of free beta subunit of human chorionic gonadotropin (free ß-hCG) multiples of the median (MoM) or pregnancy-associated plasma protein A (PAPP-A) MoM were defined with ≥ 2.75 or ≤ 0.5, 7.72% (2,194/28,405) in the serum biochemical screening group and 12.36% (4,005/32,403) in CFTS group could be detected as abnormal results for further NIPS. Finally, 55.56% (5/9) and 85.71% (6/7) of trisomy 21 cases with false-negative results were detected, and the overall detection rate for trisomy 21 was improved by 10.64% (5/47) and 12.77% (6/47), respectively. CONCLUSIONS: The new contingent screening strategy can increase the detection rate of trisomy 21 compared with the traditional contingent screening strategy.

Meta-analysis for the relationship between circulating pregnancy-associated plasma protein A and placenta accreta spectrum.

BACKGROUND: Changes in circulating pregnancy-associated plasma protein A (PAPP-A) have been observed in women with a placenta accreta spectrum (PAS). However, no consensus has been reached according to the previous studies. Our study investigated the relationship between circulating PAPP-A and PAS risk through a systematic review and meta-analysis. METHODS: Studies comparing the circulating level of PAPP-A between pregnant women with and without PAS were obtained by searching the Medline, Cochrane Library, Embase, CNKI, and Wanfang databases from the inception of the databases until February 12, 2023. Heterogeneity was considered in the pooling of results via a random-effects model. RESULTS: Eight observational studies were obtained for the meta-analysis, which included 243 pregnant women with PAS and 1599 pregnant women without PAS. For all these women, the first-trimester circulating level of PAPP-A was measured by immunoassay and reported as multiples of the median (MoM) values. The pooled results showed that compared to those who did not develop PAS, women with PAS had significantly higher first-trimester serum level PAPP-A (mean difference: 0.43 MoM, 95% confidence interval [CI]: 0.30 to 0.56, P < .001; I2 = 32%). Furthermore, a high first-trimester serum PAPP-A level was related to a high PAS risk (odds ratio: 2.89, 95% CI: 2.13 to 3.92, P < .001; I2 = 0%). Sensitivity analysis which excluded one study at a time, also obtained similar results (p all < 0.05). CONCLUSION: Pregnant women with a high serum PAPP-A level in the first trimester may be at an increased risk for PAS.

Elevated first-trimester PAPP-A is a marker in high-risk pregnancies with an increased risk of placenta accreta in predicting adverse outcomes.

OBJECTIVE: Our work aims to determine whether there is an association between first-trimester serum pregnancy-associated plasma protein A (PAPP-A) multiples of the median (MoM) value and placenta previa with or without placenta accreta spectrum disorders (PAS) in women. PATIENTS AND METHODS: A retrospective analysis was performed on 267 patients who had first-trimester screening test results for aneuploidy, including nonadherent placenta previa (n=106), placenta previa with PAS (n=60), and control group (healthy pregnant women with previous cesarean section and normal placental location, n=101). To assess the significant difference between these groups, PAPP-A MoMs were compared. RESULTS: The median PAPP-A MoM of 1.96 in placenta previa with PAS was significant (>0.88) in nonadherent placenta previa and 0.89 in the control group (p<0.001). Serum PAPP-A was found to be significantly associated with the severity of bleeding, such that patients with severe bleeding of 1,500 mL or more (n=54) had a higher mean PAPP-A MoM (1.93±0.69; p<0.001). Furthermore, the mean PAPP-A MoM was found to be 1.96±0.74 in the hysterectomy group and 0.89±0.47 in the conservative management group, and the difference was found to be significantly higher (p<0.001). CONCLUSIONS: Elevated PAPP-A values in the first trimester of pregnancy may be a useful marker for identifying women at higher risk of PAS and adverse outcomes.

First and second-trimester biochemical serum markers in maternal familial Mediterranean fever: The impact of colchicine use.

