[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: To determine the optimal timing of delivery in late preterm intrauterine growth restriction (IUGR) fetuses with abnormal umbilical artery Doppler (UAD) indices. Methods: A decision-analytic model was built to determine the optimal gestational age (GA) of delivery in a theoretic cohort of 10 000 IUGR fetuses with elevated UAD systolic/diastolic ratios diagnosed at 34 weeks. All inputs were derived from the literature. Strategies involving expectant management accounted for the probabilities of stillbirth, spontaneous delivery and induction of labor for UAD absent or reversed end-diastolic flow (AREDF) at each successive week. Outcomes included short- and long-term neonatal morbidity and mortality with quality-adjusted life years (QALYs) generated based on these outcomes. Base case, sensitivity analyses and a Monte Carlo simulation were performed. Results: The optimal GA for delivery is 35 weeks, which minimized perinatal deaths and maximized total QALYs. Earlier delivery became optimal once the risk of stillbirth was threefold our baseline assumption; our model was also robust until the risk of AREDF at 35 weeks was half our baseline assumption, after which delivery at 36 weeks was preferred. Delivery at 35 weeks was the optimal strategy in 77% of trials in Monte Carlo multivariable sensitivity analysis. Conclusions: Weighing the risks of iatrogenic prematurity against the poor outcomes associated with AREDF, the ideal GA to deliver late preterm IUGR fetuses with elevated UAD indices is 35 weeks.
Journal of Maternal-Fetal and Neonatal Medicine 03/2015; DOI:10.3109/14767058.2015.1018170 · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: We assessed the association of glycosylated fibronectin (GlyFn) with preeclampsia and its performance in a point-of-care (POC) test. STUDY DESIGN: GlyFn, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor 1 (sFlt1) levels were determined in serum samples from 107 pregnant women. In all, 45 were normotensive and 62 were diagnosed with preeclampsia. The ability of GlyFn to assess preeclampsia status and relationships between GlyFn and maternal characteristics and pregnancy outcomes were analyzed. RESULTS: GlyFn serum levels in the first trimester were significantly higher in women with preeclampsia (P < .01) and remained higher throughout pregnancy (P <. 01). GlyFn, sFlt1, PlGF, and the sFlt1/PlGF ratio were significantly associated (P < .01) with preeclampsia status, and the classification performance of these analytes represented by area under the receiver operating characteristic curve was 0.99, 0.96, 0.94, and 0.98, respectively, with 95% confidence intervals of 0.98-1.00, 0.89-1.00, 0.86-1.00, and 0.94-1.00, respectively. Increased GlyFn levels were significantly associated with gestational age at delivery (P < .01), blood pressure (P = .04), and small-for-gestational-age neonates. Repeated-measures analysis of the difference in weekly GlyFn change in the third trimester demonstrated that mild preeclampsia was associated with a weekly change of 81.7 mu g/mL (SE 94.1) vs 195.2 mu g/mL (SE 88.2) for severe preeclampsia. The GlyFn POC demonstrated similar performance to a plate assay with an area under the receiver operating characteristic curve of 0.93 and 95% confidence interval of 0.85-1.00. CONCLUSION: GlyFn is a robust biomarker for monitoring of preeclampsia in both a standard and POC format, which supports its utility in diverse settings.
American Journal of Obstetrics and Gynecology 07/2014; 212(1). DOI:10.1016/j.ajog.2014.07.052 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the potential clinical utility of serum biomarkers for first-trimester prediction of gestational diabetes mellitus (GDM).
Maternal serum concentrations of glycosylated (Sambucus nigra lectin-reactive) fibronectin, adiponectin, sex hormone-binding globulin, placental lactogen, and high-sensitivity C-reactive protein (CRP) were measured at 5-13 weeks of gestation in a case-control study of 90 pregnant women with subsequent development of GDM and in 92 control group participants. Ability to detect GDM was assessed using logistic regression modeling and receiver operating characteristic (ROC) curves. Classification performance and positive and negative predictive values were reported at specific thresholds. Glycosylated fibronectin variation across trimesters was evaluated using a serial-measures analysis of 35 nondiabetic control group participants.
