Search

Purpose: P-glycoprotein (P-gp) has been hypothesized to be involved in drug-resistance of epilepsy by actively extruding antiseizure medications (ASMs) from the brain. The P-gp inhibitor tariquidar (TQD) has been shown to effectively inhibit P-gp at the human blood-brain barrier, improving brain entry of several ASMs. A potential strategy to overcome drug-resistance is the co-administration of P-gp inhibitors such as TQD to ASMs. Here we present data on the tolerability of single-dose TQD as a potential add-on medication to ASMs., Methods: We performed a multi-centre cohort study including drug-resistant epilepsy patients and healthy controls from the United Kingdom and Austria. TQD was administered intravenously at five different doses (2 mg/kg or 3 mg/kg of TQD were given to drug-resistant epilepsy patients and healthy controls, higher doses of TQD at 4 mg/kg, 6 mg/kg and 8 mg/kg as well as a prolonged infusion aiming at a dose of 6 mg/kg were only given to healthy controls). Adverse events were recorded and graded using the Common Terminology Criteria (CTCAE) scale. Additionally, TQD plasma concentration levels were measured and compared between drug-resistant patients and healthy controls., Results: In total, 108 participants received TQD once at variable doses and it was overall well tolerated. At doses of 2 or 3 mg/kg TQD, only two of the 19 drug-resistant epilepsy patients and a third of the healthy controls (n = 14/42) reported adverse events probably related to TQD. The majority of those adverse events (96 %) were reported as mild. One drug-resistant epilepsy patient reported adverse events 24-hours after TQD administration possibly related to TQD-induced increased ASMs levels in the brain., Conclusions: TQD is an effective and well tolerated P-gp inhibitor as a single dose and could potentially be used intermittently in conjunction with ASMs to improve efficacy. This promising strategy to overcome drug-resistance in epilepsy should be investigated further in clinical randomised controlled trials., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Radiochemists/radiopharmacists, involved in the preparation of radiopharmaceuticals are regularly confronted with the requirement of continuous high quality productions in their day-to-day business. One of these requirements is high specific or molar activity of the radiotracer in order to avoid e.g. receptor saturation and pharmacological or even toxic effects of the applied tracer for positron emission tomography. In the case of 11 C-labeled radiotracers, the reasons for low molar activity are manifold and often the search for potential 12 C-contaminations is time-consuming., Methods: In this study, diverse 12 C-contaminations were analyzed and quantified, which occurred during >450 syntheses of six PET tracers using [ 11 C]CO 2 or [ 11 C]CH 3 I generated via the gas phase method in a commercially available synthesizer. Additionally, non-radioactive syntheses were performed in order to identify the origins of carbon-12., Results: The manifold contributions to low molar activity can be attributed to three main categories, namely technical parameters (e.g. quality of target gases, reagents or tubings), inter/intralaboratory parameters (e.g. maintenance interval, burden of the module, etc.) and interoperator parameters (e.g. handling of the module)., Conclusion: Our study provides a better understanding of different factors contributing to the overall carbon load of a synthesis module, which facilitates maintenance of high molar activity of carbon-11-labeled radiopharmaceuticals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The obesity and diabetes epidemic is an unintended consequence of economic, social, and technological changes. In nonpregnancy, people identified as high risk to develop type 2 diabetes may delay progression by 30-70% with lifestyle interventions and pharmacological agents. In pregnancy, lifestyle interventions have been the primary focus to prevent fetal short- and long-term complications that may evolve into substantial weight gain and gestational diabetes mellitus. The dilemma for obstetricians is whether diabetes and obesity can be prevented and not simply treated after the fact. Interventions after women become pregnant may be too late to see the kinds of meaningful improvements in child and maternal health because there is a short interval from gestational diabetes mellitus diagnosis to delivery. Therefore, future efforts need to incorporate quality research, lifestyle interventions that designate time of initiation and duration during pregnancy, the preventative intervention of a prepregnant "fourth trimester," coupled with the concept of precision medicine so that there is the potential to make the impossible dream a reality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Controversies persist over the most efficacious pharmacologic treatment for gestational diabetes mellitus. For purposes of accuracy in this article, the individual American College of Obstetricians and Gynecologists Practice Bulletin and American Diabetes Association Standards of Medical Care positions on each issue are quoted and then deliberated with evidence of counter claims presented in point/counterpoint. This is a review of all the relevant evidence for the most holistic picture possible. The main issues are (1) which diabetic drugs cross the placenta, (2) the quality of evidence and data source validity, (3) the rationale for the designation of glucose control as the primary outcome in gestational diabetes mellitus, and (4) which drugs (metformin, glyburide, or insulin) are most effective in improving secondary outcomes. The concept that 1 drug fits all, whether it be insulin, glyburide, or metformin, is a fallacy. Different drugs provide certain benefits but not all the benefits and not to all patients. In addition, the steps in the gestational diabetes mellitus management decision path and the current cost of the use of insulin, glyburide, or metformin are addressed. In the future, we must consider studying the potential of diabetic drugs that currently are used in nonpregnancy and incorporating the concept of precision medicine in the decision tree to maximize pregnancy outcomes., (Copyright © 2018. Published by Elsevier Inc.)

The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions between the model Pgp substrate (R)-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration-time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration-time profiles and rank the magnitude of the Pgp-mediated brain drug-drug interaction potential for both Pgp and Pgp/BCRP substrates in humans., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: [ 11 C]Erlotinib PET has shown promise to distinguish non-small cell lung cancer (NSCLC) tumors harboring the activating epidermal growth factor receptor (EGFR) mutation delE746-A750 from tumors with wild-type EGFR. To assess the suitability of [ 11 C]erlotinib PET to detect the emergence of acquired erlotinib resistance in initially erlotinib-responsive tumors, we performed in vitro binding and PET experiments in mice bearing tumor xenografts using a range of different cancer cells, which were erlotinib-sensitive or exhibited clinically relevant resistance mechanisms to erlotinib., Methods: The following cell lines were used for in vitro binding and PET experiments: the epidermoid carcinoma cell line A-431 (erlotinib-sensitive, wild-type EGFR) and the three NSCLC cell lines HCC827 (erlotinib-sensitive, delE746-A750), HCC827 EPR (erlotinib-resistant, delE746-A750 and T790M) and HCC827 ERLO (erlotinib-resistant, delE746-A750 and MET amplification). BALB/c nude mice with subcutaneous tumor xenografts underwent two consecutive [ 11 C]erlotinib PET scans, a baseline scan and a second scan in which unlabeled erlotinib (10mg/kg) was co-injected. Logan graphical analysis was used to estimate total distribution volume (V T ) of [ 11 C]erlotinib in tumors., Results: In vitro experiments revealed significantly higher uptake of [ 11 C]erlotinib (5.2-fold) in the three NSCLC cell lines as compared to A-431 cells. In all four cell lines co-incubation with unlabeled erlotinib (1μM) led to significant reductions in [ 11 C]erlotinib uptake (-19% to -66%). In both PET scans and for all four studied cell lines there were no significant differences in tumoral [ 11 C]erlotinib V T values. For all three NSCLC cell lines, but not for the A-431 cell line, tumoral V T was significantly reduced following co-injection of unlabeled erlotinib (-20% to -35%)., Conclusions: We found no significant differences in the in vitro and in vivo binding of [ 11 C]erlotinib between erlotinib-sensitive and erlotinib-resistant NSCLC cells. Our findings suggest that [ 11 C]erlotinib PET will not be suitable to distinguish erlotinib-sensitive NSCLC tumors from tumors with acquired resistance to erlotinib., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: In recent years extra-corporal application of boron neutron capture therapy (BNCT) was evaluated for liver primary tumors or liver metastases. A prerequisite for such a high-risk procedure is proof of preferential delivery and high uptake of a 10 B-pharmaceutical in liver malignancies. In this work we evaluated in a preclinical tumor model if [ 18 F]FBPA tissue distribution measured with PET is able to predict the tissue distribution of [ 10 B]L-BPA., Methods: Tumor bearing mice (hepatocellular carcinoma cell line, HuH-7) were either subject of a [ 18 F]FBPA-PET scan with subsequent measurement of radioactivity content in extracted organs using a gamma counter or injected with [ 10 B]L-BPA with tissue samples analyzed by prompt gamma activation analysis (PGAA) or quantitative neutron capture radiography (QNCR). The impact of L-tyrosine, L-DOPA and L-BPA preloading on the tissue distribution of [ 18 F]FBPA and [ 10 B]L-BPA was evaluated and the pharmacokinetics of [ 18 F]FBPA investigated by compartment modeling., Results: We found a significant correlation between [ 18 F]FBPA and [ 10 B]L-BPA uptake in tumors and various organs as well as high accumulation levels in pancreas and kidneys as reported in previous studies. Tumor-to-liver ratios of [ 18 F]FBPA ranged from 1.2 to 1.5. Preloading did not increase the uptake of [ 18 F]FBPA or [ 10 B]L-BPA in any organ and compartment modeling showed no statistically significant differences in [ 18 F]FBPA tumor kinetics., Conclusions: [ 18 F]FBPA-PET predicts [ 10 B]L-BPA concentration after amino acid preloading in HuH-7 hepatocellular carcinoma models. Preloading had no effect on tumor uptake of [ 18 F]FBPA., Advances in Knowledge: Despite differences in chemical structure and administered dose [ 18 F]FBPA and [ 10 B]L-BPA demonstrate an equivalent biodistribution in a preclinical tumor model. IMPLICATIONS FOR PATIENT CARE: [ 18 F]FBPA-PET is suitable for treatment planning and dose calculations in BNCT applications for liver malignancies. However, alternative tracers with more favorable tumor-to-liver ratios should be investigated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

