Prediction of pre-eclampsia and its subtypes in high-risk cohort: hyperglycosylated human chorionic gonadotropin in multivariate models.

BACKGROUND: The proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGß, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. METHODS: We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. RESULTS: We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGß higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.

Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study.

OBJECTIVES: Preeclampsia is divided into early-onset (delivery before 34 weeks of gestation) and late-onset (delivery at or after 34 weeks) subtypes, which may rise from different etiopathogenic backgrounds. Early-onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function. Our aim was to use cluster analysis to investigate clinical factors predicting the onset and severity of preeclampsia in a cohort of women with known clinical risk factors. METHODS: We recruited 903 pregnant women with risk factors for preeclampsia at gestational weeks 12+0-13+6. Each individual outcome diagnosis was independently verified from medical records. We applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, we computed the risk ratio of each disease outcome, relative to the risk in the general population. RESULTS: The risk of preeclampsia increased exponentially with respect to the number of risk factors. Our analysis revealed 25 number of clusters. Preeclampsia in a previous pregnancy (n = 138) increased the risk of preeclampsia 8.1 fold (95% confidence interval (CI) 5.7-11.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset preeclampsia 17.5 fold (95%CI 2.1-60.5). Cluster of those two risk factors together (n = 21) increased the risk of severe preeclampsia to 23.8-fold (95%CI 5.1-60.6), intermediate onset (delivery between 34+0-36+6 weeks of gestation) to 25.1-fold (95%CI 3.1-79.9) and preterm preeclampsia (delivery before 37+0 weeks of gestation) to 16.4-fold (95%CI 2.0-52.4). Body mass index over 30 kg/m2 (n = 228) as a sole risk factor increased the risk of preeclampsia to 2.1-fold (95%CI 1.1-3.6). Together with preeclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.5-20.9). Chronic hypertension (n = 60) increased the risk of preeclampsia 5.3-fold (95%CI 2.4-9.8), of severe preeclampsia 22.2-fold (95%CI 9.9-41.0), and risk of early-onset preeclampsia 16.7-fold (95%CI 2.0-57.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier preeclampsia, the risk of term preeclampsia increased 4.8-fold (95%CI 0.1-21.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of preeclampsia. CONCLUSION: The risk of preeclampsia increases exponentially with respect to the number of risk factors. Early-onset preeclampsia and severe preeclampsia have different risk profile from term preeclampsia.

Fetal pelvic index to predict cephalopelvic disproportion - a retrospective clinical cohort study.

OBJECTIVE: To investigate the diagnostic accuracy of the fetal pelvic index to predict cephalopelvic disproportion. DESIGN: Retrospective observational cohort study. SETTING: Pregnant women who had been examined by X-ray or magnetic resonance imaging pelvimetry because of an increased risk of fetal-pelvic disproportion during 2000-2008 in North Karelia Central Hospital. POPULATION: A total of 274 pregnant women. METHODS: Univariable and multivariable regression analyses were carried out to identify risk factors for cesarean section. Diagnostic accuracy was tested with a receiver operating characteristic curve, and the optimal cut-off value for fetal pelvic index was calculated. MAIN OUTCOME MEASURE: Cesarean section rates. RESULTS: A total of 242 women delivered vaginally, and 32 delivered with cesarean section caused by labor arrest. In multivariable modeling, the fetal pelvic index, maternal pelvic inlet size, fetal head circumference and maternal age were significantly associated with a risk of cesarean section. In the receiver operating characteristic analysis, the area under curve was 0.686 with a p-value of 0.001 and a 95% confidence interval of 0.595-0.778. The optimal fetal pelvic index cut-off value according to the receiver operating characteristic was -0.65. The cesarean section rate was 8% below the fetal pelvic index value of -0.65 and 20% above the fetal pelvic index value of -0.65. CONCLUSIONS: The fetal pelvic index was not a clinically useful tool to predict the mode of delivery for patients at high risk of cephalopelvic disproportion. The pooled analysis of the current and previous studies strengthened this conclusion.

Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort.

