Guideline-based development of quality indicators for prevention and management of postpartum hemorrhage.

INTRODUCTION: To systematically develop a set of guideline-based quality indicators for postpartum hemorrhage (PPH) as a tool to measure guideline adherence in actual PPH care. MATERIAL AND METHODS: A Rand-modified Delphi procedure was used to systematically achieve consensus among a panel of 22 experts on PPH care on recommendations extracted from evidence-based guidelines, Managing-Obstetrics-Emergencies-Trauma (MOET) instructions and international literature. The selected recommendations were individually rated on health gain (prevention of maternal mortality and morbidity) and overall efficiency by the expert panel. Subsequently, consensus about the most important recommendations to measure quality of PPH care among the panel members was reached, followed by a final approval. Last, definition of the final set by critical appraisal of the recommendations regarding measurability took place. The main outcome measure was a set of valid quality indicators for prevention and management of PPH. RESULTS: From the 69 extracted recommendations, 50 were selected and translated into 22 quality indicators on professional performance (n = 17) and organization of PPH care (n = 5). The professional performance indicators covered all fields of PPH care, such as prevention (n = 2) and management of PPH, including communication and documentation (n = 4), monitoring and prevention of shock (n = 3), use of blood products (n = 3) and treatment of PPH (n = 5). Organizational indicators (n = 5) were clustered into protocols and agreements, audit, accessibility and documentation. CONCLUSIONS: This study describes a stepwise systematic development of 22 performance and organizational indicators to use for measuring the whole care process of prevention and management of PPH.

Cardiovascular effects of aerobic exercise training in formerly preeclamptic women and healthy parous control subjects.

OBJECTIVE: Women who have had preeclampsia demonstrate higher prevalence of metabolic syndrome (MetS), impaired vascular function, and increased sympathetic activity and are at increased risk of cardiovascular disease. The aim of this study was to assess the effects of 12 weeks of exercise training (70-80% maximum volume of oxygen utilization) in women who had had preeclampsia on physical fitness, components of MetS, vasculature, and autonomic functions compared with healthy control subjects. STUDY DESIGN: Our prospective case-control study included 24 normotensive women who had had preeclampsia and 20 control subjects who were matched for age and postpartum interval (all 6-12 months after delivery). Before and after training, we measured all components of MetS (ie, BP, lipids, glucose/insulin, and albuminuria), carotid intima media thickness (IMT) and brachial and superficial femoral artery endothelial function that used flow-mediated dilation (FMD). Autonomic activity was quantified with power spectral analysis (low-frequency/high-frequency power [LF/HF] ratio). RESULTS: At baseline, women who had had preeclampsia demonstrated higher values of most components of MetS. Compared with the control subjects, women who had had preeclampsia had increased IMT (580 ± 92 µm vs 477 ± 65 µm, respectively), impaired endothelial function (FMD brachial artery, 5.3% ± 2.2% vs 10.8% ± 3.5%, respectively; FMD superficial femoral artery, 4.9% ± 2.1% vs 8.7% ± 3.2%, respectively) and increased LF/HF power ratio (2.2 ± 1.0 vs 1.3 ± 0.4, respectively; all P < .05). In both groups, exercise training decreased values of most components of MetS and IMT, improved FMD, and concurrently reduced LF/HF. Despite these improvements, vascular and autonomic variables did not normalize by 12 weeks of training in women who had had preeclampsia. CONCLUSION: This study demonstrates that exercise training in women who had had preeclampsia and control subjects improves components of MetS, endothelial function, vascular wall thickness, and autonomic control. Nonetheless, trained women who had had preeclampsia only reached a cardiovascular status that is comparable with sedentary healthy control subjects.

Effect of maintenance tocolysis with nifedipine in threatened preterm labor on perinatal outcomes: a randomized controlled trial.

IMPORTANCE: In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE: To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS: APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION: Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES: Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS: Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE: In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION: trialregister.nl Identifier: NTR1336.

Unexplained first trimester recurrent pregnancy loss and low venous reserves.