24-nor-ursodeoxycholic acid (norUDCA) is a novel therapeutic approach to cholestatic liver diseases. In mouse models of cholestasis, norUDCA induces basolateral multidrug resistance-associated proteins 4 (Mrp4) and 3 in hepatocytes, which provide alternative escape routes for bile acids accumulating during cholestasis but could also result in altered hepatic disposition of concomitantly administered substrate drugs. We used positron emission tomography imaging to study the influence of norUDCA on hepatic disposition of the model Mrp4 substrate [(18)F]ciprofloxacin in wild-type and Mdr2((-/-)) mice, a model of cholestasis. Animals underwent [(18)F]ciprofloxacin positron emission tomography at baseline and after norUDCA treatment. After norUDCA treatment, liver-to-blood area under the curve ratio of [(18)F]ciprofloxacin was significantly decreased compared to baseline, both in wild-type (-34.0 ± 2.1%) and Mdr2((-/-)) mice (-20.5 ± 6.0%). [(18)F]Ciprofloxacin uptake clearance from blood into liver was reduced by -17.1 ± 9.0% in wild-type and by -20.1 ± 7.3% in Mdr2((-/-)) mice. Real-time PCR analysis showed significant increases in hepatic Mrp4 and multidrug resistance-associated protein 3 mRNA after norUDCA. Transport experiments in organic anion transporting polypeptide (OATP)1B1-, OATP1B3-, and OATP2B1-transfected cells revealed weak transport of [(14)C]ciprofloxacin by OATP1B3 and OATP2B1 and no inhibition by norUDCA. In conclusion, our data suggest that changes in hepatic [(18)F]ciprofloxacin disposition in mice after norUDCA treatment were caused by induction of basolateral Mrp4 in hepatocytes., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Introduction: Transport of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier (BBB) may confound the interpretation of [(18)F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [(18)F]FDG in vivo by performing [(18)F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [(18)F]FDG brain distribution after transporter inhibition., Methods: Dynamic small-animal PET experiments (60min) were performed with [(18)F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b((-/-)), Abcg2((-/-)) and Abcb1a/b((-/-))Abcg2((-/-))) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15mg/kg, given at 2h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of [(18)F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (Kb,brain)., Results: Kb,brain values of [(18)F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of [(18)F]FDG was significantly lower in tariquidar-treated as compared with vehicle-treated rats (0.350±0.025mL/min/g versus 0.416±0.024mL/min/g, p=0.026, paired t-test) but Kb,brain values were not significantly different between both rat groups., Conclusion: Our results show that [(18)F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of [(18)F]FDG at the mouse BBB., Advances in Knowledge and Implications for Patient Care: Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when interpreting brain [(18)F]FDG PET data., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Positron emission tomography (PET) with [(11)C]verapamil, either in racemic form or in form of the (R)-enantiomer, has been used to measure the functional activity of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) at the blood-brain barrier (BBB). There is some evidence in literature that verapamil inhibits two other ABC transporters expressed at the BBB, i.e. multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). However, previous data were obtained with micromolar concentrations of verapamil and do not necessarily reflect the transporter selectivity of verapamil at nanomolar concentrations, which are relevant for PET experiments. The aim of this study was to assess the selectivity of verapamil, in nanomolar concentrations, for Pgp over MRP1 and BCRP., Methods: Concentration equilibrium transport assays were performed with [(3)H]verapamil (5 nM) in cell lines expressing murine or human Pgp, human MRP1, and murine Bcrp1 or human BCRP. Paired PET scans were performed with (R)-[(11)C]verapamil in female FVB/N (wild-type), Mrp1((-/-)), Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice, before and after Pgp inhibition with 15 mg/kg tariquidar., Results: In vitro transport experiments exclusively showed directed transport of [(3)H]verapamil in Mdr1a- and MDR1-overexpressing cells which could be inhibited by tariquidar (0.5μM). In PET scans acquired before tariquidar administration, brain-to-blood ratio (Kb,brain) of (R)-[(11)C]verapamil was low in wild-type (1.3 ± 0.1), Mrp1((-/-)) (1.4 ± 0.1) and Bcrp1((-/-)) mice (1.8 ± 0.1) and high in Mdr1a/b((-/-)) (6.9 ± 0.8) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (7.9 ± 0.5). In PET scans after tariquidar administration, Kb,brain was significantly increased in Pgp-expressing mice (wild-type: 5.0 ± 0.3-fold, Mrp1((-/-)): 3.2 ± 0.6-fold, Bcrp1((-/-)): 4.3 ± 0.1-fold) but not in Pgp knockout mice (Mdr1a/b((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)))., Conclusion: Our combined in vitro and in vivo data demonstrate that verapamil, in nanomolar concentrations, is selectively transported by Pgp and not by MRP1 and BCRP at the BBB, which supports the use of (R)-[(11)C]verapamil or racemic [(11)C]verapamil as PET tracers of cerebral Pgp function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood-brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer's or Parkinson's disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [(11)C]elacridar and [(11)C]tariquidar to visualize Pgp density in rat brain with PET., Methods: Rats underwent a first PET scan with [(11)C]elacridar (n = 5) or [(11)C]tariquidar (n = 6) followed by a second scan with the Pgp substrate (R)-[(11)C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3 mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution (VT) of radiotracers in different brain regions., Results: Brain PET signals of [(11)C]elacridar and [(11)C]tariquidar were very low (~0.5 standardized uptake value, SUV). There was a significant negative correlation between VT and K1 (i.e. influx rate constant from plasma into brain) values of [(11)C]elacridar or [(11)C]tariquidar and VT and K1 values of (R)-[(11)C]verapamil in different brain regions which was consistent with binding of [(11)C]inhibitors to Pgp and efflux of (R)-[(11)C]verapamil by Pgp., Conclusion: The small Pgp binding signals obtained with [(11)C]elacridar and [(11)C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: With the aim to develop a PET tracer to visualize P-glycoprotein (Pgp) expression levels in different organs, the Pgp inhibitor MC113 was labeled with (11)C and evaluated using small-animal PET., Methods: [(11)C]MC113 was synthesized by reaction of O-desmethyl MC113 with [(11)C]methyl triflate. Small-animal PET was performed with [(11)C]MC113 in FVB wild-type and Mdr1a/b((-/-)) mice (n=3 per group) and in a mouse model of high (EMT6Ar1.0) and low (EMT6) Pgp expressing tumor grafts (n=5). In the tumor model, PET scans were performed before and after administration of the reference Pgp inhibitor tariquidar (15mg/kg)., Results: Brain uptake of [(11)C]MC113, expressed as area under the time-activity curve from time 0 to 60min (AUC(0-60)), was moderately but not significantly increased in Mdr1a/b((-/-)) compared with wild-type mice (mean±SD AUC(0-60), Mdr1a/b((-/-)): 88±7min, wild-type: 62±6min, P=0.100, Mann Whitney test). In the tumor model, AUC(0-60) values were not significantly different between EMT6Ar1.0 and EMT6 tumors. Neither in brain nor in tumors was activity concentration significantly changed in response to tariquidar administration. Half-maximum effect concentrations (IC(50)) for inhibition of Pgp-mediated rhodamine 123 efflux from CCRFvcr1000 cells were 375±60nM for MC113 versus 8.5±2.5nM for tariquidar., Conclusion: [(11)C]MC113 showed higher brain uptake in mice than previously described Pgp PET tracers, suggesting that [(11)C]MC113 was only to a low extent effluxed by Pgp. However, [(11)C]MC113 was found unsuitable to visualize Pgp expression levels presumably due to insufficiently high Pgp binding affinity of MC113 in relation to Pgp densities in brain and tumors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: The multidrug efflux transporter breast cancer resistance protein (BCRP) is highly expressed in the blood-brain barrier (BBB), where it limits brain entry of a broad range of endogenous and exogenous substrates. Methyl is a recently discovered BCRP-selective inhibitor, which is structurally derived from the potent P-glycoprotein (P-gp) inhibitor tariquidar. The aim of this study was to develop a new PET tracer based on 1 to map BCRP expression levels in vivo., Methods: Compound 1 was labelled with (11)C in its methyl ester function by reaction of the corresponding carboxylic acid 2 with [(11)C]methyl triflate. Positron emission tomography (PET) imaging of [(11)C]-1 was performed in wild-type, Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3 per mouse type) and radiotracer metabolism was assessed in plasma and brain., Results: Brain-to-plasma ratios of unchanged [(11)C]-1 were 4.8- and 10.3-fold higher in Mdr1a/b((-/-)) and in Mdr1a/b((-/-))Bcrp1((-/-)) mice, respectively, as compared to wild-type animals, but only modestly increased in Bcrp1((-/-)) mice. [(11)C]-1 was rapidly metabolized in vivo giving rise to a polar radiometabolite which was taken up into brain tissue., Conclusion: Our data suggest that [(11)C]-1 preferably interacts with P-gp rather than BCRP at the murine BBB which questions its reported in vitro BCRP selectivity. Consequently, [(11)C]-1 appears to be unsuitable as a PET tracer to map cerebral BCRP expression., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to determine whether a model for predicting vaginal birth after cesarean (VBAC) can also predict the probabilty of morbidity associated with a trial of labor (TOL)., Study Design: Using a previously published prediction model, we categorized women with 1 prior cesarean by chance of VBAC. Prevalence of maternal and neonatal morbidity was stratfied by probability of VBAC success and delivery approach., Results: Morbidity became less frequent as the predicted chance of VBAC increased among women who underwent TOL (P < .001) but not elective repeat cesarean section (ERCS) (P > .05). When the predicted chance of VBAC was less than 70%, women undergoing a TOL were more likely to have maternal morbidity (relative risk [RR], 2.2; 95% confidence interval [CI], 1.5-3.1) than those who underwent an ERCS; when the predicted chance of VBAC was at least 70%, total maternal morbidity was not different between the 2 groups (RR, 0.8; 95% CI, 0.5-1.2). The results were similar for neonatal morbidity., Conclusion: A prediction model for VBAC provides information regarding the chance of TOL-related morbidity and suggests that maternal morbidity is not greater for those women who undergo TOL than those who undergo ERCS if the chance of VBAC is at least 70%.