BACKGROUND: To evaluate the soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio for the prediction of early- and late-onset preeclampsia in a high-risk cohort. METHODS: We studied serial serum samples collected prospectively at 12+0-14+0, 18+0-20+0, and 26+0-28+0 weeks+days of gestation in 6 women who developed early-onset preeclampsia (before 34 weeks of gestation) and in 21 women who developed late-onset preeclampsia (after 34 weeks of gestation) with automated ElecSys 2010 immunoanalyzer (Roche Diagnostics, Germany). Twenty-six high-risk women and 53 women without risk factors with normal pregnancies served as controls. RESULTS: Serum PlGF concentrations were lower at 18+0 to 20+0, and 26+0 to 28+0 weeks of gestation in women who developed early-onset preeclampsia compared to women who developed late-onset preeclampsia and to controls (p<0.05 for all comparisons). At 18+0 to 20+0 weeks of gestation area under the receiver-operating characteristic curve (AUC) for serum PlGF was 99.8% (p=0.0007, 95% CI 99.0-100.0). At 26+0 to 28+0 weeks of gestation serum sFlt-1/PlGF ratio explicitly detects those women who developed early-onset preeclampsia (AUC 100.0%, p=0.0007, 95% CI 100-100). Amongst women with late-onset preeclampsia, those who developed severe form of the disease (N=8) had significantly higher serum sFlt-1 concentrations at all three timepoints (p=0.004, p=0.006, and p=0.003, respectively) compared to women with non-severe form (N=13). CONCLUSIONS: Low serum PlGF concentration predicts early-onset preeclampsia from the second trimester and elevated serum sFlt-1/PlGF ratio from 26 to 28 weeks of gestation. Elevated serum sFlt-1 concentration in the first trimester in women who later develop late-onset, severe preeclampsia may suggest different etiology compared to the late-onset non-severe form of the disease.

Assessment of bony pelvis and vaginally assisted deliveries.

Objective. To evaluate whether pelvic measurements have any association with operative vaginal deliveries and the duration of the second stage of the delivery. Study design. A retrospective study of pregnant women at an increased risk of fetal-pelvic disproportion during 2000-2008 in North-Carelian Central Hospital. The mode of the vaginal delivery was chosen to represent the reference standard. The target condition was spontaneous vaginal delivery. Patients were divided into subgroups according to the size of the fetus and also by the parity to evaluate the variability reflecting differences in patient groups. Receiver operating characteristic (ROC) curves were established. Results. A total of 226 participants with fetal cephalic presentation delivered vaginally; of these, 184 women delivered spontaneously, and 42 women required operative vaginal delivery with vacuum extraction. There were no clinically or statistically significant differences between the size of the maternal pelvic outlet and the different modes of delivery types within these subgroups. With respect to the pelvic inlet and outlet, the areas under the curve in ROC were 0.566 with the P value of 0.18 and 95% confidence interval (CI) of 0.465-0.667 and 0.573 (95% CI: 0.484-0.622; P = 0.14). Conclusions. The maternal bony pelvic dimensions exhibited virtually no correlation with the need for operative vaginal deliveries.

Two-stage ultrasonography in screening for fetal anomalies at 13-14 and 18-22 weeks of gestation.

BACKGROUND: The aim of this study was to assess the value of two-stage screening by ultrasonography in detecting selected major fetal anomalies in a low-risk obstetric population. METHODS: In a defined geographic area, 4789 consecutive low-risk pregnant women participated in screening by two-stage ultrasonography as part of routine maternal care. The examinations were usually performed by specially trained midwives at 13-14 and 18-22 weeks of gestation. Of the women, 4073 had both scans, 440 had the early one only, and 276 the late scan only. Pregnancy outcomes were ascertained from obstetric and pediatric records, and the data were supplemented with information from the national birth and malformation registries. RESULTS: Of the 4855 fetuses, 33 (0.7%) had major structural defects considered detectable by ultrasonography. Of these, six (18%) were identified at the early scan, and an additional 10 (30%) at the late scan, yielding a total sensitivity of 48% for the two-stage screening. Twenty offspring had chromosomal abnormalities; 10 were identified by increased nuchal translucency at the early scan, one additional one (by hydronephrosis) at the late scan, and the remaining nine at birth. CONCLUSIONS: In a low-risk population, first-trimester scanning is useful in finding fetuses with chromosomal anomalies, but a second-trimester scan is needed for other types of defects. The sensitivity of routine screening by midwives for fetal structural defects in a general obstetric population remains lower than that reported by specialized centers.