First-trimester serum concentrations of glycosylated fibronectin, adiponectin, high-sensitivity CRP, and placental lactogen were significantly associated (P<.001) with GDM. After adjustment for maternal factors and other biomarkers, glycosylated fibronectin demonstrated an independent association with GDM (P<.001). Adiponectin, high-sensitivity CRP, and placental lactogen demonstrated modest classification performance compared with glycosylated fibronectin (respectively: area under the curve [AUC] 0.63; 95% confidence interval [CI] 0.53-0.71; AUC 0.68; 95% CI 0.60-0.76; and AUC 0.67, 95% CI 0.59-0.75; compared with AUC 0.91; 95% CI 0.87-0.96). Glycosylated fibronectin levels above a threshold of 120 mg/L correctly identified 57 GDM case group participants with a positive predictive value of 63% (95% CI 53-72%) and a negative predictive value of 95% (95% CI 94-95%) at a population prevalence of 12%. There was no association between sex hormone-binding globulin and GDM.
First-trimester glycosylated fibronectin is a potential pregnancy-specific biomarker for early identification of women at risk for GDM. LEVEL OF EVIDENCE:: II.
Obstetrics and Gynecology 08/2013; 122(3). DOI:10.1097/AOG.0b013e3182a0c88b · 4.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Accelerated fetal myocardial growth with altered cardiac function is a well-documented complication of human diabetic pregnancy but its pathophysiology is still largely unknown. Our aim was to explore the mechanisms of fetal cardiac remodeling and cardiovascular hemodynamics in a rat model of maternal pregestational streptozotocin-induced hyperglycemia. The hyperglycemic group comprised 107 fetuses (10 dams) and the control group 219 fetuses (20 dams). Fetal cardiac function was assessed serially by Doppler ultrasonography. Fetal cardiac to thoracic area ratio, newborn heart weight, myocardial cell proliferative and apoptotic activities, and cardiac gene expression patterns were determined. Maternal hyperglycemia was associated with increased cardiac size, proliferative, apoptotic and mitotic activities, and upregulation of genes encoding A- and B-type natriuretic peptides, myosin heavy chain types 2 and 3, uncoupling proteins 2 and 3, and the angiogenetic tumor necrosis factor receptor superfamily member 12A. The genes encoding Kv channel interacting protein 2, a regulator of electrical cardiac phenotype, and the insulin-regulated glucose transporter 4 were downregulated. The heart rate was lower in fetuses of hyperglycemic dams. At 13-14 gestational days, 98% of fetuses of hyperglycemic dams had holosystolic atrioventricular valve regurgitation and decreased outflow mean velocity indicating diminished cardiac output. Maternal hyperglycemia may lead to accelerated fetal myocardial growth by cardiomyocyte hyperplasia. In fetuses of hyperglycemic dams, expression of key genes that control and regulate cardiomyocyte electrophysiologic properties, contractility and metabolism are altered and may lead to major functional and clinical implications on the fetal heart.
[Show abstract][Hide abstract] ABSTRACT: Objective: We tested the hypothesis that fetal pulmonary arterial circulation reacts to changes in fetal oxygenation status at near-term gestation. Study Design: A total of 20 rhesus macaques underwent fetal Doppler ultrasonography at near-term gestation. Right pulmonary artery (RPA), umbilical artery (UA), ductus arteriosus (DA), and ductus venosus (DV) blood velocity waveforms were obtained, and pulsatility index (PI) values were calculated. Fetal right and left ventricular cardiac outputs were determined. Ultrasonographic data were collected during 3 maternal oxygenation states: room air (baseline), hyperoxemia, and hypoxemia. Results: Fetal RPA PI values increased (P < .05) during maternal hypoxemia and decreased (P < .05) during maternal hyperoxemia, compared with baseline. Maternal hyperoxemia increased (P < .05) DA PI values from baseline. Fetal cardiac outputs, UA, and DV PI values were not affected. Conclusions: Our results demonstrate that at near-term gestation, fetal pulmonary arterial circulation is a dynamic vascular bed that reflects acute and short-term changes in fetal oxygenation.