Objective: The objective of the study was to determine whether myometrial electrical activity can differentiate false from true preterm labor., Study Design: Electrical uterine myography (EUM) was measured prospectively on 87 women, gestational age less than 35 weeks. The period between contractions, power of contraction peaks and movement of center of electrical activity (RMS), was used to develop an index score (1-5) for prediction of preterm delivery (PTD) within 14 days of the test. The score was compared with fetal fibronectin (fFN) and cervical length (CL)., Results: Patients delivering within 14 days from testing showed a higher index and mean RMS (P = .000). No patients with EUM index scores of 1-2 delivered in this time frame. Combining EUM with CL or fFN increased predictability. Logistic regression revealed that history of PTD and EUM index had 4- to 5-fold increased risk for PTD. Gestational age at testing, body mass index, fFN, and CL were nonsignificant contributors to PTD risk., Conclusion: Measuring myometrial electrical activity may enhance identification of patients in true premature labor.

Objective: The purpose of this study was to develop a model that predicts individual-specific risk of uterine rupture during an attempted vaginal birth after cesarean delivery., Study Design: Women with 1 previous low-transverse cesarean delivery who underwent a trial of labor with a term singleton were identified in a concurrently collected database of deliveries that occurred at 19 academic centers during a 4-year period. We analyzed different classification techniques in an effort to develop an accurate prediction model for uterine rupture., Results: Of the 11,855 women who were available for analysis, 83 women (0.7%) had had a uterine rupture. The optimal final prediction model, which was based on a logistic regression, included 2 variables: any previous vaginal delivery (odds ratio, 0.44; 95% CI, 0.27-0.71) and induction of labor (odds ratio, 1.73; 95% CI, 1.11-2.69). This model, with a c-statistic of 0.627, had poor discriminating ability and did not allow the determination of a clinically useful estimate of the probability of uterine rupture for an individual patient., Conclusion: Factors that were available before or at admission for delivery cannot be used to predict accurately the relatively small proportion of women at term who will experience a uterine rupture during an attempted vaginal birth after cesarean delivery.

Objective: This study was undertaken to evaluate the effect of change of shift for physicians and nurses on complications associated with cesarean delivery., Study Design: 17,996 term women undergoing an unscheduled cesarean delivery in 13 centers from 1999-2000 were included. Maternal and neonatal morbidities were evaluated by time of infant delivery vis-à-vis nursing change of shift (6 AM-8 AM, 2 PM-4 PM, 10 PM-12 AM vs all other hours). The sample was then limited to weekdays only and physician shift changes were evaluated (physician shift change 6 AM-8 AM, 5 PM-7 PM vs all others). A composite of 30 maternal morbidities was also evaluated by logistic regression, controlling for potentially confounding factors., Results: Physician change of shift had no measurable effect on maternal and neonatal outcomes. Neonatal facial nerve palsies were increased at nursing change of shift (5 vs 0) as were hysterectomies (33 [0.24%] vs 23 [0.53%]; P < .007). Nursing change of shift had no impact on composite maternal morbidity after controlling for age, race, insurance, medical problems, prior incision type, weekend day, and prenatal care (odds ratio = 0.98; 95% confidence interval = 0.89-1.08)., Conclusion: Physician change of shift does not appear to be associated with an increase in morbidities. However, cesarean delivery during nursing change of shift is associated with increased risk of neonatal facial nerve palsy and hysterectomy. Further investigation is needed to understand the cause of this association.

Objective: Studies suggest that sleep deprivation adversely affects performance. We hypothesized that cesarean delivery complications would be more frequent during the night shift (11 pm-7 am), and evaluated morbidities by delivery shift., Study Design: Eighteen thousand nine hundred and thirty-nine term women undergoing an unscheduled cesarean delivery in 13 centers from 1999 to 2000 within a prospective observational study were included. Maternal/neonatal morbidities and time from decision to cesarean delivery were evaluated by time of delivery (7 am-3 pm, 3 pm-11 pm, 11 pm-7 am). A composite of maternal morbidities was evaluated by logistic regression controlling for potentially confounding factors., Results: Controlling for age, race, insurance, cardiac disease, preeclampsia, diabetes, previous incision type, and prenatal care, shift of delivery had no impact on maternal morbidity (11 pm-7 am OR 0.9 [95% CI 0.81-1.0]). NICU admissions were slightly increased at night but neonatal complications were not., Conclusion: Maternal and neonatal complications of cesarean delivery do not increase with delivery during the night shift.