BACKGROUND: More than half of recurrent pregnancy loss (RPL) remains unexplained. We hypothesized that women with a history of unexplained RPL (URPL) have low venous reserve. METHODS: Case-control study in 12 women with a history of URPL, 11 healthy nulliparous controls and 12 primiparous controls with a history of uncomplicated pregnancy. To quantify venous reserve, we measured plasma volume (PV, ml/m(2)) and venous compliance in forearm and calf (VC(arm), VC(calf), (ml/dl)/mmHg) during the follicular phase of the menstrual cycle. Mean arterial blood pressure (mmHg) was measured by oscillometry. Arterial demand was evaluated by cardiac index (CI, (l/min)/m(2)). RESULTS: Baseline characteristics were comparable between groups. All groups had similar CI. Women with a history of RPL had 14% and 9% lower mean PV compared with nulliparous and primiparous controls (P < 0.01 and P = 0.04, respectively). In women with URPL, the mean VC(arm) was 25% and 32% lower compared with nulliparous and primiparous controls (P = 0.04 and P < 0.01, respectively), while the mean VC(calf) was 29 and 22% lower compared with the two control groups (P < 0.01 and P = 0.03, respectively). CONCLUSIONS: Women with URPL have lower venous reserves when compared with controls at comparable arterial demand. Interventions that increase venous reserve may improve pregnancy outcome.

Comparison of two point-of-care testing (POCT) devices for fetal lactate during labor.

BACKGROUND: Point-of-care testing (POCT) of fetal scalp blood lactate is used as an alternative for pH analysis. Lactate measurements have not been standardized and values vary with each device used. The aim of this study was to evaluate the performance of two POCT lactate meters for intrapartum use. METHODS: Analytical performance of StatStrip Lactate (Nova Biomedical) and Lactate Pro (Arkray) was evaluated using CLSI EP10. Both POCT meters were compared with our lactate reference method (RapidLab 860; Siemens Healthcare Diagnostics) using fetal scalp and neonatal cord blood. Deming regression analysis was performed. RESULTS: StatStrip Lactate coefficients of variation (CVs) were 5.1%, 5.0% and 2.6% at 0.9, 7.5 and 14.1 mmol/L lactate, respectively. CVs for Lactate Pro were 10.7%, 5.2% and 5.7% at 1.7, 4.1 and 6.4 mmol/L lactate, respectively. Consecutive lactate measurements in 37 fetal scalp and 122 cord blood samples revealed different test characteristics for the two POCT devices. In fetal scalp blood: StatStrip Lactate=1.13*RapidLab-0.39 (R(2)=0.907) and Lactate Pro=0.95*RapidLab-0.03 (R(2)=0.823). In cord artery blood: StatStrip Lactate=1.08*RapidLab-0.09 (R(2)=0.810) and Lactate Pro=0.72*RapidLab+0.59 (R(2)=0.807). CONCLUSIONS: Overall performance of both Lactate Pro and StatStrip Lactate was good, with StatStrip Lactate having smallest CVs and closest correlation to our reference method. Both StatStrip Lactate and Lactate Pro can be used as a lactate POCT device for obstetric use.

Scalp blood lactate for intra-partum assessment of fetal metabolic acidosis.

OBJECTIVE: To study to what extent the fetal scalp blood lactate concentration during labor correlates with fetal scalp pH and base deficit, and metabolic acidosis at birth, and to suggest lactate cut-off values to serve as indicators for either reassurance or immediate intervention. DESIGN: A retrospective observational study. SETTING: Labor ward at a university medical center. SAMPLE: Fetal scalp and cord blood samples with acid-base and lactate values from 486 singleton pregnancies beyond 34 weeks' gestation. METHODS: The relation between lactate, pH and base deficit (BD) in fetal scalp blood was tested by Spearman's rho correlation coefficient. Lactate cut-off values indicating either reassuring fetal status or immediate intervention were estimated using percentile distribution and compared with pH and BD. MAIN OUTCOME MEASURES: Metabolic acidosis, defined as umbilical cord artery pH below 7.05 and BD calculated for the blood compartment above 12 mmol/l. RESULTS: After 127 (21%) exclusions, 486 cases were available for analysis. Fetal lactate values increased with evolving metabolic acidosis. Lactate concentration correlated with both pH (r=-0.50, p<0.01) and BD (r=0.48, p<0.01). Lactate <5.4 mmol/l indicated reassuring fetal status, whereas lactate ≥6.6 mmol/l indicated metabolic acidosis. Fetal lactate correlated better with either the absence or presence of metabolic acidosis at birth than did fetal pH and BD. CONCLUSIONS: In the case of a non-reassuring fetal heart rate, fetal scalp blood lactate provides more accurate information on fetal acid-base status than does pH and/or BD.