Prenatal diagnosis of placenta accreta and percreta with ultrasonography, color Doppler, and magnetic resonance imaging.

BACKGROUND: The risk of placenta previa and accreta is increased in females with previous cesarean deliveries, and there has been an increasing number of these operations. CASES: We present 2 cases with previous cesarean and placenta previa in the following pregnancy. One patient had placenta accreta and the other, placenta percreta. In both cases, prenatal diagnosis was based on ultrasonography, where features such as loss of the hypoechoic retroplacental zone and irregular uterine serosa were found in grayscale ultrasonography. In color Doppler imaging, in both cases, increased vascularity between myometrium and placenta, as well as intraplacental lacunae, were seen. Thinning of the uterine wall, found in magnetic resonance imaging, contributed to the diagnosis of placenta percreta. CONCLUSION: Prenatal diagnosis of placenta accreta is of importance because it reduces fetal and maternal morbidity as appropriate preoperative and perioperative procedures are possible.

Cloacal anomaly simulating megalocystis in the first trimester.

We present a case of cloacal anomaly that simulated megalocystis in the first trimester of gestation of a female fetus. During the second trimester, repeated paracentesis was necessary to treat increasing ascites, oligohydramnios, and hydronephrosis. Our data support findings that ascites presenting with a multiloculated cystic structure on sonography during the second trimester may be typical for cloacal anomalies. Active treatment of the fetal ascites is recommended to improve the child's prospects for survival.

Learning curve in ultrasonographic screening for selected fetal structural anomalies in early pregnancy.

OBJECTIVE: To assess the value of first trimester screening by ultrasonography in detecting structural anomalies of the fetus in a general obstetric population. METHODS: During 1993-1998, 20,465 consecutive pregnant women who resided in a defined geographic area participated in ultrasonographic screening for major malformations. These included anomalies of the central nervous system, urinary tract, abdominal wall, and long bones. Heart anomalies were not expected to be detected. The examinations were offered at 13-14 weeks' gestation as part of routine maternal care and were done by specially trained midwives. The pregnancy outcomes were ascertained from obstetric and pediatric records, and the data were completed by information from the national birth and malformation registries. RESULTS: A total of 307 fetuses (1.5%) with a major malformation were found; 67 fetuses (0.3%) had noncardiac major structural defects expected to be detectable by ultrasonography in early pregnancy. Thirty-five of 67 (52%) were identified at the early scan. Sensitivity for these defects increased from 22% to 79% from the first to the last (sixth) study year (P =.009). CONCLUSION: In a low-risk population, adequate sensitivity in screening for major malformations by early ultrasonography can be achieved after a learning curve of 3-4 years.

Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model.

Previous studies have shown that fibroblast growth factor (FGF)-1, FGF-2, and FGF-5 induce therapeutic angiogenesis. Here, we investigated the potential of FGF-4 for therapeutic neovascularization in comparison to vascular endothelial growth factor (VEGF), using adenoviral gene transfer in a novel rabbit hind limb ischemia model, with ischemia restricted to the calf. Magnetic resonance imaging and a modified Miles assay showed that both AdFGF-4 and AdVEGF given intramuscularly (i.m.) resulted in increases in vascular permeability and edema in transduced muscles 6 days after the gene transfer. In contrast, recombinant FGF-4 protein injected in the rabbit skin did not induce acute vascular permeability. Injections (i.m.) of AdFGF-4 and AdVEGF, but not intra-arterially administered AdVEGF, increased collateral growth, popliteal blood flow, and muscle perfusion compared with controls. The angiogenesis response consisted mainly of the enlargement of pre-existing vessels rather than an increase in capillary density. Adenoviral FGF-4 overexpression up-regulated endogenous VEGF, which may explain many of the effects thought to be specific for VEGF such as the increase in vascular permeability. This study demonstrates for the first time that FGF-4 induces vascular permeability, therapeutic angiogenesis, and arteriogenesis comparable to that of VEGF and could be useful for the treatment of peripheral vascular disease.