Objective: This study was undertaken to compare success rates of vaginal birth after cesarean (VBAC) delivery, and uterine rupture as well as maternal/perinatal outcomes between women with preterm and term pregnancies undergoing trial of labor (TOL), and to compare maternal and neonatal morbidities in those women with preterm pregnancies undergoing a TOL versus repeat cesarean delivery without labor (RCD)., Study Design: Prospective 4-year observational study of women with a singleton gestation and a prior cesarean delivery at 19 academic centers. Clinical characteristics, maternal complications and VBAC delivery success for those with a preterm (24(0)-36(6) weeks) TOL, preterm RCD and term TOL (> or = 37 weeks) were analyzed., Results: Among 3119 preterm pregnancies with prior cesarean delivery, 2338 (75%) underwent a TOL. 15,331 women undergoing TOL at term were also analyzed as a control group. TOL success rates for preterm and term pregnancies were similar (72.8% vs 73.3%, P = .64). Rates of uterine rupture (0.34% vs 0.74%, P = .03) and dehiscence (0.26% vs 0.67%, P = .02) were lower in preterm compared with term TOL. Thromboembolic disease, coagulopathy and transfusion were more common in women undergoing a preterm TOL than those at term. Among women undergoing a preterm TOL, rates of uterine dehiscence, coagulopathy, transfusion, and endometritis were similar to those having a preterm RCD. After controlling for gestational age at delivery and race, neonatal outcomes such as Neonatal Intensive Care Unit (NICU) admission, intraventricular hemorrhage, sepsis, and ventilatory support were similar in both groups except for a higher rate of respiratory distress syndrome in those delivered after a TOL., Conclusion: The likelihood of VBAC success after TOL in preterm pregnancies is comparable to term gestations, with a lower risk of uterine rupture. Perinatal outcomes are similar with preterm TOL and RCD. TOL should be considered as an option for women undergoing preterm delivery with a history of prior cesarean delivery.

Objective: The purpose of this study was to determine the influence of change in infant birth weight between pregnancies on the outcome of a trial of labor for women whose first cesarean delivery was performed for dystocia., Study Design: Secondary analysis of 7081 patients with 1 previous cesarean delivery and no other deliveries after 20 weeks' gestation, undergoing a trial of labor with a singleton gestation. Cases were classified as dystocia if the listed indication for the cesarean delivery in the first pregnancy was failed induction, cephalo-pelvic disproportion, failure to progress, or failed forceps or vacuum. Outcomes of the trial of labor were correlated with fetal size relative to birth weight in the initial pregnancy for those women whose initial cesarean delivery was for dystocia and those with other indications., Results: For the cohort being studied (n = 7081), dystocia was the indication for the first cesarean delivery for 3182 (44.9%). Trial of labor resulted in vaginal delivery for 54% of patients whose first cesarean delivery was performed for dystocia, compared with 67% for those with other indications (P < .01). For those whose first cesarean delivery was for dystocia, trial of labor success was correlated with birth weight differences between the pregnancies, with only 38% delivering vaginally if the trial of labor birth weight exceeded the initial pregnancy birth weight by more than 500 g. Using logistic regression and adjusting for other potential confounding factors, the odds of success decreased by 3.8% for each increase of 100 g in birth weight in the trial of labor relative to the first birth weight., Conclusion: For women with previous cesarean delivery for dystocia, increasing birth weight in the subsequent trial of labor relative to the first birth weight diminishes the chances of successful vaginal delivery.

Objective: The objective of the study was to estimate whether midpregnancy genitourinary tract infection with Chlamydia trachomatis is associated with an increased risk of subsequent preterm delivery., Study Design: Infection with C. trachomatis was determined using a ligase chain reaction assay (performed in batch after delivery) of voided urine samples collected at the randomization visit (16(0/7) to 23(6/7) weeks' gestation) and the follow-up visit (24(0/7) to 29(6/7) weeks) among 2470 gravide women with bacterial vaginosis or Trichomonas vaginalis infection enrolled in 2 multicenter randomized antibiotic treatment trials (metronidazole versus. placebo)., Results: The overall prevalence of genitourinary tract C. trachomatis infection at both visits was 10%. Preterm delivery less than 37 weeks' or less than 35 weeks' gestational age was not associated with the presence or absence of C. trachomatis infection at either the randomization (less than 37 weeks: 14% versus 13%, P=.58; less than 35 weeks: 6.4% versus 5.5%, P=.55) or the follow-up visit (less than 37 weeks: 13% versus 11%, P=.33; less than 35 weeks: 4.4% versus 3.7, P=.62). Treatment with an antibiotic effective against chlamydia infection was not associated with a statistically significant difference in preterm delivery., Conclusion: In this secondary analysis, midtrimester chlamydia infection was not associated with an increased risk of preterm birth. Treatment of chlamydia was not associated with a decreased frequency of preterm birth.

Objective: This study was undertaken to estimate the frequency of inflammatory cytokine and Toll-like receptor gene polymorphisms in women with and without bacterial vaginosis (BV) in pregnancy., Study Design: A secondary analysis was performed of pregnant women at less than 30 weeks' gestation enrolled as part of 2 multicenter studies. Eight hundred eighty-five women were assessed for BV (defined as Nugent's vaginal Gram stain score 7-10 and a pH > 4.5). Comparisons were made between women with or without BV. Extracted maternal DNA was analyzed for 7 cytokine (interleukin [IL] 1beta-511, IL1beta Exon 5 +3954, IL6-174, IL8-845, IL10-1082, tumor necrosis factor alpha-238 [TNFalpha-238], TNFalpha-308) and 2 Toll-like receptor (TLR-4 299, TLR-4 399) gene polymorphisms., Results: BV was diagnosed in 497 women and 388 did not have BV. Genotype and allele frequency analyses revealed associations with BV and polymorphisms at the IL1beta Exon 5 +3954, IL6-174, IL10-1082, and TLR-4 399 loci. Women with BV were less likely to be homozygous (C/C) for IL1beta Exon 5 +3954 (P = .04). Women with BV were also less likely to have polymorphisms at the IL10-1082 (P = .03) and TLR-4 399 (P = .04) loci in the univariate analysis. Women with BV were more likely to be heterozygous (G/C) for the IL6-174 genotype (P < .0001). Multivariate analysis, controlling for maternal race, confirmed the following associations with BV: IL1beta Exon 5 +3954 (odds Ratio [OR] 0.5, 95% CI 0.3-0.9) and IL6-174 (OR 2.2, 95% CI 1.6-3.1). In addition, polymorphism at the IL8-845 locus was associated with a decreased risk for BV (OR 0.6, 95% CI 0.4-1.0)., Conclusion: After controlling for race, polymorphisms at the IL1beta Exon 5 +3954, IL6-174, and IL8-845 loci were associated with an altered rate of BV in pregnancy.

Objective: The purpose of this study was to determine which factors influence the likelihood of successful trial of labor (TOL) after 1 previous cesarean delivery (CD)., Study Design: We performed a multicenter 4-year prospective observational study (1999-2002) of all women with previous CD undergoing TOL. Women with term singleton pregnancies with 1 previous low transverse CD or unknown incision were included for analysis., Results: Fourteen thousand five hundred twenty-nine women underwent TOL, with 10,690 (73.6%) achieving successful VBAC. Women with previous vaginal birth had an 86.6% success rate compared with 60.9% in women without such a history (odds ratio [OR] 4.2; 95% CI 3.8-4.5; P < .001). TOL success rates were affected by previous indication for CD, need for induction or augmentation, cervical dilation on admission, birth weight, race, and maternal body mass index. Multivariate logistic regression analysis identified as predictive of TOL success: previous vaginal delivery (OR 3.9; 95% CI 3.6-4.3), previous indication not being dystocia (CPD/FTP) (OR 1.7; 95% CI 1.5-1.8), spontaneous labor (OR 1.6; 95% CI 1.5-1.8), birth weight <4000 g (OR 2.0; 95% CI 1.8-2.3), and Caucasian race (OR 1.8, 95% CI 1.6-1.9) (all P < .001). The overall TOL success rate in obese women (BMI > or = 30) was lower (68.4%) than in nonobese women (79.6%) (P < .001), and when combined with induction and lack of previous vaginal delivery, successful VBAC occurred in only 44.2% of cases., Conclusion: Previous vaginal delivery including previous VBAC is the greatest predictor for successful TOL. Previous indication as dystocia, need for labor induction, or a maternal BMI > or = 30 significantly lowers success rates.