[Show abstract][Hide abstract] ABSTRACT: Fetal chronic anemia causes lengthening of cardiomyocytes. In adults, severe left ventricular overload may lead to irreversible ventricular dysfunction. We hypothesized that in sheep fetuses with chronic anemia, remodeled myocardium would less successfully respond to angiotensin II (AT II) infusion than in fetuses without anemia. A total of 14 ewes with twin pregnancy underwent surgery at 113 ± 1 days of gestation. After a recovery period, anemia was induced by isovolumic hemorrhage in 1 fetus of each pair. At 126 ± 1 days of gestation, longitudinal myocardial velocities of the right (RV) and left (LV) ventricles were assessed at the level of the atrioventricular valve annuli via tissue Doppler imaging. Cardiac outputs were calculated by pulsed Doppler ultrasound. All measurements were performed at baseline and during fetal AT II infusion. Fetal serum cardiac natriuretic peptide (N-terminal peptide of proatrial natriuretic peptide [NT-proANP] and B-type natriuretic peptide [BNP]) concentrations were determined. Nine ewes successfully completed the experiment. At baseline, ventricular free wall thicknesses, cardiac outputs, and NT-proANP levels were significantly greater in the anemic fetuses than in the controls. The LV isovolumic contraction velocity (IVCV) acceleration and isovolumic relaxation velocity (IVRV) deceleration were lower (P < .05) in the anemic fetuses than in the controls. In the anemic fetuses, there was a positive correlation (R = .93, P < .01) between RV IVRV deceleration and NT-proANP concentration. Angiotensin II infusion increased (P < .05) LV IVCV acceleration in the anemic fetuses. We conclude that in anemic sheep fetuses, myocardial adaptation is associated with impaired LV early contraction and relaxation. However, the LV can improve its contractility with an inotropic stimulus, even in the presence of increased afterload.
[Show abstract][Hide abstract] ABSTRACT: Aortic isthmus acts as an arterial watershed between the cerebral and placental circulations, connecting 2 parallel fetal ventricular pumps. It plays a crucial role in the fetal circulatory dynamics. Information about aortic isthmus blood flow may improve the management of sick fetuses. However, perceived technical difficulties limit the clinical use of aortic isthmus Doppler for fetal hemodynamic monitoring. Changes in aortic isthmus blood flow pattern seem to reflect fetal cardiovascular status accurately and predict perinatal and long-term neurodevelopmental outcome in intrauterine growth restriction. This review evaluates the available scientific information and discusses the role of aortic isthmus in fetal circulation.
[Show abstract][Hide abstract] ABSTRACT: Prepregnancy maternal obesity confers an increased risk of stillbirth, but the mechanisms are unknown. Maternal obesity is associated with placental inflammation. We considered that maternal diet may predispose to the increased risk of placental inflammation and stillbirth. We hypothesized that a chronic high-fat diet (HFD) is associated with abnormal uteroplacental circulation and placental inflammation. Here we used a nonhuman primate model to determine the effect of chronic HFD on the uterine and placental hemodynamics, placental histology, and inflammation in a prospective, observational study of 24 Japanese macaques. Overall, there was a statistically significant (38-56%) reduction in uterine volume blood flow from HFD animals, whether they were lean or obese. Consumption of a HFD, independent of obesity, increased placental inflammatory cytokines and the expression of Toll-like receptor 4. We show that HFD consumption by obese mothers with hyperinsulinemia also reduced volume blood flow on the fetal side of the placenta and significantly increased the frequency of both placental infarctions and stillbirth. These results suggest that a HFD, independent of obesity, decreases uterine volume blood flow. Maternal obesity and insulin resistance further exacerbates the placental dysfunction and results in an increased frequency of stillbirth.