Haemorrhagia post partum; an implementation study on the evidence-based guideline of the Dutch Society of Obstetrics and Gynaecology (NVOG) and the MOET (Managing Obstetric Emergencies and Trauma-course) instructions; the Fluxim study.

BACKGROUND: One of the most important causes of maternal mortality and severe morbidity worldwide is post partum haemorrhage (PPH). Factors as substandard care are frequently reported in the international literature and there are similar reports in the Netherlands. The incidence of PPH in the Dutch population is 5% containing 10.000 women a year. The introduction of an evidence-based guideline on PPH by the Dutch society of Obstetrics and Gynaecology (NVOG) and the initiation of the MOET course (Managing Obstetrics Emergencies and Trauma) did not lead to a reduction of PPH. This implies the possibility of an incomplete implementation of both the NVOG guideline and MOET-instructions. Therefore, the aim of this study is to develop and test a tailored strategy to implement both the NVOG guideline and MOET-instructions METHODS/DESIGN: One step in the development procedure is to evaluate the implementation of the guideline and MOET-instructions in the current care. Therefore measurement of the actual care will be performed in a representative sample of 20 hospitals. This will be done by prospective observation of the third stage of labour of 320 women with a high risk of PPH using quality indicators extracted from the NVOG guideline and MOET instructions. In the next step barriers and facilitators for guideline adherence will be analyzed by performance of semi structured interviews with 30 professionals and 10 patients, followed by a questionnaire study among all Dutch gynaecologists and midwives to quantify the barriers mentioned. Based on the outcomes, a tailored strategy to implement the NVOG guideline and MOET-instructions will be developed and tested in a feasibility study in 4 hospitals, including effect-, process- and cost evaluation. DISCUSSION: This study will provide insight into current Dutch practice, in particular to what extent the PPH guidelines of the NVOG and the MOET-instructions have been implemented in the actual care, and into the barriers and facilitators regarding guideline adherence. The knowledge of the feasibility study regarding the effects and costs of the tailored strategy and the experiences of the users can be used in countries with a relatively high incidence of PPH. TRIAL REGISTRATION: ClinicTrials.gov NCT00928863.

Treatment of retained placenta with misoprostol: a randomised controlled trial in a low-resource setting (Tanzania).

BACKGROUND: Retained placenta is one of the common causes of maternal mortality in developing countries where access to appropriate obstetrical care is limited. Current treatment of retained placenta is manual removal of the placenta under anaesthesia, which can only take place in larger health care facilities. Medical treatment of retained placenta with prostaglandins E1 (misoprostol) could be cost-effective and easy-to-use and could be a life-saving option in many low-resource settings. The aim of this study is to assess the efficacy and safety of sublingually administered misoprostol in women with retained placenta in a low resource setting. DESIGN: Multicentered randomised, double-blind, placebo-controlled trial, to be conducted in 5 hospitals in Tanzania, Africa. INCLUSION CRITERIA: Women with retained placenta, at a gestational age of 28 weeks or more and blood loss less than 750 ml, 30 minutes after delivery of the newborn despite active management of third stage of labour. Trial Entry & Randomisation & Study Medication: After obtaining informed consent, eligible women will be allocated randomly to the treatment groups using numbered envelopes that will be randomized in variable blocks containing identical capsules with either 800 microgram of misoprostol or placebo. The drugs will be given sublingually. The women, maternal care providers and researchers will be blinded to treatment allocation. SAMPLE SIZE: 117 women, to show a 40% reduction in manual removals of the placenta (p = 0.05, 80% power). The randomization will be misoprostol: placebo = 2:1. PRIMARY STUDY OUTCOME: Expulsion of the placenta without manual removal. Secondary outcome is the number of blood transfusions. DISCUSSION: This is a protocol for a randomized trial in a low resource setting to assess if medical treatment of women with retained placenta with misoprostol reduces the incidence of manual removal of the placenta. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN16104753.

Assessment of perinatal outcome after sustained tocolysis in early labour (APOSTEL-II trial).

BACKGROUND: Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. METHODS/DESIGN: The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.

Cost-effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL-I trial).

BACKGROUND: At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. METHODS/DESIGN: We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. DISCUSSION: This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. TRIAL REGISTRATION: Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.