Objective: The purpose of this study was to define independent risk factors for uterine atony after primary cesarean delivery, and to assess their overall association with atony in the study cohort., Study Design: This was a 13-university center prospective observational study. All women who underwent primary cesarean from January 1, 1999 to December 31, 2000 were eligible. Trained and certified research nurses performed systematic data abstraction. The definition of atony required both the clinical diagnosis and the use of methergine or a prostaglandin preparation. Risk factors for uterine atony were assessed in univariable and multivariable logistic regression analyses, and these analyses then used to inform an assessment of the association of the various risk factors with the occurrence of uterine atony in the overall cohort., Results: Twenty-three thousand, three hundred and ninety pregnancies were analyzed. Uterine atony occurred in 1416 women (6%). Several variables were independently associated with atony in a multivariable model, including multiple gestation (odds ratio [OR] 2.40, 95% CI 1.95-2.93), maternal Hispanic race (2.21, 1.90-2.57), induced or augmented labor for >18 hours (2.23, 1.92-2.60), infant birth weight >4500 g (2.05, 1.53-2.69), and clinically diagnosed chorioamnionitis (1.80, 1.55-2.09). However, because the various risk factors were not very powerful, approximately half of the cases of atony were associated with the 2/3 of women lacking a given risk factor or combination of risk factors., Conclusion: Although certain risk factors and uterine atony were clearly associated, the associations are of limited practical clinical use.

Objective: The purpose of this study was to identify the success rates and risks in women with a twin pregnancy who attempt a trial of labor after cesarean delivery., Study Design: Cases were identified in the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network's Cesarean Registry with a woman with a twin pregnancy who had had at least 1 previous cesarean delivery., Results: During the study period (1999-2002), 412 women fulfilled the study criteria, and 226 women had elective repeat cesarean delivery. Of the 186 women (45.1% of total) who attempted a trial of labor, 120 women were delivered successfully (success rate, 64.5%), and 66 women (35.5%) had a failed trial of labor. Thirty of the failed trials of labor involved a vaginal delivery for twin A and cesarean delivery for twin B. Women who attempted a trial of labor with twins had no increased risk of transfusion, endometritis, intensive care unit admissions, or uterine rupture when compared with elective repeat cesarean delivery. Fetal and neonatal complications were uncommon in either group at>or=34 weeks of gestation., Conclusion: A trial of labor with twins after previous cesarean delivery does not appear to increase maternal morbidity. Perinatal morbidity is uncommon at>or=34 weeks of gestation.

Objective: We sought to investigate the relationship between prepregnancy weight, treatment modality (diet or insulin), level of glycemic control, and pregnancy outcome., Study Design: We recruited women with gestational diabetes (GDM) from inner city prenatal clinics. All women were instructed in the use of an intensified management protocol using memory reflectance meters. Outcomes were analyzed according to maternal prepregnancy body mass index (BMI, kg/m 2 ) categories: normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), and obese (BMI > or =30), and by diet or insulin therapy and glycemic control (mean blood glucose <100 mg/dL = good control). Pregnancy outcome variables included a composite outcome (at least 1 of the following: neonatal metabolic complications, large-for-gestational age or macrosomic infants, NICU admission for >24 hours, and the need for respiratory support) (not including oxygen therapy). In addition to composite outcome, a bivariate analysis was performed for each single variable, including preeclampsia and cesarean section delivery., Results: Four thousand and one women were enrolled. Obese women who achieved targeted levels of glycemic control had comparable pregnancy outcomes to normal weight and overweight women only when they were treated with insulin. Normal weight women treated with diet therapy who achieved targeted levels of glycemic control had good outcomes, but obese women treated with diet therapy who achieved targeted levels of glycemic control, nevertheless, had a 2- to 3-fold higher risk for adverse pregnancy outcome when compared with overweight and normal weight patients with well-controlled GDM. Women with GDM who failed to achieve established levels of glycemic control had significantly higher adverse pregnancy outcomes in all 3 maternal weight groups., Conclusion: In obese women with BMI > or =30 with GDM, achievement of targeted levels of glycemic control was associated with enhanced outcome only in women treated with insulin.

Objective: Untreated gestational diabetes mellitus carries significant risks of perinatal morbidity at all severity levels; treatment will enhance outcome., Study Design: A matched control of 555 gravidas, gestational diabetes mellitus diagnosed after 37 weeks, were compared with 1110 subjects treated for gestational diabetes mellitus and 1110 nondiabetic subjects matched from the same delivery year for obesity, parity, ethnicity, and gestational age at delivery. The nondiabetic subjects and those not treated for gestational diabetes mellitus were matched for prenatal visits., Results: A composite adverse outcome was 59% for untreated, 18% for treated, and 11% for nondiabetic subjects. A 2- to 4-fold increase in metabolic complications and macrosomia/large for gestational age was found in the untreated group with no difference between nondiabetic and treated subjects. Comparison of maternal size, parity, and disease severity revealed a 2- to 3-fold higher morbidity rate for the untreated groups, compared with the other groups., Conclusion: Untreated gestational diabetes mellitus carries significant risks for perinatal morbidity in all disease severity levels. Timely and effective treatment may substantially improve outcome.

Objective: It is stated commonly that the earlier in pregnancy bacterial vaginosis is diagnosed, the greater is the increase in risk of preterm birth compared with women without bacterial vaginosis. However, this contention is based on small numbers of women., Study Design: In this analysis of 12,937 women who were screened for bacterial vaginosis as part of a previously conducted clinical trial, the odds ratio of preterm birth (<7 weeks of gestation) for asymptomatic bacterial vaginosis-positive versus bacterial vaginosis-negative women was evaluated among women who were screened from 8 to 22 weeks of gestation., Results: The odds ratio of preterm birth among bacterial vaginosis-positive versus bacterial vaginosis-negative women ranged from 1.1 to 1.6 and did not vary significantly according to the gestational age at which bacterial vaginosis was screened. The odds ratio for preterm birth did not vary significantly by gestational age at diagnosis when bacterial vaginosis was subdivided into Gram stain score 7 to 8 or 9 to 10., Conclusion: Although bacterial vaginosis was associated with an increased risk of preterm birth, the gestational age at which bacterial vaginosis was screened for and diagnosed did not influence the increase.

Objective: We sought to investigate the association between glyburide dose, degree of severity in gestational diabetes mellitus (GDM), level of glycemic control, and pregnancy outcome in insulin- and glyburide-treated patients., Study Design: In a secondary analysis of our previous randomized study, 404 women were analyzed. The association among glyburide dose, severity of GDM, and selected maternal and neonatal factors was evaluated. Severity levels of GDM were stratified by fasting plasma glucose (FPG) from the oral glucose tolerance test (OGTT). Infants with birth weight at or above the 90th percentile were considered large-for-gestational age (LGA). Macrosomia was defined as birth weight > or =4000 g. Well-controlled was defined as mean blood glucose < or =95 mg/dL. The association between glyburide- and insulin-treated patients by severity of GDM and neonatal outcome was evaluated., Results: The dose received for the glyburide-treated patients was 2.5 mg-32%; 5 mg-23%; 10 mg-17%; 15 mg-8%; and 20 mg-20%. Patients were grouped into low (< or =10 mg) and high (>10 mg) daily dose of glyburide. A comparison between severity of the disease (fasting plasma glucose categories) and highest dose of glyburide revealed a significant difference between the low-95 FPG and the other severity categories (P = .02). Of patients in the well-controlled glycemic group, only 6% required the high dose of glyburide (>10 mg). In patients with poor glycemic control (mean blood glucose >95 mg/dL), 38% received the high dose of glyburide (P = .0001). Comparison between the high glyburide (>10 mg) and the low glyburide dosages (< or =10 mg) revealed that the rate of macrosomia was 16% vs 5% and LGA 22% vs 8%, (P = .01), respectively. No significant difference was found in composite outcome, metabolic complications, and Ponderal Index between the 2 dose groups. Stratification by disease severity revealed a significantly lower rate of LGA for both the glyburide- and insulin-treated subjects. No significant difference was found between metabolic, respiratory, and neonatal intensive care unit (NICU) for patients within each fasting plasma glucose severity category., Conclusion: Glyburide and insulin are equally efficient for treatment of GDM in all levels of disease severity. Achieving the established level of glycemic control, not the mode of pharmacologic therapy, is the key to improving the outcome in GDM.