INTRODUCTION: We aimed to investigate the effects of colchicine use on first and second trimester screening markers in pregnancies complicated with familial Mediterranean fever (FMF) and to evaluate the overall impact of these effects on perinatal outcomes. METHODS: A retrospective case-control study was conducted in pregnancies complicated with FMF using colchicine and healthy pregnancies as controls without any defined risk factors and medication use. Biochemical markers for the aneuploidy screening, including free ß-hCG and PAPP-A in the first trimester, and AFP, HCG, and unconjugated estriol (uE3) in the second trimester, were recorded, and MoM levels of these markers were compared between the FMF and control groups. Obstetric history and outcomes were also compared between groups. We used propensity score matching to form a cohort in which patients had similar baseline characteristics. RESULTS: Among 93 eligible pregnant women, 31 women in FMF group and 31 in control group had similar propensity scores and were included in the analyses. Levels of serum-free ß-hCG, PAPP-A and AFP were similar between FMF and control groups (p = 0.671, p = 0.387 and p = 0.963, respectively). For the second-trimester markers, maternal serum uE3 MoM level were significantly lower in the FMF group using colchicine than in the controls (p = 0.045). We also compared these markers according to the daily colchicine dose between FMF subgroups. We did not detect significant difference between the different colchicine treatment modalities (0.5-1 mg/day vs. 1.5-2 mg/day, p > 0.05). CONCLUSION: Maternal biochemical serum markers of an aneuploidy screening test in the second trimester may be affected by FMF with colchicine use, leading to misinterpretation of the risk level of tests. For these tests with decreased uE3 levels, FMF and colchicine use should be considered as a causative etiology after ruling out common etiologies and confounding factors before recommending invasive diagnostic testing.

First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

OBJECTIVES: Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. METHODS: Singleton pregnancies recruited at 11-14 weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. RESULTS: Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. CONCLUSIONS: First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

Combined first trimester screening for trisomy 21: Assessment of excess risk in case of free ß-human chorionic gonadotrophin between 5 and 10 multiples of the median.

OBJECTIVE: The first trimester combined risk of trisomy 21 is obtained by multiplying the risk related to maternal age by the likelihood ratios of nuchal translucency, free beta-human chorionic gonadotrophin (ß-hCG) and placenta associated plasma protein-A. Beyond five multiples of the median (MoM) of ß-hCG, the risk of trisomy 21 is truncated. The objective of the present study was to evaluate the evolution of the first trimester combined risk of trisomy 21 in individuals with first-trimester free-ß-hCG levels between 5 and 10 MoM. METHODS: We conducted a non-interventional cohort study from a 6-year database of combined first-trimester trisomy 21 screening of all individuals who underwent the screening in a French specialized medical analysis center. We included all pregnant individuals who had a serum-free ß-hCG between 5 and 10 MoM. Patients for whom the status of the fetus, with or without trisomy 21, was not identified by the outcome of the pregnancy or by a karyotype result were excluded from the study. The discriminatory capacity of free-ß-hCG above 5 MoM was studied by a receiver operating characteristic curve. We used an orthogonal polynomial regression to represent the evolution of likelihood ratios according to free-ß-hCG in MoM. RESULTS: Among 413 216 combined first-trimester screens of trisomy 21, 2239 (0.5%) screens met the inclusion criteria. In the selected population, 801 (35.8%) were excluded from the study because of missing fetal or neonatal status, and 46 (3.2%) fetuses out of 1438 included were diagnosed with trisomy 21. For free ß-hCG values between 5 and 10 MoM, the area under the curve is 0.56 (0.46-0.65). The scatterplot of the likelihood ratio of ß-hCG showed an increasing parabolic pattern: the likelihood of trisomy 21 increases with the free-ß-hCG threshold. CONCLUSION: To override the truncated risk of trisomy 21 in case of free ß-hCG values between 5 and 10 MoM, the study has allowed us to estimate the adjusted risk of trisomy 21, enabling health professionals to offer appropriate prenatal counseling.

Clinical consequences of maternal serum PAPP-A and free beta hCG levels above 2.0 multiple of median in the first trimester screening.

INTRODUCTION: Extreme levels of either PAPP-A or free ß-hCG may be a serious clinical concern. A multicentre study was carried out to determine the frequency and clinical consequences of high (minimum 2,0 MoM) maternal (PAPP)-A and free beta hCG. METHODS: A total number of 8591 patients with singleton pregnancies between 11 + 0-13 + 6 weeks of gestation were enrolled. A total number of 612 cases with first trimester serum level of PAPP-A corresponding to ≥ 2,0 MoM and/or free ß-hCG to ≥ 2,0 MoM were included in the statistical analysis. All serum samples were analysed with Roche (Cobas) or Kryptor (Brahms) devices. A retrospective analysis of perinatal outcomes was conducted. RESULTS: Values of PAPP-A ≥ 2,0 MoM and free ß-hCG < 2.0 MoM were detected in 48,5% of patients (n = 297), free ß-hCG ≥ 2,0 MoM and PAPP-A concentration < 2,0 MoM in 38,1% of patients (n = 233) and both PAPP-A and free ß-hCG ≥ 2,0 multiple of median in 13,4% of patients (n = 82). The highest PAPP-A and free ß-hCG concentrations were 19,2 MoM and 16,3 MoM respectively. Patients with both PAPP-A and free ß-hCG above 2,0 MoM had a slightly higher (but statistically not significant) prevalence of history of low birthweight (8,3%). DISCUSSION: Pregnancy outcomes in women with normal ultrasound findings and high PAPP-A /free ß-hCG concentration are good. Higher prevalence of pregnancy complications was not detected in either extremely high PAPP-A and free ß-hCG concentration groups. In cases of normal ultrasound and isolated high (even extreme) biochemical markers levels the counselling should be comforting.