Fetal bladder wall regeneration with a collagen biomatrix and histological evaluation of bladder exstrophy in a fetal sheep model.

OBJECTIVES: To evaluate histological changes in an animal model for bladder exstrophy and fetal repair of the bladder defect with a molecular-defined dual-layer collagen biomatrix to induce fetal bladder wall regeneration. METHODS: In 12 fetal lambs the abdominal wall and bladder were opened by a midline incision at 79 days' gestation. In 6 of these lambs an uncorrected bladder exstrophy was created by suturing the edges of the opened bladder to the abdominal wall (group 1). The other 6 lambs served as a repair group, where a dual-layer collagen biomatrix was sutured into the bladder wall and the abdominal wall was closed (group 2). A caesarean section was performed at 140 days' gestation, followed by macroscopic and histological examination. RESULTS: Group 1 showed inflammatory and maturational changes in the mucosa, submucosa and detrusor muscle of all the bladders. In group 2, bladder regeneration was observed, with urothelial coverage, ingrowth of fibroblasts and smooth muscle cells, deposition of collagen, neovascularization and nerve fibre formation. This tissue replaced the collagen biomatrix. No structural changes of the bladder were seen in group 2. CONCLUSIONS: The animal model, as in group 1, for bladder exstrophy shows remarkable histological resemblance with the naturally occurring anomaly in humans. This model can be used to develop new methods to salvage or regenerate bladder tissue in bladder exstrophy patients. Fetal bladder wall regeneration with a collagen biomatrix is feasible in this model, resulting in renewed formation of urothelium, blood vessels, nerve fibres, ingrowth of smooth muscle cells and salvage of the native bladder.

Sulprostone reduces the need for the manual removal of the placenta in patients with retained placenta: a randomized controlled trial.

OBJECTIVE: The purpose of this study was to determine the extent that the administration of sulprostone reduces the need for manual removal of the placenta in patients with retained placenta. STUDY DESIGN: A double-blinded sequential randomized controlled trial of sulprostone versus placebo was conducted among 103 patients with retained placenta. RESULTS: In the first phase of this sequential study, sulprostone was compared with placebo. The null hypothesis of equal effectiveness of both treatments was rejected after 50 patients. In patients with retained placenta, the placenta was expelled after sulprostone in 13 of 24 cases (51.8%, bias adjusted), whereas expulsion after placebo was achieved in only 4 of 26 cases (17.6%, bias adjusted). The difference was significant (P = .034). In the second phase of the study, in which the placebo arm was stopped, results were confirmed; in 25 of 53 patients (47%), the placenta was expelled. CONCLUSION: Sulprostone reduces the need for the manual removal of the placenta by 49%.

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.

History of preeclampsia is more predictive of cardiometabolic and cardiovascular risk factors than obesity.

OBJECTIVE: To determine to what extent a history of preeclampsia affects traditional cardiometabolic (insulin resistance and dyslipidemia) and cardiovascular (hypertension and micro-albuminuria) risk factors of the metabolic syndrome irrespective of BMI. STUDY DESIGN: In a retrospective case-control study we compared 90 formerly preeclamptic women, divided in 3 BMI-classes (BMI 19.5-24.9, 25.0-29.9, ≥30.0kg/m(2)) to 30 controls, matched for BMI, age and parity. Cardiometabolic and cardiovascular risk factors (WHO-criteria) were tested 6-18 months post partum. Statistical analysis included unpaired t-tests, Mann-Whitney U test, or Chi square test and two-way ANOVA. RESULTS: Constituents of the metabolic syndrome (glucose, insulin, HOMAIR, HDL-cholesterol, triglycerides, blood pressure, micro-albuminuria) were higher in formerly preeclamptic women than in BMI-matched controls. Resultantly, traditional risk factors were more prevalent in formerly preeclamptic women than in controls (insulin resistance 80% vs 30%, dyslipidemia 52% vs 3%, hypertension 24% vs 0%, micro-albuminuria 30% vs 0%). Cardiometabolic risk factors increased with BMI, to the same extent in both groups. Formerly preeclamptic women had metabolic syndrome more often than their BMI-matched controls (38% vs 3%, p<0.001). CONCLUSION: Traditional risk factors of the metabolic syndrome are more prevalent in formerly preeclamptic women than in BMI-matched controls and increase with BMI to the same extent in both groups. A history of preeclampsia seems to be a stronger indicator of cardiovascular risk than obesity per se.