Objectives: We sought to determine if the rate of preeclampsia is related to the severity of gestational diabetes mellitus (GDM), and if it can be decreased by optimizing glycemic control., Study Design: A retrospective analysis of prospectively collective data of 1813 patients with GDM was performed to determine the rate of preeclampsia. Patients were stratified after treatment was begun by level of glycemic control (well controlled was defined as mean blood glucose <95 mg/dL). The extent of hyperglycemia was analyzed by the level of the abnormality in the oral GTT and by the degree of abnormality of daily glucose control after treatment has begun. Severity of GDM was categorized using fasting plasma glucose (FPG) on a 3-hour oral GTT by 10 mg/dL increments., Results: Overall, preeclampsia was diagnosed in 9.6% (174/1813) of diabetic patients. The GDM subjects who developed preeclampsia were significantly younger, had a higher nulliparity rate, were more obese, and gained significantly more weight during pregnancy. However, no difference was found in glycemic profile characteristics between the 2 groups. A comparison between patients with FPG <105 and FPG >105 revealed that the rate of preeclampsia increased significantly, 7.8% vs 13.8%, (O.R 1.81, 95%CI 1.3-2.51). For GDM patients with only mild hyperglycemia (FPG <105 mg/dL), no significant difference was found in the rate of preeclampsia. Preeclampsia rate was further evaluated in relation to level of glycemic control; for the well-controlled patients (mean blood glucose [MBG] <95 mg/dL, n=994), similar rates of preeclampsia were found between each category of FPG severity. In contrast, in poorly controlled patients (MBG >95 mg/dL, n=819), a comparison between severity threshold of FPG <115 and FPG >115 revealed that the preeclampsia rate was 9.8% vs 18% (O.R 2.56, 95%C.I. 1.5-4.3). In a logistic regression model, only prepregnancy BMI (O.R 2.3, 95%CI 1.16-2.30) and severity of GDM (O.R 1.7, 95%CI 1.21-2.38) were independently and significantly associated with an increased risk of preeclampsia., Conclusion: The rate of preeclampsia is influenced by the severity of GDM and prepregnancy BMI. Optimizing glucose control during pregnancy may decrease the rate of preeclampsia, even in those with a greater severity of GDM.

Objective: A paucity of data exists concerning the normal glycemic profile in nondiabetic pregnancies. Using a novel approach that provides continuous measurement of blood glucose, we sought to evaluate the ambulatory daily glycemic profile in the second half of pregnancy in nondiabetic women., Study Design: Fifty-seven obese and normal weight nondiabetic subjects were evaluated for 72 consecutive hours with continuous glucose monitoring by measurement interstitial glucose levels in subcutaneous tissue every 5 minutes. Subjects were instructed not to modify their lifestyle or to follow any dietary restriction. For each woman, mean and fasting blood glucose values were determined; for each meal during the study period, the first 180 minutes were analyzed., Results: For the study group, the fasting blood glucose level was 75 +/- 12 mg/dL; the mean blood glucose level was 83.7 +/- 18 mg/dL; the postprandial peak glucose value level was 110 +/- 16 mg/dL, and the time interval that was needed to reach peak postprandial glucose level was 70 +/- 13 minutes. A similar postprandial glycemic profile was obtained for breakfast, lunch, and dinner. Obese women were characterized by a significantly higher postprandial glucose peak value, increased 1- and 2-hour postprandial glucose levels, increased time interval for glucose peak, and significantly lower mean blood glucose during the night. No difference was found in fasting and mean blood glucose between obese and nonobese subjects., Conclusion: Glycemic profile characterization in both obese and normal weight nondiabetic subjects provide a measure for the desired level of glycemic control in pregnancy that is complicated with diabetes mellitus.

Objective: A controversy exists regarding the time to monitor blood glucose in the diabetic pregnancy (60 or 120 minutes after meals). Using a novel approach that provides continuous measurement of blood glucose, we sought to determine postprandial glucose profile in the diabetic pregnancy., Study Design: Subjects were connected to a continuous glucose monitoring system for 72 consecutive hours. A continuous glucose monitoring system measures the interstitial glucose levels in subcutaneous tissue every 5 minutes. Women were instructed to record the time of each meal during the study period. For each meal, the first 240 minutes were analyzed., Results: Sixty-five women participated in the study: 26 women were treated by diet alone; 19 women received insulin therapy, and 20 women had type 1 diabetes mellitus. The time interval from meal to peak postprandial glucose levels was similar in all the evaluated types of diabetic pregnancies and in good and poor control insulin-treated patients with gestational diabetes mellitus (approximately 90 minutes). Failure to return to preprandial glucose values within a 3-hour observation period was identified in approximately 50% of the patients. A similar postprandial glucose peak time was obtained for breakfast, lunch, and dinner in all study groups. Postprandial hypoglycemia events were noted in approximately 10% of the meals and occurred about 160 minutes after mealtime., Conclusion: The time interval for postprandial glucose peak in diabetic pregnancies is approximately 90 minutes after meals throughout the day and is not affected by the level of glycemic control. This information should be considered in the treatment of diabetes mellitus in pregnancy.

Objective: This study was undertaken to determine whether the number and gestational age of prior preterm deliveries modifies the significance of endovaginal sonographic cervical length less than 25 mm for the prediction of recurrent preterm birth less than 35 weeks' gestation., Study Design: Secondary analysis of a multicenter, blinded, observational study. Endovaginal ultrasonographic examinations were scheduled at 2-week intervals between 16 and 23 weeks' gestation in singleton pregnancies of 181 gravid women with at least 1 prior spontaneous preterm birth between 16 and 32 weeks' gestation., Results: The earliest prior preterm birth occurred before 23 weeks in 61 women and at 23.0 to 31 weeks in 115; 5 had missing gestational age data. Cervical length was not different between these 2 groups both at the initial scan (median 38 vs 37 mm, P=.54) and considering the shortest ever observed cervical length over the entire study period (median 30 vs 30 mm, P=.97). Cervical length less than 25 mm was associated with spontaneous preterm birth less than 35 weeks for both groups (positive predictive value 80% vs 71%, P>.99). There were 134 women with 1 prior preterm delivery (74%) and 47 with 2 or more. Cervical lengths were not different between these 2 groups at the initial scan (median 36.5 vs 37 mm, P=.52) or over the entire study period (median 30 vs 32 mm, P=.31). The positive predictive value of cervical length less than 25 mm for subsequent spontaneous premature birth was not significantly higher in gravid women with multiple prior preterm births (100% vs 73%, P>.99)., Conclusion: Neither the number nor the gestational age of prior preterm births modify the predictive value of a cervical length less than 25 mm at 16 to 19 weeks for recurrent spontaneous preterm birth.

Objective: The study was undertaken to test the hypothesis that shortened midtrimester cervical length is more predictive of early (<26 weeks) than later (26-34 weeks) spontaneous preterm birth., Study Design: This is a secondary analysis of a blinded, multicenter observational study of 183 women with a prior preterm birth. Vaginal sonography was begun at 16 to18 weeks' gestation and scheduled every 2 weeks (maximum 4 scans per patient). Cervical length and any observed dynamic shortening were recorded at each visit to determine the shortest observed cervical length from 16 to 24 weeks' gestation. The shortest cervical length measurements were categorized as less than 25 mm, 25 to 29 mm and 30 mm or greater. The initial cervical length was also compared with the shortest cervical length to categorize patients on the basis of the timing of cervical shortening 30 mm or less. Contingency table, linear regression, and survival analysis were used to analyze the relationship between cervical length groups and spontaneous preterm birth., Results: In both the less than 25 mm and 25 to 29 mm groups, the incidence of spontaneous midtrimester birth (<26 weeks) was higher than the incidence of later (26-34 weeks) preterm birth (<25 mm group: 37% vs 19%; 25-29 mm group: 16% vs 3%, respectively) as compared with women with a shortest cervical length 30 mm or greater, who had rates of 1% and 9% respectively (P <.0001). Similarly, women who had an initial cervical length 30 mm or less and those who shortened their cervix to 30 mm or less before 22 weeks were also more likely to experience a midtrimester than later preterm birth, whereas women who shortened their cervix 30 mm or less later (22-24 weeks) or who maintained a cervical length greater than 30 mm had lower rates of midtrimester than later preterm birth (P <.0001)., Conclusion: Shortened cervical length in the midtrimester preferentially predicts early, as opposed to later, spontaneous preterm birth in high-risk women.

[(11)C]Flumazenil, a highly selective benzodiazepine antagonist is the most extensively used GABA(A) ligand for PET so far. To overcome half life disadvantages of (11)C a [(18)F]-labeled flumazenil derivative, 2'-[(18)F]fluoroflumazenil (FFMZ) was developed and biologically evaluated with respect to the GABA(A) receptor. Organ with the highest uptake was the pituitary gland. Brain uptake was high and followed the order cortex>thalamus>cerebellum>rest brain. Fluoroflumazenil displaced [(3)H]flumazenil binding from membrane GABA(A) receptors with an IC(50)value (3.5 nM) comparable to that of Flumazenil (2.8 nM). The presented data confirm the potential of [(18)F]FFMZ for PET imaging of the GABA-ergic system.