The role of serum markers PAPP-A ß-hCG, AFP, and uE3 in predicting the risk of preeclampsia in early, middle, and late pregnancy.

BACKGROUND: Preeclampsia (PE) has adverse effects on pregnant women, fetuses, and newborns [1], and accounts for 3%-10% of pregnancy-related diseases globally. OBJECTIVE: This study aimed to screen a series of prenatal markers (pregnancy-associated plasma protein [PAPP-A], ß-human chorionic gonadotropin [ß-hCG], alpha fetoprotein [AFP], and estriol [uE3]) to establish a risk model and evaluate the diagnostic values of the markers for predicting PE. METHODS: Sixty-five pregnant women were enrolled in this study. They were divided into two groups containing healthy pregnant women (n= 51, the non-PE group) and pregnant women with PE (n= 14, the PE group). According to the stage of pregnancy, the pregnant women in each group were divided into early, middle, and late pregnancy groups for statistical analysis. The levels of PAPPA-A ß-hCG, AFP, and uE3 were compared among these groups. Then, a risk model was established, and PE was diagnosed using receiver operating characteristic (ROC) curve results. RESULTS: In the early pregnancy group, the differences in the levels of PAPP-A, AFP, and uE3 between the PE and non-PE groups were statistically significant (P< 0.001, P= 0.029, and P= 0.033, respectively), while the difference in the single remaining marker was not statistically significant. A ROC curve analysis revealed that in early pregnancy, the sensitivity and specificity of PAPP-A were 76.5% and 71.4%, respectively, and the sensitivity and specificity of ß-hCG were 82.4% and 57.1%, respectively. The sensitivity and specificity of the combination of the two markers for diagnosing PE were 86.3% and 57.1%, respectively. CONCLUSION: This study demonstrated that the combination of PAPP-A and ß-hCG has diagnostic value for PE in pregnant women. Accordingly, we should formulate innovative PE screening strategies to target the prevention of PE and create important conditions for predictive and preventive personalized medical treatments.

The predictive value of the first trimester combined test for gestational diabetes mellitus.

OBJECTIVES: To investigate the predictive importance of first trimester combined test markers pregnancy-associated plasma protein-A (PAPP-A), human chorionic gonadotropin ß (ß-hCG) and nuchal translucency (NT) for gestational diabetes mellitus (GDM). MATERIAL AND METHODS: Pregnant women which both first trimester combined test and GDM screening were performed during antenatal follow-up were included in this retrospective case-control study. The cases were divided into two groups as GDM screening positive and negative. Demographic, clinical and laboratory data of both groups were compared. Predictive tests were applied to the first trimester combined test data for the detection of GDM. RESULTS: A total of 378 patients, 171 (45.2%) in the control group and 207 (54.8%) in the GDM group. The age (control: 30.9 ± 5.2; GDM: 30.5 ± 5.1; p = 0.844) and NT (control: 1.254 ± 0.289; GDM: 1.319 ± 0.299; p = 0.074) data of the groups were statistically similar. MoM PAPP-A (GDM:0.967 ± 0.685; ontrol:1.191 ± 0.624; p < 0.001) and MoM f-ßhCG (GDM: 0.9 ± 0.602; control: 1.103 ± 0.746; p = 0.001) levels of the GDM group were lower than the control group. In the binary logistic regression model, MoM PAPP-A and MoM f-ßhCG variables were found to be effective on GDM. In the ROC analysis of these variables, the MoM PAPP-A (0.654) had the highest area under the curve. According to the optimum cut-off point (≤ 0.885) of the MoM PAPP-A, we found a sensitivity of 66.7% and a specificity of 65.50% for predicting GDM. CONCLUSIONS: Our study showed that serum PAPP-A and f-ßhCG MoM values, which are among the first trimester combined test parameters, can be used in the early pregnancy period for the prediction of GDM.

The impact of preimplantation genetic testing on first- and second-trimester maternal serum analyte levels.