Aerobic Exercise Training in Formerly Preeclamptic Women: Effects on Venous Reserve.

UNLABELLED: In women with a history of preeclampsia, low plasma volume (≤1373 mL/m(2)) is associated with recurrent preeclampsia and chronic hypertension. Interventions that improve volume reserve may reduce these risks in formerly preeclamptic women. In this study, we examined the effects of aerobic exercise training on venous reserves in 24 normotensive formerly preeclamptic women and 20 controls. Before and after 12-week aerobic exercise training, we measured plasma volume with albumin indicator dilution technique and venous compliance with venous occlusion plethysmography. Venous compliance and hemodynamic responses were assessed dynamically during graded head-up tilt (HUT). Formerly preeclamptic women had lower pretraining plasma volume and venous compliance than controls (1348±78 versus 1529±112 mL/m(2); P<0.01 and 0.04±0.02 versus 0.07±0.01 mL·dL(-1)·mm Hg(-1); P<0.01, respectively). Blood pressure decreased comparably between groups in response to HUT (P=0.11); the increase in heart rate in response to HUT was however more pronounced in preeclamptic women than in controls (P=0.01) Training increased plasma volume comparably in both groups (+180 versus +135 mL/m(2), P=0.22) and similarly physical fitness (+3.4 and +3.7 mL·min(-1)·kg(-1), P=0.43). Venous compliance increased twice as much in formerly preeclamptic women than in controls (supine +0.02 versus +0.01 mL·dL(-1)·mm Hg(-1); P<0.01). After training, HUT decreased mean blood pressure comparable with pretraining responses in both groups, whereas both groups fulfilled the HUT testing at a persistently lower heart rate. These results demonstrate that 12 weeks of aerobic exercise training improve venous reserve in postpartum women. Training normalized plasma volume and venous compliance in formerly preeclamptic women to pretraining levels of controls. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00900458.

Low Plasma Volume in Normotensive Formerly Preeclamptic Women Predisposes to Hypertension.

Formerly preeclamptic women are at risk for cardiovascular disease. Low plasma volume may reflect latent hypertension and potentially links preeclampsia with chronic cardiovascular disease. We hypothesized that low plasma volume in normotensive formerly preeclamptic women predisposes to hypertension. We longitudinally studied n=104 formerly preeclamptic women in whom plasma volume was measured 3 to 30 months after the preeclamptic pregnancy. Cardiovascular variables were assessed at 2 points in time (3-30 months postpartum and 2-5 years thereafter). Study population was divided into low plasma volume (≤1373 mL/m(2)) and normal plasma volume (>1373 mL/m(2)). Primary end point was hypertension at the second visit: defined as ≥140 mm Hg systolic or ≥90 mm Hg diastolic. Secondary outcome of this study was change in traditional cardiovascular risk profile between visits. Variables correlating univariately with change in blood pressure between visits were introduced in regression analysis. Eighteen of 104 (17%) formerly preeclamptic women who were normotensive at first visit had hypertension at second evaluation 2 to 5 years later. Hypertension developed more often in women with low plasma volume (10/35 [29%]) than in women with normal plasma volume (8/69 [12%]; odds ratio, 3.2; 95% confidence interval, 1.4-8.6). After adjustments, relationship between plasma volume status and subsequent hypertension persisted (adjusted odds ratio, 3.0; 95% confidence interval, 1.1-8.5). Mean arterial pressure at second visit correlated inverse linearly with plasma volume (r=-0.49; P<0.01). Initially normotensive formerly preeclamptic women have 17% chance to develop hypertension within 5 years. Women with low plasma volume have higher chance to develop hypertension than women with normal plasma volume. Clinically, follow-up of blood pressure seems warranted in women with history of preeclampsia, even when initially normotensive.

Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.

Absence of robust ischemic preconditioning by five 1-minute total umbilical cord occlusions in fetal sheep.