(1R,2S)-4-[18F]fluorometaraminol (4-[18F]FMR), a tracer for cardiac sympathetic innervation, was synthesized by electrophilic aromatic substitution. A trimethylstannyl precursor, protected with tert-butoxycarbonyl protecting groups, was radiofluorinated with high specific radioactivity [18F]F2. Specific radioactivity of 4-[18F]FMR, in average 11.8 +/-3.3 GBq/micromol, was improved 40-800-fold in comparison to the previous electrophilic fluorinations. The biodistribution of 4-[18F]FMR in rat was in accordance with the known distribution of sympathetic innervation. 4-[18F]FMR showed no metabolic degradation in left ventricle of rat heart, where the uptake was high, rapid and specific.

Ciprofloxacin (1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid), a widely-prescribed antibiotic, was labeled with fluorine-18 with the aim to perform positron emission tomography studies in humans for pharmacokinetic measurements. Due to a lack of chemical activation of ciprofloxacin for a direct nucleophilic exchange reaction a novel two-step synthetic approach, which employed an activated 6-fluoro-7-chloro substituted precursor molecule, was developed. The radiosynthesis yielded, starting from 52.5 +/- 11.3 GBq of [(18)F]fluoride, 1.3 +/- 0.6 GBq (n = 13) [(18)F]ciprofloxacin ready for intravenous administration in about 130 min synthesis time. A series of analytical tests was performed in order to prove the identity of the radiolabeled compound and its suitability for human applications.

Objective: The purpose of this study was to determine whether sexual intercourse was associated with the treatment efficacy or the incidence of preterm birth in two large randomized trials in which metronidazole treatment of bacterial vaginosis or Trichomonas vaginalis did not reduce preterm birth., Study Design: Secondary analysis of two multicenter, double-blind, placebo-controlled trials in which women with asymptomatic bacterial vaginosis on Gram stain or asymptomatic T vaginalis on culture were randomized at 16 to 23 weeks of gestation to metronidazole or placebo. In both studies, women took 2 g of metronidazole or placebo in the presence of a nurse (first dose) and were given a second dose to take 48 hours later. This regimen was repeated (third and fourth doses) at 24 to 29 weeks. At the time of the third dose, bacterial vaginosis and T vaginalis specimens were collected again. Patients who were randomly selected to receive metronidazole were analyzed for bacterial vaginosis and T vaginalis at 24 to 29 weeks and for preterm birth of <37 weeks of gestation, according to intercourse between first and second doses and between the second and third doses. Continuous variables were compared with the use of the Wilcoxon rank-sum test; categoric variables were compared with the use of the chi(2 ) test, Fisher exact test, or the Mantel-Haenzel test of trend., Results: Sexual intercourse between the first and second doses or between the second and third doses did not influence the incidence of bacterial vaginosis (18% vs 24%; relative risk, 0.7; 95% CI, 0.5-1.1; and 23% vs 20%; relative risk, 1.2; 95% CI, 0.9-1.6, respectively) or T vaginalis (4% vs 8%; relative risk, 0.5; 95% CI, 0.1-3.6; and 5% vs 10%; relative risk, 0.5; 95% CI, 0.2-1.1; respectively) at 24 to 29 weeks of gestation compared with no intercourse. In the T vaginalis trial, sexual intercourse between the first and second doses or between the second and third doses did not influence the incidence of preterm birth (13% vs 17%; relative risk, 0.8; 95% CI, 0.3-2.1; and 16% vs 17%; relative risk, 1.0; 95% CI, 0.6-1.6; respectively) compared with no intercourse. In the bacterial vaginosis trial, although sexual intercourse between the first and second doses did not influence the incidence of preterm birth (11% vs 12%; relative risk, 0.9; 95 % CI, 0.6-1.5), sexual intercourse between the second and third doses was associated with a reduction in the incidence of preterm birth (10% vs 16%; relative risk, 0.6; 95% CI, 0.4-0.9) compared with no intercourse., Conclusion: Sexual intercourse was associated with neither the efficacy of metronidazole treatment of bacterial vaginosis or T vaginalis nor with the incidence of preterm birth. In the bacterial vaginosis study, intercourse between the second and third doses had a negative association with preterm birth.

The dopamine D(4) receptor (D(4)R) is expressed in low density in various extrastriatal brain regions. This receptor subtype is discussed in relation to the pathophysiology and treatment of schizophrenia but no selective positron emission tomography (PET) ligand is available to date to study the distribution in vivo. The arylpiperazine derivative N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (PB-12) is a novel, high-affinity ( K(i)=0.040 nM) and selective D(4)R ligand. We radiolabeled PB-12 with carbon-11 (t(1/2) 20.4 min) by O-methylation of the corresponding desmethyl analogue N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-hydroxybenzamide (LM-190) with [(11)C]methyl triflate. Derivative LM-190 was prepared by condensing 3-hydroxybenzoic acid with the appropriate amine. For the radiolabeling, the incorporation yield was >90% and the total synthesis time including high performance liquid chromatography (HPLC) purification was about 35 min. The specific radioactivity of [(11)C]PB-12 at time of injection was 67-118 GBq x micromol(-1). PET studies in a cynomolgus monkey showed a high uptake and widespread distribution of radioactivity in the brain, including the neocortex and thalamus. About 40% of total radioactivity in plasma represented unchanged radioligand at 60 min after injection as determined by HPLC. Pretreatment with the D(4)R ligand 3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1H-pyrollo[2,3-b]pyridine (L-745,870) prior to radioligand injection failed to demonstrate receptor-specific binding in the monkey brain. Furthermore, the brain radioactivity distribution was left unaffected by pretreating with unlabeled PB-12. This failure to detect a D(4)R-specific signal may be related to a very low density of the D(4)R in primate brain, insufficient binding affinity of the radioligand, and a high background of nonspecific binding. It can be concluded from these findings that [(11)C]PB-12 is not suitable to visualize the D(4)R in the primate brain with PET.

Objective: We sought to determine the range of fetal fibronectin values in the vagina from 8 to 22 weeks' gestation, the factors associated with both low and high values, and whether high values are associated with gestational age at birth., Study Design: Vaginal fetal fibronectin was quantitatively determined in a prospective cohort study of 13,360 women being evaluated for participation in the National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit treatment trials for bacterial vaginosis and Trichomonas vaginalis. Fetal fibronectin values were correlated with gestational age at screening, race, the presence of bacterial vaginosis and Trichomonas vaginalis, and gestational age at delivery., Results: Vaginal fetal fibronectin values at each gestational age ranged from unmeasurable to >1000 ng/mL, with median values always being <10 ng/mL. Fetal fibronectin values declined progressively with increasing gestational age at sampling. Bacterial vaginosis and black race were associated with higher values, whereas nulliparity was associated with lower values. High values after 13 weeks' gestation were associated with a 2- to 3-fold increased risk of subsequent spontaneous preterm birth overall and a 4-fold increased risk of very early preterm birth., Conclusion: Elevated vaginal fetal fibronectin levels from 13 to 22 weeks' gestation are associated with a significantly increased risk of spontaneous preterm birth.

The radiolabeled catecholamine analogue (1R, 2S)-6-[(18)F]fluorometaraminol (6-[(18)F]FMR) is a substrate for the neuronal norepinephrine transporter. It has been used as a positron emission tomography (PET) ligand to map sympathetic nerves in dog heart. 6-[(18)F]FMR could be only synthesized with low specific radioactivity, which precluded its use in human subjects. We have recently prepared (1R,2S)-4-[(18)F]fluorometaraminol (4-[(18)F]FMR), a new fluoro-analogue of metaraminol, with high specific radioactivity (56-106 GBq/micromol). In the present study, we demonstrate in rats that 4-[(18)F]FMR possesses similar affinity toward myocardial norepinephrine transport mechanisms as 6-[(18)F]FMR. When compared with control animals, an 80% and 76% reduction in myocardial uptake was observed in animals pretreated with desipramine (an inhibitor of the neuronal norepinephrine transporter) and with reserpine (a blocker of the vesicular storage of monoamines), respectively. The entire radioactivity in rat myocardium represented unmetabolized parent tracer as determined by high performance liquid chromatography analysis of tissue extracts. In dogs, myocardial kinetics of 4-[(18)F]FMR were assessed using PET. A rapid and high uptake was observed, followed by prolonged cardiac retention. A heart-to-lung ratio of 15 was reached 10 min after injection of the radiotracer. Pretreatment with desipramine reduced the heart half-life of 4-[(18)F]FMR by 90% compared with control. Moreover, an infusion of tyramine caused a rapid decline of radioactivity in the heart. This demonstrates that 4-[(18)F]FMR specifically visualizes sympathetic neurons in dog heart. High specific radioactivity 4-[(18)F]FMR is a promising alternative to 6-[(18)F]FMR for myocardial neuronal mapping with PET in humans.