OBJECTIVE: To determine whether preimplantation genetic testing (PGT) is associated with a change in maternal serum analyte levels in pregnancies conceived via in vitro fertilization (IVF). METHODS: Retrospective cohort of singleton and twin IVF pregnancies with available first- or second-trimester serum analyte data from 01/2014 to 09/2019. Multiple of the median (MoM) values for free ß-human chorionic gonadotropin (ß-hCG), pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), inhibin A, and unconjugated estriol, were compared between two groups: pregnancies conceived after transfer of PGT screened euploid embryos vs. those conceived after transfer of untested embryos. Multiple linear regression of log MoM values with F test was performed to adjust for potential confounders. RESULTS: Nine hundred and sixty-two singleton and 165 twin IVF pregnancies with serum analyte data available for analysis were included. PGT was associated with a higher median first- and second-trimester AFP compared to no PGT in singletons (1.23 MoM vs. 1.13 MoM; parameter estimate [PE] 1.08, 95% CI 1.00-1.17, p= .04, and 1.21 MoM vs. 1.07 MoM; PE 1.07, 95% CI 1.01-1.13, p= .01, respectively). PGT was also associated with a lower median PAPP-A compared to no PGT in twins (0.75 MoM vs. 1.18 MoM, PE 0.74, 95% CI 0.60-0.92, p= .006). CONCLUSIONS: Our data suggest that PGT is associated with higher maternal serum levels of second-trimester AFP in singleton and lower levels of first-trimester PAPP-A in twin pregnancies conceived via IVF.

The association of maternal serum biomarkers and birth weight in twin pregnancy: a retrospective cohort study.

We retrospectively reviewed the medical records of 524 women with twin pregnancies who underwent antenatal care and gave birth in the past 12 years. Birth weight (BW) data were classified into three groups. We analysed the association between maternal serum biomarkers and BW in twin pregnancies using multiple logistic regression analysis. There were significant differences in the MoM values of pregnancy-associated plasma protein-A (PAPP-A), unconjugated oestriol (uE3) and inhibin A between low BW and healthy newborns. The inhibin A value was significantly higher in women with small-for-gestational-age (SGA) foetuses and the PAPP-A, and uE3 values were lower in the SGA group than in the other groups using the generalised linear mixed model (hierarchical modelling considering cluster effects for twins). Maternal serum biomarkers, including PAPP-A, uE3, and inhibin A, may be associated with SGA in twin pregnancy. Our results might provide useful information for SGA prediction during prenatal period in twin pregnancy. IMPACT STATEMENTWhat is already known on this subject? The SGA is more frequent in twin pregnancies than in singleton, but there is no clearly identification of the aetiology of SGA. Further, most studies have been conducted in singleton pregnancies.What do the results of this study add? The association of each maternal serum marker with SGA was assessed in the current study, and it is demonstrated that the levels of PAPP-A and uE3 in maternal serum of SGA foetuses were significantly lower than those in the other groups. In contrast, the levels of inhibin A were significantly increased in the SGA.What are the implications of these findings for clinical practice and/or further research? The maternal serum biomarker of inhibin A was a more valuable predictive factor for SGA prediction in twins. The results of this study can be used in counselling prenatal screening. Further prospective research is needed to combine with ultrasound growth parameters, which can be generalised for the prediction of SGA in twins.

Value of PAPP-A combined with BMI in predicting the prognosis of gestational diabetes mellitus: an observational study.

The aim of this study was to investigate the potential of pregnancy-associated plasma protein A (PAPP-A) and clinical data in predicting gestational diabetes mellitus (GDM). Clinical data of 318 pregnant women with GDM and 200 healthy pregnant women were retrospectively analysed. The age, BMI and caesarean section in GDM were significantly higher than in normal group. Serum and placental levels of PAPP-A were significantly lower in GDM than in normal group. Pearson's correlation analysis showed that serum levels of PAPP-A were negatively correlated with BMI and blood glucose level. Binary logistic regression analysis displayed that PAPP-A were the potential factors influencing GDM. The area under the ROC curve (AUC) for PAPP-A combined with BMI in predicting GDM was 0.941, significantly higher than that of the single one. The potential of PAPP-A in the first trimester is limited in predicting GDM. PAPP-A combined with BMI is highly conductive for predicting GDM.Impact statementWhat is already known on this subject? GDM not only increases the risk of perinatal morbidity, but also results in an increased risk of long-term sequelae for both mother and child including diabetes, cardiovascular disease obesity. Previous data indicate that besides glycemic control in the second trimester, interventions initiated early in pregnancy can reduce the rate of GDM in pregnant women. The expression of PAPP-A in serum of GDM pregnant women was decreased in the first trimester. Whereas, whether PAPP-A can be as an early predictor of GDM is not clear.What do the results of this study add? The present study shows that PAPP-A MoM was less than 0.6757 in the first trimester of pregnancy is more prone to GDM. The potential of PAPP-A in the first trimester is limited in predicting GDM. PAPP-A combined with BMI is highly conductive for predicting GDM.What are the implications of these findings for clinical practice and/or further research? Early GDM prediction is crucial for prevention and management of GDM, to cope with the rising prevalence of GDM and reduce later life chronic disease of both mother and child. Based on the level of PAPP-A MoM and BMI, interventions such as lifestyle changes initiated early in pregnancy shouldbeenabledin pregnant women.