Glycosylated fibronectin as a first trimester marker for gestational diabetes.

PURPOSE: To evaluate the performance of first trimester maternal serum glycosylated (Sambucus nigra lectin-reactive) fibronectin in prediction of gestational diabetes mellitus (GDM). METHODS: In this case-control study, first trimester maternal serum glycosylated fibronectin and fibronectin were measured in 19 women who consequently developed GDM and in 59 control women with normal pregnancy outcomes. Adiponectin was used as a reference protein to evaluate relation of glycoprotein to SNA-lectin-reactive assay format. Samples were taken during gestational weeks 9+6-11+6. Data concerning GDM was obtained from the National Institute for Health and Welfare, which records the pregnancy outcomes of all women in Finland. RESULTS: There was no difference in maternal serum glycosylated fibronectin concentrations between women with consequent GDM [447.5 µg/mL, interquartile range (IQR) 254.4-540.9 µg/mL] and control women (437.6 µg/mL, IQR 357.1-569.1 µg/mL). Maternal serum fibronectin levels were significantly lower in GDM group (224.2 µg/mL, IQR 156.8-270.6 µg/mL), compared to the control group (264.8 µg/mL, IQR 224.6-330.6 µg/mL, p < 0.01). There was no difference in assay formats for adiponectin. CONCLUSION: There was no association between first trimester maternal serum glycosylated (SNA-reactive) fibronectin and GDM.

A Novel Early Pregnancy Risk Prediction Model for Gestational Diabetes Mellitus.

INTRODUCTION: Accurate early risk prediction for gestational diabetes mellitus (GDM) would target intervention and prevention in women at the highest risk. We evaluated novel biomarker predictors to develop a first-trimester risk prediction model in a large multiethnic cohort. METHODS: Maternal clinical, aneuploidy and pre-eclampsia screening markers (PAPP-A, free hCGß, mean arterial pressure, uterine artery pulsatility index) were measured prospectively at 11-13+6 weeks' gestation in 980 women (248 with GDM; 732 controls). Nonfasting glucose, lipids, adiponectin, leptin, lipocalin-2, and plasminogen activator inhibitor-2 were measured on banked serum. The relationship between marker multiples-of-the-median and GDM was examined with multivariate regression. Model predictive performance for early (< 24 weeks' gestation) and overall GDM diagnosis was evaluated by receiver operating characteristic curves. RESULTS: Glucose, triglycerides, leptin, and lipocalin-2 were higher, while adiponectin was lower, in GDM (p < 0.05). Lipocalin-2 performed best in Caucasians, and triglycerides in South Asians with GDM. Family history of diabetes, previous GDM, South/East Asian ethnicity, parity, BMI, PAPP-A, triglycerides, and lipocalin-2 were significant independent GDM predictors (all p < 0.01), achieving an area under the curve of 0.91 (95% confidence interval [CI] 0.89-0.94) overall, and 0.93 (95% CI 0.89-0.96) for early GDM, in a combined multivariate prediction model. CONCLUSIONS: A first-trimester risk prediction model, which incorporates novel maternal lipid markers, accurately identifies women at high risk of GDM, including early GDM.

Evaluation of a dried blood spot assay to measure prenatal screening markers pregnancy-associated plasma protein a and free ß-subunit of human chorionic gonadotropin.

BACKGROUND: First-trimester prenatal screening for aneuploidy by use of dried blood spots (DBSs) may offer practical benefits in settings where the instability of intact human chorionic gonadotropin (hCG) is problematic. We evaluated a DBS pregnancy-associated plasma protein A (PAPP-A) and free ß-subunit of hCG (free hCGß) dual assay and compared it to serum screening. METHODS: Hematocrit-corrected DBS PAPP-A and free-hCGß concentrations were measured and compared with serum concentrations in 252 first-trimester samples. Serum intact hCG was also measured and, with serum free hCGß, was used to fit a model to predict serum-equivalent DBS free-hCGß concentrations. In a separate experiment, we investigated the effects of temperature and relative humidity during the blood spot drying process. RESULTS: The DBS assay for PAPP-A performed similarly to the serum assay, whereas free-hCGß DBS measurements were consistently higher than in serum. Purifying blood spots of intact hCG suggested that the free-hCGß DBS assay is measuring a composite of free hCGß and additional ß-subunits from intact hCG. The drying experiment showed that increased temperature and relative humidity during the drying process resulted in increased free hCGß and reduced PAPP-A. CONCLUSIONS: Despite measuring additional free hCGß compared to the serum assay, DBS analysis has a role in first-trimester combined screening for trisomy 21.