Objective: Our purpose was to determine the impact of the 1997 American Diabetes Association diagnostic criteria for type 2 diabetes mellitus on the rate of postpartum glucose intolerance in women with gestational diabetes., Study Design: Women identified as having gestational diabetes were instructed to undergo a 75-g, 2-hour glucose tolerance test 4 to 6 weeks after delivery. The results were retrospectively categorized with both the 1979 National Diabetes Data Group criteria and those recommended by the American Diabetes Association in 1997., Results: Though the rate of overt diabetes mellitus did not increase when the 1997 American Diabetes Association criteria were used (7.8% vs 5.6%, P = not significant), the rate of impaired glucose metabolism was higher (20.1% vs 5%, P <.001). Most women (28/30, 93%) with a nondiagnostic glucose tolerance test result by the older criteria had abnormal results by the newer criteria. Fifty women had abnormalities of glucose metabolism under 1997 American Diabetes Association criteria; 34% of these women had fasting plasma glucose values in the normal range. Of the 25 women with impaired glucose tolerance, 16 (64%) had only an abnormal 2-hour value, with normal fasting glucose values., Conclusions: The rate of postpartum abnormalities in glucose metabolism more than doubles when the 1997 American Diabetes Association criteria are applied; more women are identified with lesser degrees of impairment. However, relying on fasting glucose levels alone, without glucose tolerance testing, may miss one third of women with such abnormalities.

Epidepride [(S)-(-)-N-([1-ethyl-2-pyrrolidinyl]methyl)-5-iodo-2,3-dimethoxybenza mide] binds with a picomolar affinity (Ki = 24 pM) to the dopamine D2 receptor. Iodine-123-labeled epidepride has been used previously to study striatal and extrastriatal dopamine D2 receptors with single photon emission computed tomography (SPECT). Our aim was to label epidepride with carbon-11 for comparative quantitative studies between positron emission tomography (PET) and SPECT. Epidepride was synthesized from its bromo-analogue FLB 457 via the corresponding trimethyl-tin derivative. In an alternative synthetic pathway, the corresponding substituted benzoic acid was reacted with the optically pure aminomethylpyrrolidine-derivative. Demethylation of epidepride gave the desmethyl-derivative, which was reacted with [11C]methyl triflate. Total radiochemical yield was 40-50% within a total synthesis time of 30 min. The specific radioactivity at the end of synthesis was 37-111 GBq/micromol (1,000-3,000 Ci/mmol). Human postmortem whole-hemisphere autoradiography demonstrated dense binding in the caudate putamen, and also in extrastriatal areas such as the thalamus and the neocortex. The binding was inhibited by unlabeled raclopride. PET studies in a cynomolgus monkey demonstrated high uptake in the striatum and in several extrastriatal regions. At 90 min after injection, uptake in the striatum, thalamus and neocortex was about 11, 4, and 2 times higher than in the cerebellum, respectively. Pretreatment experiment with unlabeled raclopride (1 mg/kg) inhibited 50-70% of [11C]epidepride binding. The fraction of unchanged [11C]epidepride in monkey plasma determined by a gradient high performance liquid chromatography (HPLC) method was about 30% of the total radioactivity at 30 min after injection of [11C]epidepride. The availability of [11C]epidepride allows the PET-verification of the data obtained from quantitation studies with SPECT.

Objective: We sought to test the hypothesis that elective delivery of infants diagnosed with macrosomia by ultrasonographic studies in diabetic women will significantly reduce the rate of shoulder dystocia without significantly increasing cesarean section rate., Study Design: In a prospective study diabetic women with ultrasonographic estimated fetal weight > or = 4250 gm underwent elective cesarean section; women with estimated fetal weight > or = 90th percentile but < 4250 gm underwent induction of labor. Maternal and neonatal outcomes were analyzed and compared for the periods before and after initiation of the protocol., Results: A total of 2604 diabetic patients were included in this study. The rate of shoulder dystocia was significantly lower after instituting the protocol (2.4% vs 1.1%, odds ratio 2.2). The cesarean section rate increased significantly between the two periods (21.7% vs 25.1%, p < 0.04). Ultrasonography correctly identified the presence or absence of macrosomia in 87% of patients. Only 10.6% of diabetic patients at term required intervention under the protocol (6.8% labor induction, 3.8% elective cesarean section). The rate of shoulder dystocia was 7.4% in macrosomic infants delivered vaginally., Conclusion: An ultrasonographically estimated weight threshold as an indication for elective delivery in diabetic women reduces the rate of shoulder dystocia without a clinically meaningful increase in cesarean section rate. This practice, in conjunction with an intensified management approach to diabetes, improves the outcome of these high-risk women and their infants.

Objective: Our purpose was to determine whether the biguanide oral antihyperglycemic agent metformin increases human placental uptake and transport of glucose to the fetal circulation., Study Design: The human single-cotyledon model was used to compare transport of tritiated glucose in the maternal to fetal direction in eight human placentas between control placentas and those exposed to metformin in vitro. Transport was calculated from the serial perfusate glucose levels obtained in each 3-hour experiment, and placental uptake was determined from homogenates of the perfused cotyledon. Liquid scintillation spectrometry measured levels of both glucose and the reference substance antipyrine. Transport was compared by the Mann-Whitney U test., Results: Mean maternal and fetal glucose levels were 77.5 +/- 4.9 mg/dl and 61.3 +/- 5.9 mg/dl, respectively, in the metformin group and 83.8 +/- 4.3 mg/dl and 60.4 +/- 12.4 mg/dl, respectively, in controls at 2 hours. Placental glucose uptake was 91.1 +/- 42.2 microg/gm placenta in the metformin experiments and 104.9 +/- 76.9 microg/gm placenta in controls. No difference in placental glucose uptake or transport could be demonstrated., Conclusion: Metformin does not affect human placental glucose uptake or transport.

Objective: Our purpose was to compare the efficacy and safety of low-dose versus high-dose oxytocin regimens in the augmentation of labor., Study Design: Three hundred ten term pregnancies requiring augmentation of labor underwent randomization to receive either a low-dose or high-dose oxytocin augmentation regimen. Maternal demographics, labor-delivery data, and neonatal outcome were compared., Results: The high-dose oxytocin group had a significantly lower cesarean section rate, regardless of parity (10.4% vs 25.7%, p < 0.001), with no differences in maternal complications and neonatal outcomes. The time needed to correct the labor abnormality was also significantly decreased (1.24 +/- 1.4 hours vs 3.12 +/- 1.6 hours, p < 0.001) in the high-dose group., Conclusions: The use of high-dose oxytocin regimen benefits both nulliparous and multiparous women requiring labor augmentation by significantly lowering both the time necessary to correct the labor abnormality and the need for cesarean section.

Objective: Our objective was to determine the association between labor abnormalities and shoulder dystocia., Study Design: All consecutive cases of shoulder dystocia from January 1986 to August 1994 were reviewed (n = 276). For purposes of comparison a control group of vaginally delivered patients was randomly selected in a 2:1 ratio (n = 600). Charts were reviewed for demographic information, labor and delivery events, and neonatal outcome., Results: Labor abnormalities were comparable in the shoulder dystocia and control groups, both in the active phase and in the second stage. When patients with diabetes and those with macrosomic infants were analyzed separately, no significant differences in labor abnormalities were identified. The rate of operative vaginal delivery was significantly higher in the shoulder group, and one third of the operative deliveries were midpelvic. In addition, the induction rate was higher in the shoulder group., Conclusions: Our data suggest that labor abnormalities may not serve as clinical predictors for subsequent development of shoulder dystocia, thus emphasizing the unpredictability of this condition.