OBJECTIVE: To determine to what extent a series of five 1-minute total umbilical cord occlusions, intended to induce ischemic preconditioning (IP), affects the physiologic responses to a 10-minute total umbilical cord occlusion (damaging insult [DI]) 1 hour later and provides cardio- and neuroprotection. METHODS: In 14 chronically catheterized late gestation fetal sheep (127-131 days' gestation), we performed a 10-minute total umbilical cord occlusion (DI), preceded by a series of five 1-minute total cord occlusions with 2-minute intervals (5CO, n = 7) or sham occlusions (n = 7) 1 hour prior to DI. RESULTS: The 5CO induced a reduction in the arterial partial pressure of oxygen (Po(2)) from 21 +/-1 to 14 +/-3 Torr, arterial O(2) content from 6.9 +/- 0.4 to 3.1 +/- 0.7 vol%, and increases in the partial pressure of carbon dioxide (Pco(2)) from 46 +/- 2 to 58 +/- 3 Torr, and [H(+)] from 43 +/- 1 to 54 +/- 2 nM. 5CO reduced fetal heart rate from 178 +/- 6 to 151 +/- 6 beats per minute (bpm), and increased arterial pressure from 45 +/- 1 to 57 +/- 2 mmHg, cerebral blood flow (CBF) from 100 +/- 3 to 129 +/- 10%, and cerebral heat production (H(brain)) from 25 +/- 2 to 29 +/- 1% degrees C. The responses to DI were not significantly different between the groups without and with 5CO; values for Po(2) were 5.6 +/- 1.5 and 5.8 +/- 1.9 Torr, O(2) content 0.6 +/- 0.1 and 0.8 +/- 0.1 vol%, lactate 10.7 +/- 0.7 and 10.8 +/- 0.7 mM, fetal heart rate 97 +/- 5 and 87 +/- 8 bpm, mean arterial pressure 22 +/- 3 and 21 +/- 2 mmHg, CBF 50 +/- 10 and 36 +/- 5%, and H(brain) 7.0 +/- 1.4 and 5.9 +/- 1.1% degrees C, respectively, except for Pco(2) (126 +/- 4 and 112 +/- 2 Torr) and [H(+)] (126 +/- 3 and 114 +/- 3 nM). Histologic proof of cardio- or neuroprotection by 5CO could not be obtained because five fetuses died before they were to be killed at day 3 after the experiment; two fetuses in the 5CO group demonstrated major histologic damage of myocardium and brain. CONCLUSION: In the late gestation fetal sheep, a series of five 1-minute total umbilical cord occlusions did not result in major changes in physiologic responses to a hypoxic-ischemic DI 1 hour later. In addition, the procedure did not result in robust cardio- and neuroprotection, in contrast to IP reported in adults.

Recommendations for pregnancies in patients with crigler-najjar syndrome.

During pregnancy, the developing foetus in mothers with Crigler-Najjar type 1 and 2 is exposed to raised levels of unconjugated bilirubin, with the risk of neurotoxicity. We describe two pregnancies in a patient with Crigler-Najjar type 2, who was carefully monitored prior to and during pregnancy and phototherapy adjusted to maintain serum bilirubin levels below 200 µmol/l and the bilirubin/albumin molar ratio below 50%. Both pregnancies resulted in normal delivery of healthy infants who had normal neurological development. A review of all reported pregnancies in Crigler-Najjar patients and a set of recommendations are presented.

A randomized controlled trial on the value of misoprostol for the treatment of retained placenta in a low-resource setting.

OBJECTIVE: To evaluate the efficacy and safety of misoprostol among patients with retained placenta in a low-resource setting. METHODS: A prospective, multicenter, randomized, double-blind, placebo-controlled trial was carried out in Tanzania between April 2008 and November 2011. It included patients who delivered at a gestational age of 28 weeks or more and had blood loss of 750 mL or less at 30 minutes after delivery. Sublingual misoprostol (800 µg) was compared with placebo as the primary treatment. Power analysis showed that 117 patients would be required to observe a reduction of 40% in the incidence of manual removal of the placenta (MRP; P=0.05, 80% power), the primary outcome. The secondary outcomes were blood loss and number of blood transfusions. RESULTS: Interim analysis after recruitment of 95 patients showed that incidence of MRP, total blood loss, and incidence of blood transfusions were similar in the misoprostol (MRP, 40%; blood loss, 803 mL; blood transfusion, 15%) and placebo (MRP, 33%, blood loss 787 mL, blood transfusion, 23%) groups. The trial was stopped because continuation would not alter the interim conclusion that misoprostol was ineffective. CONCLUSION: Treatment with misoprostol was found to have no clinically significant beneficial effect among women with retained placenta. CLINICAL TRIAL REGISTRATION: Current Controlled Trials ISRCTN16104753.