Fetal nuchal translucency in severe congenital heart defects: experiences in Northern Finland.

OBJECTIVE: To evaluate the performance of first-trimester measurement of fetal nuchal translucency (NT) in the detection of severe congenital heart defects (CHDs). METHODS: During the study period of 1 January 2008 - 31 December 2011, NT was measured in 31,144 women as a part of voluntary first-trimester screening program for Down's syndrome in Northern Finland. NT was measured by personnel trained on the job by the experienced staff. No certification or annual audits are required in Finland. However, the recommendation is that the examiner should perform 200 scans on average per year. Severe CHD was classified as a defect requiring surgery in the first year of life or a defect that led to the termination of the pregnancy. All severe CHDs diagnosed during the study period in Northern Finland could not be included in this study since all women did not participate in the first-trimester screening and some cases were missing important data. RESULTS: Fourteen (17.7%) out of 79 severe CHDs were found with NT cutoff of 3.5 mm. Amongst the 79 severe CHD cases, there were 17 chromosomal abnormalities. With NT cutoffs of 2.0 and 1.5 mm the detection rates would have increased to 25.3% (n = 20) and 46.8% (n = 37). Using a randomly selected control group of 762 women with normal pregnancy outcomes, false positive rates (FPRs) were calculated. For NT cutoffs of 1.5, 2.0 and 3.5 mm, the FPRs were, 18.5, 3.3 and 0.4%, respectively. CONCLUSIONS: A greater than 3.5 mm NT measurement in the first-trimester ultrasound is an indication to suspect a fetal heart defect but its sensitivity to detect severe CHD is poor. In our study, only 17.7% of severe CHDs would have been detected with an NT cutoff of 3.5 mm.

First trimester combined screening biochemistry in detection of congenital heart defects.

Objective: To evaluate the performance of first trimester biochemical markers, pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (fß-hCG), and nuchal translucency (NT) in detection of severe congenital heart defects (CHDs). Methods: During the study period from 1 January 2008 to 31 December 2011, biochemical markers and NT were measured in 31,144 women as part of voluntary first trimester screening program for Down's syndrome in Northern Finland. Data for 71 severe CHD cases and 762 controls were obtained from the hospital records and from the National Medical Birth Register, which records the birth of all liveborn and stillborn infants, and from the National Register of Congenital Malformations that receives information about all the CHD cases diagnosed in Finland. Results: Both PAPP-A and fß-hCG multiple of median (MoM) values were decreased in all severe CHDs: 0.71 and 0.69 in ventricular septal defects (VSDs), 0.58 and 0.88 in tetralogy of Fallot cases (TOFs), 0.82 and 0.89 in hypoplastic left heart syndromes (HLHSs), and 0.88 and 0.96 in multiple defects, respectively. NT was increased in all study groups except of VSD group. ROC AUC was 0.72 for VSD when combining prior risk with PAPP-A and fß-hCG. Adding NT did not improve the detection rate. With normal NT but decreased (<0.5 MoM) PAPP-A and fß-hCG odds ratios for VSD and HLHS were 19.5 and 25.6, respectively. Conclusions: Maternal serum biochemistry improves the detection of CHDs compared to NT measurement only. In cases with normal NT measurement but low concentrations of both PAPP-A and fß-hCG, an alert for possible CHD, especially VSD, could be given with thorough examination of fetal heart in later ultrasound scans.

A first trimester prediction model for gestational diabetes utilizing aneuploidy and pre-eclampsia screening markers.

OBJECTIVE: We examined whether first trimester aneuploidy and pre-eclampsia screening markers predict gestational diabetes mellitus (GDM) in a large multi-ethnic cohort and the influence of local population characteristics on markers. METHODS: Clinical and first trimester markers (mean arterial pressure (MAP), uterine artery pulsatility index (UtA PI), pregnancy associated plasma protein A (PAPP-A), free-ß human chorionic gonadotropin (free-hCGß)) were measured in a case-control study of 980 women (248 with GDM, 732 controls) at 11 to 13 + 6 weeks' gestation. Clinical parameters, MAP-, UtA PI-, PAPP-A-, and free-hCGß-multiples-of-the-median (MoM) were compared between GDM and controls; stratified by ethnicity, parity, and GDM diagnosis <24 versus ≥24 weeks' gestation. GDM model screening performance was evaluated using AUROC. RESULTS: PAPP-A- and UtA PI-MoM were significantly lower in GDM versus controls (median ((IQR) PAPP-A-MoM 0.81 (0.58-1.20) versus 1.00 (0.70-1.46); UtA PI-MoM 1.01 (0.82-1.21) versus 1.05 (0.84-1.29); p < .05). Previous GDM, family history of diabetes, south/east Asian ethnicity, parity, BMI, MAP, UtA PI, and PAPP-A were significant predictors in multivariate analysis (p < .05). The AUC for a model based on clinical parameters was 0.88 (95%CI 0.85-0.92), increasing to 0.90 (95%CI 0.87-0.92) with first trimester markers combined. The combined model best predicted GDM <24 weeks' gestation (AUC 0.96 (95%CI 0.94-0.98)). CONCLUSIONS: Addition of aneuploidy and pre-eclampsia markers is cost-effective and enhances early GDM detection, accurately identifying early GDM, a high-risk cohort requiring early detection, and intervention. Ethnicity and parity modified marker association with GDM, suggesting differences in pathophysiology and vascular risk.

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

OBJECTIVE: To 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). METHODS: This 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 (fß-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. RESULTS: Single 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. CONCLUSION: Based 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 prediction of gestational diabetes mellitus: A clinical model based on maternal demographic parameters.

AIM: Develop a first trimester risk prediction model for GDM based on maternal clinical characteristics in a large metropolitan multi-ethnic population and compare its performance to that of other recently published GDM prediction models and clinical risk scoring systems. METHODS: A retrospective case control study of 248 women who developed GDM and 732 controls who did not. Maternal clinical parameters were prospectively obtained at 11-13+6 weeks' gestation. A predictive multivariate regression model for GDM was developed, evaluated using areas under the receiver-operating characteristic (AUC) curve. The performance of this model was then compared with other published GDM prediction models applied to our cohort and our existing clinical risk scoring system. RESULTS: Previous GDM, family history of diabetes, age, south/east Asian ethnicity, parity and body mass index (BMI) were significant predictors for GDM. The AUC of our multivariate regression model was 0.88 (95% Confidence Interval 0.85-0.92). This performed better than other predictive models applied to our cohort (AUCs 0.77-0.82). CONCLUSION: A multivariate model based on weighted maternal clinical risk factors accurately predicts GDM in early pregnancy and performs better than other proposed multivariate and clinical risk scoring models in a multiethnic cohort.

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

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

First trimester placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in the prediction of early-onset severe pre-eclampsia.

OBJECTIVE: In a retrospective case-control study, we examined the levels of placental retinol-binding protein 4 (RBP4) and pregnancy-associated placental protein A (PAPP-A) in first-trimester maternal serum samples as well as maternal characteristics to predict early-onset and severe pre-eclampsia. METHODS: In this retrospective case-control study, we identified females who delivered a singleton pregnancy on or after 24 weeks' gestation from 2003 to 2010 at Oulu University Hospital and had a retrospective first trimester trisomy screening, including serum PAPP-A measurement. Within this cohort, we identified 65 females who experienced early onset pre-eclampsia (EO-PE) and 742 controls who had uncomplicated deliveries. Retrospectively, we thawed all previously collected serum samples to measure placental retinol binding protein 4 (RBP4). PAPP-A and RBP4 were measured using automatic immunoassay systems and converted to multiples of the median (MoMs). Logistic regression analysis was performed to determine whether these biomarkers separately and in combination with maternal characteristics (maternal age, weight and smoking status) can be used to predict the development of early onset pre-eclampsia. RESULTS: The expected log(10) PAPP-A concentration and the expected log(10) RBP4 concentration in the control group were both affected by maternal weight and smoking status. The expected log(10) PAPP-A concentration was also affected by gestational age (GA). RBP4 levels in first-trimester serum were significantly higher in females who subsequently developed EO-PE outcome compared to those with normal pregnancy outcome (1.14 vs. 1.01 MoMs, p<0.0001). Maternal serum PAPP-A levels from the same pregnancy period were significantly lower in the EO-PE group compared to controls (0.80 vs. 1.05 MoMs, p=0.005). The risk model including maternal characteristics with PAPP-A log(10) MoM and RBP4 log(10) MoM had the best EO-PE prediction ability. It detected 34% (23%-46%) of females with subsequent EO-PE with a 10% false positive rate. CONCLUSION: This study showed that first-trimester maternal serum RBP4 was significantly increased and that PAPP-A decreased in pregnancies that ended in EO-PE compared to normal pregnancies. Thus, these markers may be useful members in a panel of markers for the early detection of early-onset and severe pre-eclampsia.